Placebo treatment facilitates social trust and approach behavior.

PubMed

Yan, Xinyuan; Yong, Xue; Huang, Wenhao; Ma, Yina

2018-05-29

Placebo effect refers to beneficial changes induced by the use of inert treatment, such as placebo-induced relief of physical pain and attenuation of negative affect. To date, we know little about whether placebo treatment could facilitate social functioning, a crucial aspect for well-being of a social species. In the present study, we develop and validate a paradigm to induce placebo effects on social trust and approach behavior (social placebo effect), and show robust evidence that placebo treatment promotes trust in others and increases preference for a closer interpersonal distance. We further examine placebo effects in real-life social interaction and show that placebo treatment makes single, but not pair-bonded, males keep closer to an attractive first-met female and perceive less social anxiety in the female. Finally, we show evidence that the effects of placebo treatment on social trust and approach behavior can be as strong as the effect of intranasal administration of oxytocin, a neuropeptide known for its function in facilitating social cognition and behavior. The finding of the social placebo effect extends our understanding of placebo effects on improvement of physical, mental, and social well-being and suggests clinical potentials in the treatment of social dysfunction.

Regulation with placebo effects.

PubMed

Malani, Anup

2008-12-01

A growing scientific literature supports the existence of placebo effects from a wide range of health interventions and for a range of medical conditions. This Article reviews this literature, examines the implications for law and policy, and suggests future areas for research on placebo effects. In particular, it makes the case for altering the drug approval process to account for, if not credit, placebo effects. It recommends that evidence of placebo effects be permitted as a defense in cases alleging violations of informed consent or false advertising. Finally, it finds that tort law already has doctrines such as joint and several liability to account for placebo effects. Future research on placebo effects should focus on whether awareness of placebo effects can disable these effects and whether subjects can control their own placebo effects.

Expectancies and memory for an emotional film fragment: a placebo study.

PubMed

Van Oorsouw, Kim; Merckelbach, Harald

2007-01-01

This study investigated whether positive ("memory-enhancing") and negative ("memory-impairing") placebos may enhance and undermine, respectively, memory of a film fragment. After watching an emotional film fragment, participants were assigned to a "memory-enhancing" placebo group (n = 30), control group (n = 30), or "memory-impairing" placebo group (n = 30). Only participants who believed in the placebo effect were included in the analyses. In the positive placebo group, memory for the film fragment was better than that of participants who received negative placebos or control participants. Participants in the negative placebo group made more distortion errors than participants in the positive placebo or control group. Our findings show that people's expectancies about their memory may affect their memory performance. These results may have implications for both clinical practice and the legal domain.

The moral case for the clinical placebo.

PubMed

Gold, Azgad; Lichtenberg, Pesach

2014-04-01

Placebos are arguably the most commonly prescribed drug, across cultures and throughout history. Nevertheless, today many would consider their use in the clinic unethical, since placebo treatment involves deception and the violation of patients' autonomy. We examine the placebo's definition and its clinical efficacy from a biopsychosocial perspective, and argue that the intentional use of the placebo and placebo effect, in certain circumstances and under several conditions, may be morally acceptable. We highlight the role of a virtue-based ethical orientation and its implications for the beneficent use of the placebo. In addition, the definitions of lying and deception are discussed, clarified and applied to the clinical placebo dilemma. Lastly, we suggest that concerns about patient autonomy, when invoked as a further argument against administering placebos, are extended beyond their reasonable and coherent application.

Placebo prescription and empathy of the physician: A cross-sectional study.

PubMed

Braga-Simões, João; Costa, Patrício Soares; Yaphe, John

2017-12-01

Empathy in the patient-physician relationship is a major component in an effective placebo treatment, as in every medical treatment. Understanding the role of empathy of the physician in the placebo effect may help dissect some of the context variables responsible for the effectiveness of the placebo. To determine the frequency of placebo prescription, doctors' beliefs, motivation, and attitudes to placebos in general practice in northern Portugal and to test the association between placebo prescription and physician empathy. A cross-sectional study was conducted between November 2014 and January 2015 among general practice specialists and interns from 14 health centres in a northern Portuguese health region. The self-report questionnaire included the Portuguese version of the Jefferson scale of physician empathy (JSPE) and a questionnaire about placebo prescription. Associations between demographic variables, JSPE score, prescription of placebo, and the attitudes to placebo score were tested with the chi-squared statistic, student t-tests for independent samples, and Pearson correlation. The study included 93 general practitioners (GP) (response rate: 74%). Placebos were prescribed by 73% (n = 68) of the respondents. GPs who prescribe placebo are significantly younger (mean age = 38.4 years; SD = 11.1; t (90) = 2.98, P <.05, d = 0.67) than non-prescribers (mean age =46.5 years; SD =13.3). Favourable attitudes towards placebo prescription are associated with higher empathy scores (R = 0.310, P <.01). Placebo prescription is frequent and associated with empathy from the prescriber, especially among younger GPs.

Partial reinforcement, extinction, and placebo analgesia

PubMed Central

Yeung, Siu Tsin Au; Colagiuri, Ben; Lovibond, Peter F.; Colloca, Luana

2014-01-01

Numerous studies indicate that placebo analgesia can be established via conditioning procedures. However, these studies have exclusively involved conditioning under continuous reinforcement. Thus, it is currently unknown whether placebo analgesia can be established under partial reinforcement and how durable any such effect would be. We tested this possibility using electro-cutaneous pain in healthy volunteers. Sixty undergraduates received placebo treatment (activation of a sham electrode) under the guise of an analgesic trial. The participants were randomly allocated to different conditioning schedules, namely continuous reinforcement (CRF), partial reinforcement (PRF), or control (no conditioning). Conditioning was achieved by surreptitiously reducing pain intensity during training when the placebo was activated compared with when it was inactive. For the CRF group, the placebo was always followed by a surreptitious reduction in pain during training. For the PRF group, the placebo was followed by a reduction in pain stimulation on 62.5% of trials only. In the test phase, pain stimulation was equivalent across placebo and no placebo trials. Both continuous and partial reinforcement produced placebo analgesia, with the magnitude of initial analgesia being larger following continuous reinforcement. However, while the placebo analgesia established under continuous reinforcement extinguished during test phase, the placebo analgesia established under partial reinforcement did not. These findings indicate that partial reinforcement can induce placebo analgesia and that these effects are more resistant to extinction than those established via continuous reinforcement. Partial reinforcement may, therefore, reflect a novel way of enhancing clinical outcomes via the placebo effect. PMID:24602997

[Placebo and the relationship between doctors and patients. Overview].

PubMed

Scriba, P C

2012-09-01

In medicine, placebos are used both in scientific studies and for practical therapeutic purposes. In evidence-based medicine, the efficacy of treatment may be determined as the difference between the effects of the verum (the active study drug) and the placebo, the latter being a substance lacking specific action on the disease under consideration. However, the improvements in patients' conditions under placebo treatment may be substantial and comparable to those with verum. Genuine placebos predominate in clinical studies, while pseudoplacebos prevail in practical therapy. The term pseudoplacebo can also be applied to many procedures in complementary medicine, including homeopathic medicine (Büchel et al., Placebo in der Medizin, 2011). The comprehensive definition of placebo, as used in a report by the German Medical Association (Büchel et al., Placebo in der Medizin, 2011), states that a placebo effect may occur even when treating with verum. The placebo effect is modulated by the context of the treatment, by the expectations of the patients and the doctors, and by the success of the relationship between doctors and patients. A number of unspecific effects, e.g., spontaneous alleviation, statistical effects, variance with time, methodological errors, in addition to the placebo effect make up the total response that is called"placebo reaction." A complete list of the effectiveness of placebo for all important diseases is still lacking. Further, it is not possible to predict which patients will respond to placebo. Which characteristics of doctors are important (competence, empathy, communicative ability and partnership, trust) in order to achieve a placebo effect, particularly in addition to the verum effect measures of evidence-based medicine? Are there doctors who are better in this than others? Could the nocebo effect weaken the efficacy of treatment in evidence-based medicine? Since a placebo effect may occur in almost any standard therapy, information about placebos should be provided during medical education and continuing medical education (CME). The use of placebo in clinical studies is ethically justified and lawful in consenting patients if there is no other effective treatment available with which the test substance could be compared. For daily practical therapeutic purposes, placebos may be ethically acceptable and lawful if there is no effective therapy available, if the complaints are minor, if the patient expressly wishes treatment, and if there is a reasonable likelihood of success. However, an explanation of the expected benefits and risks must be provided to the patients. At present, there are two explanatory theories for the mechanism of action of placebo, namely, the associative and the mentalistic explanation (Büchel et al., Placebo in der Medizin, 2011). Interestingly, effects of placebo and of verum can be localized in the brain by physiological and anatomical techniques. With many open questions remaining, research on placebo is currently very active. These aspect and neurobiological findings in particular may facilitate for "scientifically" educated doctors to accept that ineffective materials, i.e., placebos, are in fact effective.

Motivation and placebos: do different mechanisms occur in different contexts?

PubMed

Hyland, Michael E

2011-06-27

This paper challenges the common assumption that the mechanisms underlying short-term placebo paradigms (where there is no motivation for health improvement) and long-term placebo paradigms (where patients value improvement in their health) are the same. Three types of motivational theory are reviewed: (i) classical placebo motivation theory that the placebo response results from the desire for therapeutic improvement; (ii) goal activation model that expectancy-driven placebo responses are enhanced when the placebo response satisfies an activated goal; and (iii) motivational concordance model that the placebo response is the consequence of concordance between the placebo ritual and significant intrinsic motives. It is suggested that current data are consistent with the following theory: response expectancy, conditioning and goal activation are responsible for short-term placebo effects but long-term therapeutic change is achieved through the effects of goal satisfaction and affect on the inflammatory response system and hypothalamic-pituitary-adrenal axis. Empirical predictions of this new theory are outlined, including ways in which placebo effects can be combined with other psychologically mediated effects on short-term and long-term psychological and physiological state.

Motivation and placebos: do different mechanisms occur in different contexts?

PubMed Central

Hyland, Michael E.

2011-01-01

This paper challenges the common assumption that the mechanisms underlying short-term placebo paradigms (where there is no motivation for health improvement) and long-term placebo paradigms (where patients value improvement in their health) are the same. Three types of motivational theory are reviewed: (i) classical placebo motivation theory that the placebo response results from the desire for therapeutic improvement; (ii) goal activation model that expectancy-driven placebo responses are enhanced when the placebo response satisfies an activated goal; and (iii) motivational concordance model that the placebo response is the consequence of concordance between the placebo ritual and significant intrinsic motives. It is suggested that current data are consistent with the following theory: response expectancy, conditioning and goal activation are responsible for short-term placebo effects but long-term therapeutic change is achieved through the effects of goal satisfaction and affect on the inflammatory response system and hypothalamic–pituitary–adrenal axis. Empirical predictions of this new theory are outlined, including ways in which placebo effects can be combined with other psychologically mediated effects on short-term and long-term psychological and physiological state. PMID:21576140

Comparison between the combination of gabapentin, ketamine, lornoxicam, and local ropivacaine and each of these drugs alone for pain after laparoscopic cholecystectomy: a randomized trial.

PubMed

Kotsovolis, Georgios; Karakoulas, Konstantinos; Grosomanidis, Vasileios; Tziris, Nikolaos

2015-04-01

The main purpose of the study was to test whether the combination of gabapentin (600 mg 4 hours before surgery, 600 mg after 24 hours), ketamine (0.3 mg/kg before anesthesia), lornoxicam (8 mg before anesthesia and 8 mg/12 hours), and local ropivacaine (5 mL 7.5% at insertion sites) provides superior analgesia to each of these drugs alone in the first 24 hours after laparoscopic cholecystectomy. The secondary purpose was to examine whether this combination has less opioid-related side effects. This was a 2-center randomized placebo-controlled trial. One hundred forty-eight patients, between 18 and 70 years of age, were randomly assigned to 6 groups (28 in each group) with the use of computer software: A(gabapentin/ketamine/lornoxicam/ropivacaine); B(gabapentin/placebo/placebo/placebo); C (placebo/ketamine/placebo/placebo); D (placebo/placebo/lornoxicam/placebo); E (placebo/placebo/placebo/ropivacaine); and F (placebo/placebo/placebo/placebo). Only the principal investigator was aware of patients' allocation and provided drugs and placebo in covered prefilled syringes. The primary outcome of the study was the 24-hour morphine consumption. Secondary outcomes were frequency of opioid-related side effects (nausea, vomiting, sedation, pruritus, and dysuria). Only groups A (6.4 mg), B (9.46 mg), and D (9.36 mg) had lower morphine consumption than control group (20.29 mg) (P < 0.001, P = 0.01, and P = 0.008, respectively). Group A was not different from B and D (P = 0.92, P = 0.93). The only difference was in episodes of nausea between groups A (n = 5) and the control group (n = 12) (P = 0.018). The combination of gabapentin, ketamine, lornoxicam, and local ropivacaine does not provide superior analgesia than gabapentin alone or lornoxicam alone after laparoscopic cholecystectomy. The combination reduces only the frequency of postoperative nausea, but larger studies are needed for safer results. © 2014 World Institute of Pain.

Selective REM Sleep Deprivation Improves Expectation-Related Placebo Analgesia

PubMed Central

Chouchou, Florian; Chauny, Jean-Marc; Rainville, Pierre; Lavigne, Gilles J.

2015-01-01

The placebo effect is a neurobiological and psychophysiological process known to influence perceived pain relief. Optimization of placebo analgesia may contribute to the clinical efficacy and effectiveness of medication for acute and chronic pain management. We know that the placebo effect operates through two main mechanisms, expectations and learning, which is also influenced by sleep. Moreover, a recent study suggested that rapid eye movement (REM) sleep is associated with modulation of expectation-mediated placebo analgesia. We examined placebo analgesia following pharmacological REM sleep deprivation and we tested the hypothesis that relief expectations and placebo analgesia would be improved by experimental REM sleep deprivation in healthy volunteers. Following an adaptive night in a sleep laboratory, 26 healthy volunteers underwent classical experimental placebo analgesic conditioning in the evening combined with pharmacological REM sleep deprivation (clonidine: 13 volunteers or inert control pill: 13 volunteers). Medication was administered in a double-blind manner at bedtime, and placebo analgesia was tested in the morning. Results revealed that 1) placebo analgesia improved with REM sleep deprivation; 2) pain relief expectations did not differ between REM sleep deprivation and control groups; and 3) REM sleep moderated the relationship between pain relief expectations and placebo analgesia. These results support the putative role of REM sleep in modulating placebo analgesia. The mechanisms involved in these improvements in placebo analgesia and pain relief following selective REM sleep deprivation should be further investigated. PMID:26678391

Importance of placebo effect in cough clinical trials.

PubMed

Eccles, Ron

2010-01-01

Cough is a unique symptom because, unlike sneeze and other symptoms, it can be under voluntary control and this complicates clinical trials on cough medicines. All over-the-counter cough medicines (OTC) are very effective treatments because of their placebo effect. The placebo effect is enhanced by expectancy related to advertising, brand, packaging, and formulation. This placebo effect creates a problem for the conduct of clinical trials on OTC cough medicines that attempt to demonstrate the efficacy of a pharmacological agent above that of any placebo effect. Up to 85% of the efficacy of some cough medicines can be attributed to a placebo effect. The placebo effect apparent in clinical trials consists of several components: natural recovery, regression of cough response toward mean, demulcent effect, effect of sweetness, voluntary control, and effects related to expectancy and meaning of the treatment. The placebo effect has been studied most in the pain model, and placebo analgesia is reported to depend on the activation of endogenous opioid systems in the brain; this model may be applicable to cough. A balanced placebo design may help to control for the placebo effect, but this trial design may not be acceptable due to deception of patients. The placebo effect in clinical trials may be controlled by use of a crossover design, where feasible, and the changes in the magnitude of the placebo effect in this study design are discussed.

Selective REM Sleep Deprivation Improves Expectation-Related Placebo Analgesia.

PubMed

Chouchou, Florian; Chauny, Jean-Marc; Rainville, Pierre; Lavigne, Gilles J

2015-01-01

The placebo effect is a neurobiological and psychophysiological process known to influence perceived pain relief. Optimization of placebo analgesia may contribute to the clinical efficacy and effectiveness of medication for acute and chronic pain management. We know that the placebo effect operates through two main mechanisms, expectations and learning, which is also influenced by sleep. Moreover, a recent study suggested that rapid eye movement (REM) sleep is associated with modulation of expectation-mediated placebo analgesia. We examined placebo analgesia following pharmacological REM sleep deprivation and we tested the hypothesis that relief expectations and placebo analgesia would be improved by experimental REM sleep deprivation in healthy volunteers. Following an adaptive night in a sleep laboratory, 26 healthy volunteers underwent classical experimental placebo analgesic conditioning in the evening combined with pharmacological REM sleep deprivation (clonidine: 13 volunteers or inert control pill: 13 volunteers). Medication was administered in a double-blind manner at bedtime, and placebo analgesia was tested in the morning. Results revealed that 1) placebo analgesia improved with REM sleep deprivation; 2) pain relief expectations did not differ between REM sleep deprivation and control groups; and 3) REM sleep moderated the relationship between pain relief expectations and placebo analgesia. These results support the putative role of REM sleep in modulating placebo analgesia. The mechanisms involved in these improvements in placebo analgesia and pain relief following selective REM sleep deprivation should be further investigated.

Placebo - More hatred than love.

PubMed

Zhang, Hong-Liang

2011-01-01

A placebo is a sham medical intervention that can produce a placebo effect. Laboratory evidence supports the existence of several mechanisms of placebo effects in both healthy population and patients with a variety of medical conditions. The ethics of placebos have long been debated. However, accumulating ethical concern has arisen from the worldwide use of placebo in randomized control trials (RCTs), which may render their participants without early and optimal treatment. Although the pilgrimage of placebo is still on the way, refinement of controls in RCTs is worth paying new attention to.

Lower Placebo Responses After Long-Term Exposure to Fibromyalgia Pain.

PubMed

Kosek, Eva; Rosen, Annelie; Carville, Serena; Choy, Ernest; Gracely, Richard H; Marcus, Hanke; Petzke, Frank; Ingvar, Martin; Jensen, Karin B

2017-07-01

Knowledge about placebo mechanisms in patients with chronic pain is scarce. Fibromyalgia syndrome (FM) is associated with dysfunctions of central pain inhibition, and because placebo analgesia entails activation of endogenous pain inhibition, we hypothesized that long-term exposure to FM pain would negatively affect placebo responses. In our study we examined the placebo group (n = 37, mean age 45 years) from a 12-week, randomized, double-blind, placebo-controlled trial investigating the effects of milnacipran or placebo. Twenty-two patients were classified as placebo nonresponders and 15 as responders, according to the Patient Global Impression of Change scale. Primary outcome was the change in pressure pain sensitivity from baseline to post-treatment. Secondary outcomes included ratings of clinical pain (visual analog scale), FM effect (Fibromyalgia Impact Questionnaire), and pain drawing. Among placebo responders, longer FM duration was associated with smaller reductions in pressure pain sensitivity (r = .689, P = .004), but not among nonresponders (r = -.348, P = .112). In our study we showed that FM duration influences endogenous pain regulation, because pain levels and placebo-induced analgesia were negatively affected. Our results point to the importance of early FM interventions, because endogenous pain regulation may still be harnessed at that early time. Also, placebo-controlled trials should take FM duration into consideration when interpreting results. This study presents a novel perspective on placebo analgesia, because placebo responses among patients with chronic pain were analyzed. Long-term exposure to fibromyalgia pain was associated with lower placebo analgesia, and the results show the importance of taking pain duration into account when interpreting the results from placebo-controlled trials. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Placebos in clinical practice and research.

PubMed Central

De Deyn, P P; D'Hooge, R

1996-01-01

The main current application of placebo is in clinical research. The term placebo effect refers to diverse non-specific, desired or non-desired effects of substances or procedures and interactions between patient and therapist. Unpredictability of the placebo effect necessitates placebo-controlled designs for most trials. Therapeutic and diagnostic use of placebo is ethically acceptable only in few well-defined cases. While "therapeutic" application of placebo almost invariably implies deception, this is not the case for its use in research. Conflicts may exist between the therapist's Hippocratic and scientific obligations. The authors provide examples in neuropsychiatry, illustrating that objective scientific data and well-considered guidelines may solve the ethical dilemma. Placebo control might even be considered an ethical obligation but some provisos should be kept in mind: (a) no adequate therapy for the disease should exist and/or (presumed) active therapy should have serious side-effects; (b) placebo treatment should not last too long; (c) placebo treatment should not inflict unacceptable risks, and (d) the experimental subject should be adequately informed and informed consent given. PMID:8798935

How Placebo Needles Differ From Placebo Pills?

PubMed Central

Chae, Younbyoung; Lee, Ye-Seul; Enck, Paul

2018-01-01

Because acupuncture treatment is defined by the process of needles penetrating the body, placebo needles were originally developed with non-penetrating mechanisms. However, whether placebo needles are valid controls in acupuncture research is subject of an ongoing debate. The present review provides an overview of the characteristics of placebo needles and how they differ from placebo pills in two aspects: (1) physiological response and (2) blinding efficacy. We argue that placebo needles elicit physiological responses similar to real acupuncture and therefore provide similar clinical efficacy. We also demonstrate that this efficacy is further supported by ineffective blinding (even in acupuncture-naïve patients) which may lead to opposite guesses that will further enhances efficacy, as compared to no-treatment, e.g., with waiting list controls. Additionally, the manner in which placebo needles can exhibit therapeutic effects relative to placebo pills include enhanced touch sensations, direct stimulation of the somatosensory system and activation of multiple brain systems. We finally discuss alternative control strategies for the placebo effects in acupuncture therapy.

The contribution of suggestibility and expectation to placebo analgesia phenomenon in an experimental setting.

PubMed

De Pascalis, Vilfredo; Chiaradia, Carmela; Carotenuto, Eleonora

2002-04-01

This study reports how placebo analgesia was produced by conditioning whereby the intensity of electric stimulation was surreptitiously reduced in order to examine the contribution of psychological factors of suggestibility and expectancy on placebo analgesia. This strategy was used in order to manipulate expectancy for pain reduction. The magnitudes of the placebo effects were estimated after a manipulation procedure and during experimental trials in which stimulus intensities were reset to original baseline levels. Individual differences in suggestibility, verbal expectancy for drug efficacy and manipulation procedure for pain reduction were tested as possible mediators of placebo analgesia. The following dependent variables were measured: (a) subjective expectancy for drug efficacy in pain relief, (b) expected pain intensity and unpleasantness, (c) concurrent pain intensity and unpleasantness and (d) remembered pain intensity and unpleasantness. Statistically significant placebo effects on sensory and affective measures of pain were obtained independently of the extent of the surreptitious lowering of stimulus strength during manipulation trials. The pairing of placebo administration with painful stimulation was sufficient to produce a generalized placebo analgesic effect. However, verbal expectancy for drug efficacy and individual differences in suggestibility were found to contribute significantly to the magnitude of placebo analgesia. The highest placebo effect was shown by the most pronounced reductions in pain ratings in highly suggestible subjects who received suggestions presumed to elicit high expectancy for drug efficacy. The results also demonstrated that placebo effects established on remembered pain were at least twice as great as those obtained on concurrent placebo effects. This was mainly because baseline pain was remembered as being much more intense than it really was. Moreover, remembered placebo effects, like the concurrent placebo effects, were highly correlated with expected pain scores obtained just after manipulation trials. These results indicate that multiple factors contribute to the placebo effect, including suggestibility, expectancy and conditioning, and that the judgement of placebo analgesia is critically determined by whether pain relief is assessed concurrently or after treatment.

[The relationship between the placebo effect and spontaneous improvement in research on antidepressants. Are placebos powerless?].

PubMed

Hougaard, Esben

2005-08-08

Clinical trials of antidepressant medications have generally found large changes in groups given a placebo, which may be due to either spontaneous remission or a true placebo effect. This paper reviews the evidence for a true placebo effect in the treatment of unipolar depressed outpatients. Although there is no evidence from experimental studies, a rather substantial amount of circumstantial evidence indicates a true placebo effect. This article raises the question of whether it is meaningful to require experimental evidence for a loose and unspecified concept involving varying components such as placebo.

Relieving Pain using Dose-Extending Placebos: A Scoping Review

PubMed Central

Colloca, Luana; Enck, Paul; DeGrazia, David

2017-01-01

Placebos are often used by clinicians, usually deceptively and with little rationale or evidence of benefit, making their use ethically problematic. In contrast with their typical current use, a provocative line of research suggests that placebos can be intentionally exploited to extend analgesic therapeutic effects. Is it possible to extend the effects of drug treatments by interspersing placebos? We reviewed a database of placebo studies, searching for studies that indicate that placebos given after repeated administration of active treatments acquire medication-like effects. We found a total of 22studies in both animals and humans hinting of evidence that placebos may work as a sort of dose extender of active painkillers. Wherever effective in relieving clinical pain, such placebo use would offer several advantages. First, extending the effects of a painkiller through the use of placebos may reduce total drug intake and side effects. Second, dose-extending placebos may decrease patient dependence. Third, using placebos along with active medication, for part of the course of treatment, should limit dose escalation and lower costs. Importantly, provided that nondisclosure is pre-authorized in the informed consent process and that robust evidence indicates therapeutic benefit comparable to that of standard full-dose therapeutic regimens, introducing dose-extending placebos into the clinical arsenal should be considered. This novel prospect of placebo use has the potential to change our general thinking about painkiller treatments, the typical regimens of painkiller applications, and the ways in which treatments are evaluated. PMID:27023425

Beliefs About Pharmaceutical Medicines and Natural Remedies Explain Individual Variation in Placebo Analgesia.

PubMed

Watkinson, Andrew; Chapman, Sarah C E; Horne, Rob

2017-08-01

This study examined whether placebo responses were predicted by a theoretical model of specific and general treatment beliefs. Using a randomized crossover, experimental design (168 healthy individuals) we assessed whether responses to a cold pressor task were influenced by 2 placebo creams described as pharmaceutical versus natural. We assessed whether placebo responses were predicted by pretreatment beliefs about the treatments (placebo) and by beliefs about the pain. The efficacy of pharmaceutical as well as natural placebos in reducing pain intensity was predicted by aspects of pain catastrophizing including feelings of helplessness (pharmaceutical: B = .03, P < .01, natural: B = .02, P < .05) and magnification of pain (pharmaceutical: B = .04, P < .05, natural: B = .05, P < .05) but also by pretreatment necessity beliefs (pharmaceutical: B = .21, P < .01, natural: B = .16, P < .05) and, for the pharmaceutical condition, by more general beliefs about personal sensitivity to pharmaceuticals (B = .14, P < .05). Treatment necessity beliefs also partially mediated the effects of helplessness on placebo responses. Treatment necessity beliefs for the pharmaceutical placebo were influenced by general pharmaceutical beliefs whereas necessity beliefs for the natural placebo were informed by general background beliefs about holistic treatments. Our findings show that treatment beliefs influence the placebo effect suggesting that they may offer an additional approach for understanding the placebo effect. Placebo effects contribute to responses to active analgesics. Understanding how beliefs about different types of treatment influence placebo analgesia may be useful in understanding variations in treatment response. Using the cold pressor paradigm we found that placebo analgesia was influenced by beliefs about natural remedies, pharmaceutical medicines, and about pain. Copyright © 2017. Published by Elsevier Inc.

Placebo Trends across the Border: US versus Canada.

PubMed

Harris, Cory S; Campbell, Natasha K J; Raz, Amir

2015-01-01

Physicians around the world report to using placebos in a variety of situations and with varying degrees of frequency. Inconsistent methodologies, however, complicate interpretation and prevent direct comparisons across studies. While US- and Canada-based physicians share similar professional standards, Canada harbours a less-litigious universal healthcare model with no formal placebo-related policy-factors that may impact how physicians view and use placebos. To compare American and Canadian data, we circulated an online survey to academic physicians practicing in Canada, collected anonymous responses, and extracted those of internists and rheumatologists for comparison to US data obtained through parallel methodologies. Whereas our data show overall concordance across the border-from definitions to ethical limitations and therapeutic potential-differences between American- and Canadian-based placebo practices merit acknowledgement. For example, compared to 45%-80% among US-based respondents, only 23±7% of Canada-based respondents reported using placebos in clinical practice. However, 79±7% of Canada-respondents-a figure comparable to US data-professed to prescribing at least one form of treatment without proven or expected efficacy. Placebo interventions including unwarranted vitamins and herbal supplements (impure placebos) as well as sugar pills and saline injections (pure placebos) appear more common in Canada, where more doctors described placebos as "placebos" (rather than "medications") and used them as a "diagnostic" tool (rather than a means of placating patient demands for treatment). Cross-border variation in the use of clinical placebos appears minor despite substantial differences in health care delivery system, malpractice climate, and placebo-related policy. The prevalence of impure placebos in both Canadian and US clinics raises ethical and practical questions currently unaddressed by policy and warranting investigation.

Placebo effects in competitive sport: qualitative data.

PubMed

Beedie, Christopher J

2007-01-01

The paper examines the placebo effect in sports performance. The possibility that the placebo effect is a more common phenomenon than the quantity of published research would suggest is briefly addressed. It is suggested that the placebo control design often used in sports performance research masks any placebo effects and thus presents a false picture of the mechanisms underlying performance-enhancing interventions in the real world. An electronic survey was sent to 48 competitive, international and professional athletes. Questions related to the placebo effect in competitive sport. Thirty responses were received. Data indicate that the majority (97%) of respondents believe that the placebo effect can exert an influence on sports performance, and that a significant number (73%) have experienced what they defined as a placebo effect. Inductive content analysis reveals that these experiences fall into several categories such as explicit placebo effects, inadvertent false beliefs, ritual and reverse placebo effects. Furthermore, 10 respondents (33%) offer explanations as to the nature of the placebo effect. Again, inductive content analysis reveals that these explanations fall into several categories including deliberate changes in competitive strategy, belief/expectancy, faith in a third party, and marketing. Overall, responses support previous experimental research and anecdotal reports that have found a relationship between belief and sports performance. It is suggested that further research be structured to not simply control for the placebo effect, but to elucidate it. Key pointsA survey of 30 athletes revealed that 73% have experienced a placebo effect in sport.Athletes suggest several potential explanations for these effects.Findings support the idea that placebo effects might be common in sport.Researchers and practitioners should be aware of the possible impact of these effects on research findings and competitive performance.

Effects of subtle cognitive manipulations on placebo analgesia - An implicit priming study.

PubMed

Rosén, A; Yi, J; Kirsch, I; Kaptchuk, T J; Ingvar, M; Jensen, K B

2017-04-01

Expectancy is widely accepted as a key contributor to placebo effects. However, it is not known whether non-conscious expectancies achieved through semantic priming may contribute to placebo analgesia. In this study, we investigated if an implicit priming procedure, where participants were unaware of the intended priming influence, affected placebo analgesia. In a double-blind experiment, healthy participants (n = 36) were randomized to different implicit priming types; one aimed at increasing positive expectations and one neutral control condition. First, pain calibration (thermal) and a credibility demonstration of the placebo analgesic device were performed. In a second step, an independent experimenter administered the priming task; Scrambled Sentence Test. Then, pain sensitivity was assessed while telling participants that the analgesic device was either turned on (placebo) or turned off (baseline). Pain responses were recorded on a 0-100 Numeric Response Scale. Overall, there was a significant placebo effect (p < 0.001), however, the priming conditions (positive/neutral) did not lead to differences in placebo outcome. Prior experience of pain relief (during initial pain testing) correlated significantly with placebo analgesia (p < 0.001) and explained 34% of placebo variance. Trait neuroticism correlated positively with placebo analgesia (p < 0.05) and explained 21% of placebo variance. Priming is one of many ways to influence behaviour, and non-conscious activation of positive expectations could theoretically affect placebo analgesia. Yet, we found no SST priming effect on placebo analgesia. Instead, our data point to the significance of prior experience of pain relief, trait neuroticism and social interaction with the treating clinician. Our findings challenge the role of semantic priming as a behavioural modifier that may shape expectations of pain relief, and affect placebo analgesia. © 2016 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC®.

Enhancing Placebo Effects in Somatic Symptoms Through Oxytocin.

PubMed

Skvortsova, Aleksandrina; Veldhuijzen, Dieuwke S; Van Middendorp, Henriët; Van den Bergh, Omer; Evers, Andrea W M

2018-05-01

Placebo effects relieve various somatic symptoms, but it is unclear how they can be enhanced to maximize positive treatment outcomes. Oxytocin administration may potentially enhance placebo effects, but few studies have been performed, and they have had conflicting findings. The study aim was to investigate the influence of positive verbal suggestions and oxytocin on treatment expectations and placebo effects for pain and itch. One hundred eight female participants were allocated to one of the following four groups: (1) oxytocin with positive verbal suggestions, (2) placebo with positive verbal suggestions, (3) oxytocin without suggestions, and (4) placebo without suggestions. The administration of 24 IU oxytocin or a placebo spray was preceded by positive verbal suggestions regarding the pain- and itch-relieving properties of the spray or no suggestions, depending on group allocation. Pain was assessed with a cold pressor test, and itch was assessed with histamine iontophoresis. Positive verbal suggestions induced expectations of lower pain (F = 4.77, p = .031) and itch (F = 5.38, p = .022). Moreover, positive verbal suggestions elicited placebo analgesia (F = 5.48, p = .021) but did not decrease itch. No effect of oxytocin on the placebo effect or on expectations was found. Positive suggestions induced placebo analgesia but oxytocin did not enhance the placebo effect. Study limitations are that we only included a female sample and a failure to induce placebo effect for itch. Future studies should focus on how oxytocin might influence placebo effects, taken into account the role of sex, dose-dependent effects, and various expectation manipulations. The study was registered as a clinical trial on www.trialregister.nl (number 6376).

Placebo and nocebo reactions in randomized trials of pharmacological treatments for persistent depressive disorder. A meta-regression analysis.

PubMed

Meister, Ramona; Jansen, Alessa; Härter, Martin; Nestoriuc, Yvonne; Kriston, Levente

2017-06-01

We aimed to investigate placebo and nocebo reactions in randomized controlled trials (RCT) of pharmacological treatments for persistent depressive disorder (PDD). We conducted a systematic electronic search and included RCTs investigating antidepressants for the treatment of PDD. Outcomes were the number of patients experiencing response and remission in placebo arms (=placebo reaction). Additional outcomes were the incidence of patients experiencing adverse events and related discontinuations in placebo arms (=nocebo reaction). A priori defined effect modifiers were analyzed using a series of meta-regression analyses. Twenty-three trials were included in the analyses. We found a pooled placebo response rate of 31% and a placebo remission rate of 22%. The pooled adverse event rate and related discontinuations were 57% and 4%, respectively. All placebo arm outcomes were positively associated with the corresponding medication arm outcomes. Placebo response rate was associated with a greater proportion of patients with early onset depression, a smaller chance to receive placebo and a larger sample size. The adverse event rate in placebo arms was associated with a greater proportion of patients with early onset depression, a smaller proportion of females and a more recent publication. Pooled placebo and nocebo reaction rates in PDD were comparable to those in episodic depression. The identified effect modifiers should be considered to assess unbiased effects in RCTs, to influence placebo and nocebo reactions in practice. Limitations result from the methodology applied, the fact that we conducted only univariate analyses, and the number and quality of included trials. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of clinical response to active drugs and placebo on antipsychotics and mood stabilizers relative efficacy for bipolar depression and mania: A meta-regression analysis.

PubMed

Bartoli, Francesco; Clerici, Massimo; Di Brita, Carmen; Riboldi, Ilaria; Crocamo, Cristina; Carrà, Giuseppe

2018-04-01

Randomised placebo-controlled trials investigating treatments for bipolar disorder have been hampered by wide variations of active drugs and placebo clinical response rates. It is important to estimate whether the active drug or placebo response has a greater influence in determining the relative efficacy of drugs for psychosis (antipsychotics) and relapse prevention (mood stabilisers) for bipolar depression and mania. We identified 53 randomised, placebo-controlled trials assessing antipsychotic or mood stabiliser monotherapy ('active drugs') for bipolar depression or mania. We carried out random-effects meta-regressions, estimating the influence of active drugs and placebo response rates on treatment relative efficacy. Meta-regressions showed that treatment relative efficacy for bipolar mania was influenced by the magnitude of clinical response to active drugs ( p=0.002), but not to placebo ( p=0.60). On the other hand, treatment relative efficacy for bipolar depression was influenced by response to placebo ( p=0.047), but not to active drugs ( p=0.98). Despite several limitations, our unexpected findings showed that antipsychotics / mood stabilisers relative efficacy for bipolar depression seems unrelated to active drugs response rates, depending only on clinical response to placebo. Future research should explore strategies to reduce placebo-related issues in randomised, placebo-controlled trials for bipolar depression.

Is Skin-Touch Sham Needle Not Placebo? A Double-Blind Crossover Study on Pain Alleviation

PubMed Central

Homma, Ikuo; Izumizaki, Masahiko

2015-01-01

It remains an open question whether placebo/sham acupuncture, in which the needle tip presses the skin, can be used as a placebo device for research on pain. We compare the analgesic effect of the skin-touch placebo needle with that of the no-touch placebo needle, in which the needle tip does not touch the skin, in a double-blind crossover manner including no-treatment control in 23 healthy volunteers. The subjects received painful electrical stimulation in the forearm before and during needle retention to the LI 4 acupoint and after the removal of the needle and rated pain intensity using a visual analogue scale. We found no significant difference in analgesic effects among the skin-touch placebo needle, no-touch placebo needle, and no-treatment control at every point before, during, and after the treatments (p > 0.05). The results indicate that the skin-touch placebo needle can be used as a placebo device in clinical studies on pain. PMID:26064153

A two-way enriched clinical trial design: combining advantages of placebo lead-in and randomized withdrawal.

PubMed

Ivanova, Anastasia; Tamura, Roy N

2015-12-01

A new clinical trial design, designated the two-way enriched design (TED), is introduced, which augments the standard randomized placebo-controlled trial with second-stage enrichment designs in placebo non-responders and drug responders. The trial is run in two stages. In the first stage, patients are randomized between drug and placebo. In the second stage, placebo non-responders are re-randomized between drug and placebo and drug responders are re-randomized between drug and placebo. All first-stage data, and second-stage data from first-stage placebo non-responders and first-stage drug responders, are utilized in the efficacy analysis. The authors developed one, two and three degrees of freedom score tests for treatment effect in the TED and give formulae for asymptotic power and for sample size computations. The authors compute the optimal allocation ratio between drug and placebo in the first stage for the TED and compare the operating characteristics of the design to the standard parallel clinical trial, placebo lead-in and randomized withdrawal designs. Two motivating examples from different disease areas are presented to illustrate the possible design considerations. © The Author(s) 2011.

Caffeine withdrawal and high-intensity endurance cycling performance.

PubMed

Irwin, Christopher; Desbrow, Ben; Ellis, Aleisha; O'Keeffe, Brooke; Grant, Gary; Leveritt, Michael

2011-03-01

In this study, we investigated the impact of a controlled 4-day caffeine withdrawal period on the effect of an acute caffeine dose on endurance exercise performance. Twelve well-trained and familiarized male cyclists, who were caffeine consumers (from coffee and a range of other sources), were recruited for the study. A double-blind placebo-controlled cross-over design was employed, involving four experimental trials. Participants abstained from dietary caffeine sources for 4 days before the trials and ingested capsules (one in the morning and one in the afternoon) containing either placebo or caffeine (1.5 mg · kg(-1) body weight · day(-1)). On day 5, capsules containing placebo or caffeine (3 mg · kg(-1) body weight) were ingested 90 min before completing a time trial, equivalent to one hour of cycling at 75% peak sustainable power output. Hence the study was designed to incorporate placebo-placebo, placebo-caffeine, caffeine-placebo, and caffeine-caffeine conditions. Performance time was significantly improved after acute caffeine ingestion by 1:49 ± 1:41 min (3.0%, P = 0.021) following a withdrawal period (placebo-placebo vs. placebo-caffeine), and by 2:07 ± 1:28 min (3.6%, P = 0.002) following the non-withdrawal period (caffeine-placebo vs. caffeine-caffeine). No significant difference was detected between the two acute caffeine trials (placebo-caffeine vs. caffeine-caffeine). Average heart rate throughout exercise was significantly higher following acute caffeine administration compared with placebo. No differences were observed in ratings of perceived exertion between trials. A 3 mg · kg(-1) dose of caffeine significantly improves exercise performance irrespective of whether a 4-day withdrawal period is imposed on habitual caffeine users.

Placebo Trends across the Border: US versus Canada

PubMed Central

Harris, Cory S.; Campbell, Natasha K. J.; Raz, Amir

2015-01-01

Background Physicians around the world report to using placebos in a variety of situations and with varying degrees of frequency. Inconsistent methodologies, however, complicate interpretation and prevent direct comparisons across studies. While US- and Canada-based physicians share similar professional standards, Canada harbours a less-litigious universal healthcare model with no formal placebo-related policy—factors that may impact how physicians view and use placebos. Methods To compare American and Canadian data, we circulated an online survey to academic physicians practicing in Canada, collected anonymous responses, and extracted those of internists and rheumatologists for comparison to US data obtained through parallel methodologies. Results Whereas our data show overall concordance across the border—from definitions to ethical limitations and therapeutic potential—differences between American- and Canadian-based placebo practices merit acknowledgement. For example, compared to 45%-80% among US-based respondents, only 23±7% of Canada-based respondents reported using placebos in clinical practice. However, 79±7% of Canada-respondents—a figure comparable to US data—professed to prescribing at least one form of treatment without proven or expected efficacy. Placebo interventions including unwarranted vitamins and herbal supplements (impure placebos) as well as sugar pills and saline injections (pure placebos) appear more common in Canada, where more doctors described placebos as “placebos” (rather than “medications”) and used them as a “diagnostic” tool (rather than a means of placating patient demands for treatment). Interpretation Cross-border variation in the use of clinical placebos appears minor despite substantial differences in health care delivery system, malpractice climate, and placebo-related policy. The prevalence of impure placebos in both Canadian and US clinics raises ethical and practical questions currently unaddressed by policy and warranting investigation. PMID:26606749

Dose finding with the sequential parallel comparison design.

PubMed

Wang, Jessie J; Ivanova, Anastasia

2014-01-01

The sequential parallel comparison design (SPCD) is a two-stage design recommended for trials with possibly high placebo response. A drug-placebo comparison in the first stage is followed in the second stage by placebo nonresponders being re-randomized between drug and placebo. We describe how SPCD can be used in trials where multiple doses of a drug or multiple treatments are compared with placebo and present two adaptive approaches. We detail how to analyze data in such trials and give recommendations about the allocation proportion to placebo in the two stages of SPCD.

Twelve Months of Nightly Zolpidem Does Not Lead to Dose Escalation: A Prospective Placebo-Controlled Study

PubMed Central

Roehrs, Timothy A.; Randall, Surilla; Harris, Erica; Maan, Renee; Roth, Thomas

2011-01-01

Study Objectives: To assess hypnotic self-administration and likelihood of dose escalation over 12 months of nightly use of zolpidem versus placebo in primary insomniacs. Design: Randomized, double-blind, placebo-controlled, clinical trial. Setting: Outpatient with tri-monthly one-week, sleep laboratory assessments. Participants: Thirty-three primary insomniacs, without psychiatric disorders or drug and alcohol abuse, 32–64 yrs old, 14 men and 19 women. Interventions: Participants were randomized to take zolpidem 10 mg (n = 17) or placebo (n = 16) nightly for 12 months. In probes during month 1, 4, and 12, after sampling color-coded placebo or zolpidem capsules on 2 nights, color-coded zolpidem or placebo was chosen on 5 consecutive nights and 1, 2, or 3 of the chosen capsules (5 mg each) could be self-administered on a given choice night. Results: Zolpidem was chosen more nights than placebo (80% of nights) and number of nights zolpidem was chosen did not differ over the 12 months. More zolpidem than placebo capsules were self-administered, and the total number of placebo or zolpidem capsules self-administered did not differ as a function of duration of use. In contrast, the total number of placebo capsules self-administered by the placebo group increased across time. The nightly capsule self-administration on zolpidem nights did not differ from that on placebo nights and neither nightly self-administration rates increased over the 12 months. An average 9.3 mg nightly dose was self-administered. Conclusions: Zolpidem was preferred to placebo, but its self-administration did not increase with 12 months of use. Chronic hypnotic use by primary insomniacs does not lead to dose escalation. Clinical Trial Registration: Safety and Efficacy of Chronic Hypnotic Use; # NCT01006525; http://www.clinicaltrials.gov/ Citation: Roehrs TA; Randall S; Harris E; Maan R; Roth T. Twelve months of nightly zolpidem does not lead to dose escalation: a prospective placebo-controlled study. SLEEP 2011;34(2):207–212. PMID:21286241

Are Children the Better Placebo Analgesia Responders? An Experimental Approach.

PubMed

Wrobel, Nathalie; Fadai, Tahmine; Sprenger, Christian; Hebebrand, Johannes; Wiech, Katja; Bingel, Ulrike

2015-10-01

There is little information regarding changes in placebo responsiveness with age, although first predictors of placebo responders such as psychological and physiological processes have been identified. Reviews and meta-analyses indicate that placebo response rates in randomized controlled trials (RCTs) are higher in children and adolescents compared with adults. As these studies cannot control for age-dependent differences in the natural course of the disease, biases might contribute to different placebo rates in RCTs. To avoid these biases, this study investigated age-related differences in placebo responsiveness between children and adults in a well-established experimental model of placebo analgesia combining classic conditioning and expectation. Our data confirm placebo analgesic responses in children, which did not differ in magnitude from those of adults. The influence of previous experience on subsequent treatment outcome was stronger in children than in adults, indicating an increased relevance of learning processes for treatment outcomes in children. Further studies are needed to understand the influence of treatment-related learning processes in children and adolescents, which might critically determine treatment responsiveness during adulthood. This study is the first to experimentally explore placebo analgesia and influences of previous experience on placebo responses in children compared with adults. We found comparable placebo responses in both groups and an increased relevance of learning processes for treatment outcomes in children. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

Randomized study of placebo and framing information in direct-to-consumer print advertisements for prescription drugs.

PubMed

O'Donoghue, Amie C; Sullivan, Helen W; Aikin, Kathryn J

2014-12-01

Research suggests that quantitative information in direct-to-consumer (DTC) prescription drug ads may be helpful for consumers. The objective was to examine the effect of adding placebo rates and framing to DTC ads. In study 1, 2,000 Internet panel members with chronic pain participated in a randomized controlled experiment of DTC ads varying in placebo rate and framing. In study 2, 596 physicians ranked DTC ads varying in placebo rate and framing by how well they conveyed scientific information and their usefulness for patients. In study 1, participants who viewed placebo rates were able to recall them and use them to form certain perceptions. A mixed frame led to lower placebo rate recall and perceived efficacy. In study 2, overall, physicians preferred a placebo/single frame ad. Adding placebo rates to DTC ads may be useful for consumers. The evidence does not support using a mixed frame.

Clinical evaluation of liquid placebos for an herbal supplement, STW5, in healthy volunteers.

PubMed

Yoon, Saunjoo L; Grundmann, Oliver; Keane, Devan; Urbano, Theodore; Moshiree, Baharak

2012-10-01

Although clinical trials are needed to evaluate the efficacy of liquid herbal medicinal products, design of feasible placebos that mimic the appearance, taste, and smell of such products is particularly challenging. The design and feasibility of a liquid placebo for STW5, an herbal medicinal product used for various gastrointestinal problems, was explored in this study. Four sample products-STW5, a fresh and aged version of a placebo made from a seasoning mix (Maggi™), and a placebo with aged artificial flavor and food coloring-were compared in two organoleptic (sensory), single-blind trials with a total of 60 (N=60) healthy volunteers (n(1)=30, n(2)=30). The appearance, smell, and taste of each solution were evaluated using a Likert scale questionnaire. The liquid placebos evaluated were similar in regard to appearance, smell, and taste. However, participants indicated that for a clinical trial with STW5, the aged Maggi™ placebo would be more viable compared to the fresh Maggi placebo or the aged artificial food coloring placebo with licorice flavor. Participants also noted that the mint flavor and smell of STW5 was distinctly different from the placebo solutions. The trials were conducted in healthy volunteers, not in actual patients. The aged Maggi™ liquid mix may be more favorable as a placebo than the artificially created one. However, further adjustment will need to be made to the Maggi™ placebo to simulate the complex aromatic composition of STW5 for clinical studies in the future. Copyright © 2012 Elsevier Ltd. All rights reserved.

A renewed, ethical defense of placebo-controlled trials of new treatments for major depression and anxiety disorders.

PubMed

Dunlop, B W; Banja, J

2009-06-01

The use of placebo as a control condition in clinical trials of major depressive disorder and anxiety disorders continues to be an area of ethical concern. Typically, opponents of placebo controls argue that they violate the beneficent-based, "best proven diagnostic and therapeutic method" that the original Helsinki Declaration of 1964 famously asserted participants are owed. A more consequentialist, oppositional argument is that participants receiving placebo might suffer enormously by being deprived of their usual medication(s). Nevertheless, recent findings of potential for suicidality in young people treated with antidepressants, along with meta-analyses suggesting that antidepressants add no significant clinical benefit over placebos, warrant a re-evaluation of the arguments against placebo. Furthermore, the nature of placebo treatment in short-term clinical trials is often not well understood, and lack of understanding can foster opposition to it. This paper will show how scientific justifications for placebo use are morally relevant. The fundamental ethical importance of placebo controls is discussed in relation to several aspects of clinical trials, including detection of adverse events, accurate assessment of clinical benefit, advancing understanding of the heterogeneity of depression and anxiety disorders and respecting informed consent requirements. Prohibiting the use of placebo controls is morally concerning in that such prohibitions allow for the possibility of serious adverse public health consequences. Moral worries that research participants receiving placebo are being unduly jeopardised will be shown to be exaggerated, especially in relation to the net benefits for end-users to be gained from the quality of data resulting from using placebo controls.

Confusing placebo effect with natural history in epilepsy: A big data approach.

PubMed

Goldenholz, Daniel M; Moss, Robert; Scott, Jonathan; Auh, Sungyoung; Theodore, William H

2015-09-01

For unknown reasons, placebos reduce seizures in clinical trials in many patients. It is also unclear why some drugs showing statistical superiority to placebo in one trial may fail to do so in another. Using Seizuretracker.com, a patient-centered database of 684,825 seizures, we simulated "placebo" and "drug" trials. These simulations were employed to clarify the sources of placebo effects in epilepsy, and to identify methods of diminishing placebo effects. Simulation 1 included 9 trials with a 6-week baseline and 6-week test period, starting at time 0, 3, 6…24 months. Here, "placebo" reduced seizures regardless of study start time. Regression-to-the-mean persisted only for 3 to 6 months. Simulation 2 comprised a 6-week baseline and then 2 years of follow-up. Seizure frequencies continued to improve throughout follow-up. Although the group improved, individuals switched from improvement to worsening and back. Simulation 3 involved a placebo-controlled "drug" trial, to explore methods of placebo response reduction. An efficacious "drug" failed to demonstrate a significant effect compared with "placebo" (p = 0.12), although modifications either in study start time (p = 0.025) or baseline population reduction (p = 0.0028) allowed the drug to achieve a statistically significant effect compared with placebo. In epilepsy clinical trials, some seizure reduction traditionally attributed to placebo effect may reflect the natural course of the disease itself. Understanding these dynamics will allow future investigations into optimal clinical trial design and may lead to identification of more effective therapies. Ann Neurol 2015;78:329-336. © 2015 American Neurological Association.

Mechanisms of placebo analgesia: A dual-process model informed by insights from cross-species comparisons.

PubMed

Schafer, Scott M; Geuter, Stephan; Wager, Tor D

2018-01-01

Placebo treatments are pharmacologically inert, but are known to alleviate symptoms across a variety of clinical conditions. Associative learning and cognitive expectations both play important roles in placebo responses, however we are just beginning to understand how interactions between these processes lead to powerful effects. Here, we review the psychological principles underlying placebo effects and our current understanding of their brain bases, focusing on studies demonstrating both the importance of cognitive expectations and those that demonstrate expectancy-independent associative learning. To account for both forms of placebo analgesia, we propose a dual-process model in which flexible, contextually driven cognitive schemas and attributions guide associative learning processes that produce stable, long-term placebo effects. According to this model, the placebo-induction paradigms with the most powerful effects are those that combine reinforcement (e.g., the experience of reduced pain after placebo treatment) with suggestions and context cues that disambiguate learning by attributing perceived benefit to the placebo. Using this model as a conceptual scaffold, we review and compare neurobiological systems identified in both human studies of placebo analgesia and behavioral pain modulation in rodents. We identify substantial overlap between the circuits involved in human placebo analgesia and those that mediate multiple forms of context-based modulation of pain behavior in rodents, including forebrain-brainstem pathways and opioid and cannabinoid systems in particular. This overlap suggests that placebo effects are part of a set of adaptive mechanisms for shaping nociceptive signaling based on its information value and anticipated optimal response in a given behavioral context. Copyright © 2017 Elsevier Ltd. All rights reserved.

Are we drawing the right conclusions from randomised placebo-controlled trials? A post-hoc analysis of data from a randomised controlled trial

PubMed Central

2009-01-01

Background Assumptions underlying placebo controlled trials include that the placebo effect impacts on all study arms equally, and that treatment effects are additional to the placebo effect. However, these assumptions have recently been challenged, and different mechanisms may potentially be operating in the placebo and treatment arms. The objective of the current study was to explore the nature of placebo versus pharmacological effects by comparing predictors of the placebo response with predictors of the treatment response in a randomised, placebo-controlled trial of a phytotherapeutic combination for the treatment of menopausal symptoms. A substantial placebo response was observed but no significant difference in efficacy between the two arms. Methods A post hoc analysis was conducted on data from 93 participants who completed this previously published study. Variables at baseline were investigated as potential predictors of the response on any of the endpoints of flushing, overall menopausal symptoms and depression. Focused tests were conducted using hierarchical linear regression analyses. Based on these findings, analyses were conducted for both groups separately. These findings are discussed in relation to existing literature on placebo effects. Results Distinct differences in predictors were observed between the placebo and active groups. A significant difference was found for study entry anxiety, and Greene Climacteric Scale (GCS) scores, on all three endpoints. Attitude to menopause was found to differ significantly between the two groups for GCS scores. Examination of the individual arms found anxiety at study entry to predict placebo response on all three outcome measures individually. In contrast, low anxiety was significantly associated with improvement in the active treatment group. None of the variables found to predict the placebo response was relevant to the treatment arm. Conclusion This study was a post hoc analysis of predictors of the placebo versus treatment response. Whilst this study does not explore neurobiological mechanisms, these observations are consistent with the hypotheses that 'drug' effects and placebo effects are not necessarily additive, and that mutually exclusive mechanisms may be operating in the two arms. The need for more research in the area of mechanisms and mediators of placebo versus active responses is supported. Trial Registration International Clinical Trials Registry ISRCTN98972974. PMID:19549306

Enhancing the placebo response: fMRI Evidence of Memory and Semantic Processing in Placebo Analgesia

PubMed Central

Craggs, Jason G.; Price, Donald D.; Robinson, Michael E.

2014-01-01

Two groups of patients with irritable bowel syndrome (IBS) rated pain and underwent fMRI brain scanning during experimentally induced rectal distension (20 sec, 7 stimuli). Group #1 was tested under baseline (natural history) and a verbally induced placebo condition, whereas Group #2 was tested under baseline, and standard placebo (no verbal suggestion for pain reduction) and intrarectal lidocaine conditions. As hypothesized, intrarectal lidocaine reduced evoked pain and pain-related brain activity within Group #2Between-group comparisons showed that adding a verbal suggestion to a placebo condition increased neural activity involved in memory and semantic processing, areas that process the placebo suggestions. These areas, in turn, are likely to influence brain areas involved in emotions and analgesia and consequently the placebo effect. These placebo suggestions also added significant decreases in activity of brain areas that process pain. The test stimulus itself seems to cue these effects and is consistent with previous explanations that somatic focus and sensory feedback reinforce expectations and other factors that mediate placebo analgesic effects. PMID:24412799

Should we reconsider the routine use of placebo controls in clinical research?

PubMed

Avins, Andrew L; Cherkin, Daniel C; Sherman, Karen J; Goldberg, Harley; Pressman, Alice

2012-04-27

Modern clinical-research practice favors placebo controls over usual-care controls whenever a credible placebo exists. An unrecognized consequence of this preference is that clinicians are more limited in their ability to provide the benefits of the non-specific healing effects of placebos in clinical practice. We examined the issues in choosing between placebo and usual-care controls. We considered why placebo controls place constraints on clinicians and the trade-offs involved in the choice of control groups. We find that, for certain studies, investigators should consider usual-care controls, even if an adequate placebo is available. Employing usual-care controls would be of greatest value for pragmatic trials evaluating treatments to improve clinical care and for which threats to internal validity can be adequately managed without a placebo-control condition. Intentionally choosing usual-care controls, even when a satisfactory placebo exists, would allow clinicians to capture the value of non-specific therapeutic benefits that are common to all interventions. The result could be more effective, patient-centered care that makes the best use of both specific and non-specific benefits of medical interventions.

Placebo effects in psychiatry: mediators and moderators

PubMed Central

Weimer, Katja; Colloca, Luana; Enck, Paul

2015-01-01

A strong placebo response in psychiatric disorders has been noted for the past 50 years and various attempts have been made to identify predictors of it, by use of meta-analyses of randomised controlled trials and laboratory studies. We reviewed 31 meta-analyses and systematic reviews of more than 500 randomised placebo-controlled trials across psychiatry (depression, schizophrenia, mania, attention-deficit hyperactivity disorder, autism, psychosis, binge-eating disorder, and addiction) for factors identified to be associated with increased placebo response. Of 20 factors discussed, only three were often linked to high placebo responses: low baseline severity of symptoms, more recent trials, and unbalanced randomisation (more patients randomly assigned to drug than placebo). Randomised controlled trials in non-drug therapy have not added further predictors, and laboratory studies with psychological, brain, and genetic approaches have not been successful in identifying predictors of placebo responses. This comprehensive Review suggests that predictors of the placebo response are still to be discovered, the response probably has more than one mediator, and that different and distinct moderators are probably what cause the placebo response within psychiatry and beyond. PMID:25815249

Low-Dose Iron Supplementation in Infancy Modestly Increases Infant Iron Status at 9 Mo without Decreasing Growth or Increasing Illness in a Randomized Clinical Trial in Rural China123

PubMed Central

Lozoff, Betsy; Jiang, Yaping; Li, Xing; Zhou, Min; Richards, Blair; Xu, Guobin; Clark, Katy M; Liang, Furong; Kaciroti, Niko; Zhao, Gengli; Santos, Denise CC; Zhang, Zhixiang; Tardif, Twila; Li, Ming

2016-01-01

Background: Previous trials of iron supplementation in infancy did not consider maternal iron supplementation. Objective: This study assessed effects of iron supplementation in infancy and/or pregnancy on infant iron status, illnesses, and growth at 9 mo. Methods: Enrollment occurred from December 2009 to June 2012 in Hebei, China. Infants born to women in a pregnancy iron supplementation trial were randomly assigned 1:1 to iron [∼1 mg Fe/(kg · d) as oral iron proteinsuccynilate] or placebo from 6 wk to 9 mo, excluding infants with cord ferritin <35 μg/L. Study groups were pregnancy placebo/infancy placebo (placebo/placebo), pregnancy placebo/infancy iron (placebo/iron), pregnancy iron/infancy placebo (iron/placebo), and pregnancy iron/infancy iron (iron/iron). The primary outcome was 9-mo iron status: iron deficiency (ID) by cutoff (≥2 abnormal iron measures) or body iron <0 mg/kg and ID + anemia (hemoglobin <110 g/L). Secondary outcomes were doctor visits or hospitalizations and weight or length gain from birth to 9 mo. Statistical analysis by intention to treat and dose-response (between number of iron bottles received and outcome) used logistic regression with concomitant RRs and general linear models, with covariate control as applicable. Results: Of 1482 infants randomly allocated, 1276 had 9-mo data (n = 312–327/group). Iron supplementation in infancy, but not pregnancy, reduced ID risk: RRs (95% CIs) were 0.89 (0.79, 0.998) for placebo/iron compared to placebo/placebo, 0.79 (0.63, 0.98) for placebo/iron compared to iron/placebo, 0.87 (0.77, 0.98) for iron/iron compared to placebo/placebo, and 0.86 (0.77, 0.97) for iron/iron compared to iron/placebo. However, >60% of infants still had ID at 9 mo. Receiving more bottles of iron in infancy was associated with better infant iron status at 9 mo but only among iron-supplemented infants whose mothers were also iron supplemented (i.e., the iron/iron group). There were no group differences in hospitalizations or illnesses and no adverse effects on growth overall or among infants who were iron sufficient at birth. Conclusions: Iron supplementation in Chinese infants reduced ID at 9 mo without adverse effects on growth or illness. Effects of iron supplementation in pregnancy were observed only when higher amounts of iron were distributed in infancy. This trial was registered at clinicaltrials.gov as NCT00613717. PMID:26791556

Psychotherapy: The Powerful Placebo.

ERIC Educational Resources Information Center

Wilkins, Wallace

1984-01-01

Discusses research designs in which psychotherapy treatments are compared to placebo conditions, and suggests that chemotherapy and psychotherapy research efforts are complementary rather than analogous. Recommends the elimination of placebo groups in psychotherapy research. Discusses the negative connotation of psychotherapy as a placebo. (JAC)

Parental Attitudes About Placebo Use in Children.

PubMed

Faria, Vanda; Kossowsky, Joe; Petkov, Mike P; Kaptchuk, Ted J; Kirsch, Irving; Lebel, Alyssa; Borsook, David

2017-02-01

To assess parental attitudes regarding placebo use in pediatric randomized controlled trials and clinical care. Parents with children under age 18 years living in the US completed and submitted an online survey between September and November 2014. Among all 1300 participants, 1000 (76.9%; 538 mothers and 462 fathers) met the study inclusion criteria. The majority of surveyed parents considered the use of placebos acceptable in some pediatric care situations (86%) and some pediatric trials (91.5%), whereas only 5.7% of parents found the use of placebos in children always unacceptable. The clinical use of placebo was considered acceptable by a majority of parents for only 7 (mostly psychological) of the 17 conditions presented. Respondents' judgment about acceptability was influenced by the doctors' opinions about the therapeutic benefits of placebo treatment, the conditions for pediatric placebo use, transparency, safety, and purity of placebos. Most surveyed parents accepted the idea of using placebos in pediatric trials and within the clinic for some conditions without the practice of deception and with the creation of guidelines for ethical and safe use. This study suggests a need to reconsider pediatric trial design and clinical therapy in the light of generally positive parental support of appropriate placebo use. Copyright © 2016 Elsevier Inc. All rights reserved.

Mechanisms of the placebo response in pain in osteoarthritis.

PubMed

Abhishek, A; Doherty, M

2013-09-01

Administration of a placebo associates with symptomatic improvement in many conditions--the so-called placebo response. In this review we explain the concept of placebo response, examine the data that supports existence in osteoarthritis (OA), and discuss its possible mechanisms and determinants. A Pubmed literature search was carried out. Key articles were identified, and their findings discussed in a narrative review. Pain, stiffness, self-reported function and physician-global assessment in OA clearly improve in response to placebo. However, more objective measures such as quadriceps strength and radiographic progression appear less responsive. Although not directly studied in OA, contextual effects, patient expectation and conditioning are believed to be the main mechanisms. Neurotransmitter changes that mediate placebo-induced analgesia include increased endogenous opioid levels, increased dopamine levels, and reduced levels of cholecystokinin. Almost all parts of the brain involved in pain processing are influenced during placebo-induced analgesia. Determinants of the magnitude of placebo response include the patient-practitioner interaction, treatment response expectancy, knowledge of being treated, patient personality traits and placebo specific factors such as the route and frequency of administration, branding, and treatment costs. Clearer understanding of the neurobiology of placebo response validates its existence as a real phenomenon. Although routine administration of placebo for symptomatic improvement is difficult to justify, contextual factors that enhance treatment response should be employed in the management of chronic painful conditions such as OA where available treatments have only modest efficacy. Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

The power of the placebo.

PubMed

Eccles, Ron

2007-05-01

The placebo is much more than a control medicine in a clinical trial. The placebo response is the largest component of any allergy treatment and consists of two components: nonspecific effects (eg, natural recovery) and a "true placebo effect" that is the psychological therapeutic effect of the treatment. Belief in the beneficial nature of the treatment is a key component of the true placebo effect, and can be enhanced by factors such as interaction with the physician and the sensory impact of the treatment. Negative beliefs can generate a nocebo effect that may explain some psychogenic illnesses; this is the basis of much research in psychoneuroimmunology. An understanding of the placebo and nocebo effects is important for general allergy practice, and harnessing the power of the true placebo effect is a major challenge to modern medicine.

Predictive factors for the placebo effect in clinical trials for dry eye: a pooled analysis of three clinical trials.

PubMed

Imanaka, Takahiro; Sato, Izumi; Tanaka, Shiro; Kawakami, Koji

2017-11-01

Placebo effect is one of the methodological difficulties in dry eye clinical trials. If we could elucidate the tendencies of the placebo response and find predictors, we could reduce the placebo response in clinical trials for dry eye. In this study, we investigated the predictive factors for the placebo effect in dry eye clinical trials. A total of 205 patients with dry eye assigned to the placebo arms of three placebo-controlled randomised clinical trials were analysed by simple and multivariable regression analysis. The corneal fluorescein (FL) staining score and dry eye symptoms were studied at week 4. The variables of interest included gender, age, complications of Sjögren's syndrome, Schirmer's test I value, tear break-up time and conjunctival hyperaemia score. We also conducted a stratified analysis according to the patients' age. Among all the studied endpoints, the baseline scores were significantly related to the corresponding placebo response. In addition, for the FL score and the dryness score, age was a significant predictor of the placebo response (p=0.04 and p<0.0001, respectively). Stratified analysis by age showed that patients more than 40 years of age are more likely to have a stronger placebo response in the FL and dryness scores. The baseline scores and age were predictive factors of the placebo response in frequently used endpoints, such as FL score or dryness symptoms. These patient characteristics can be controlled by study design, and our findings enable the design of more efficient placebo-controlled studies with good statistical power. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Use of placebo controls in the evaluation of surgery: systematic review

PubMed Central

Judge, Andrew; Hopewell, Sally; Collins, Gary S; Dean, Benjamin J F; Rombach, Ines; Brindley, David; Savulescu, Julian; Beard, David J; Carr, Andrew J

2014-01-01

Objective To investigate whether placebo controls should be used in the evaluation of surgical interventions. Design Systematic review. Data sources We searched Medline, Embase, and the Cochrane Controlled Trials Register from their inception to November 2013. Study selection Randomised clinical trials comparing any surgical intervention with placebo. Surgery was defined as any procedure that both changes the anatomy and requires a skin incision or use of endoscopic techniques. Data extraction Three reviewers (KW, BJFD, IR) independently identified the relevant trials and extracted data on study details, outcomes, and harms from included studies. Results In 39 out of 53 (74%) trials there was improvement in the placebo arm and in 27 (51%) trials the effect of placebo did not differ from that of surgery. In 26 (49%) trials, surgery was superior to placebo but the magnitude of the effect of the surgical intervention over that of the placebo was generally small. Serious adverse events were reported in the placebo arm in 18 trials (34%) and in the surgical arm in 22 trials (41.5%); in four trials authors did not specify in which arm the events occurred. However, in many studies adverse events were unrelated to the intervention or associated with the severity of the condition. The existing placebo controlled trials investigated only less invasive procedures that did not involve laparotomy, thoracotomy, craniotomy, or extensive tissue dissection. Conclusions Placebo controlled trial is a powerful, feasible way of showing the efficacy of surgical procedures. The risks of adverse effects associated with the placebo are small. In half of the studies, the results provide evidence against continued use of the investigated surgical procedures. Without well designed placebo controlled trials of surgery, ineffective treatment may continue unchallenged. PMID:24850821

Low level laser therapy before eccentric exercise reduces muscle damage markers in humans.

PubMed

Baroni, Bruno Manfredini; Leal Junior, Ernesto Cesar Pinto; De Marchi, Thiago; Lopes, André Luiz; Salvador, Mirian; Vaz, Marco Aurélio

2010-11-01

The purpose of the present study was to determine the effect of low level laser therapy (LLLT) treatment before knee extensor eccentric exercise on indirect markers of muscle damage. Thirty-six healthy men were randomized in LLLT group (n = 18) and placebo group (n = 18). After LLLT or placebo treatment, subjects performed 75 maximal knee extensors eccentric contractions (five sets of 15 repetitions; velocity = 60° seg(-1); range of motion = 60°). Muscle soreness (visual analogue scale--VAS), lactate dehydrogenase (LDH) and creatine kinase (CK) levels were measured prior to exercise, and 24 and 48 h after exercise. Muscle function (maximal voluntary contraction--MVC) was measured before exercise, immediately after, and 24 and 48 h post-exercise. Groups had no difference on kineanthropometric characteristics and on eccentric exercise performance. They also presented similar baseline values of VAS (0.00 mm for LLLT and placebo groups), LDH (LLLT = 186 IU/l; placebo = 183 IU/l), CK (LLLT = 145 IU/l; placebo = 155 IU/l) and MVC (LLLT = 293 Nm; placebo = 284 Nm). VAS data did not show group by time interaction (P = 0.066). In the other outcomes, LLLT group presented (1) smaller increase on LDH values 48 h post-exercise (LLLT = 366 IU/l; placebo = 484 IU/l; P = 0.017); (2) smaller increase on CK values 24 h (LLLT = 272 IU/l; placebo = 498 IU/l; P = 0.020) and 48 h (LLLT = 436 IU/l; placebo = 1328 IU/l; P < 0.001) post-exercise; (3) smaller decrease on MVC immediately after exercise (LLLT = 189 Nm; placebo = 154 Nm; P = 0.011), and 24 h (LLLT = 249 Nm; placebo = 205 Nm; P = 0.004) and 48 h (LLLT = 267 Nm; placebo = 216 Nm; P = 0.001) post-exercise compared with the placebo group. In conclusion, LLLT treatment before eccentric exercise was effective in terms of attenuating the increase of muscle proteins in the blood serum and the decrease in muscle force.

Hypnotizability and Placebo Analgesia in Waking and Hypnosis as Modulators of Auditory Startle Responses in Healthy Women: An ERP Study.

PubMed

De Pascalis, Vilfredo; Scacchia, Paolo

2016-01-01

We evaluated the influence of hypnotizability, pain expectation, placebo analgesia in waking and hypnosis on tonic pain relief. We also investigated how placebo analgesia affects somatic responses (eye blink) and N100 and P200 waves of event-related potentials (ERPs) elicited by auditory startle probes. Although expectation plays an important role in placebo and hypnotic analgesia, the neural mechanisms underlying these treatments are still poorly understood. We used the cold cup test (CCT) to induce tonic pain in 53 healthy women. Placebo analgesia was initially produced by manipulation, in which the intensity of pain induced by the CCT was surreptitiously reduced after the administration of a sham analgesic cream. Participants were then tested in waking and hypnosis under three treatments: (1) resting (Baseline); (2) CCT-alone (Pain); and (3) CCT plus placebo cream for pain relief (Placebo). For each painful treatment, we assessed pain and distress ratings, eye blink responses, N100 and P200 amplitudes. We used LORETA analysis of N100 and P200 waves, as elicited by auditory startle, to identify cortical regions sensitive to pain reduction through placebo and hypnotic analgesia. Higher pain expectation was associated with higher pain reductions. In highly hypnotizable participants placebo treatment produced significant reductions of pain and distress perception in both waking and hypnosis condition. P200 wave, during placebo analgesia, was larger in the frontal left hemisphere while placebo analgesia, during hypnosis, involved the activity of the left hemisphere including the occipital region. These findings demonstrate that hypnosis and placebo analgesia are different processes of top-down regulation. Pain reduction was associated with larger EMG startle amplitudes, N100 and P200 responses, and enhanced activity within the frontal, parietal, and anterior and posterior cingulate gyres. LORETA results showed that placebo analgesia modulated pain-responsive areas known to reflect the ongoing pain experience.

Hypnotizability and Placebo Analgesia in Waking and Hypnosis as Modulators of Auditory Startle Responses in Healthy Women: An ERP Study

PubMed Central

De Pascalis, Vilfredo; Scacchia, Paolo

2016-01-01

We evaluated the influence of hypnotizability, pain expectation, placebo analgesia in waking and hypnosis on tonic pain relief. We also investigated how placebo analgesia affects somatic responses (eye blink) and N100 and P200 waves of event-related potentials (ERPs) elicited by auditory startle probes. Although expectation plays an important role in placebo and hypnotic analgesia, the neural mechanisms underlying these treatments are still poorly understood. We used the cold cup test (CCT) to induce tonic pain in 53 healthy women. Placebo analgesia was initially produced by manipulation, in which the intensity of pain induced by the CCT was surreptitiously reduced after the administration of a sham analgesic cream. Participants were then tested in waking and hypnosis under three treatments: (1) resting (Baseline); (2) CCT-alone (Pain); and (3) CCT plus placebo cream for pain relief (Placebo). For each painful treatment, we assessed pain and distress ratings, eye blink responses, N100 and P200 amplitudes. We used LORETA analysis of N100 and P200 waves, as elicited by auditory startle, to identify cortical regions sensitive to pain reduction through placebo and hypnotic analgesia. Higher pain expectation was associated with higher pain reductions. In highly hypnotizable participants placebo treatment produced significant reductions of pain and distress perception in both waking and hypnosis condition. P200 wave, during placebo analgesia, was larger in the frontal left hemisphere while placebo analgesia, during hypnosis, involved the activity of the left hemisphere including the occipital region. These findings demonstrate that hypnosis and placebo analgesia are different processes of top-down regulation. Pain reduction was associated with larger EMG startle amplitudes, N100 and P200 responses, and enhanced activity within the frontal, parietal, and anterior and posterior cingulate gyres. LORETA results showed that placebo analgesia modulated pain-responsive areas known to reflect the ongoing pain experience. PMID:27486748

Decline in placebo-controlled trial results suggests new directions for comparative effectiveness research.

PubMed

Olfson, Mark; Marcus, Steven C

2013-06-01

The Affordable Care Act offers strong support for comparative effectiveness research, which entails comparisons among active treatments, to provide the foundation for evidence-based practice. Traditionally, a key form of research into the effectiveness of therapeutic treatments has been placebo-controlled trials, in which a specified treatment is compared to placebo. These trials feature high-contrast comparisons between treatments. Historical trends in placebo-controlled trials have been evaluated to help guide the comparative effectiveness research agenda. We investigated placebo-controlled trials reported in four leading medical journals between 1966 and 2010. We found that there was a significant decline in average effect size or average difference in efficacy (the ability to produce a desired effect) between the active treatment and placebo. On average, recently studied treatments offered only small benefits in efficacy over placebo. A decline in effect sizes in conventional placebo-controlled trials supports an increased emphasis on other avenues of research, including comparative studies on the safety, tolerability, and cost of treatments with established efficacy.

Nocebo in chronic inflammatory demyelinating polyneuropathy; a systematic review and meta-analysis of placebo-controlled clinical trials.

PubMed

Zis, Panagiotis; Hadjivassiliou, Marios; Sarrigiannis, Ptolemaios G; Jenkins, Thomas M; Mitsikostas, Dimos-Dimitrios

2018-05-15

Nocebo is very prevalent among neurological disorders, resulting in low adherence and treatment outcome. We sought to examine the adverse events (AE) following placebo administration in placebo-controlled randomized clinical trials (RCTs) for chronic inflammatory demyelinating polyneuropathy (CIDP). After a systematic literature search for RCTs for CIDP pharmacotherapy treatments, we assessed the number of AE in the placebo groups and the number discontinuations because of placebo intolerance. Our literature search strategy revealed 82 papers. Data were extracted from three RCTs fulfilling our inclusion criteria. Approximately two in five placebo-treated patients (42.0%) reported at least one AE and approximately one in fifty placebo-treated patients discontinued placebo treatment because of AEs (2.1%). All patients participating in the CIDP trials reported similar AEs independently of the study arm they belonged. Compared to other neurological diseases the nocebo effect in CIDP is significantly smaller. Copyright © 2018 Elsevier B.V. All rights reserved.

Homeopathic pathogenetic trials produce specific symptoms different from placebo.

PubMed

Möllinger, Heribert; Schneider, Rainer; Walach, Harald

2009-04-01

Homeopathy uses information gathered from healthy volunteers taking homeopathic substances (pathogenetic trials) for clinical treatment. It is controversial whether such studies produce symptoms different from those produced by placebo. To test whether homeopathic preparations produce different symptoms than placebo in healthy volunteers. Three armed, double-blind, placebo controlled randomised experimental pathogenetic study in 25 healthy volunteers who took either one of two homeopathic remedies, Natrum muriaticum and Arsenicum album in 30CH or identical placebo. Main outcome parameter was the number of remedy-specific symptoms per group. On average, 6 symptoms typical for Arsenicum album were experienced by participants taking arsenicum album, 5 symptoms typical for Natrum muriaticum by those taking natrum muriaticum, and 11 non-specific symptoms by those in the placebo group. Differences were significant overall (Kruskall Wallis test, p = 0.0002,) and significantly different from placebo (Mann-Whitney test, p = 0.001). Homeopathic remedies produce different symptoms than placebo. Copyright (c) 2009 S. Karger AG, Basel.

Characteristics of women with nausea and vomiting of pregnancy who chose to continue compassionate use of placebo after a randomised trial.

PubMed

Matok, I; Umans, J; Feghali, M N; Clark, S; Caritis, S; Miodovnik, M; Hankins, G; Mattison, D R; Nordeng, H; Koren, G

2013-08-01

The placebo effect has not been characterised in pregnant women suffering from nausea and vomiting of pregnancy (NVP). Our aim was to characterise determinants of the placebo effect in women treated with placebo for NVP. We analysed data from a multicentre, double blind randomised controlled trial of Diclectin (delayed release doxylamine and pyridoxine) vs placebo for the treatment of NVP. A total of 127 women in the placebo arm and 130 in the active arm provided evaluable data for this analysis. Women who chose to continue placebo on a compassionate basis (n = 41) had significantly better improvement in symptoms of NVP and higher Wellbeing scores than those who did not ask to continue compassionate use. Results were similar in the active drug arm. The request to continue compassionate use of either placebo or active drug could be predicted by greater improvement in symptoms of NVP during the trial period.

Sample size re-estimation and other midcourse adjustments with sequential parallel comparison design.

PubMed

Silverman, Rachel K; Ivanova, Anastasia

2017-01-01

Sequential parallel comparison design (SPCD) was proposed to reduce placebo response in a randomized trial with placebo comparator. Subjects are randomized between placebo and drug in stage 1 of the trial, and then, placebo non-responders are re-randomized in stage 2. Efficacy analysis includes all data from stage 1 and all placebo non-responding subjects from stage 2. This article investigates the possibility to re-estimate the sample size and adjust the design parameters, allocation proportion to placebo in stage 1 of SPCD, and weight of stage 1 data in the overall efficacy test statistic during an interim analysis.

Celecoxib Versus Placebo in Tonsillectomy: A Prospective, Randomized, Double-Blind Placebo-Controlled Trial.

PubMed

Van Daele, Douglas J; Bodeker, Kellie L; Trask, Douglas K

2016-10-01

Celecoxib is a cyclooxygenase-2-specific inhibitor indicated to treat acute pain and pain secondary to osteoarthritis and rheumatoid arthritis. Surgical models of acute pain have demonstrated superior pain relief to placebo. The objective of this study was to test the safety and efficacy of celecoxib for pain relief after tonsillectomy compared to placebo. Adult subjects were randomized to 200 mg celecoxib versus placebo with a loading dose the night before surgery then twice daily for 10 days. Subjects were instructed to supplement the study drug with hydrocodone/acetaminophen liquid or acetaminophen for pain as needed. Subjects completed a daily diary regarding their pain, nausea, vomiting, diet, and activity. Seventeen subjects enrolled. Intraoperative blood loss was similar between groups, and no subject had postoperative bleeding. Three patients returned to the emergency department for treatment, and 2 patients could not complete the diaries, all in the placebo group. Subjects in the placebo group required statistically significant (P < .05) higher doses of narcotic and acetaminophen to control pain. Pain and diet rating scores were slightly better in the celecoxib group compared to placebo. In this small cohort, celecoxib reduced postoperative narcotic and acetaminophen requirements compared to placebo without complications. © The Author(s) 2016.

New insights into the placebo and nocebo responses.

PubMed

Enck, Paul; Benedetti, Fabrizio; Schedlowski, Manfred

2008-07-31

In modern medicine, the placebo response or placebo effect has often been regarded as a nuisance in basic research and particularly in clinical research. The latest scientific evidence has demonstrated, however, that the placebo effect and the nocebo effect, the negative effects of placebo, stem from highly active processes in the brain that are mediated by psychological mechanisms such as expectation and conditioning. These processes have been described in some detail for many diseases and treatments, and we now know that they can represent both strength and vulnerability in the course of a disease as well as in the response to a therapy. However, recent research and current knowledge raise several issues that we shall address in this review. We will discuss current neurobiological models like expectation-induced activation of the brain reward circuitry, Pavlovian conditioning, and anxiety mechanisms of the nocebo response. We will further explore the nature of the placebo responses in clinical trials and address major questions for future research such as the relationship between expectations and conditioning in placebo effects, the existence of a consistent brain network for all placebo effects, the role of gender in placebo effects, and the impact of getting drug-like effects without drugs.

Laterality of pain: modulation by placebo and participants' paranormal belief.

PubMed

Klemenz, Caroline; Regard, Marianne; Brugger, Peter; Emch, Oliver

2009-09-01

To investigate the effects of placebo and paranormal belief on the laterality of pain perception. The right hemisphere is dominantly involved in both the mediation of pain sensation and the belief in paranormal phenomena. We set out to assess a possible influence of long-term belief systems on placebo analgesia in response to unilateral nociceptive stimuli. Forty healthy participants (20 high and 20 low believers as indexed by the Magical Ideation Scale) underwent a placebo analgesia study measuring stimulus detection, pain threshold, and pain tolerance by electrostimulation on the right and left hand. Placebo treatment consisted of the application of a sham cream on the hands. Placebo had a positive influence on pain perception in the 3 variables. Enhanced pain sensitivity for the left side was only found for the disbelievers. Placebo treatment resulted in a double dissociation: in believers, it increased tolerance exclusively on the left side, in disbelievers on the right side. Our results confirm laterality effects in pain perception. However, only disbelievers conformed to the expected higher left-sided sensitivity. Placebo effects were dissociated between believers and disbelievers suggesting that short-term reactions to a placebo are modulated by a person's long-term belief system.

Labeling of Medication and Placebo Alters the Outcome of Episodic Migraine Attacks

PubMed Central

Kam-Hansen, Slavenka; Jakubowski, Moshe; Kelley, John M.; Kirsch, Irving; Hoaglin, David C.; Kaptchuk, Ted J.; Burstein, Rami

2014-01-01

Information provided to patients is thought to influence placebo and drug effects. We investigated the potential relationship between treatment labeling and its outcome in a prospective, within-subjects, repeated measures study of episodic migraine. A cohort of 66 participants documented 7 separate migraine attack: one untreated attack, followed by six attacks that were randomly assigned for either rizatriptan (10 mg Maxalt) or placebo treatments, each of which labeled once as ‘Maxalt’, once as ‘Placebo’, and once as ‘Maxalt or Placebo’ (459 documented attacks). Data were analyzed using generalized linear mixed model statistics. While Maxalt was generally superior to placebo, the placebo effect, and to a lesser extent Maxalt efficacy, increased monotonically with treatment labeling as follows: ‘Placebo’ label < ‘Maxalt or placebo’ label ≤ ‘Maxalt’ label. Efficacy of Maxalt mislabeled as placebo was not significantly different from the efficacy of placebo mislabeled as Maxalt. The placebo effect was significant under each labeling condition relative to no treatment, amounting in magnitude to >50% of Maxalt effect under the corresponding labeling condition. Thus, incremental “positive” information yielded incremental efficacy of placebo and medication during migraine attacks. PMID:24401940

Active placebo control groups of pharmacological interventions were rarely used but merited serious consideration: a methodological overview.

PubMed

Jensen, Jakob Solgaard; Bielefeldt, Andreas Ørsted; Hróbjartsson, Asbjørn

2017-07-01

Active placebos are control interventions that mimic the side effects of the experimental interventions in randomized trials and are sometimes used to reduce the risk of unblinding. We wanted to assess how often randomized clinical drug trials use active placebo control groups; to provide a catalog, and a characterization, of such trials; and to analyze methodological arguments for and against the use of active placebo. An overview consisting of three thematically linked substudies. In an observational substudy, we assessed the prevalence of active placebo groups based on a random sample of 200 PubMed indexed placebo-controlled randomized drug trials published in October 2013. In a systematic review, we identified and characterized trials with active placebo control groups irrespective of publication time. In a third substudy, we reviewed publications with substantial methodological comments on active placebo groups (searches in PubMed, The Cochrane Library, Google Scholar, and HighWirePress). The prevalence of trials with active placebo groups published in 2013 was 1 out of 200 (95% confidence interval: 0-2), 0.5% (0-1%). We identified and characterized 89 randomized trials (published 1961-2014) using active placebos, for example, antihistamines, anticholinergic drugs, and sedatives. Such trials typically involved a crossover design, the experimental intervention had noticeable side effects, and the outcomes were patient-reported. The use of active placebos was clustered in specific research settings and did not appear to reflect consistently the side effect profile of the experimental intervention, for example, selective serotonin reuptake inhibitors were compared with active placebos in pain trials but not in depression trials. We identified and analyzed 25 methods publications with substantial comments. The main argument for active placebo was to reduce risk of unblinding; the main argument against was the risk of unintended therapeutic effect. Pharmacological active placebo control interventions are rarely used in randomized clinical trials, but they constitute a methodological tool which merits serious consideration. We suggest that active placebos are used more often in trials of drugs with noticeable side effects, especially in situations where the expected therapeutic effects are modest and the risk of bias due to unblinding is high. Copyright © 2017 Elsevier Inc. All rights reserved.

Clinical and ethical implications of placebo effects: enhancing patients' benefits from pain treatment.

PubMed

Klinger, Regine; Flor, Herta

2014-01-01

Expectancy and learning are the core psychological mechanisms of placebo analgesia. They interact with further psychological processes such as emotions and motivations (e.g., anxiety, desire for relief), somatic focus, or cognitions (e.g., attitudes toward the treatment). The development of placebo responsiveness and the actual placebo response in a person is the result of the complex interaction between factors traced back to the individual learning history related to analgesic drugs or treatments and factors of the current context referring to the analgesic or placebo treatment. The aim of this chapter is to depict these complex interactions in a new model of analgesic placebo effects. It joins aspects of the learning history (preexisting experiences and preexisting expectations) of a patient with aspects of the current context (current expectation as a result of external and internal situation in which a pain medication/treatment/placebo is taken, e.g., current information about pain medication, current specific context/cues, desire for pain relief, certainty about upcoming pain relief, current expectation about pain reducing course, current selective attention, increased pain experience, or decreased pain experience). In order to exploit placebo efficacy for an analgesic treatment it is worthwhile to assess in which direction each of these factors exerts its influence in order to maximize placebo effects for a specific patient. By applying placebo mechanisms in this differentiated way, the efficacy of pain treatment can be deliberately boosted.

The placebo effect: from concepts to genes

PubMed Central

Colagiuri, Ben; Schenk, Lieven A.; Kessler, Michael D.; Dorsey, Susan G.; Colloca, Luana

2017-01-01

Despite its initial treatment as a nuisance variable, the placebo effect is now recognized as a powerful determinant of health across many different diseases and encounters. This is in light of some remarkable findings ranging from demonstrations that the placebo effect significantly modulates the response to active treatments in conditions such as pain, anxiety, Parkinson’s disease, and some surgical procedures. Here, we review pioneering studies and recent advances in behavioral, neurobiological, and genetic influences on the placebo effect. Based on a previous developed conceptual framework, the placebo effect is presented as the product of a general expectancy learning mechanism in which verbal, conditioned and social cues are centrally integrated to change behaviors and outcomes. Examples of the integration of verbal and conditioned cues, such as instructed reversal of placebo effects are also incorporated into this model. We discuss neuroimaging studies that using well-established behavioral paradigms have identified key brain regions and modulatory mechanisms underlying placebo effects. Finally, we present a synthesis of recent genetics studies on the placebo effect, highlighting a promising link between genetic variants in the dopamine, opioid, serotonin, and endocannabinoid pathways and placebo responsiveness. Greater understanding of the behavioral, neurobiological, and genetic influences on the placebo effect is critical for evaluating medical interventions and may allow health professionals to tailor and personalize interventions in order to maximize treatment outcomes in clinical settings. PMID:26272535

Validation of a New Placebo Interferential Current Method: A New Placebo Method of Electrostimulation.

PubMed

Mendonça Araújo, Fernanda; Alves Menezes, Mayara; Martins de Araújo, Ariane; Abner Dos Santos Sousa, Thiago; Vasconcelos Lima, Lucas; Ádan Nunes Carvalho, Elyson; Melo DeSantana, Josimari

2017-01-01

The present study aimed to investigate if a new placebo device for interferential current (IFC) that delivers current during only the first 40 seconds of stimulation is effective at promoting adequate subject blinding. Seventy-five subjects were recruited and enrolled into three groups: active IFC, inactive placebo, and new placebo. Pressure pain threshold (PPT), cutaneous sensory threshold (CST), and pain intensity were measured before and after the intervention. After the final assessment, the subjects and the investigator who applied the current were asked about the type of stimulation administered. None of the placebo forms studied resulted in significant changes to PPT, CST, or pain intensity. The subjects stimulated with active IFC at high intensities (> 17 mA) of stimulation showed higher PPT and CST and lower pain intensity than subjects stimulated at low intensities ( p < 0.03). The new placebo method blinded the investigator in 100% of cases of IFC and 60% of subjects stimulated, whereas for inactive placebo, the investigator was blinded at a rate of 0% and 34% of subjects. The new method of placebo IFC was effective for blinding of research investigators and most of the active IFC-treated subjects, promoting an appropriate placebo method. © 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

How to study placebo responses in motion sickness with a rotation chair paradigm in healthy participants.

PubMed

Weimer, Katja; Horing, Björn; Muth, Eric R; Enck, Paul

2014-12-14

Placebo responses occur in every medical intervention when patients or participants expect to receive an effective treatment to relieve symptoms. However, underlying mechanisms of placebo responses are not fully understood. It has repeatedly been shown that placebo responses are associated with changes in neural activity but for many conditions it is unclear whether they also affect the target organ, such as the stomach in motion sickness. Therefore, we present a methodology for the multivariate assessment of placebo responses by subjective, behavioral and objective measures in motion sickness with a rotation chair paradigm. The physiological correlate of motion sickness is a shift in gastric myoelectrical activity towards tachygastria that can be recorded with electrogastrography. The presented study applied the so-called balanced placebo design (BPD) to investigate the effects of ginger compared to placebo and the effects of expectations by verbal information. However, the study revealed no significant main or interactional effects of ginger (as a drug) or information on outcome measures but showed interactions when sex of participants and experimenters are taken into considerations. We discuss limitations of the presented study and report modifications that were used in subsequent studies demonstrating placebo responses when rotation speed was lowered. In general, future placebo studies have to identify the appropriate target organ for the studied placebo responses and to apply the specific methods to assess the physiological correlates.

Triiodothyronine Administration in a Model of Septic Shock: A Randomized Blinded Placebo-Controlled Trial.

PubMed

Maiden, Matthew J; Chapman, Marianne J; Torpy, David J; Kuchel, Timothy R; Clarke, Iain J; Nash, Coralie H; Fraser, Jonathan D; Ludbrook, Guy L

2016-06-01

Triiodothyronine concentration in plasma decreases during septic shock and may contribute to multiple organ dysfunction. We sought to determine the safety and efficacy of administering triiodothyronine, with and without hydrocortisone, in a model of septic shock. Randomized blinded placebo-controlled trial. Preclinical research laboratory. Thirty-two sheep rendered septic with IV Escherichia coli and receiving protocol-guided sedation, ventilation, IV fluids, and norepinephrine infusion. Two hours following induction of sepsis, 32 sheep received a 24-hour IV infusion of 1) placebo + placebo, 2) triiodothyronine + placebo, 3) hydrocortisone + placebo, or 4) triiodothyronine + hydrocortisone. Primary outcome was the total amount of norepinephrine required to maintain a target mean arterial pressure; secondary outcomes included hemodynamic and metabolic indices. Plasma triiodothyronine levels increased to supraphysiological concentrations with hormonal therapy. Following 24 hours of study drug infusion, the amount of norepinephrine required was no different between the study groups (mean ± SD μg/kg; placebo + placebo group 208 ± 392; triiodothyronine + placebo group 501 ± 370; hydrocortisone + placebo group 167 ± 286; triiodothyronine + hydrocortisone group 466 ± 495; p = 0.20). There was no significant treatment effect on any hemodynamic variable, metabolic parameter, or measure of organ function. A 24-hour infusion of triiodothyronine, with or without hydrocortisone, in an ovine model of septic shock did not markedly alter norepinephrine requirement or any other physiological parameter.

Adherence to placebo and mortality in the Beta Blocker Evaluation of Survival Trial (BEST).

PubMed

Pressman, Alice; Avins, Andrew L; Neuhaus, John; Ackerson, Lynn; Rudd, Peter

2012-05-01

Randomized controlled trials have reported lower mortality among patients who adhere to placebo compared with those who do not. We explored this phenomenon by reanalyzing data from the placebo arm of the Beta Blocker Evaluation of Survival Trial (BEST), a randomized, double-blind, placebo-controlled trial of bucindolol and mortality. Our primary aim was to measure and explain the association between adherence to placebo and total mortality among the placebo-allocated participants in the BEST trial. Secondary aims included assessment of the association between placebo adherence and cause-specific mortality. Participants with "higher placebo adherence" were defined as having taken at least 75% of their placebo study medication over the entire course of each individual's participation in the study, while those with "lower placebo adherence" took <75%. Primary outcome was in-study all-cause mortality. To account for confounding, we adjusted for all available modifiable, non-modifiable and psychosocial variables. Adherent participants had a significantly lower total mortality compared to less-adherent participants (HR=0.61, 95% Confidence Interval: 0.46-0.82). Adjusting for available confounders did not change the magnitude or significance of the estimates. When considering cause-specific mortality, CVD and pump failure showed similar associations. Analyses of the BEST trial data support a strong association between adherence to placebo study medication and total mortality. While probably not due to publication bias or simple confounding by healthy lifestyle factors, the underlying explanation for the association remains a mystery. Prospective examination of this association is necessary to better understand the underlying mechanism of this observation. Copyright © 2012 Elsevier Inc. All rights reserved.

Implications of Placebo and Nocebo Effects for Clinical Practice: Expert Consensus.

PubMed

Evers, Andrea W M; Colloca, Luana; Blease, Charlotte; Annoni, Marco; Atlas, Lauren Y; Benedetti, Fabrizio; Bingel, Ulrike; Büchel, Christian; Carvalho, Claudia; Colagiuri, Ben; Crum, Alia J; Enck, Paul; Gaab, Jens; Geers, Andrew L; Howick, Jeremy; Jensen, Karin B; Kirsch, Irving; Meissner, Karin; Napadow, Vitaly; Peerdeman, Kaya J; Raz, Amir; Rief, Winfried; Vase, Lene; Wager, Tor D; Wampold, Bruce E; Weimer, Katja; Wiech, Katja; Kaptchuk, Ted J; Klinger, Regine; Kelley, John M

2018-06-12

Placebo and nocebo effects occur in clinical or laboratory medical contexts after administration of an inert treatment or as part of active treatments and are due to psychobiological mechanisms such as expectancies of the patient. Placebo and nocebo studies have evolved from predominantly methodological research into a far-reaching interdisciplinary field that is unravelling the neurobiological, behavioural and clinical underpinnings of these phenomena in a broad variety of medical conditions. As a consequence, there is an increasing demand from health professionals to develop expert recommendations about evidence-based and ethical use of placebo and nocebo effects for clinical practice. A survey and interdisciplinary expert meeting by invitation was organized as part of the 1st Society for Interdisciplinary Placebo Studies (SIPS) conference in 2017. Twenty-nine internationally recognized placebo researchers participated. There was consensus that maximizing placebo effects and minimizing nocebo effects should lead to better treatment outcomes with fewer side effects. Experts particularly agreed on the importance of informing patients about placebo and nocebo effects and training health professionals in patient-clinician communication to maximize placebo and minimize nocebo effects. The current paper forms a first step towards developing evidence-based and ethical recommendations about the implications of placebo and nocebo research for medical practice, based on the current state of evidence and the consensus of experts. Future research might focus on how to implement these recommendations, including how to optimize conditions for educating patients about placebo and nocebo effects and providing training for the implementation in clinical practice. © 2018 S. Karger AG, Basel.

Systematic Review and Meta-analysis: Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis

PubMed Central

Zou, Guangyong; Parker, Claire E.; Macdonald, John K.; Mosli, Mahmoud H.; Khanna, Reena; Shackelton, Lisa M.; Vandervoort, Margaret K.; AlAmeel, Turki; Al Beshir, Mohammad; AlMadi, Majid; Al-Taweel, Talal; Atkinson, Nathan S. S.; Biswas, Sujata; Chapman, Thomas P.; Dulai, Parambir S.; Glaire, Mark A.; Hoekman, Daniel; Koutsoumpas, Andreas; Minas, Elizabeth; Samaan, Mark A.; Travis, Simon; D’Haens, Geert; Levesque, Barrett G.; Sandborn, William J.; Feagan, Brian G.

2016-01-01

Background and Aims: Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis [UC] clinical trials, and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them. Methods: MEDLINE, EMBASE, and the Cochrane Library were searched from inception through April 2014 for placebo-controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant, or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool. Results: In all, 51 trials [48 induction and 10 maintenance phases] were identified. Placebo response and remission rates were pooled according to random-effects models, and mixed-effects meta-regression models were used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10% (95% confidence interval [CI] 7-13%) and 33% [95% CI 29-37%], respectively. Corresponding values for maintenance trials were 19% [95% CI 11-30%] and 22% [95% CI 17-28%]. Trials enrolling patients with more active disease confirmed by endoscopy [endoscopy subscore ≥ 2] were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits. Conclusions: Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials. PMID:26746169

Predicting Individual Differences in Placebo Analgesia: Contributions of Brain Activity during Anticipation and Pain Experience

PubMed Central

Wager, Tor D.; Atlas, Lauren Y.; Leotti, Lauren A.; Rilling, James K.

2012-01-01

Recent studies have identified brain correlates of placebo analgesia, but none have assessed how accurately patterns of brain activity can predict individual differences in placebo responses. We reanalyzed data from two fMRI studies of placebo analgesia (N = 47), using patterns of fMRI activity during the anticipation and experience of pain to predict new subjects’ scores on placebo analgesia and placebo-induced changes in pain processing. We used a cross-validated regression procedure, LASSO-PCR, which provided both unbiased estimates of predictive accuracy and interpretable maps of which regions are most important for prediction. Increased anticipatory activity in a frontoparietal network and decreases in a posterior insular/temporal network predicted placebo analgesia. Patterns of anticipatory activity across the cortex predicted a moderate amount of variance in the placebo response (~12% overall, ~40% for study 2 alone), which is substantial considering the multiple likely contributing factors. The most predictive regions were those associated with emotional appraisal, rather than cognitive control or pain processing. During pain, decreases in limbic and paralimbic regions most strongly predicted placebo analgesia. Responses within canonical pain-processing regions explained significant variance in placebo analgesia, but the pattern of effects was inconsistent with widespread decreases in nociceptive processing. Together, the findings suggest that engagement of emotional appraisal circuits drives individual variation in placebo analgesia, rather than early suppression of nociceptive processing. This approach provides a framework that will allow prediction accuracy to increase as new studies provide more precise information for future predictive models. PMID:21228154

[Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, double-blind, placebo- and active-controlled clinical trial performed in Europe].

PubMed

Chapple, Ch R; Montorsi, F; Tammela, T L J; Wirth, M; Koldewijn, E; Fernandez Fernandez, E

2012-01-01

Silodosin is a new selective therapy with a high pharmacologic selectivity for the a (1A)-adrenoreceptor. Our aim was to test silodosin's superiority to placebo and noninferiority to tamsulosin and discuss the findings in the context of a comprehensive literature review of the new compound silodosin. We conducted a multicenter double-blind, placebo-and active-controlled parallel group study. A total of 1228 men > or = 50 yr of age with an International Prostate Symptom Score (IPSS) < or = 13 and a urine maximum flow rate (Q(max))> 4 and < or = 15 ml/s were selected at 72 sites in 11 European countries. The patients were entered into a 2-wk wash-out and a 4-wk placebo run-in period. A total of 955 patients were randomized (2:2:1) to silodosin 8 mg (n = 381), tamsulosin 0.4 mg (n = 384), or placebo (n = 190) once daily for 12 wk. We calculated the change from baseline in IPSS total score (primary), storage and voiding subscores, quality of life (QoL) due to urinary symptoms, and Q(max). Responders were defined on the basis of IPSS and Q(max) by a decrease of > or = 25% and an increase of > or = 30% from baseline, respectively. The change from baseline in the IPSS total score with silodosin and tamsulosin was significantly superior to that with placebo (p < 0.001): difference active placebo of -2.3 (95% confidence interval [CI], -3.2, -1.4) with silodosin and -2.0 (95% CI, -2.9, -1.1) with tamsulosin. Responder rates according to total IPSS were significantly higher (p < 0.001) with silodosin (66.8%) and tamsulosin (65.4%) than with placebo (50.8%). Active treatments were also superior to placebo in the IPSS storage and voiding subscore analyses, as well as in QoL due to urinary symptoms. Of note, only silodosin significantly reduced nocturia versus placebo (the change from baseline was -0.9, -0.8, and -0.7 for silodosin, tamsulosin, and placebo, respectively; p = 0.013 for silodosin vs placebo). An increase in Q(max) was observed in all groups. The adjusted mean change from baseline to end point was 3.77 ml/s for silodosin, 3.53 ml/s for tamsulosin, and 2.93 ml/s for placebo, but the change for silodosin and tamsulosin was not statistically significant versus placebo because of a particularly high placebo response (silodosin vs placebo: p = 0.089; tamsulosin vs placebo: p = 0.221). At end point, the percentage of responders by Q(max) was 46.6%, 46.5%, and 40.5% in the silodosin, tamsulosin, and placebo treatment groups, respectively. This difference was not statistically significant (p = 0.155 silodosin vs placebo and p = 0.141 tamsulosin vs placebo). Active treatments were well tolerated, and discontinuation rates due to adverse events were low in all groups (2.1%, 1.0%, and 1.6% with silodosin, tamsulosin, and placebo, respectively). The most frequent adverse event with silodosin was a reduced or absent ejaculation during orgasm (14%), a reversible effect as a consequence of the potent and selective a(1A)-adrenoreceptor antagonism of the drug. The incidence was higher than that observed with tamsulosin (2%); however, only 1.3% of silodosin-treated patients discontinued treatment due to this adverse event. Silodosin is an effective and well-tolerated treatment for the relief of both voiding and storage symptoms in patients with lower urinary tract symptoms suggestive of bladder outlet obstruction thought to be associated with benign prostatic hyperplasia. Its overall efficacy is not inferior to tamsulosin. Only silodosin showed a significant effect on nocturia over placebo.

Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, double-blind, placebo- and active-controlled clinical trial performed in Europe.

PubMed

Chapple, Christopher R; Montorsi, Francesco; Tammela, Teuvo L J; Wirth, Manfred; Koldewijn, Evert; Fernández Fernández, Eldiberto

2011-03-01

Silodosin is a new selective therapy with a high pharmacologic selectivity for the α(1A)-adrenoreceptor. Our aim was to test silodosin's superiority to placebo and noninferiority to tamsulosin and discuss the findings in the context of a comprehensive literature review of the new compound silodosin. We conducted a multicenter double-blind, placebo- and active-controlled parallel group study. A total of 1228 men ≥50 yr of age with an International Prostate Symptom Score (IPSS) ≥13 and a urine maximum flow rate (Q(max)) >4 and ≤15 ml/s were selected at 72 sites in 11 European countries. The patients were entered into a 2-wk wash-out and a 4-wk placebo run-in period. A total of 955 patients were randomized (2:2:1) to silodosin 8 mg (n=381), tamsulosin 0.4 mg (n=384), or placebo (n=190) once daily for 12 wk. We calculated the change from baseline in IPSS total score (primary), storage and voiding subscores, quality of life (QoL) due to urinary symptoms, and Q(max). Responders were defined on the basis of IPSS and Q(max) by a decrease of ≥25% and an increase of ≥30% from baseline, respectively. The change from baseline in the IPSS total score with silodosin and tamsulosin was significantly superior to that with placebo (p<0.001): difference active placebo of -2.3 (95% confidence interval [CI], -3.2, -1.4) with silodosin and -2.0 (95% CI,-2.9, -1.1) with tamsulosin. Responder rates according to total IPSS were significantly higher (p<0.001) with silodosin (66.8%) and tamsulosin (65.4%) than with placebo (50.8%). Active treatments were also superior to placebo in the IPSS storage and voiding subscore analyses, as well as in QoL due to urinary symptoms. Of note, only silodosin significantly reduced nocturia versus placebo (the change from baseline was -0.9, -0.8, and -0.7 for silodosin, tamsulosin, and placebo, respectively; p=0.013 for silodosin vs placebo). An increase in Q(max) was observed in all groups. The adjusted mean change from baseline to end point was 3.77 ml/s for silodosin, 3.53 ml/s for tamsulosin, and 2.93 ml/s for placebo, but the change for silodosin and tamsulosin was not statistically significant versus placebo because of a particularly high placebo response (silodosin vs placebo: p=0.089; tamsulosin vs placebo: p=0.221). At end point, the percentage of responders by Q(max) was 46.6%, 46.5%, and 40.5% in the silodosin, tamsulosin, and placebo treatment groups, respectively. This difference was not statistically significantly (p=0.155 silodosin vs placebo and p=0.141 tamsulosin vs placebo). Active treatments were well tolerated, and discontinuation rates due to adverse events were low in all groups (2.1%, 1.0%, and 1.6% with silodosin, tamsulosin, and placebo, respectively). The most frequent adverse event with silodosin was a reduced or absent ejaculation during orgasm (14%), a reversible effect as a consequence of the potent and selective α(1A)-adrenoreceptor antagonism of the drug. The incidence was higher than that observed with tamsulosin (2%); however, only 1.3% of silodosin-treated patients discontinued treatment due to this adverse event. Silodosin is an effective and well-tolerated treatment for the relief of both voiding and storage symptoms in patients with lower urinary tract symptoms suggestive of bladder outlet obstruction thought to be associated with benign prostatic hyperplasia. Its overall efficacy is not inferior to tamsulosin. Only silodosin showed a significant effect on nocturia over placebo. ClinicalTrials.gov Identifier NCT00359905. Copyright © 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Can sequential parallel comparison design and two-way enriched design be useful in medical device clinical trials?

PubMed

Ivanova, Anastasia; Zhang, Zhiwei; Thompson, Laura; Yang, Ying; Kotz, Richard M; Fang, Xin

2016-01-01

Sequential parallel comparison design (SPCD) was proposed for trials with high placebo response. In the first stage of SPCD subjects are randomized between placebo and active treatment. In the second stage placebo nonresponders are re-randomized between placebo and active treatment. Data from the population of "all comers" and the subpopulations of placebo nonresponders then combined to yield a single p-value for treatment comparison. Two-way enriched design (TED) is an extension of SPCD where active treatment responders are also re-randomized between placebo and active treatment in Stage 2. This article investigates the potential uses of SPCD and TED in medical device trials.

Pacing for neurally mediated syncope: is placebo powerless?

PubMed

Brignole, M; Sutton, R

2007-01-01

After two recent controlled trials failed to prove superiority of cardiac pacing over placebo in patients affected by neurally mediated syncope, a widely accepted opinion is that cardiac pacing therapy is not very effective and that a strong placebo effect exists. To measure the effect of placebo pacing therapy. We compared the recurrence rate of syncope during placebo vs. no treatment in controlled trials of drug or pacing therapy. Syncope recurred in 38% of 252 patients randomized to placebo pooled from five trials vs. 34% of 881 patients randomized to no treatment pooled from eight trials. The corresponding recurrence rate with active cardiac pacing was 15% in 203 patients from six trials. Placebo is not an effective therapy for neurally mediated syncope. Different selection criteria in patients who are candidates for cardiac pacing-for example, presence, absence, or severity of the cardioinhibitory reflex may separate positive from negative trials.

Patient Expectancy as a Mediator of Placebo Effects in Antidepressant Clinical Trials.

PubMed

Rutherford, Bret R; Wall, Melanie M; Brown, Patrick J; Choo, Tse-Hwei; Wager, Tor D; Peterson, Bradley S; Chung, Sarah; Kirsch, Irving; Roose, Steven P

2017-02-01

Causes of placebo effects in antidepressant trials have been inferred from observational studies and meta-analyses, but their mechanisms have not been directly established. The goal of this study was to examine in a prospective, randomized controlled trial whether patient expectancy mediates placebo effects in antidepressant studies. Adult outpatients with major depressive disorder were randomly assigned to open or placebo-controlled citalopram treatment. Following measurement of pre- and postrandomization expectancy, participants were treated with citalopram or placebo for 8 weeks. Independent samples t tests determined whether patient expectancy differed between the open and placebo-controlled groups, and mixed-effects models assessed group effects on Hamilton Depression Rating Scale (HAM-D) scores over time while controlling for treatment assignment. Finally, mediation analyses tested whether between-group differences in patient expectancy mediated the group effect on HAM-D scores. Postrandomization expectancy scores were significantly higher in the open group (mean=12.1 [SD=2.1]) compared with the placebo-controlled group (mean=11.0 [SD=2.0]). Mixed-effects modeling revealed a significant week-by-group interaction, indicating that HAM-D scores for citalopram-treated participants declined at a faster rate in the open group compared with the placebo-controlled group. Patient expectations postrandomization partially mediated group effects on week 8 HAM-D. Patient expectancy is a significant mediator of placebo effects in antidepressant trials. Expectancy-related interventions should be investigated as a means of controlling placebo responses in antidepressant clinical trials and improving patient outcome in clinical treatment.

Andrographis paniculata extract (HMPL-004) for active ulcerative colitis.

PubMed

Sandborn, William J; Targan, Stephan R; Byers, Vera S; Rutty, Dean A; Mu, Hua; Zhang, Xun; Tang, Tom

2013-01-01

Andrographis paniculata has in vitro inhibitory activity against TNF-α, IL-1β and NF-κB. A pilot study of A. paniculata extract (HMPL-004) suggested similar efficacy to mesalamine for ulcerative colitis. A randomized, double-blind, placebo-controlled trial evaluated the efficacy of A. paniculata extract (HMPL-004) in 224 adults with mild-to-moderate ulcerative colitis. Patients were randomized to A. paniculata extract (HMPL-004) 1,200 mg or 1,800 mg daily or placebo for 8 weeks. In total, 45 and 60% of patients receiving A. paniculata 1,200 mg and 1,800 mg daily, respectively, were in clinical response at week 8, compared with 40% of those who received placebo (P=0.5924 for 1,200 mg vs. placebo and P=0.0183 for 1,800 mg vs. placebo). In all, 34 and 38% of patients receiving A. paniculata 1,200 mg and 1,800 mg daily, respectively, were in clinical remission at week 8, compared with 25% of those who received placebo (P=0.2582 for 1,200 mg vs. placebo and P=0.1011 for 1,800 mg vs. placebo). Adverse events developed in 60 and 53% of patients in the A. paniculata 1,200 mg and 1,800 mg daily groups, respectively, and 60% in the placebo group. Patients with mildly to moderately active ulcerative colitis treated with A. paniculata extract (HMPL-004) at a dose of 1,800 mg daily were more likely to achieve clinical response than those receiving placebo.

How placebos change the patient's brain.

PubMed

Benedetti, Fabrizio; Carlino, Elisa; Pollo, Antonella

2011-01-01

Although placebos have long been considered a nuisance in clinical research, today they represent an active and productive field of research and, because of the involvement of many mechanisms, the study of the placebo effect can actually be viewed as a melting pot of concepts and ideas for neuroscience. Indeed, there exists not a single but many placebo effects, with different mechanisms and in different systems, medical conditions, and therapeutic interventions. For example, brain mechanisms of expectation, anxiety, and reward are all involved, as well as a variety of learning phenomena, such as Pavlovian conditioning, cognitive, and social learning. There is also some experimental evidence of different genetic variants in placebo responsiveness. The most productive models to better understand the neurobiology of the placebo effect are pain and Parkinson's disease. In these medical conditions, the neural networks that are involved have been identified: that is, the opioidergic-cholecystokinergic-dopaminergic modulatory network in pain and part of the basal ganglia circuitry in Parkinson's disease. Important clinical implications emerge from these recent advances in placebo research. First, as the placebo effect is basically a psychosocial context effect, these data indicate that different social stimuli, such as words and rituals of the therapeutic act, may change the chemistry and circuitry of the patient's brain. Second, the mechanisms that are activated by placebos are the same as those activated by drugs, which suggests a cognitive/affective interference with drug action. Third, if prefrontal functioning is impaired, placebo responses are reduced or totally lacking, as occurs in dementia of the Alzheimer's type.

Attitudes toward placebo-controlled clinical trials among depressed patients in Japan.

PubMed

Sugawara, Norio; Ishioka, Masamichi; Tsuchimine, Shoko; Tsuruga, Koji; Sato, Yasushi; Tarakita, Natsumi; Furukori, Hanako; Kudo, Shuhei; Tomita, Tetsu; Nakagami, Taku; Yasui-Furukori, Norio

2018-01-01

Placebo-controlled clinical trials are the standard in the design of clinical studies for the licensing of new drugs. Medical and ethical concerns regarding placebo use still exist in clinical trials of depressed patients. The aim of this study was to investigate the attitudes toward placebo-controlled clinical trials and to assess factors related to the willingness to participate in such trials among depressed patients in Japan. A total of 206 depressed patients aged 49.5 ± 15.7 years (mean ± SD) who were admitted to three psychiatric hospitals were recruited for a cross-sectional study from June 2015 to March 2016. After a thorough explanation of the placebo, the study participants completed a brief 14-item questionnaire developed to evaluate patients' attitudes regarding possible participation in placebo-controlled clinical trials. The Quick Inventory of Depressive Symptomatology was also administered to assess depressive symptoms. The results indicated that 47% of the patients would be willing to participate in a placebo-controlled clinical trial. Expectations for the improvement of disease, desire to receive more medical care, encouragement by family or friends, and desire to support the development of new drugs were associated with the willingness to participate in such trials, whereas a belief that additional time would be required for medical examinations and fear of exacerbation of symptoms due to placebo use were associated with non-participation. Patients were asked about possible participation in placebo-controlled clinical trials. Less than half of the respondents were willing to participate in placebo-controlled clinical trials. Attitudes toward participation in a placebo-controlled clinical trial need to be considered when deciding whether to conduct such a trial. Copyright © 2017. Published by Elsevier B.V.

A safety analysis of edaravone (MCI-186) during the first six cycles (24 weeks) of amyotrophic lateral sclerosis (ALS) therapy from the double-blind period in three randomized, placebo-controlled studies.

PubMed

Kalin, Alexander; Medina-Paraiso, Elvia; Ishizaki, Kaoru; Kim, Alex; Zhang, Yannong; Saita, Takanori; Wasaki, Masahiko

2017-10-01

There continues to be a need for new therapies to treat ALS. Provide an overview of safety for edaravone in ALS patients during the first six cycles of treatment. Analysis was based on three randomised, placebo-controlled clinical trials. Endpoints included treatment-emergent adverse events (TEAEs), including AEs leading to discontinuation, serious adverse events (SAEs), and deaths. The analysis included a total of 368 patients (184 in the edaravone group and placebo group, respectively). Of those, 94.6% of the edaravone group and 90.2% of placebo group completed six cycles of therapy. Baseline characteristics were comparable between the two groups. TEAE incidence in the edaravone group and placebo group was 87.5% and 87.0%, respectively. TEAEs ocurring at ≥2% incidence in the edaravone group compared to placebo were contusion (14.7% vs. 8.7%), gait disturbance (12.5% vs. 9.2%), headache (8.2% vs. 5.4%), eczema (6.5% vs. 2.2%), dermatitis contact (6.0% vs. 3.3%), respiratory disorder (4.3% vs. 1.1%), and glucose urine present (3.8% vs. 1.6%). There was no imbalance in TEAEs leading to discontinuation (2.2% [edaravone], and 5.4% [placebo]). SAE incidence was 17.4% in the edaravone group and 22.3% in placebo group. Treatment-emergent deaths occurred in 2.2% in the edaravone group and 1.1% in placebo group, all respiratory in nature and attributed to worsening ALS. Data collected from three double-blind assessments found that while some TEAEs were more common in the edaravone group compared to placebo, the overall incidences of SAEs, deaths, and discontinuations due to AEs were similar or less for edaravone compared to placebo.

Adherence to placebo and mortality in the Beta Blocker Evaluation of Survival Trial (BEST)

PubMed Central

Pressman, Alice; Avins, Andrew L.; Neuhaus, John; Ackerson, Lynn; Rudd, Peter

2012-01-01

Background Randomized controlled trials have reported lower mortality among patients who adhere to placebo compared with those who do not. We explored this phenomenon by reanalyzing data from the placebo arm of the Beta Blocker Evaluation of Survival Trial (BEST), a randomized, double-blind, placebo-controlled trial of bucindolol and mortality. Aims Our primary aim was to measure and explain the association between adherence to placebo and total mortality among the placebo-allocated participants in the BEST trial. Secondary aims included assessment of the association between placebo adherence and cause-specific mortality. Methods Participants with "higher placebo adherence" were defined as having taken at least 75% of their placebo study medication over the entire course of each individual’s participation in the study, while those with “lower placebo adherence” took <75%. Primary outcome was in-study all-cause mortality. To account for confounding, we adjusted for all available modifiable, non-modifiable and psychosocial variables. Results Adherent participants had a significantly lower total mortality compared to less-adherent participants (HR = 0.61, 95% Confidence Interval: 0.46–0.82). Adjusting for available confounders did not change the magnitude or significance of the estimates. When considering cause-specific mortality, CVD and pump failure showed similar associations. Conclusions Analyses of the BEST trial data support a strong association between adherence to placebo study medication and total mortality. While probably not due to publication bias or simple confounding by healthy lifestyle factors, the underlying explanation for the association remains a mystery. Prospective examination of this association is necessary to better understand the underlying mechanism of this observation. PMID:22265975

Network analysis of the genomic basis of the placebo effect

PubMed Central

Wang, Rui-Sheng; Hall, Kathryn T.; Giulianini, Franco; Passow, Dani; Kaptchuk, Ted J.

2017-01-01

The placebo effect is a phenomenon in which patients who are given an inactive treatment (e.g., inert pill) show a perceived or actual improvement in a medical condition. Placebo effects in clinical trials have been investigated for many years especially because placebo treatments often serve as the control arm of randomized clinical trial designs. Recent observations suggest that placebo effects may be modified by genetics. This observation has given rise to the term “placebome,” which refers to a group of genome-related mediators that affect an individual’s response to placebo treatments. In this study, we conduct a network analysis of the placebome and identify a placebome module in the comprehensive human interactome using a seed-connector algorithm. The placebome module is significantly enriched with neurotransmitter signaling pathways and brain-specific proteins. We validate the placebome module using a large cohort of the Women’s Genome Health Study (WGHS) trial and demonstrate that the placebome module is significantly enriched with genes whose SNPs modify the outcome in the placebo arm of the trial. To gain insights into placebo effects in different diseases and drug treatments, we use a network proximity measure to examine the closeness of the placebome module to different disease modules and drug target modules. The results demonstrate that the network proximity of the placebome module to disease modules in the interactome significantly correlates with the strength of the placebo effect in the corresponding diseases. The proximity of the placebome module to molecular pathways affected by certain drug classes indicates the existence of placebo-drug interactions. This study is helpful for understanding the molecular mechanisms mediating the placebo response, and sets the stage for minimizing its effects in clinical trials and for developing therapeutic strategies that intentionally engage it. PMID:28570268

The early history of the placebo.

PubMed

Jütte, Robert

2013-04-01

In the late 18th century the term "placebo" became part of medical jargon. In contrast to the prevailing opinion that it was the Scottish physician and pharmacologist William Cullen (1710-1790) who introduced this expression into medical language in 1772, the credit must be given to another English physician, Alexander Sutherland (born before 1730 - died after 1773). The main reason for administering placebos in late 18th-century medical practice was to satisfy the patient's demand and his expectations. Another reason was obstinancy of the patient: the motivation behind such prescriptions may be summarized as prescribing inert drugs for the satisfaction of the patient's mind, and not with the view of producing any direct remedial effect. In most cases these 18th century physicians did not administer "pure" placebos but resorted to any kind of medicine which they thought simple, feeble, or altogether powerless, non-perturbing medicines. Today we make the distinction between pure placebos (substances with no pharmacological effect, e.g. sugar pills) and impure placebos (substances with pharmacological effect but not on the condition being treated). In the 18th century those physicians who prescribed placebo usually thought of drugs which were considered not very effective in the particular case, e.g. a mild ointment. At the same time, only very few brilliant minds came up with the ingenious idea of using inert substances as placebo. An alternative to milk sugar used as placebo in homeopathy was breadpills. Recent research suggests that expectancy is an integral part of the placebo effect. As early as 1775 the English bishop John Douglas (1721-1807) anticipated the findings of modern research on the placebo effect. Copyright © 2012 Elsevier Ltd. All rights reserved.

Systematic Review and Meta-analysis: Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis.

PubMed

Jairath, Vipul; Zou, Guangyong; Parker, Claire E; Macdonald, John K; Mosli, Mahmoud H; Khanna, Reena; Shackelton, Lisa M; Vandervoort, Margaret K; AlAmeel, Turki; Al Beshir, Mohammad; AlMadi, Majid; Al-Taweel, Talal; Atkinson, Nathan S S; Biswas, Sujata; Chapman, Thomas P; Dulai, Parambir S; Glaire, Mark A; Hoekman, Daniel; Koutsoumpas, Andreas; Minas, Elizabeth; Samaan, Mark A; Travis, Simon; D'Haens, Geert; Levesque, Barrett G; Sandborn, William J; Feagan, Brian G

2016-05-01

Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis [UC] clinical trials, and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them. MEDLINE, EMBASE, and the Cochrane Library were searched from inception through April 2014 for placebo-controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant, or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool. In all, 51 trials [48 induction and 10 maintenance phases] were identified. Placebo response and remission rates were pooled according to random-effects models, and mixed-effects meta-regression models were used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10% (95% confidence interval [CI] 7-13%) and 33% [95% CI 29-37%], respectively. Corresponding values for maintenance trials were 19% [95% CI 11-30%] and 22% [95% CI 17-28%]. Trials enrolling patients with more active disease confirmed by endoscopy [endoscopy subscore ≥ 2] were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits. Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials. Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Melatonin for sedative withdrawal in older patients with primary insomnia: a randomized double-blind placebo-controlled trial

PubMed Central

Lähteenmäki, Ritva; Puustinen, Juha; Vahlberg, Tero; Lyles, Alan; Neuvonen, Pertti J; Partinen, Markku; Räihä, Ismo; Kivelä, Sirkka-Liisa

2014-01-01

Aim We compared the efficacy of melatonin and placebo as adjuvants in the withdrawal of patients from long term temazepam, zopiclone or zolpidem (here ‘BZD’) use. Methods A double-blind, placebo-controlled, randomized trial was conducted in a primary health care outpatient clinic. Ninety-two men or women (≥55 years) with primary insomnia and chronic BZD use received controlled release melatonin 2 mg (CRM) (n = 46) or placebo (n = 46) during the 1 month withdrawal from BZDs. Psychosocial support was provided. Follow-up continued for up to 6 months. Successful BZD withdrawal by the end of 1 month was confirmed by BZD plasma determinations, while reduction in BZD use and abstinence continuing for 6 months were noted. Results There were two drop-outs on CRM and one on placebo. After a 1 month withdrawal, 31 participants (67%; 95% CI 54, 81) on CRM and 39 (85%; 74, 95) on placebo had withdrawn completely (intention-to-treat analysis between groups, P = 0.051; per protocol P = 0.043). Reduction in BZD use was similar or even more rare in the CRM than in the placebo group (P = 0.052 per protocol). After 6 months, 14 participants in the CRM group and 20 in the placebo group remained non-users of BZD (NS between groups). BZD doses were higher in the CRM than in the placebo group at the end of the 6 month follow-up (P = 0.025). Withdrawal symptoms did not differ between the groups. Conclusions Gradual dose reduction of BZDs combined with CRM or placebo, and psychosocial support produced high short term and moderate long term BZD abstinence. CRM showed no withdrawal benefit compared with placebo. PMID:24286360

Antidepressant Efficacy of the Antimuscarinic Drug Scopolamine

PubMed Central

Furey, Maura L.; Drevets, Wayne C.

2010-01-01

Context The need for improved therapeutic agents that more quickly and effectively treat depression is critical. In a pilot study we evaluated the role of the cholinergic system in cognitive symptoms of depression and unexpectedly observed rapid reductions in depression severity following the administration of the antimuscarinic drug scopolamine hydrobromide (4 μg/kg intravenously) compared with placebo (P=.002). Subsequently a clinical trial was designed to assess more specifically the antidepressant efficacy of scopolamine. Objective To evaluate scopolamine as a potential antidepressant agent. Design Two studies were conducted: a double-blind, placebo-controlled, dose-finding study followed by a double-blind, placebo-controlled, crossover clinical trial. Setting The National Institute of Mental Health. Patients Currently depressed outpatients aged 18 to 50 years meeting DSM-IV criteria for recurrent major depressive disorder or bipolar disorder. Of 39 eligible patients, 19 were randomized and 18 completed the trial. Interventions Multiple sessions including intravenous infusions of placebo or scopolamine hydrobromide (4 μg/kg). Individuals were randomized to a placebo/ scopolamine or scopolamine/placebo sequence (series of 3 placebo sessions and series of 3 scopolamine sessions). Sessions occurred 3 to 5 days apart. Main Outcome Measures Psychiatric evaluations using the Montgomery-Asberg Depression Rating Scale and the Hamilton Anxiety Rating Scale were performed to assess antidepressant and antianxiety responses to scopolamine. Results The placebo/scopolamine group showed no significant change during placebo infusion vs baseline; reductions in depression and anxiety rating scale scores (P<.001 for both) were observed after the administration of scopolamine compared with placebo. The scopolamine/placebo group also showed reductions in depression and anxiety rating scale scores (P<.001 for both) after the administration of scopolamine, relative to baseline, and these effects persisted as they received placebo. In both groups, improvement was significant at the first evaluation after scopolamine administration (P≤.002). Conclusion Rapid, robust antidepressant responses to the antimuscarinic scopolamine occurred in currently depressed patients who predominantly had poor prognoses. PMID:17015814

Placebo can enhance creativity.

PubMed

Rozenkrantz, Liron; Mayo, Avraham E; Ilan, Tomer; Hart, Yuval; Noy, Lior; Alon, Uri

2017-01-01

The placebo effect is usually studied in clinical settings for decreasing negative symptoms such as pain, depression and anxiety. There is interest in exploring the placebo effect also outside the clinic, for enhancing positive aspects of performance or cognition. Several studies indicate that placebo can enhance cognitive abilities including memory, implicit learning and general knowledge. Here, we ask whether placebo can enhance creativity, an important aspect of human cognition. Subjects were randomly assigned to a control group who smelled and rated an odorant (n = 45), and a placebo group who were treated identically but were also told that the odorant increases creativity and reduces inhibitions (n = 45). Subjects completed a recently developed automated test for creativity, the creative foraging game (CFG), and a randomly chosen subset (n = 57) also completed two manual standardized creativity tests, the alternate uses test (AUT) and the Torrance test (TTCT). In all three tests, participants were asked to create as many original solutions and were scored for originality, flexibility and fluency. The placebo group showed higher originality than the control group both in the CFG (p<0.04, effect size = 0.5) and in the AUT (p<0.05, effect size = 0.4), but not in the Torrance test. The placebo group also found more shapes outside of the standard categories found by a set of 100 CFG players in a previous study, a feature termed out-of-the-boxness (p<0.01, effect size = 0.6). The findings indicate that placebo can enhance the originality aspect of creativity. This strengthens the view that placebo can be used not only to reduce negative clinical symptoms, but also to enhance positive aspects of cognition. Furthermore, we find that the impact of placebo on creativity can be tested by CFG, which can quantify multiple aspects of creative search without need for manual coding. This approach opens the way to explore the behavioral and neural mechanisms by which placebo might amplify creativity.

Placebo can enhance creativity

PubMed Central

Rozenkrantz, Liron; Mayo, Avraham E.; Ilan, Tomer; Hart, Yuval

2017-01-01

Background The placebo effect is usually studied in clinical settings for decreasing negative symptoms such as pain, depression and anxiety. There is interest in exploring the placebo effect also outside the clinic, for enhancing positive aspects of performance or cognition. Several studies indicate that placebo can enhance cognitive abilities including memory, implicit learning and general knowledge. Here, we ask whether placebo can enhance creativity, an important aspect of human cognition. Methods Subjects were randomly assigned to a control group who smelled and rated an odorant (n = 45), and a placebo group who were treated identically but were also told that the odorant increases creativity and reduces inhibitions (n = 45). Subjects completed a recently developed automated test for creativity, the creative foraging game (CFG), and a randomly chosen subset (n = 57) also completed two manual standardized creativity tests, the alternate uses test (AUT) and the Torrance test (TTCT). In all three tests, participants were asked to create as many original solutions and were scored for originality, flexibility and fluency. Results The placebo group showed higher originality than the control group both in the CFG (p<0.04, effect size = 0.5) and in the AUT (p<0.05, effect size = 0.4), but not in the Torrance test. The placebo group also found more shapes outside of the standard categories found by a set of 100 CFG players in a previous study, a feature termed out-of-the-boxness (p<0.01, effect size = 0.6). Conclusions The findings indicate that placebo can enhance the originality aspect of creativity. This strengthens the view that placebo can be used not only to reduce negative clinical symptoms, but also to enhance positive aspects of cognition. Furthermore, we find that the impact of placebo on creativity can be tested by CFG, which can quantify multiple aspects of creative search without need for manual coding. This approach opens the way to explore the behavioral and neural mechanisms by which placebo might amplify creativity. PMID:28892513

Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment.

PubMed

Hróbjartsson, A; Gøtzsche, P C

2001-05-24

Placebo treatments have been reported to help patients with many diseases, but the quality of the evidence supporting this finding has not been rigorously evaluated. We conducted a systematic review of clinical trials in which patients were randomly assigned to either placebo or no treatment. A placebo could be pharmacologic (e.g., a tablet), physical (e.g., a manipulation), or psychological (e.g., a conversation). We identified 130 trials that met our inclusion criteria. After the exclusion of 16 trials without relevant data on outcomes, there were 32 with binary outcomes (involving 3795 patients, with a median of 51 patients per trial) and 82 with continuous outcomes (involving 4730 patients, with a median of 27 patients per trial). As compared with no treatment, placebo had no significant effect on binary outcomes (pooled relative risk of an unwanted outcome with placebo, 0.95; 95 percent confidence interval, 0.88 to 1.02), regardless of whether these outcomes were subjective or objective. For the trials with continuous outcomes, placebo had a beneficial effect (pooled standardized mean difference in the value for an unwanted outcome between the placebo and untreated groups, -0.28; 95 percent confidence interval, -0.38 to -0.19), but the effect decreased with increasing sample size, indicating a possible bias related to the effects of small trials. The pooled standardized mean difference was significant for the trials with subjective outcomes (-0.36; 95 percent confidence interval, -0.47 to -0.25) but not for those with objective outcomes. In 27 trials involving the treatment of pain, placebo had a beneficial effect (-0.27; 95 percent confidence interval, -0.40 to -0.15). This corresponded to a reduction in the intensity of pain of 6.5 mm on a 100-mm visual-analogue scale. We found little evidence in general that placebos had powerful clinical effects. Although placebos had no significant effects on objective or binary outcomes, they had possible small benefits in studies with continuous subjective outcomes and for the treatment of pain. Outside the setting of clinical trials, there is no justification for the use of placebos.

A Randomized Trial of Ketorolac vs. Sumatripan vs. Placebo Nasal Spray (KSPN) for Acute Migraine.

PubMed

Rao, Aruna S; Gelaye, Bizu; Kurth, Tobias; Dash, Paul D; Nitchie, Haley; Peterlin, B Lee

2016-02-01

To compare the efficacy of ketorolac nasal spray (NS) vs. placebo and sumatriptan NS for the acute treatment of migraine. This was a randomized, double-blind, placebo and active-comparator, crossover study. Adult migraineurs were randomized to ketorolac NS 31.5 mg, sumatriptan NS 20 mg, or placebo to treat three moderate to severe migraine attacks and switched treatments with each attack. Patients seeking headache care at a headache center or in response to community advertisement were recruited. Adult participants with episodic migraine who experienced ≥2 migraine attacks per month were eligible for the Ketorolac vs. Sumatriptan vs. Placebo Nasal Spray migraine study. Participants were randomized to treatment arms by a research pharmacist, in a 1:1:1 ratio using computer-generated lists. The primary outcome was 2-hour pain relief. Secondary outcomes included 2-hour pain freedom and absence of migraine associated symptoms, and 24-hour sustained pain relief and pain freedom. Of the 72 randomized participants, 54 (75%) treated at least one attack and 49 (68%) completed all three treatments, for a total of 152 treated migraine attacks. Both ketorolac NS (72.5%, P < .001) and sumatriptan NS (69.4%, P = .001) were more effective than placebo (38.3%) for 2-hour pain relief and 2-hour pain freedom (ketorolac: 43.1%, P = .004; sumatriptan: 36.7%, P = .046; placebo: 18.4%). Ketorolac NS, but not sumatriptan NS, was more effective than placebo in 2-hour absence of nausea. Both ketorolac NS and sumatriptan NS were more effective than placebo for 24-hour sustained pain relief (ketorolac: 49%, P < .001; sumatriptan: 31%, P = .01, placebo: 20%). Only ketorolac NS was superior to placebo for 24-hour (ketorolac: 35.3%, P = .003; sumatriptan: 22.4%, P = .18, placebo: 12.2%) sustained pain freedom. Nasal burning and dysgeusia were the most common adverse effects for active treatments. This study supports that ketorolac NS is superior to placebo and that it is non-inferior to sumatriptan NS for the acute abortive treatment of migraine. © 2016 American Headache Society.

A Randomized Trial of Ketorolac vs Sumatripan vs Placebo Nasal Spray (KSPN) for Acute Migraine

PubMed Central

Rao, Aruna S.; Gelaye, Bizu; Kurth, Tobias; Dash, Paul D.; Nitchie, Haley; Peterlin, B. Lee

2016-01-01

Objective To compare the efficacy of ketorolac nasal spray (NS) vs placebo and sumatriptan NS for the acute treatment of migraine. Methods This was a randomized, double-blind, placebo and active-comparator, crossover study. Adult migraineurs were randomized to ketorolac NS 31.5 mg, sumatriptan NS 20 mg, or placebo to treat three moderate to severe migraine attacks and switched treatments with each attack. Patients seeking headache care at a headache center or in response to community advertisement were recruited. Adult participants with episodic migraine who experienced ≥2 migraine attacks per month were eligible for the Ketorolac vs Sumatriptan vs Placebo Nasal Spray migraine study. Participants were randomized to treatment arms by a research pharmacist, in a 1:1:1 ratio using computer-generated lists. The primary outcome was 2-hour pain relief. Secondary outcomes included 2-hour pain freedom and absence of migraine associated symptoms, and 24-hour sustained pain relief and pain freedom. Results Of the 72 randomized participants, 54 (75%) treated at least one attack and 49 (68%) completed all three treatments, for a total of 152 treated migraine attacks. Both ketorolac NS (72.5%, P < .001) and sumatriptan NS (69.4%, P=.001) were more effective than placebo (38.3%) for 2-hour pain relief and 2-hour pain freedom (ketorolac: 43.1%, P=.004; sumatriptan: 36.7%, P=.046; placebo: 18.4%). Ketorolac NS, but not sumatriptan NS, was more effective than placebo in 2-hour absence of nausea. Both ketorolac NS and sumatriptan NS were more effective than placebo for 24-hour sustained pain relief (ketorolac: 49%, P < .001; sumatriptan: 31%, P=.01, placebo: 20%). Only ketorolac NS was superior to placebo for 24-hour (ketorolac: 35.3%, P=.003; sumatriptan: 22.4%, P=.18, placebo: 12.2%) sustained pain freedom. Nasal burning and dysgeusia were the most common adverse effects for active treatments. Conclusions This study supports that ketorolac NS is superior to placebo and that it is non-inferior to sumatriptan NS for the acute abortive treatment of migraine. PMID:26840902

Escitalopram in the Treatment of Adolescent Depression: A Randomized, Double-Blind, Placebo-Controlled Extension Trial

PubMed Central

Robb, Adelaide; Bose, Anjana

2013-01-01

Abstract Objective The purpose of this study was to evaluate the extended efficacy, safety, and tolerability of escitalopram relative to placebo in adolescents with major depressive disorder (MDD). Methods Adolescents (12–17 years) who completed an 8-week randomized, double-blind, flexible-dose, placebo-controlled, lead-in study of escitalopram 10–20 mg versus placebo could enroll in a 16–24-week, multisite extension trial; patients maintained the same lead-in randomization (escitalopram or placebo) and dosage (escitalopram 10 or 20 mg/day, or placebo) during the extension. The primary efficacy was Children's Depression Rating Scale-Revised (CDRS-R) change from the lead-in study baseline to treatment week 24 (8-week lead-in study plus 16-week extension); the secondary efficacy was Clinical Global Impressions-Improvement (CGI-I) score at week 24. All efficacy analyses used the last observation carried forward (LOCF) approach; sensitivity analyses used observed cases (OC) and mixed-effects model for repeated measures (MMRM). Safety was evaluated via adverse event (AE) reports and the clinician-rated Columbia-Suicide Severity Rating Scale (C-SSRS). Results Following lead-in, 165 patients enrolled in the double-blind extension (82 placebo; 83 escitalopram); 40 (48.8%) placebo and 37 (44.6%) escitalopram patients completed treatment. CDRS-R total score improvement was significantly greater for escitalopram than for placebo (p=0.005, LOCF; p=0.014; MMRM). Response rates (CDRS-R ≥40% reduction from baseline [adjusted and unadjusted] and CGI-I ≤2) were significantly higher for escitalopram than for placebo (LOCF); remission rates (CDRS-R ≤28) were 50.6% for escitalopram and 35.7% for placebo (p=0.002). OC analyses were not significantly different between groups. The most frequent escitalopram AEs (≥5% and more frequent than placebo) were headache, nausea, insomnia, vomiting, influenza-like symptoms, diarrhea, and urinary tract infection. Most AEs were mild/moderate and not related to the study drug. AEs suggestive of self-harm occurred in 5.7% and 7.1% of placebo and escitalopram patients. Occurrence of suicidal behavior and/or suicidal ideation assessed by C-SSRS was 10.9% (14/128) for placebo and 14.5% (19/131) for escitalopram. Conclusions Extended use of escitalopram was generally safe and resulted in modest improvement in efficacy in adolescents with MDD. PMID:24041408

Escitalopram in the treatment of adolescent depression: a randomized, double-blind, placebo-controlled extension trial.

PubMed

Findling, Robert L; Robb, Adelaide; Bose, Anjana

2013-09-01

The purpose of this study was to evaluate the extended efficacy, safety, and tolerability of escitalopram relative to placebo in adolescents with major depressive disorder (MDD). Adolescents (12-17 years) who completed an 8-week randomized, double-blind, flexible-dose, placebo-controlled, lead-in study of escitalopram 10-20 mg versus placebo could enroll in a 16-24-week, multisite extension trial; patients maintained the same lead-in randomization (escitalopram or placebo) and dosage (escitalopram 10 or 20 mg/day, or placebo) during the extension. The primary efficacy was Children's Depression Rating Scale-Revised (CDRS-R) change from the lead-in study baseline to treatment week 24 (8-week lead-in study plus 16-week extension); the secondary efficacy was Clinical Global Impressions-Improvement (CGI-I) score at week 24. All efficacy analyses used the last observation carried forward (LOCF) approach; sensitivity analyses used observed cases (OC) and mixed-effects model for repeated measures (MMRM). Safety was evaluated via adverse event (AE) reports and the clinician-rated Columbia-Suicide Severity Rating Scale (C-SSRS). Following lead-in, 165 patients enrolled in the double-blind extension (82 placebo; 83 escitalopram); 40 (48.8%) placebo and 37 (44.6%) escitalopram patients completed treatment. CDRS-R total score improvement was significantly greater for escitalopram than for placebo (p=0.005, LOCF; p=0.014; MMRM). Response rates (CDRS-R ≥ 40% reduction from baseline [adjusted and unadjusted] and CGI-I ≤ 2) were significantly higher for escitalopram than for placebo (LOCF); remission rates (CDRS-R ≤ 28) were 50.6% for escitalopram and 35.7% for placebo (p=0.002). OC analyses were not significantly different between groups. The most frequent escitalopram AEs (≥ 5% and more frequent than placebo) were headache, nausea, insomnia, vomiting, influenza-like symptoms, diarrhea, and urinary tract infection. Most AEs were mild/moderate and not related to the study drug. AEs suggestive of self-harm occurred in 5.7% and 7.1% of placebo and escitalopram patients. Occurrence of suicidal behavior and/or suicidal ideation assessed by C-SSRS was 10.9% (14/128) for placebo and 14.5% (19/131) for escitalopram. Extended use of escitalopram was generally safe and resulted in modest improvement in efficacy in adolescents with MDD.

Molecular and functional PET-fMRI measures of placebo analgesia in episodic migraine: Preliminary findings.

PubMed

Linnman, Clas; Catana, Ciprian; Petkov, Mike P; Chonde, Daniel Burje; Becerra, Lino; Hooker, Jacob; Borsook, David

2018-01-01

Pain interventions with no active ingredient, placebo, are sometimes effective in treating chronic pain conditions. Prior studies on the neurobiological underpinnings of placebo analgesia indicate endogenous opioid release and changes in brain responses and functional connectivity during pain anticipation and pain experience in healthy subjects. Here, we investigated placebo analgesia in healthy subjects and in interictal migraine patients (n = 9) and matched healthy controls (n = 9) using 11 C-diprenoprhine Positron Emission Tomography (PET) and simultaneous functional Magnetic Resonance Imaging (fMRI). Intravenous saline injections (the placebo) led to lower pain ratings, but we did not find evidence for an altered placebo response in interictal migraine subjects as compared to healthy subjects.

Efficacy and safety of vardenafil in men with erectile dysfunction caused by spinal cord injury.

PubMed

Giuliano, F; Rubio-Aurioles, E; Kennelly, M; Montorsi, F; Kim, E D; Finkbeiner, A E; Pommerville, P J; Colopy, M W; Wilkins, H J; Wachs, B H

2006-01-24

To assess the efficacy and tolerability of vardenafil in men with erectile dysfunction (ED) due to traumatic spinal cord injury (SCI). In this multicenter, double-blind, placebo-controlled, parallel-group 12-week study, 418 men aged 18 years and older with ED for more than 6 months consequent to SCI were randomized to vardenafil (n = 207) or placebo (n = 211) (10 mg for 4 weeks, then maintained or titrated to 5 or 20 mg at weeks 4 and 8). Efficacy assessments included the erectile function (EF) domain score of the International Index of Erectile Function questionnaire and diary questions regarding penetration, maintenance of erection to completion of intercourse, and ejaculation. Baseline patient characteristics were similar in the vardenafil (mean age 40 years) and placebo (mean age 39 years) groups. Mean baseline EF domain scores were 11.6 in the vardenafil group and 12.1 (moderate ED) in the placebo group. EF domain score in the vardenafil group improved to 22.0 (mild ED) at last observation carried forward vs 13.5 in the placebo group (p < 0.001). Over 12 weeks of treatment, mean per-patient penetration (76% vs 41%), maintenance (59% vs 22%), and ejaculation (19% vs 10%) success rates were significantly greater vs placebo (all p < 0.001). The most frequently reported drug-related adverse events were headache (vardenafil 15%, placebo 4%), flushing (vardenafil 6%, placebo 0%), nasal congestion (vardenafil 5%, placebo 0%), and dyspepsia (vardenafil 4%, placebo 0%). Vardenafil significantly improved erectile and ejaculatory function and was generally well tolerated in men with erectile dysfunction due to spinal cord injury.

Soy in hypercholesterolaemia: a double-blind, placebo-controlled trial.

PubMed

Puska, P; Korpelainen, V; Høie, L H; Skovlund, E; Lahti, T; Smerud, K T

2002-04-01

To study whether Abacor, a product based on isolated soy protein with high and standardised levels of isoflavones and cotyledon soy fibres, was more effective in lowering total and LDL cholesterol than placebo. Randomised, placebo-controlled, double-blind, parallel group, single centre study. Primary care in Joensuu, North Karelia, Finland. Subjects were screened from the patient database of the health centre; 30 were randomised to the Abacor group and 30 subjects to placebo. Eight subjects were withdrawn, six from the active group, two from the placebo group. The preparations were given as two daily liquid supplements in addition to the subjects' regular diets for 6 weeks. Abacor showed a statistically significant lipid-lowering effect as compared to placebo, although an unexpected reduction was seen in the placebo group. The estimated difference between active treatment and placebo was 0.25 mmol/l (95% CI 0.01, 0.50; P=0.049) for total cholesterol, corresponding to reductions of 8.3 and 5.1%, respectively. The difference in reduction of LDL-cholesterol was 0.27 mmol/l (95% CI 0.06, 0.49; P=0.014) and corresponded to a reduction of 13.2% in the active treatment group, and 8.0% in the placebo group. Abacor showed a rapid onset of effect, as compared with placebo. During a wash-out period of 4 weeks after treatment, the subjects returned to pre-treatment cholesterol levels. Added to a regular diet, Abacor significantly reduced LDL-cholesterol and total cholesterol. These beneficial effects occurred within 6 weeks of treatment.

Andrographis paniculata Extract (HMPL-004) for Active Ulcerative Colitis

PubMed Central

Sandborn, William J; Targan, Stephan R; Byers, Vera S; Rutty, Dean A; Mu, Hua; Zhang, Xun; Tang, Tom

2013-01-01

OBJECTIVES: Andrographis paniculata has in vitro inhibitory activity against TNF-α, IL-1β and NF-κB. A pilot study of A. paniculata extract (HMPL-004) suggested similar efficacy to mesalamine for ulcerative colitis. METHODS: A randomized, double-blind, placebo-controlled trial evaluated the efficacy of A. paniculata extract (HMPL-004) in 224 adults with mild-to-moderate ulcerative colitis. Patients were randomized to A. paniculata extract (HMPL-004) 1,200 mg or 1,800 mg daily or placebo for 8 weeks. RESULTS: In total, 45 and 60% of patients receiving A. paniculata 1,200 mg and 1,800 mg daily, respectively, were in clinical response at week 8, compared with 40% of those who received placebo (P=0.5924 for 1,200 mg vs. placebo and P=0.0183 for 1,800 mg vs. placebo). In all, 34 and 38% of patients receiving A. paniculata 1,200 mg and 1,800 mg daily, respectively, were in clinical remission at week 8, compared with 25% of those who received placebo (P=0.2582 for 1,200 mg vs. placebo and P=0.1011 for 1,800 mg vs. placebo). Adverse events developed in 60 and 53% of patients in the A. paniculata 1,200 mg and 1,800 mg daily groups, respectively, and 60% in the placebo group. CONCLUSIONS: Patients with mildly to moderately active ulcerative colitis treated with A. paniculata extract (HMPL-004) at a dose of 1,800 mg daily were more likely to achieve clinical response than those receiving placebo. PMID:23044768

Design of clinical trials of antidepressants: should a placebo control arm be included?

PubMed

Fritze, J; Möller, H J

2001-01-01

There is no doubt that available antidepressants are efficacious and effective. Nevertheless, more effective drugs with improved tolerability are needed. With this need in mind, some protagonists claim that future antidepressants should be proved superior to, or at least as effective as, established antidepressants, making placebo control methodologically dispensable in clinical trials. Moreover, the use of placebo control is criticised as unethical because it might result in effective treatment being withheld. There are, however, a number of methodological reasons why placebo control is indispensable for the proof of efficacy of antidepressants. Comparing investigational antidepressants only with standard antidepressants and not placebo yields ambiguous results that are difficult to interpret, be it in superiority or equivalence testing, and this method of assessment requires larger sample sizes than those required with the use of placebo control. Experimental methodology not adhering to the optimal study design is ethically questionable. Restricting the testing of investigational antidepressants only to superiority over standard antidepressants is an obstacle to therapeutic progress in terms of tolerability and the detection of innovative mechanisms of action from which certain subgroups of future patients might benefit. The use of a methodology that requires larger samples for testing of superiority or equivalence is also ethically questionable. In view of the high placebo response rates in trials of antidepressants, placebo treatment does not mean withholding effective treatment. Accepting the necessity of the clinical evaluation of new, potentially ineffective antidepressants implicitly means accepting placebo control as ethically justified. Three- or multi-arm comparisons including placebo and an active reference represent the optimal study design.

The placebo effect and its determinants in fibromyalgia: meta-analysis of randomised controlled trials.

PubMed

Chen, Xi; Zou, Kun; Abdullah, Natasya; Whiteside, Nicola; Sarmanova, Aliya; Doherty, Michael; Zhang, Weiya

2017-07-01

The aims of this study were to determine whether placebo treatment in randomised controlled trials (RCTs) is effective for fibromyalgia and to identify possible determinants of the magnitude of any such placebo effect. A systematic literature search was undertaken for RCTs in people with fibromyalgia that included a placebo and/or a no-treatment (observation only or waiting list) control group. Placebo effect size (ES) for pain and other outcomes was measured as the improvement of each outcome from baseline divided by the standard deviation of the change from baseline. This effect was compared with changes in the no-treatment control groups. Meta-analysis was undertaken to combine data from different studies. Subgroup analysis was conducted to identify possible determinants of the placebo ES. A total of 3912 studies were identified from the literature search. After scrutiny, 229 trials met the inclusion criteria. Participants who received placebo in the RCTs experienced significantly better improvements in pain, fatigue, sleep quality, physical function, and other main outcomes than those receiving no treatment. The ES of placebo for pain relief was clinically moderate (0.53, 95%CI 0.48 to 0.57). The ES increased with increasing strength of the active treatment, increasing participant age and higher baseline pain severity, but decreased in RCTS with more women and with longer duration of fibromyalgia. In addition, placebo treatment in RCTs is effective in fibromyalgia. A number of factors (expected strength of treatment, age, gender, disease duration) appear to influence the magnitude of the placebo effect in this condition.

The treatment of severe premenstrual syndrome with goserelin with and without 'add-back' estrogen therapy: a placebo-controlled study.

PubMed

Leather, A T; Studd, J W; Watson, N R; Holland, E F

1999-02-01

The study aimed to determine if the addition of daily low-dose oral estrogen with a cyclical progestogen given to young women using a depot gonadotropin-releasing hormone (GnRH) analog implant for the treatment of their premenstrual syndrome (PMS) would affect the clinical outcome. In a double-blind placebo-controlled study in a specialist premenstrual syndrome clinic setting, 60 women aged between 20 and 45 years were randomized to one of three treatment groups: Group A (placebo implant four weekly + placebo tablets daily), Group B (goserelin 3.6 mg implant four weekly + estradiol valerate 2 mg daily with norethisterone 5 mg from days 21-28 of a 28-day cycle) or Group C (goserelin 3.6 mg implant four weekly + placebo tablets daily). Differences between PMS scores at 2, 4 and 6 months were compared with pretreatment values. There was a significant improvement in PMS scores in Group C (Zoladex + placebo) after 2, 4 and 6 months of treatment when compared to pretreatment values and Group A (placebo + placebo). The addition of a low-dose oral estrogen with a cyclical progestogen to GnRH analog treatment (Group B) resulted in a less dramatic response when compared to pretreatment values and no significant improvement when compared to Group A (placebo + placebo) at 2, 4 and 6 months of treatment. The addition of a low-dose oral estrogen with a cyclical progestogen to depot GnRH analog therapy in the treatment of PMS reduces the clinical response.

The Application of Persuasion Theory to Placebo Effects.

PubMed

Geers, Andrew L; Briñol, Pablo; Vogel, Erin A; Aspiras, Olivia; Caplandies, Fawn C; Petty, Richard E

2018-01-01

Placebo effects, or positive outcomes resulting from expectations about a treatment, are powerful components of modern medical care. In this chapter, we suggest that our understanding of placebo effects may benefit from more explicitly connecting this phenomenon to the existing empirical psychological literature on persuasion. Persuasion typically involves an attempt to bring about a change in beliefs or attitudes as a result of providing information on a topic. We begin by providing a brief overview of the psychological literature on placebo effects. We then point to connections between this literature and research on persuasive communication. Although some links have been made, these initial connections have predominantly relied on classic theories of persuasion rather than on more contemporary and comprehensive models. Next, we describe a modern theory of persuasion that may facilitate the study of placebo effects and analyze two issues pertinent to the literature on placebo effects from the lens of this model. Specifically, we consider how and when characteristics of a practitioner (e.g., variables such as perceptions of a practitioner's confidence or competence) can influence the magnitude of placebo effects, and how modern persuasion theory can help in understanding the durability of placebo effects over time. We conclude that examining placebo effects as an outcome of persuasive communication would be a fruitful line of future research. © 2018 Elsevier Inc. All rights reserved.

Methylphenidate and Memory and Attention Adaptation Training for Persistent Cognitive Symptoms after Traumatic Brain Injury: A Randomized, Placebo-Controlled Trial.

PubMed

McDonald, Brenna C; Flashman, Laura A; Arciniegas, David B; Ferguson, Robert J; Xing, Li; Harezlak, Jaroslaw; Sprehn, Gwen C; Hammond, Flora M; Maerlender, Arthur C; Kruck, Carrie L; Gillock, Karen L; Frey, Kim; Wall, Rachel N; Saykin, Andrew J; McAllister, Thomas W

2017-08-01

The purpose of this multicenter, prospective, randomized, placebo-controlled study was to evaluate and compare the efficacy of two cognitive rehabilitation interventions (Memory and Attention Adaptation Training (MAAT) and Attention Builders Training (ABT)), with and without pharmacological enhancement (ie, with methylphenidate (MPH) or placebo), for treating persistent cognitive problems after traumatic brain injury (TBI). Adults with a history of TBI at least 4 months before study enrollment with either objective cognitive deficits or subjective cognitive complaints were randomized to receive MPH or placebo and MAAT or ABT, yielding four treatment combinations: MAAT/MPH (N=17), ABT/MPH (N=19), MAAT/placebo (N=17), and ABT/placebo (N=18). Assessments were conducted pre-treatment (baseline) and after 6 weeks of treatment (post treatment). Outcome measures included scores on neuropsychological measures and subjective rating scales. Statistical analyses used linear regression models to predict post-treatment scores for each outcome variable by treatment type, adjusting for relevant covariates. Statistically significant (P<0.05) treatment-related improvements in cognitive functioning were found for word-list learning (MAAT/placebo>ABT/placebo), nonverbal learning (MAAT/MPH>MAAT/placebo and MAAT/MPH>ABT/MPH), and auditory working memory and divided attention (MAAT/MPH>ABT/MPH). These results suggest that combined treatment with metacognitive rehabilitation (MAAT) and pharmacotherapy (MPH) can improve aspects of attention, episodic and working memory, and executive functioning after TBI.

Aacap 2002 Research Forum: Placebo and Alternatives to Placebo in Randomized Controlled Trials in Pediatric Psychopharmacology

ERIC Educational Resources Information Center

March, John; Kratochvil, Christopher; Clarke, Gregory; Beardslee, William; Derivan, Albert; Emslie, Graham; Green, Evelyn P.; Heiligenstein, John; Hinshaw, Stephen; Hoagwood, Kimberly; Jensen, Peter; Lavori, Philip; Leonard, Henrietta; McNulty, James; Michaels, M. Alex; Mossholder, Andrew; Osher, Trina; Petti, Theodore; Prentice, Ernest; Vitiello, Benedetto; Wells, Karen

2004-01-01

Objective: The use of placebo in the pediatric age group has come under increasing scrutiny. At the 2002 Annual Meeting of the American Academy of Child and Adolescent Psychiatry, the Academy's Workgroup on Research conducted a research forum. The purpose was to identify challenges and their solutions regarding the use of placebo in randomized…

Oral lysine clonixinate in the acute treatment of migraine: a double-blind placebo-controlled study.

PubMed

Krymchantowski, A V; Barbosa, J S; Cheim, C; Alves, L A

2001-03-01

Several oral nonsteroidal anti-inflammatory drugs (NSAIDs) are effective to treat migraine attacks. Lysine clonixinate (LC) is a NSAID derived from nicotinic acid that has proven to be effective in various pain syndromes such as renal colic and muscular pain. The aim of this double-blind, placebo-controlled study was to evaluate the efficacy of oral LC compared to placebo in the acute treatment of migraine. Sixty four patients with the diagnosis of migraine, according to the IHS criteria, were studied prospectively. Patients received LC or placebo once the headache reached moderate or severe intensity for 6 consecutive attacks. With regard to the moderate attacks, LC was superior than placebo after 1, 2 and 4 hours. The consumption of other rescue medications after 4 hours was significantly higher in the placebo group. With regard to the severe attacks, there was no difference between the active drug group and the placebo group concerning headache intensity and consumption of other rescue medications. We conclude that the NSAID lysine clonixinate is effective in treating moderately severe migraine attacks. It is not superior than placebo in treating severe migraine attacks.

Is the perceived placebo effect comparable between adults and children? A meta-regression analysis.

PubMed

Janiaud, Perrine; Cornu, Catherine; Lajoinie, Audrey; Djemli, Amina; Cucherat, Michel; Kassai, Behrouz

2017-01-01

A potential larger perceived placebo effect in children compared with adults could influence the detection of the treatment effect and the extrapolation of the treatment benefit from adults to children. This study aims to explore this potential difference, using a meta-epidemiological approach. A systematic review of the literature was done to identify trials included in meta-analyses evaluating a drug intervention with separate data for adults and children. The standardized mean change and the proportion of responders (binary outcomes) were used to calculate the perceived placebo effect. A meta-regression analysis was conducted to test for the difference between adults and children of the perceived placebo effect. For binary outcomes, the perceived placebo effect was significantly more favorable in children compared with adults (β = 0.13; P = 0.001). Parallel group trials (β = -1.83; P < 0.001), subjective outcomes (β = -0.76; P < 0.001), and the disease type significantly influenced the perceived placebo effect. The perceived placebo effect is different between adults and children for binary outcomes. This difference seems to be influenced by the design, the disease, and outcomes. Calibration of new studies for children should consider cautiously the placebo effect in children.

Challenges and Recommendations for Placebo Controls in Randomized Trials in Physical and Rehabilitation Medicine

PubMed Central

Fregni, Felipe; Imamura, Marta; Chien, Hsin Fen; Lew, Henry L.; Boggio, Paulo; Kaptchuk, Ted J; Riberto, Marcelo; Hsing, Wu Tu; Battistella, Linamara Rizzo; Furlan, Andrea

2010-01-01

Compared to other specialties, the field of Physical and Rehabilitation Medicine (PRM) has not received the deserved recognition from clinicians and researchers in the scientific community. One of the reasons is the lack of sound evidence to support the traditional PRM treatments. The best way to change this disadvantage is through well-conducted clinical research, such as the standard placebo or sham-controlled randomized clinical trials. Therefore, having placebo groups in clinical trials is essential to improve the level of evidence-based practice in PRM that ultimately translates in a better clinical care. To address the challenges for the use of placebo in PRM randomized clinical trials, and to create useful recommendations, we convened a working group during the inaugural International Symposium in Placebo (February 2009, in Sao Paulo, Brazil) in which the following topics were discussed: (1) current status of randomized clinical trials in PRM, (2) challenges for the use of placebo in PRM, (3) bioethical issues, (4) use of placebo in acupuncture trials and for the treatment of low-back pain, (5) mechanisms of placebo, and (6) insights from other specialties. The current article represents the consensus report from the working group. PMID:20090428

Placebo-Controlled Study of Pimozide Augmentation of Fluoxetine in Body Dysmorphic Disorder

PubMed Central

Phillips, Katharine A.

2006-01-01

Objective Although body dysmorphic disorder often responds to serotonin reuptake inhibitors (SRIs), most patients do not respond or respond only partially. However, placebo-controlled studies of augmentation of SRIs have not been done. Furthermore, although 40%–50% of patients are delusional, studies of antipsychotic medications have not been done. Method Twenty-eight patients with body dysmorphic disorder or its delusional variant participated in an 8-week, placebo-controlled, double-blind, parallel-group study of pimozide augmentation of fluoxetine. Results Pimozide was not more effective than placebo: two (18.2%) of 11 subjects responded to pimozide and three (17.6%) of 17 subjects responded to placebo. There was no significant effect of baseline delusionality on endpoint severity of body dysmorphic disorder. Delusionality did not decrease significantly more with pimozide than placebo. Conclusions Pimozide augmentation of fluoxetine treatment for body dysmorphic disorder was not more effective than placebo, even in more delusional patients. Further studies of augmentation for SRIs are needed. PMID:15677604

Symptom relief and the placebo effect in the trial of an anti-peptic drug.

PubMed Central

MacDonald, A J; Peden, N R; Hayton, R; Mallinson, C N; Roberts, D; Wormsley, K G

1981-01-01

In order to determine some of the factors involved in the response of duodenal ulcers to placebo treatment, the following factors were studied prospectively during a double-blind, placebo-controlled trial: demographic data; duration of illness and effect of treatment; expectation of success or failure of the new drug; presence of psychiatric problems; and suggestibility. Healing (measured by endoscopy) occurred in 37 patients, 17 of whom were receiving placebo; relief of symptoms occurred in 35 patients, 16 of whom were receiving placebo. There was no significant difference between drug and placebo. Healing was significantly associated with relief of symptoms but with no other variable. Relief of symptoms was more common in male patients and in those from higher social classes, as well as in patients who expected a complete cure and those without evidence of psychiatric problems. the natural history of the disease may be different in these patients. Unexpectedly, suggestibility was not associated with healing or relief of symptoms in the patients receiving placebo. PMID:7016689

Set and setting, psychedelics and the placebo response: An extra-pharmacological perspective on psychopharmacology.

PubMed

Hartogsohn, Ido

2016-12-01

Placebo response theory and set and setting theory are two fields which examine how non-biological factors shape the response to therapy. Both consider factors such as expectancy, preparation and beliefs to be crucial for understanding the extra-pharmacological processes which shape the response to drugs. Yet there are also fundamental differences between the two theories. Set and setting concerns itself with response to psychoactive drugs only; placebo theory relates to all therapeutic interventions. Placebo theory is aimed at medical professionals; set and setting theory is aimed at professionals and drug users alike. Placebo theory is primarily descriptive, describing how placebo acts; set and setting theory is primarily prescriptive, educating therapists and users on how to control and optimize the effects of drugs. This paper examines how placebo theory and set and setting theory can complement and benefit each other, broadening our understanding of how non-biological factors shape response to drugs and other treatment interventions. © The Author(s) 2016.

Acupuncture, psyche and the placebo response.

PubMed

Enck, Paul; Klosterhalfen, Sibylle; Zipfel, Stephan

2010-10-28

With growing use of acupuncture treatment in various clinical conditions, the question has been posed whether the reported effects reflect specific mechanisms of acupuncture or whether they represent placebo responses, as they often are similar in effect size and resemble similarities to placebo analgesia and its mechanisms. We reviewed the available literature for different placebos (sham procedures) used to control the acupuncture effects, for moderators and potential biases in respective clinical trials, and for central and peripheral mechanisms involved that would allow differentiation of placebo effects from acupuncture and sham acupuncture effects. While the evidence is still limited, it seems that biological differences exist between a placebo response, e.g. in placebo analgesia, and analgesic response during acupunture that does not occur with sham acupuncture. It seems advisable that clinical trials should include potential biomarkers of acupuncture, e.g. measures of the autonomic nervous system function to verify that acupuncture and sham acupuncture are different despite similar clinical effects. Copyright © 2010 Elsevier B.V. All rights reserved.

Utilizing placebo mechanisms for dose reduction in pharmacotherapy.

PubMed

Doering, Bettina K; Rief, Winfried

2012-03-01

The knowledge and systematic application of the placebo effect remains limited, although its importance to the treatment of various medical conditions has increasingly been recognized. A possible application of the placebo effect to pharmacotherapy is seen in conditioning processes that aim at a placebo-controlled dose reduction of drugs while maintaining the efficacy of the medical treatment. The pairing of a placebo and a pharmacological agent may achieve satisfactory treatment outcomes in combination with a lower dose of medication. This procedure includes classic and instrumental conditioning processes that involve both conscious and non-conscious information processing. Although recent studies have gathered preliminary evidence for the efficacy of placebo-controlled dose reduction (e.g. in psoriasis and attention deficit hyperactivity disorder [ADHD]), they have also illustrated the difficulties that are inherent to this approach. We critically review previous approaches and discuss designs for clinical trials that seem appropriate to the investigation of conditioned placebo effects in pharmacotherapy. Copyright © 2011 Elsevier Ltd. All rights reserved.

The ethics of placebo-controlled trials: methodological justifications.

PubMed

Millum, Joseph; Grady, Christine

2013-11-01

The use of placebo controls in clinical trials remains controversial. Ethical analysis and international ethical guidance permit the use of placebo controls in randomized trials when scientifically indicated in four cases: (1) when there is no proven effective treatment for the condition under study; (2) when withholding treatment poses negligible risks to participants; (3) when there are compelling methodological reasons for using placebo, and withholding treatment does not pose a risk of serious harm to participants; and, more controversially, (4) when there are compelling methodological reasons for using placebo, and the research is intended to develop interventions that can be implemented in the population from which trial participants are drawn, and the trial does not require participants to forgo treatment they would otherwise receive. The concept of methodological reasons is essential to assessing the ethics of placebo controls in these controversial last two cases. This article sets out key considerations relevant to considering whether methodological reasons for a placebo control are compelling. © 2013.

Placebo effects in neurological diseases.

PubMed

Dumitriu, Alina; Popescu, Bogdan O

2010-01-01

There is an imperious need of redefining placebo effect in contemporary times. The effects of sham medical intervention, combined with a careful observation of the natural evolution of a disease, could reveal the true efficiency and impact of active drugs. This interest is not driven only by a scientific curiosity, but also by the pragmatic fact that the standard process of approving new medicines through supportive clinical trials requires a comparison against placebo. A complete understanding of the placebo effect should include both its psychological mechanisms and the underlying neurobiology. In contrast to other type of conditions, neurological disorders could provide specific clues in understanding the placebo effect, since the pathogenic mechanisms of different diseases might interfere with neuronal circuitry involved in the perception of disease symptoms. However, there are ethical considerations dictating the limits of using placebo. This paper reviews recent articles about placebo effect, with an emphasis on its importance in several neurological conditions (Parkinson's disease, neuropathic pain, headache, multiple sclerosis, epilepsy), and intends to offer new insights on this major topic.

Applying evidence to support ethical decisions: is the placebo really powerless?.

PubMed

Porzsolt, Franz; Schlotz-Gorton, Nicole; Biller-Andorno, Nikola; Thim, Anke; Meissner, Karin; Roeckl-Wiedmann, Irmgard; Herzberger, Barbara; Ziegler, Renatus; Gaus, Wilhelm; Pöppe, Ernst

2004-01-01

Using placebos in day-to-day practice is an ethical problem. This paper summarises the available epidemiological evidence to support this difficult decision. Based on these data we propose to differentiate between placebo and "knowledge framing". While the use of placebo should be confined to experimental settings in clinical trials, knowledge framing--which is only conceptually different from placebo--is a desired, expected and necessary component of any doctor-patient encounter. Examples from daily practice demonstrate both, the need to investigate the effects of knowledge framing and its impact on ethical, medical, economical and legal decisions.

Does the rising placebo response impact antihypertensive clinical trial outcomes? An analysis of data from the Food and Drug Administration 1990-2016

PubMed Central

Fahl Mar, Kaysee; Schilling, Joshua; Brown, Walter A.

2018-01-01

Background Recent studies show that placebo response has grown significantly over time in clinical trials for antidepressants, ADHD medications, antiepileptics, and antidiabetics. Contrary to expectations, trial outcome measures and success rates have not been impacted. This study aimed to see if this trend of increasing placebo response and stable efficacy outcome measures is unique to the conditions previously studied or if it occurs in trials for conditions with physiologically-measured symptoms, such as hypertension. Method For this reason, we evaluated the efficacy data reported in the US Food and Drug Administration Medical and Statistical reviews for 23 antihypertensive programs (32,022 patients, 63 trials, 142 treatment arms). Placebo and medication response, effect sizes, and drug-placebo differences were calculated for each treatment arm and examined over time using meta-regression. We also explored the relationship of sample size, trial duration, baseline blood pressure, and number of treatment arms to placebo/drug response and efficacy outcome measures. Results Like trials of other conditions, placebo response has risen significantly over time (R2 = 0.093, p = 0.018) and effect size (R2 = 0.013, p = 0.187) drug-placebo difference (R2 = 0.013, p = 0.182) and success rate (134/142, 94.4%) have remained unaffected, likely due to a significant compensatory increase in antihypertensive response (R2 = 0.086, p<0.001). Treatment arms are likely overpowered with sample sizes increasing over time (R2 = 0.387, p<0.0001) and stable, large effect sizes (0.78 ±0.37). The exploratory analysis of sample size, trial duration, baseline blood pressure, and number of treatment arms yielded mixed results unlikely to explain the pattern of placebo response and efficacy outcomes over time. The magnitude of placebo response had no relationship to effect size (p = 0.877), antihypertensive-placebo differences (p = 0.752), or p-values (p = 0.963) but was correlated with antihypertensive response (R2 = 0.347, p<0.0001). Conclusions As hypothesized, this study shows that placebo response is increasing in clinical trials for hypertension without any evidence of this increase impacting trial outcomes. Attempting to control placebo response in clinical trials for hypertension may not be necessary for successful efficacy outcomes. In exploratory analysis, we noted that despite finding significant relationships, none of the trial or patient characteristics we examined offered a clear explanation of the rise in placebo and stability in outcome measures over time. Collectively, these data suggest that the phenomenon of increasing placebo response and stable efficacy outcomes may be a general trend, occurring across trials for various psychiatric and medical conditions with physiological and non-physiological endpoints. PMID:29489874

Evaluation of the effect of tofacitinib on measured glomerular filtration rate in patients with active rheumatoid arthritis: results from a randomised controlled trial.

PubMed

Kremer, Joel M; Kivitz, Alan J; Simon-Campos, Jesus A; Nasonov, Evgeny L; Tony, Hans-Peter; Lee, Soo-Kon; Vlahos, Bonnie; Hammond, Constance; Bukowski, Jack; Li, Huihua; Schulman, Seth L; Raber, Susan; Zuckerman, Andrea; Isaacs, John D

2015-04-06

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). During the clinical development programme, increases in mean serum creatinine (SCr) of approximately 0.07 mg/dL and 0.08 mg/dL were observed which plateaued early. This study assessed changes in measured glomerular filtration rate (mGFR) with tofacitinib relative to placebo in patients with active RA. This was a randomised, placebo-controlled, Phase 1 study (NCT01484561). Patients were aged ≥18 years with active RA. Patients were randomised 2:1 to oral tofacitinib 10 mg twice daily (BID) in Period 1 then placebo BID in Period 2 (tofacitinib → placebo); or oral placebo BID in both Periods (placebo → placebo). Change in mGFR was evaluated by iohexol serum clearance at four time points (run-in, pre-dose in Period 1, Period 1 end, and Period 2 end). The primary endpoint was the change in mGFR from baseline to Period 1 end. Secondary endpoints included: change in mGFR at other time points; change in estimated GFR (eGFR; Cockcroft-Gault equation) and SCr; efficacy; and safety. 148 patients were randomised to tofacitinib → placebo (N = 97) or placebo → placebo (N = 51). Baseline characteristics were similar between groups. A reduction of 8% (90% confidence interval [CI]: 2%, 14%) from baseline in adjusted geometric mean mGFR was observed during tofacitinib treatment in Period 1 vs placebo. During Period 2, mean mGFR returned towards baseline during placebo treatment, and there was no difference between the two treatment groups at the end of the study--ratio (tofacitinib → placebo/placebo → placebo) of adjusted geometric mean fold change of mGFR was 1.04 (90% CI: 0.97, 1.11). Post-hoc analyses, focussed on mGFR variability in placebo → placebo patients, were consistent with this conclusion. At study end, similar results were observed for eGFR and SCr. Clinical efficacy and safety were consistent with prior studies. Increases in mean SCr and decreases in eGFR in tofacitinib-treated patients with RA may occur in parallel with decreases in mean mGFR; mGFR returned towards baseline after tofacitinib discontinuation, with no significant difference vs placebo, even after post-hoc analyses. Safety monitoring will continue in ongoing and future clinical studies and routine pharmacovigilance. Clinicaltrials.gov NCT01484561. Registered 30 November 2011.

Placebo Response and Practice Effects in Schizophrenia Cognition Trials.

PubMed

Keefe, Richard S E; Davis, Vicki G; Harvey, Philip D; Atkins, Alexandra S; Haig, George M; Hagino, Owen; Marder, Stephen; Hilt, Dana C; Umbricht, Daniel

2017-08-01

Patients' previous experience with performance-based cognitive tests in clinical trials for cognitive impairment associated with schizophrenia can create practice-related improvements. Placebo-controlled trials for cognitive impairment associated with schizophrenia are at risk for these practice effects, which can be difficult to distinguish from placebo effects. To conduct a systematic evaluation of the magnitude of practice effects on the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) in cognitive impairment associated with schizophrenia and to examine which demographic, clinical, and cognitive characteristics were associated with improvement in placebo conditions. A blinded review was conducted of data from 813 patients with schizophrenia who were treated with placebo in 12 randomized placebo-controlled clinical trials conducted mostly in outpatient clinics in North America, Europe, Asia, and Latin America from February 22, 2007, to March 1, 2014. A total of 779 patients provided data for the primary outcome measure at baseline and at least 1 follow-up. Seven trials had prebaseline assessments wherein the patients knew that they were not receiving treatment, allowing a comparison of practice and placebo effects in the same patients. Placebo compared with various experimental drug treatments. Composite score on the MCCB. Of the 813 patients in the study (260 women and 553 men; mean [SD] age, 41.2 [11.5] years), the mean MCCB composite score at baseline was 22.8 points below the normative mean, and the mean (SEM) total change in the MCCB during receipt of placebo was 1.8 (0.2) T-score points (95% CI, 1.40-2.18), equivalent to a change of 0.18 SD. Practice effects in the 7 studies in which there was a prebaseline assessment were essentially identical to the postbaseline placebo changes. Baseline factors associated with greater improvements in the MCCB during receipt of placebo included more depression/anxiety (F1,438 = 5.41; P = .02), more motivation (F1,272 = 4.63; P = .03), and less improvement from screening to baseline (F1,421 = 59.32; P < .001). Placebo effects were minimal and associated with the number of postbaseline assessments and several patient characteristics. Given that the patients performed 2.28 SDs below normative standards on average at baseline, a mean placebo-associated improvement of less than 0.2 SD provides evidence that ceiling effects do not occur in these trials. These minimal changes in the MCCB could not be responsible for effective active treatments failing to separate from placebo.

Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women.

PubMed

Asemi, Zatollah; Samimi, Mansooreh; Tabassi, Zohreh; Shakeri, Hossein; Esmaillzadeh, Ahmad

2013-09-01

Unfavorable metabolic profiles and oxidative stress in pregnancy are associated with several complications. This study was conducted to determine the effects of vitamin D supplementation on serum concentrations of high-sensitivity C-reactive protein (hs-CRP), metabolic profiles, and biomarkers of oxidative stress in healthy pregnant women. This randomized, double-blind, placebo-controlled clinical trial was conducted in 48 pregnant women aged 18-40 y old at 25 wk of gestation. Participants were randomly assigned to receive either 400 IU/d cholecalciferol supplements (n = 24) or placebo (n = 24) for 9 wk. Fasting blood samples were taken at study baseline and after 9 wk of intervention to quantify serum concentrations of hs-CRP, lipid concentrations, insulin, and biomarkers of oxidative stress. After 9 wk of intervention, the increases in serum 25-hydroxyvitamin D and calcium concentrations were greater in the vitamin D group (+3.7 μg/L and +0.20 mg/dL, respectively) than in the placebo group (-1.2 μg/L and -0.12 mg/dL, respectively; P < 0.001 for both). Vitamin D supplementation resulted in a significant decrease in serum hs-CRP (vitamin D vs. placebo groups: -1.41 vs. +1.50 μg/mL; P-interaction = 0.01) and insulin concentrations (vitamin D vs. placebo groups: -1.0 vs. +2.6 μIU/mL; P-interaction = 0.04) and a significant increase in the Quantitative Insulin Sensitivity Check Index score (vitamin D vs. placebo groups: +0.02 vs. -0.02; P-interaction = 0.006), plasma total antioxidant capacity (vitamin D vs. placebo groups: +152 vs. -20 mmol/L; P-interaction = 0.002), and total glutathione concentrations (vitamin D vs. placebo groups: +205 vs. -32 μmol/L; P-interaction = 0.02) compared with placebo. Intake of vitamin D supplements led to a significant decrease in fasting plasma glucose (vitamin D vs. placebo groups: -0.65 vs. -0.12 mmol/L; P-interaction = 0.01), systolic blood pressure (vitamin D vs. placebo groups: -0.2 vs. +5.5 mm Hg; P-interaction = 0.01), and diastolic blood pressure (vitamin D vs. placebo groups: -0.4 vs. +3.1 mm Hg; P-interaction = 0.01) compared with placebo. In conclusion, vitamin D supplementation for 9 wk among pregnant women has beneficial effects on metabolic status.

L-arginine and Vitamin D Adjunctive Therapies in Pulmonary Tuberculosis: A Randomised, Double-Blind, Placebo-Controlled Trial

PubMed Central

Ralph, Anna P.; Waramori, Govert; Pontororing, Gysje J.; Kenangalem, Enny; Wiguna, Andri; Tjitra, Emiliana; Sandjaja; Lolong, Dina B.; Yeo, Tsin W.; Chatfield, Mark D.; Soemanto, Retno K.; Bastian, Ivan; Lumb, Richard; Maguire, Graeme P.; Eisman, John; Price, Ric N.; Morris, Peter S.; Kelly, Paul M.; Anstey, Nicholas M.

2013-01-01

Background Vitamin D (vitD) and L-arginine have important antimycobacterial effects in humans. Adjunctive therapy with these agents has the potential to improve outcomes in active tuberculosis (TB). Methods In a 4-arm randomised, double-blind, placebo-controlled factorial trial in adults with smear-positive pulmonary tuberculosis (PTB) in Timika, Indonesia, we tested the effect of oral adjunctive vitD 50,000 IU 4-weekly or matching placebo, and L-arginine 6.0 g daily or matching placebo, for 8 weeks, on proportions of participants with negative 4-week sputum culture, and on an 8-week clinical score (weight, FEV1, cough, sputum, haemoptysis). All participants with available endpoints were included in analyses according to the study arm to which they were originally assigned. Adults with new smear-positive PTB were eligible. The trial was registered at ClinicalTrials.gov NCT00677339. Results 200 participants were enrolled, less than the intended sample size: 50 received L-arginine + active vitD, 49 received L-arginine + placebo vit D, 51 received placebo L-arginine + active vitD and 50 received placebo L-arginine + placebo vitD. According to the factorial model, 99 people received arginine, 101 placebo arginine, 101 vitamin D, 99 placebo vitamin D. Results for the primary endpoints were available in 155 (4-week culture) and 167 (clinical score) participants. Sputum culture conversion was achieved by week 4 in 48/76 (63%) participants in the active L-arginine versus 48/79 (61%) in placebo L-arginine arms (risk difference −3%, 95% CI −19 to 13%), and in 44/75 (59%) in the active vitD versus 52/80 (65%) in the placebo vitD arms (risk difference 7%, 95% CI −9 to 22%). The mean clinical outcome score also did not differ between study arms. There were no effects of the interventions on adverse event rates including hypercalcaemia, or other secondary outcomes. Conclusion Neither vitD nor L-arginine supplementation, at the doses administered and with the power attained, affected TB outcomes. Registry ClinicalTrials.gov. Registry number: NCT00677339 PMID:23967066

The paradox of sham therapy and placebo effect in osteopathy

PubMed Central

Cerritelli, Francesco; Verzella, Marco; Cicchitti, Luca; D’Alessandro, Giandomenico; Vanacore, Nicola

2016-01-01

Abstract Background: Placebo, defined as “false treatment,” is a common gold-standard method to assess the validity of a therapy both in pharmacological trials and manual medicine research where placebo is also referred to as “sham therapy.” In the medical literature, guidelines have been proposed on how to conduct robust placebo-controlled trials, but mainly in a drug-based scenario. In contrast, there are not precise guidelines on how to conduct a placebo-controlled in manual medicine trials (particularly osteopathy). The aim of the present systematic review was to report how and what type of sham methods, dosage, operator characteristics, and patient types were used in osteopathic clinical trials and, eventually, assess sham clinical effectiveness. Methods: A systematic Cochrane-based review was conducted by analyzing the osteopathic trials that used both manual and nonmanual placebo control. Searches were conducted on 8 databases from journal inception to December 2015 using a pragmatic literature search approach. Two independent reviewers conducted the study selection and data extraction for each study. The risk of bias was evaluated according to the Cochrane methods. Results: A total of 64 studies were eligible for analysis collecting a total of 5024 participants. More than half (43 studies) used a manual placebo; 9 studies used a nonmanual placebo; and 12 studies used both manual and nonmanual placebo. Data showed lack of reporting sham therapy information across studies. Risk of bias analysis demonstrated a high risk of bias for allocation, blinding of personnel and participants, selective, and other bias. To explore the clinical effects of sham therapies used, a quantitative analysis was planned. However, due to the high heterogeneity of sham approaches used no further analyses were performed. Conclusion: High heterogeneity regarding placebo used between studies, lack of reporting information on placebo methods and within-study variability between sham and real treatment procedures suggest prudence in reading and interpreting study findings in manual osteopathic randomized controlled trials (RCTs). Efforts must be made to promote guidelines to design the most reliable placebo for manual RCTs as a means of increasing the internal validity and improve external validity of findings. PMID:27583913

The paradox of sham therapy and placebo effect in osteopathy: A systematic review.

PubMed

Cerritelli, Francesco; Verzella, Marco; Cicchitti, Luca; D'Alessandro, Giandomenico; Vanacore, Nicola

2016-08-01

Placebo, defined as "false treatment," is a common gold-standard method to assess the validity of a therapy both in pharmacological trials and manual medicine research where placebo is also referred to as "sham therapy." In the medical literature, guidelines have been proposed on how to conduct robust placebo-controlled trials, but mainly in a drug-based scenario. In contrast, there are not precise guidelines on how to conduct a placebo-controlled in manual medicine trials (particularly osteopathy). The aim of the present systematic review was to report how and what type of sham methods, dosage, operator characteristics, and patient types were used in osteopathic clinical trials and, eventually, assess sham clinical effectiveness. A systematic Cochrane-based review was conducted by analyzing the osteopathic trials that used both manual and nonmanual placebo control. Searches were conducted on 8 databases from journal inception to December 2015 using a pragmatic literature search approach. Two independent reviewers conducted the study selection and data extraction for each study. The risk of bias was evaluated according to the Cochrane methods. A total of 64 studies were eligible for analysis collecting a total of 5024 participants. More than half (43 studies) used a manual placebo; 9 studies used a nonmanual placebo; and 12 studies used both manual and nonmanual placebo. Data showed lack of reporting sham therapy information across studies. Risk of bias analysis demonstrated a high risk of bias for allocation, blinding of personnel and participants, selective, and other bias. To explore the clinical effects of sham therapies used, a quantitative analysis was planned. However, due to the high heterogeneity of sham approaches used no further analyses were performed. High heterogeneity regarding placebo used between studies, lack of reporting information on placebo methods and within-study variability between sham and real treatment procedures suggest prudence in reading and interpreting study findings in manual osteopathic randomized controlled trials (RCTs). Efforts must be made to promote guidelines to design the most reliable placebo for manual RCTs as a means of increasing the internal validity and improve external validity of findings.

Are There Scenarios When the Use of Non-Placebo-Control Groups in Experimental Trial Designs Increase Expected Value to Society?

PubMed

Uyei, Jennifer; Braithwaite, R Scott

2016-01-01

Despite the benefits of the placebo-controlled trial design, it is limited by its inability to quantify total benefits and harms. Such trials, for example, are not designed to detect an intervention's placebo or nocebo effects, which if detected could alter the benefit-to-harm balance and change a decision to adopt or reject an intervention. In this article, we explore scenarios in which alternative experimental trial designs, which differ in the type of control used, influence expected value across a range of pretest assumptions and study sample sizes. We developed a decision model to compare 3 trial designs and their implications for decision making: 2-arm placebo-controlled trial ("placebo-control"), 2-arm intervention v. do nothing trial ("null-control"), and an innovative 3-arm trial design: intervention v. do nothing v. placebo trial ("novel design"). Four scenarios were explored regarding particular attributes of a hypothetical intervention: 1) all benefits and no harm, 2) no biological effect, 3) only biological effects, and 4) surreptitious harm (no biological benefit or nocebo effect). Scenario 1: When sample sizes were very small, the null-control was preferred, but as sample sizes increased, expected value of all 3 designs converged. Scenario 2: The null-control was preferred regardless of sample size when the ratio of placebo to nocebo effect was >1; otherwise, the placebo-control was preferred. Scenario 3: When sample size was very small, the placebo-control was preferred when benefits outweighed harms, but the novel design was preferred when harms outweighed benefits. Scenario 4: The placebo-control was preferred when harms outweighed placebo benefits; otherwise, preference went to the null-control. Scenarios are hypothetical, study designs have not been tested in a real-world setting, blinding is not possible in all designs, and some may argue the novel design poses ethical concerns. We identified scenarios in which alternative experimental study designs would confer greater expected value than the placebo-controlled trial design. The likelihood and prevalence of such situations warrant further study. © The Author(s) 2015.

L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial.

PubMed

Ralph, Anna P; Waramori, Govert; Pontororing, Gysje J; Kenangalem, Enny; Wiguna, Andri; Tjitra, Emiliana; Sandjaja; Lolong, Dina B; Yeo, Tsin W; Chatfield, Mark D; Soemanto, Retno K; Bastian, Ivan; Lumb, Richard; Maguire, Graeme P; Eisman, John; Price, Ric N; Morris, Peter S; Kelly, Paul M; Anstey, Nicholas M

2013-01-01

Vitamin D (vitD) and L-arginine have important antimycobacterial effects in humans. Adjunctive therapy with these agents has the potential to improve outcomes in active tuberculosis (TB). In a 4-arm randomised, double-blind, placebo-controlled factorial trial in adults with smear-positive pulmonary tuberculosis (PTB) in Timika, Indonesia, we tested the effect of oral adjunctive vitD 50,000 IU 4-weekly or matching placebo, and L-arginine 6.0 g daily or matching placebo, for 8 weeks, on proportions of participants with negative 4-week sputum culture, and on an 8-week clinical score (weight, FEV1, cough, sputum, haemoptysis). All participants with available endpoints were included in analyses according to the study arm to which they were originally assigned. Adults with new smear-positive PTB were eligible. The trial was registered at ClinicalTrials.gov NCT00677339. 200 participants were enrolled, less than the intended sample size: 50 received L-arginine + active vitD, 49 received L-arginine + placebo vit D, 51 received placebo L-arginine + active vitD and 50 received placebo L-arginine + placebo vitD. According to the factorial model, 99 people received arginine, 101 placebo arginine, 101 vitamin D, 99 placebo vitamin D. Results for the primary endpoints were available in 155 (4-week culture) and 167 (clinical score) participants. Sputum culture conversion was achieved by week 4 in 48/76 (63%) participants in the active L-arginine versus 48/79 (61%) in placebo L-arginine arms (risk difference -3%, 95% CI -19 to 13%), and in 44/75 (59%) in the active vitD versus 52/80 (65%) in the placebo vitD arms (risk difference 7%, 95% CI -9 to 22%). The mean clinical outcome score also did not differ between study arms. There were no effects of the interventions on adverse event rates including hypercalcaemia, or other secondary outcomes. Neither vitD nor L-arginine supplementation, at the doses administered and with the power attained, affected TB outcomes. ClinicalTrials.gov. Registry number: NCT00677339.

Treatment satisfaction with tadalafil or tamsulosin vs placebo in men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH): results from a randomised, placebo-controlled study.

PubMed

Oelke, Matthias; Giuliano, François; Baygani, Simin K; Melby, Thomas; Sontag, Angelina

2014-10-01

To assess treatment satisfaction with tadalafil or tamsulosin vs placebo in a 12-week, randomised, double-blind study of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH). After a 4-week placebo lead-in period, men aged ≥45 years with an International Prostate Symptom Score (IPSS) of ≥13 and a maximum urinary flow rate of ≥4 to ≤15 mL/s received placebo (172 men), tadalafil 5 mg (171), or tamsulosin 0.4 mg (168) once daily for 12 weeks. Treatment Satisfaction Scale-BPH (TSS-BPH) responses were assessed based on median treatment differences using the van Elteren test. Overall treatment satisfaction was greater for tadalafil vs placebo (P = 0.005), based on greater satisfaction with efficacy (P = 0.003); neither overall treatment satisfaction nor satisfaction with efficacy was greater for tamsulosin vs placebo (P ≥ 0.409). For individual questions, 66.5% of men rated tadalafil treatment as 'effective/very effective' (Question 1, Q1) vs placebo (P = 0.011), 72.6% would 'definitely/probably recommend their treatment' (Q3; P = 0.043), 71.8% were generally 'very satisfied/satisfied with their medication' (Q8; P < 0.003), and 65.0% would 'definitely/probably continue therapy' (Q10; P = 0.035). With tamsulosin, differences vs placebo were not statistically significant. Subgroup analyses of overall TSS-BPH by baseline age (≤65/>65 years), history of erectile dysfunction (yes/no), LUTS/BPH severity (IPSS

Effects of placebos without deception compared with no treatment: protocol for a systematic review and meta-analysis.

PubMed

Petkovic, Grace; Charlesworth, James E G; Kelley, John; Miller, Franklin; Roberts, Nia; Howick, Jeremy

2015-11-26

Placebos have long provided a robust control for evaluating active pharmacological preparations, but frequently demonstrate a variable therapeutic effect when delivered in double-blinded placebo-controlled trials. Delivery of placebos as treatment alone has been considered unethical, as it has been thought that deception is essential for their effect. However, recent evidence suggests that clinical benefit can be derived from placebos delivered without deception (unblinded/open-label) manner. Here, we present a protocol for the first systematic review and meta-analysis of studies of the effects of non-deceptive placebos compared with no treatment. This protocol will compare the effect of placebos delivered non-deceptively to no treatment. It will also assess the methods of delivery used for non-deceptive placebos. Studies will be sought through relevant database searches and will include those within disease settings and those among healthy controls. To be included, trials must include both non-deceptive (open-label) placebo and no treatment groups. All data extraction and analysis will be conducted by two independent reviewers. The analysis will evaluate any differences in outcome measures between the non-deceptive placebo and no treatment groups. Outcome measures will be the clinically-relevant outcomes detailed in the primary papers. The delivery methods, such as verbal instructions, which may provide positive expectations and outcomes, of non-deceptive placebos will also be assessed. Each study will be comprehensively assessed for bias. Subgroup analyses will identify any discrepancies among heterogeneous data. This review does not require ethical approval. The completed review will be widely disseminated by publication and social media where appropriate. This protocol has been registered on PROSPERO (2015:CRD42015023347). Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Randomized trial of the effect of drug presentation on asthma outcomes: the American Lung Association Asthma Clinical Research Centers.

PubMed

Wise, Robert A; Bartlett, Susan J; Brown, Ellen D; Castro, Mario; Cohen, Rubin; Holbrook, Janet T; Irvin, Charles G; Rand, Cynthia S; Sockrider, Marianna M; Sugar, Elizabeth A

2009-09-01

Information that enhances expectations about drug effectiveness improves the response to placebos for pain. Although asthma symptoms often improve with placebo, it is not known whether the response to placebo or active treatment can be augmented by increasing expectation of benefit. The study objective was to determine whether response to placebo or a leukotriene antagonist (montelukast) can be augmented by messages that increase expectation of benefit. A randomized 20-center controlled trial enrolled 601 asthmatic patients with poor symptom control who were assigned to one of 5 study groups. Participants were randomly assigned to one of 4 treatment groups in a factorial design (ie, placebo with enhanced messages, placebo with neutral messages, montelukast with enhanced messages, or montelukast with neutral messages) or to usual care. Assignment to study drug was double masked, assignment to message content was single masked, and usual care was not masked. The enhanced message aimed to increase expectation of benefit from the drug. The primary outcome was mean change in daily peak flow over 4 weeks. Secondary outcomes included lung function and asthma symptom control. Peak flow and other lung function measures were not improved in participants assigned to the enhanced message groups versus the neutral messages groups for either montelukast or placebo; no differences were noted between the neutral placebo and usual care groups. Placebo-treated participants had improved asthma control with the enhanced message but not montelukast-treated participants; the neutral placebo group did have improved asthma control compared with the usual care group after adjusting for baseline difference. Headaches were more common in participants provided messages that mentioned headache as a montelukast side effect. Optimistic drug presentation augments the placebo effect for patient-reported outcomes (asthma control) but not lung function. However, the effect of montelukast was not enhanced by optimistic messages regarding treatment effectiveness.

Informing Patients About Placebo Effects: Using Evidence, Theory, and Qualitative Methods to Develop a New Website.

PubMed

Greville-Harris, Maddy; Bostock, Jennifer; Din, Amy; Graham, Cynthia A; Lewith, George; Liossi, Christina; O'Riordan, Tim; White, Peter; Yardley, Lucy; Bishop, Felicity L

2016-06-10

According to established ethical principles and guidelines, patients in clinical trials should be fully informed about the interventions they might receive. However, information about placebo-controlled clinical trials typically focuses on the new intervention being tested and provides limited and at times misleading information about placebos. We aimed to create an informative, scientifically accurate, and engaging website that could be used to improve understanding of placebo effects among patients who might be considering taking part in a placebo-controlled clinical trial. Our approach drew on evidence-, theory-, and person-based intervention development. We used existing evidence and theory about placebo effects to develop content that was scientifically accurate. We used existing evidence and theory of health behavior to ensure our content would be communicated persuasively, to an audience who might currently be ignorant or misinformed about placebo effects. A qualitative 'think aloud' study was conducted in which 10 participants viewed prototypes of the website and spoke their thoughts out loud in the presence of a researcher. The website provides information about 10 key topics and uses text, evidence summaries, quizzes, audio clips of patients' stories, and a short film to convey key messages. Comments from participants in the think aloud study highlighted occasional misunderstandings and off-putting/confusing features. These were addressed by modifying elements of content, style, and navigation to improve participants' experiences of using the website. We have developed an evidence-based website that incorporates theory-based techniques to inform members of the public about placebos and placebo effects. Qualitative research ensured our website was engaging and convincing for our target audience who might not perceive a need to learn about placebo effects. Before using the website in clinical trials, it is necessary to test its effects on key outcomes including patients' knowledge and capacity for making informed choices about placebos.

Effect of Apixaban on All-Cause Death in Patients with Atrial Fibrillation: a Meta-Analysis Based on Imputed Placebo Effect.

PubMed

Guimarães, Patrícia O; Lopes, Renato D; Wojdyla, Daniel M; Abdul-Rahim, Azmil H; Connolly, Stuart J; Flaker, Greg C; Wang, Junyuan; Hanna, Michael; Granger, Christopher B; Wallentin, Lars; Lees, Kennedy R; Alexander, John H; McMurray, John J V

2017-06-01

Vitamin K antagonists (VKAs) are the standard of care for stroke prevention in patients with atrial fibrillation (AF); therefore, there is not equipoise when comparing newer oral anticoagulants with placebo in this setting. To explore the effect of apixaban on mortality in patients with AF, we performed a meta-analysis of apixaban versus placebo using a putative placebo analysis based on randomized controlled clinical trials that compared warfarin, aspirin, and no antithrombotic control. We used data from two prospective randomized controlled trials for our comparison of apixaban versus warfarin (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) and apixaban versus aspirin (Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment). Using meta-analysis approaches, we indirectly compared apixaban with an imputed placebo with respect to the risk of death in patients with AF. We used results from meta-analyses of randomized trials as our reference for the comparison between warfarin and placebo/no treatment, and aspirin and placebo/no treatment. In these meta-analyses, a lower rate of death was seen both with warfarin (odds ratio [OR] 0.74, 95% confidence interval [CI] 0.57-0.97) and aspirin (OR 0.86, 95% CI 0.69-1.07) versus placebo/no treatment. Using data from ARISTOTLE and AVERROES, apixaban reduced the risk of death by 34% (95% CI 12-50%; p = 0.004) and 33% (95% CI 6-52%; p = 0.02), respectively, when compared with an imputed placebo. The pooled reduction in all-cause death with apixaban compared with an imputed placebo was 34% (95% CI 18-47%; p = 0.0002). In patients with AF, indirect comparisons suggest that apixaban reduces all-cause death by approximately one third compared with an imputed placebo.

Impact of daily Chlorella consumption on serum lipid and carotenoid profiles in mildly hypercholesterolemic adults: a double-blinded, randomized, placebo-controlled study

PubMed Central

2014-01-01

Background High level of serum cholesterol is considered to be a major risk factor for cardiovascular disease (CVD). A double-blinded, randomized, placebo-controlled trial was performed to test the hypothesis that a daily intake of Chlorella may improve serum lipid profile through enhancement of serum carotenoid concentration in mildly hypercholesterolemic subjects. Methods Eligible subjects (n = 63) were randomized to either Chlorella (5 g/day) or placebo for a double-blinded trial with a 2-week lead-in period and a 4-week intervention period. Serum triglycerides, total cholesterol, lipoproteins, apolipoproteins and carotenoids were assessed at the beginning and the end of the trial. Results Compared with the control group, the Chlorella group exhibited remarkable changes in total cholesterol (Chlorella −1.6%; placebo 0.03%; P = 0.036), triglycerides (Chlorella −10.3%; placebo 11.9%; P = 0.002), lutein/zeaxanthin (Chlorella 89.6%; placebo −1.7%; P < 0.0001), and α-carotene (Chlorella 163.6%; placebo 15%; P < 0.0001). Improvement of serum lipids was supported by significant reductions of very low-density lipoprotein cholesterol (Chlorella −11%; placebo 11.8%; P = 0.006), apolipoprotein B (Chlorella −1.5%; placebo 1.7%; P = 0.044), non high-density lipoprotein (Chlorella −2.6%; placebo −0.5%; P = 0.032), and high-density lipoprotein/triglycerides (Chlorella 4.0%; placebo −9.5%; P = 0.023), suggesting an inhibitory effect of Chlorella on the intestinal absorption of dietary and endogenous lipids. Further, the changes of serum lipids appeared to be associated with the changes of serum carotenoids. Conclusion Daily consumption of Chlorella supplements provided the potential of health benefits reducing serum lipid risk factors, mainly triglycerides and total cholesterol, in mildly hypercholesterolemic subjects. The effect was related to carotenoid consumption. Trial registration WHO International Clinical Trials Registry Platform KCT0000259. PMID:24920270

Expectancy-induced placebo analgesia in children and the role of magical thinking.

PubMed

Krummenacher, Peter; Kossowsky, Joe; Schwarz, Caroline; Brugger, Peter; Kelley, John M; Meyer, Andrea; Gaab, Jens

2014-12-01

Expectations and beliefs shape the experience of pain. This is most evident in context-induced, placebo analgesia, which has recently been shown to interact with the trait of magical thinking (MT) in adults. In children, placebo analgesia and the possible roles that MT and gender might play as modulators of placebo analgesia have remained unexplored. Using a paradigm in which heat pain stimuli were applied to both forearms, we investigated whether MT and gender can influence the magnitude of placebo analgesia in children. Participants were 49 right-handed children (aged 6-9 years) who were randomly assigned-stratified for MT and gender-to either an analgesia-expectation or a control-expectation condition. For both conditions, the placebo was a blue-colored hand disinfectant that was applied to the children's forearms. Independent of MT, the placebo treatment significantly increased both heat pain threshold and tolerance. The threshold placebo effect was more pronounced for girls than boys. In addition, independent of the expectation treatment, low-MT boys showed a lower tolerance increase on the left compared to the right side. Finally, MT specifically modulated tolerance on the right forearm side: Low-MT boys showed an increase, whereas high-MT boys showed a decrease in heat pain tolerance. This study documented a substantial expectation-induced placebo analgesia response in children (girls > boys) and demonstrated MT and gender-dependent laterality effects in pain perception. The findings may help improve individualized pain management for children. The study documents the first experimental evidence for a substantial expectancy-induced placebo analgesia response in healthy children aged 6 to 9 years (girls > boys). Moreover, the effect was substantially higher than the placebo response typically found in adults. The findings may help improve individualized pain management for children. Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.

Heartburn treatment in primary care: randomised, double blind study for 8 weeks

PubMed Central

Hatlebakk, Jan G; Hyggen, Arild; Madsen, Per H; Walle, Per O; Schulz, Tom; Mowinckel, Petter; Bernklev, Tomm; Berstad, Arnold

1999-01-01

Objective To compare the effects and tolerability of omeprazole and cisapride with that of placebo for control of heartburn in primary care patients. Design Randomised, double blind, placebo controlled study. Setting 65 primary care practices in Norway. Participants 483 untreated patients with complaints of heartburn ⩾3 days a week, with at most grade 1 reflux oesophagitis. Interventions Omeprazole 20 mg once daily, cisapride 20 mg twice daily, or placebo for 8 weeks. Main outcome measures Adequate control of heartburn, defined as ⩽1 day of the past 7 days with no more than mild heartburn, after 4 weeks of treatment. Results In the all patients treated analysis, adequate control of heartburn was achieved in 71% of patients taking omeprazole, 22% taking cisapride, and 18% taking placebo after 4 weeks of treatment (omeprazole v cisapride and placebo, P<0.0001; cisapride v placebo, non-significant). Results were comparable in patients with or without reflux oesophagitis. In patients treated with omeprazole only, symptom control was achieved significantly more often in patients positive for Helicobacter pylori. Antacid use was 2-3 times greater in patients taking cisapride or placebo than in those taking omeprazole. Relief of non-reflux symptoms did not significantly differ between the three groups. Significantly more patients taking cisapride reported adverse events than those taking omeprazole or placebo. Conclusions Omeprazole 20 mg once daily was highly effective in relieving heartburn whereas cisapride 20 mg twice daily was not significantly more effective than placebo. Key messagesIn primary care patients, heartburn is commonly treated empiricallyMost randomised clinical trials of treatment for heartburn have been conducted in specialist care, and documentation for empirical treatment is limitedOmeprazole was significantly more effective than cisapride or placebo in controlling heartburn and other symptoms of gastro-oesophageal reflux after 2, 4, and 8 weeks, whereas cisapride did not differ significantly from placeboOmeprazole should be considered as a first choice for empirical treatment of heartburn in primary care PMID:10463897

Informing Patients About Placebo Effects: Using Evidence, Theory, and Qualitative Methods to Develop a New Website

PubMed Central

Greville-Harris, Maddy; Bostock, Jennifer; Din, Amy; Graham, Cynthia A; Lewith, George; Liossi, Christina; O’Riordan, Tim; White, Peter; Yardley, Lucy

2016-01-01

Background According to established ethical principles and guidelines, patients in clinical trials should be fully informed about the interventions they might receive. However, information about placebo-controlled clinical trials typically focuses on the new intervention being tested and provides limited and at times misleading information about placebos. Objective We aimed to create an informative, scientifically accurate, and engaging website that could be used to improve understanding of placebo effects among patients who might be considering taking part in a placebo-controlled clinical trial. Methods Our approach drew on evidence-, theory-, and person-based intervention development. We used existing evidence and theory about placebo effects to develop content that was scientifically accurate. We used existing evidence and theory of health behavior to ensure our content would be communicated persuasively, to an audience who might currently be ignorant or misinformed about placebo effects. A qualitative ‘think aloud’ study was conducted in which 10 participants viewed prototypes of the website and spoke their thoughts out loud in the presence of a researcher. Results The website provides information about 10 key topics and uses text, evidence summaries, quizzes, audio clips of patients’ stories, and a short film to convey key messages. Comments from participants in the think aloud study highlighted occasional misunderstandings and off-putting/confusing features. These were addressed by modifying elements of content, style, and navigation to improve participants’ experiences of using the website. Conclusions We have developed an evidence-based website that incorporates theory-based techniques to inform members of the public about placebos and placebo effects. Qualitative research ensured our website was engaging and convincing for our target audience who might not perceive a need to learn about placebo effects. Before using the website in clinical trials, it is necessary to test its effects on key outcomes including patients’ knowledge and capacity for making informed choices about placebos. PMID:27288271

Impact of daily Chlorella consumption on serum lipid and carotenoid profiles in mildly hypercholesterolemic adults: a double-blinded, randomized, placebo-controlled study.

PubMed

Ryu, Na Hee; Lim, Yeni; Park, Ji Eeun; Kim, Joohee; Kim, Ji Yeon; Kwon, Sung Won; Kwon, Oran

2014-06-11

High level of serum cholesterol is considered to be a major risk factor for cardiovascular disease (CVD). A double-blinded, randomized, placebo-controlled trial was performed to test the hypothesis that a daily intake of Chlorella may improve serum lipid profile through enhancement of serum carotenoid concentration in mildly hypercholesterolemic subjects. Eligible subjects (n = 63) were randomized to either Chlorella (5 g/day) or placebo for a double-blinded trial with a 2-week lead-in period and a 4-week intervention period. Serum triglycerides, total cholesterol, lipoproteins, apolipoproteins and carotenoids were assessed at the beginning and the end of the trial. Compared with the control group, the Chlorella group exhibited remarkable changes in total cholesterol (Chlorella -1.6%; placebo 0.03%; P = 0.036), triglycerides (Chlorella -10.3%; placebo 11.9%; P = 0.002), lutein/zeaxanthin (Chlorella 89.6%; placebo -1.7%; P < 0.0001), and α-carotene (Chlorella 163.6%; placebo 15%; P < 0.0001). Improvement of serum lipids was supported by significant reductions of very low-density lipoprotein cholesterol (Chlorella -11%; placebo 11.8%; P = 0.006), apolipoprotein B (Chlorella -1.5%; placebo 1.7%; P = 0.044), non high-density lipoprotein (Chlorella -2.6%; placebo -0.5%; P = 0.032), and high-density lipoprotein/triglycerides (Chlorella 4.0%; placebo -9.5%; P = 0.023), suggesting an inhibitory effect of Chlorella on the intestinal absorption of dietary and endogenous lipids. Further, the changes of serum lipids appeared to be associated with the changes of serum carotenoids. Daily consumption of Chlorella supplements provided the potential of health benefits reducing serum lipid risk factors, mainly triglycerides and total cholesterol, in mildly hypercholesterolemic subjects. The effect was related to carotenoid consumption. WHO International Clinical Trials Registry Platform KCT0000259.

The effects of intranasal esketamine (84 mg) and oral mirtazapine (30 mg) on on-road driving performance: a double-blind, placebo-controlled study.

PubMed

van de Loo, Aurora J A E; Bervoets, Adriana C; Mooren, Loes; Bouwmeester, Noor H; Garssen, Johan; Zuiker, Rob; van Amerongen, Guido; van Gerven, Joop; Singh, Jaskaran; der Ark, Peter Van; Fedgchin, Maggie; Morrison, Randall; Wajs, Ewa; Verster, Joris C

2017-11-01

The purpose of this study is to evaluate the single dose effect of intranasal esketamine (84 mg) compared to placebo on on-road driving performance. Mirtazapine (oral, 30 mg) was used as a positive control, as this antidepressant drug is known to negatively affect driving performance. Twenty-six healthy volunteers aged 21 to 60 years were enrolled in this study. In the evening, 8 h after treatment administration, participants conducted the standardized 100-km on-road driving test. Primary outcome measure was the standard deviation of lateral position (SDLP), i.e., the weaving of the car. Mean lateral position, mean speed, and standard deviation of speed were secondary outcome measures. For SDLP, non-inferiority analyses were conducted, using +2.4 cm (relative to placebo) as a predefined non-inferiority margin for clinical relevant impairment. Twenty-four participants completed the study. No significant SDLP difference was found between esketamine and placebo (p = 0.7638), whereas the SDLP after mirtazapine was significantly higher when compared to placebo (p = 0.0001). The upper limit of the two-sided 95% confidence interval (CI) of the mean difference between esketamine and placebo was +0.86 cm, i.e., <+2.4 cm, thus demonstrating that esketamine was non-inferior to placebo. Non-inferiority could not be concluded for mirtazapine (+3.15 cm SDLP relative to placebo). No significant differences in mean speed, standard deviation of speed, and mean lateral position were observed between the active treatments and placebo. No significant difference in driving performance was observed 8 h after administering intranasal esketamine (84 mg) or placebo. In contrast, oral mirtazapine (30 mg) significantly impaired on road driving performance.

Prolonged Follow-Up of Patients in the U.S. Multicenter Trial of Ursodeoxycholic Acid for Primary Biliary Cirrhosis

PubMed Central

Combes, Burton; Luketic, Velimir A.; Peters, Marion G.; Zetterman, Rowen K.; Garcia-Tsao, Guadalupe; Munoz, Santiago J.; Lin, Danyu; Flye, Nancy; Carithers, Robert L.

2013-01-01

OBJECTIVE Randomized, double-blind, placebo-controlled trials of ursodeoxycholic acid (UDCA) in patients with primary biliary cirrhosis (PBC) have not demonstrated improvement in survival during the placebo-controlled phases of these trials. Analyses purporting to demonstrate a survival advantage of UDCA are largely dependent on data obtained after the placebo phases were terminated, and placebo-treated patients were offered open-label UDCA. After completion of our 2-yr placebo-controlled trial of UDCA in which we observed no survival benefit for UDCA, we provided the patients with open-label UDCA to see if delay in providing UDCA for 2 yr had any effect on subsequent liver transplantation or death without liver transplantation. METHODS In our previously reported 2-yr placebo-controlled trial, 151 patients with PBC were randomized to receive either UDCA (n = 77) or placebo (n = 74). The number of patients who progressed to liver transplantation or death without transplantation were similar in both the groups, 12 (16%) in the UDCA-treated and 11 (15%) in placebo-treated patients. All the patients were then offered open-label UDCA, with 61 original UDCA and 56 original placebo-treated patients now taking UDCA in an extended open-label phase of the trial. RESULTS No significant differences were observed in the number of patients who underwent liver transplantation or died without liver transplantation in the open-label phase of the trial. Moreover, no difference in the time to these endpoints was seen over the period of observation of as long as 6 yr from the time of initial randomization. CONCLUSIONS Results of open-label extensions of previous conducted placebo-controlled trials of UDCA in PBC leave uncertain whether UDCA impacts significantly on liver transplantation and death without liver transplantation in patients with PBC. PMID:15046215

Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses.

PubMed

Scott, David J; Stohler, Christian S; Egnatuk, Christine M; Wang, Heng; Koeppe, Robert A; Zubieta, Jon-Kar

2008-02-01

Placebo and nocebo effects, the therapeutic and adverse effects, respectively, of inert substances or sham procedures, represent serious confounds in the evaluation of therapeutic interventions. They are also an example of cognitive processes, particularly expectations, capable of influencing physiology. To examine the contribution of 2 different neurotransmitters, the endogenous opioid and the dopaminergic (DA) systems, to the development of placebo and nocebo effects. Using a within-subject design, subjects twice underwent a 20-minute standardized pain challenge, in the absence and presence of a placebo with expected analgesic properties. Studies were conducted in a university hospital setting. Twenty healthy men and women aged 20 to 30 years recruited by advertisement. Activation of DA and opioid neurotransmission by a pain stressor with and without placebo (changes in the binding potential of carbon 11 [11C]-labeled raclopride and [11C] carfentanil with positron emission tomography) and ratings of pain, affective state, and anticipation and perception of analgesia. Placebo-induced activation of opioid neurotransmission was detected in the anterior cingulate, orbitofrontal and insular cortices, nucleus accumbens, amygdala, and periaqueductal gray matter. Dopaminergic activation was observed in the ventral basal ganglia, including the nucleus accumbens. Regional DA and opioid activity were associated with the anticipated and subjectively perceived effectiveness of the placebo and reductions in continuous pain ratings. High placebo responses were associated with greater DA and opioid activity in the nucleus accumbens. Nocebo responses were associated with a deactivation of DA and opioid release. Nucleus accumbens DA release accounted for 25% of the variance in placebo analgesic effects. Placebo and nocebo effects are associated with opposite responses of DA and endogenous opioid neurotransmission in a distributed network of regions. The brain areas involved in these phenomena form part of the circuit typically implicated in reward responses and motivated behavior.

Double-blind, placebo-controlled study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder.

PubMed

Adler, Lenard A; Goodman, David W; Kollins, Scott H; Weisler, Richard H; Krishnan, Suma; Zhang, Yuxin; Biederman, Joseph

2008-09-01

To evaluate the efficacy and safety of 30, 50, and 70 mg/day lisdexamfetamine dimesylate compared with placebo in adults with attention-deficit/hyperactivity disorder (ADHD). Following a 7- to 28-day washout, 420 adults aged 18 to 55 years with moderate to severe ADHD (DSM-IV-TR criteria) were treated with 30, 50, or 70 mg/day lisdexamfetamine or placebo, respectively, for 4 weeks (N = 119, 117, 122, and 62, respectively). The 50- and 70- mg/day groups underwent forced-dose titration. The primary efficacy measure was the clinician-determined ADHD Rating Scale (ADHD-RS) total score. The study was conducted from May 2006 to November 2006. Treatment groups were well matched at baseline, including in ADHD-RS scores. At endpoint, changes in ADHD-RS scores were significantly greater for each lisdexamfetamine dose than for placebo (placebo = -8.2, 30 mg/day lisdexamfetamine = -16.2, 50 mg/day lisdexamfetamine = -17.4, 70 mg/day lisdexamfetamine = -18.6; all p < .0001 vs. placebo), with no differences between doses. Significant differences relative to placebo were observed in each lisdexamfetamine group, beginning at week 1 and for each week throughout. The percentage of subjects who improved (Clinical Global Impressions-Improvement scale rating < or = 2) was significantly greater for each lisdexamfetamine dose than for placebo at each week and at endpoint (placebo = 29%, 30 mg/day lisdexamfetamine = 57%, 50 mg/day lisdexamfetamine = 62%, 70 mg/day lisdexamfetamine = 61%; all p < .01). Adverse events were generally mild and included dry mouth, decreased appetite, and insomnia. All 3 lisdexamfetamine doses were significantly more effective than placebo in the treatment of adults with ADHD, with improvements noted within 1 week. Lisdexamfetamine was generally well tolerated by these patients. Copyright 2008 Physicians Postgraduate Press, Inc.

A Machine Learning Approach to Identifying Placebo Responders in Late-Life Depression Trials.

PubMed

Zilcha-Mano, Sigal; Roose, Steven P; Brown, Patrick J; Rutherford, Bret R

2018-01-11

Despite efforts to identify characteristics associated with medication-placebo differences in antidepressant trials, few consistent findings have emerged to guide participant selection in drug development settings and differential therapeutics in clinical practice. Limitations in the methodologies used, particularly searching for a single moderator while treating all other variables as noise, may partially explain the failure to generate consistent results. The present study tested whether interactions between pretreatment patient characteristics, rather than a single-variable solution, may better predict who is most likely to benefit from placebo versus medication. Data were analyzed from 174 patients aged 75 years and older with unipolar depression who were randomly assigned to citalopram or placebo. Model-based recursive partitioning analysis was conducted to identify the most robust significant moderators of placebo versus citalopram response. The greatest signal detection between medication and placebo in favor of medication was among patients with fewer years of education (≤12) who suffered from a longer duration of depression since their first episode (>3.47 years) (B = 2.53, t(32) = 3.01, p = 0.004). Compared with medication, placebo had the greatest response for those who were more educated (>12 years), to the point where placebo almost outperformed medication (B = -0.57, t(96) = -1.90, p = 0.06). Machine learning approaches capable of evaluating the contributions of multiple predictor variables may be a promising methodology for identifying placebo versus medication responders. Duration of depression and education should be considered in the efforts to modulate placebo magnitude in drug development settings and in clinical practice. Copyright © 2018 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Quantifying the placebo effect in psychological outcomes of exercise training: a meta-analysis of randomized trials.

PubMed

Lindheimer, Jacob B; O'Connor, Patrick J; Dishman, Rod K

2015-05-01

The placebo effect could account for some or all of the psychological benefits attributed to exercise training. The magnitude of the placebo effect in psychological outcomes of randomized controlled exercise training trials has not been quantified. The aim of this investigation was to estimate the magnitude of the population placebo effect in psychological outcomes from placebo conditions used in exercise training studies and compare it to the observed effect of exercise training. Articles published before 1 July 2013 were located using Google Scholar, MEDLINE, PsycINFO, and The Cochrane Library. To be included in the analysis, studies were required to have (1) a design that randomly assigned participants to exercise training, placebo, and control conditions and (2) an assessment of a subjective (i.e., anxiety, depression, energy, fatigue) or an objective (i.e., cognitive) psychological outcome. Meta-analytic and multi-level modeling techniques were used to analyze effects from nine studies involving 661 participants. Hedges' d effect sizes were calculated, and random effects models were used to estimate the overall magnitude of the placebo and exercise training effects. After adjusting for nesting effects, the placebo mean effect size was 0.20 (95% confidence interval [CI] -0.02, 0.41) and the observed effect of exercise training was 0.37 (95% CI 0.11, 0.63). A small body of research suggests both that (1) the placebo effect is approximately half of the observed psychological benefits of exercise training and (2) there is an urgent need for creative research specifically aimed at better understanding the role of the placebo effect in the mental health consequences of exercise training.

EDTA Chelation Therapy Alone and in Combination with Oral High-Dose Multivitamins and Minerals for Coronary Disease: The Factorial Group Results of the Trial to Assess Chelation Therapy

PubMed Central

Lamas, Gervasio A.; Boineau, Robin; Goertz, Christine; Mark, Daniel B.; Rosenberg, Yves; Stylianou, Mario; Rozema, Theodore; Nahin, Richard L.; Chappell, L. Terry; Lindblad, Lauren; Lewis, Eldrin F.; Drisko, Jeanne; Lee, Kerry L.

2014-01-01

Background Disodium ethylene diamine tetraacetic acid (EDTA) reduced adverse cardiac outcomes in a factorial trial also testing oral vitamins. Objective This report describes the intent-to-treat comparison of the 4 factorial groups overall and in patients with diabetes. Methods Double-blind placebo-controlled 2 × 2 factorial multicenter randomized trial of 1708 post-MI patients ≥ 50 years and creatinine ≤2.0 mg/dL randomized to receive 40 EDTA chelation or placebo infusions plus 6 caplets daily of a 28-component multivitaminmultimineral mixture or placebo. Primary endpoint was a composite of total mortality, MI, stroke, coronary revascularization, or hospitalization for angina. Results Median age was 65 years, 18% female, 94% Caucasian, 37% diabetic, 83% prior coronary revascularization, and 73% on statins. Five-year Kaplan-Meier estimates for the primary endpoint in the chelation + high-dose vitamin group was 31.9%, in the chelation + placebo vitamin group 33.7%, in the placebo infusion + active vitamin group 36.6%, and in the placebo infusions + placebo vitamin group 40.2 %. The reduction in primary endpoint by double active treatment compared with double placebo was significant (HR 0.74, 95% CI (0.57,0.95); p=0.016). In patients with diabetes, the primary endpoint reduction of double active compared with double placebo was more pronounced (HR 0.49, 95% CI (0.33,0.75), p<0.001). Conclusions In stable post- MI patients on evidence-based medical therapy, the combination of oral high-dose vitamins and chelation therapy compared with double placebo reduced clinically important cardiovascular events to an extent that was both statistically significant and of potential clinical relevance. PMID:24952858

Effect of opicapone multiple-dose regimens on levodopa pharmacokinetics.

PubMed

Rocha, José-Francisco; Sicard, Éric; Fauchoux, Nicolas; Falcão, Amílcar; Santos, Ana; Loureiro, Ana I; Pinto, Roberto; Bonifácio, Maria João; Nunes, Teresa; Almeida, Luís; Soares-da-Silva, Patrício

2017-03-01

To compare the levodopa/carbidopa (LC) and levodopa/benserazide (LB) pharmacokinetic profiles following repeated doses of opicapone (OPC) administered apart from levodopa. Two randomized, double blind, sex-balanced, placebo-controlled studies in four groups of 12 or 18 healthy subjects each. In each group, enrolled subjects received a once-daily morning (5, 15 and 30 mg) or evening (5, 15 and 50 mg) administration of OPC or placebo for up to 28 days. On the morning of Day 11, 12 h after the OPC or placebo evening dose, or the morning of Day 21, 1 h after the OPC or placebo dose, a single dose of immediate-release 100/25 mg LC was administered. Similarly, on Day 18 morning, 12 h after the OPC or placebo evening dose, or Day 28 morning, 1 h after the OPC or placebo dose, a single dose of immediate-release 100/25 mg LB was administered. All OPC treatments, in relation to the placebo group, presented a higher extent of exposure (AUC) to levodopa following either LC or LB doses. A relevant but not dose-dependent increase in the levodopa AUC occurred with all OPC dose groups in relation to placebo. All active treatments significantly inhibited both peak (E max ) and extent (AUEC) of the catechol-O-methyltransferase activity in relation to placebo. The tolerability profile was favourable. Opicapone, as once-daily oral evening regimen and/or 1 h apart from levodopa therapy, increases the bioavailability of levodopa associated with its pronounced, long-lasting and sustained catechol-O-methyltransferase inhibition. The tolerability profile was favourable and similar between OPC and placebo. © 2016 The British Pharmacological Society.

A brief history of placebos and clinical trials in psychiatry.

PubMed

Shorter, Edward

2011-04-01

The history of placebos in psychiatry can be understood only in the context of randomized controlled trials (RCTs). Placebo treatments are as old as medicine itself, and are particularly effective in dealing with psychosomatic symptoms. In psychiatry, placebos have mainly been featured in clinical drug trials. The earliest controlled trial in psychiatry (not involving drugs) occurred in 1922, followed by the first crossover studies during the 1930s. Meanwhile the concept of randomization was developed during the interwar years by British statistician Ronald A Fisher, and introduced in 3 trials of tuberculosis drugs between 1947 and 1951. These classic studies established the RCT as the gold standard in pharmaceutical trials, and its status was cemented during the mid-1950s. Nevertheless, while the placebo became established as a standard measure of drug action, placebo treatments became stigmatized as unethical. This is unfortunate, as they constitute one of the most powerful therapies in psychiatry. In recent years, moreover, the dogma of the placebo-controlled trial as the only acceptable data for drug licensing is also being increasingly discredited. This backlash has had 2 sources: one is the recognition that the US Food and Drug Administration has been too lax in permitting trials controlled with placebos alone, rather than also using an active agent as a test of comparative efficacy. In addition, there is evidence that in the hands of the pharmaceutical industry, the scientific integrity of RCTs themselves has been degraded into a marketing device. The once-powerful placebo is thus threatened with extinction.

Classical conditioning without verbal suggestions elicits placebo analgesia and nocebo hyperalgesia

PubMed Central

Bajcar, Elżbieta A.; Adamczyk, Wacław; Kicman, Paweł; Lisińska, Natalia; Świder, Karolina; Colloca, Luana

2017-01-01

The aim of this study was to examine the relationships among classical conditioning, expectancy, and fear in placebo analgesia and nocebo hyperalgesia. A total of 42 healthy volunteers were randomly assigned to three groups: placebo, nocebo, and control. They received 96 electrical stimuli, preceded by either orange or blue lights. A hidden conditioning procedure, in which participants were not informed about the meaning of coloured lights, was performed in the placebo and nocebo groups. Light of one colour was paired with pain stimuli of moderate intensity (control stimuli), and light of the other colour was paired with either nonpainful stimuli (in the placebo group) or painful stimuli of high intensity (in the nocebo group). In the control group, both colour lights were followed by control stimuli of moderate intensity without any conditioning procedure. Participants rated pain intensity, expectancy of pain intensity, and fear. In the testing phase, when both of the coloured lights were followed by identical moderate pain stimuli, we found a significant analgesic effect in the placebo group, and a significant hyperalgesic effect in the nocebo group. Neither expectancy nor fear ratings predicted placebo analgesia or nocebo hyperalgesia. It appears that a hidden conditioning procedure, without any explicit verbal suggestions, elicits placebo and nocebo effects, however we found no evidence that these effects are predicted by either expectancy or fear. These results suggest that classical conditioning may be a distinct mechanism for placebo and nocebo effects. PMID:28750001

[The nameless pill. The effects and side-effects of the therapeutic use of placebo preparations].

PubMed

Piechowiak, H

1981-08-22

Information is provided on the frequency of therapeutic use of placebos and on the quality and quantity of the effects observed after placebo treatment. The possible causes of these effects and theoretical explanatory models are also discussed. The ethical aspects of the clinical use of placebos are considered and more scientific investigation to enhance unspecific effects of all pharmacotherapy is called for.

The effect of the homeopathic remedies Arnica montana and Bellis perennis on mild postpartum bleeding--a randomized, double-blind, placebo-controlled study--preliminary results.

PubMed

Oberbaum, Menachem; Galoyan, Narine; Lerner-Geva, Liat; Singer, Shepherd Roee; Grisaru, Sorina; Shashar, David; Samueloff, Arnon

2005-06-01

To evaluate the effect of Arnica Montana and Bellis perennis on postpartum blood loss. Double blind, placebo-controlled, randomized, clinical trial. Department of Gynecology, Shaare Zedek Medical Center, Jerusalem. Forty parturients were randomized to one of three groups: Arnica montana C6 and Bellis perennis C6 (n=14), Arnica montana C30 and Bellis perennis C30 (n=14), or double placebo (n=12). After 48 h the Arnica/placebo was halted, and patients continued the Bellis/placebo until cessation of lochia. Hemoglobin levels (Hb) at 48 and 72 h postpartum. At 72 h postpartum, mean Hb levels remained similar after treatment with homeopathic remedies (12.7 versus 12.4) as compared to a significant decrease in Hb levels in the placebo group (12.7 versus 11.6; p<0.05), in spite of less favorable initial characteristics of the treatment group. The mean difference in Hb levels at 72 h postpartum was -0.29 (95% CI -1.09; 0.52) in the treatment group and -1.18 (95% CI -1.82; -0.54) in the placebo group (p<0.05). Treatment with homeopathic Arnica montana and Bellis perennis may reduce postpartum blood loss, as compared with placebo.

Placebo-controlled trial of mianserin and maprotiline in primary depressive illness

PubMed Central

Edwards, J. Guy; Goldie, Ann

1983-01-01

1 Preliminary results of a double-blind placebo-controlled trial of mianserin and maprotiline carried out in 58 outpatients with primary depressive illness are reported. 2 Patients received six weeks' treatment with 30 to 90 mg mianserin, 75 to 225 mg maprotiline or one to three capsules of placebo, all medication being taken at night. 3 There were statistically significant improvements in each treatment group and a better response to mianserin than to placebo or maprotiline on the Hamilton Rating Scale for Depression, after one week's treatment. 4 Neither mianserin nor maprotiline was superior to placebo after two or four weeks' treatment and relatively few patients completed six weeks' treatment because of a generally unsatisfactory response. 5 Unwanted effects were not particularly troublesome, though mianserin and maprotiline caused more drowsiness and blurred vision than did placebo, while maptrotiline produced more constipation than either of the other two treatments. 6 The importance of placebo-controlled trials of antidepressants is emphasized and the precautions that should be taken when they are carried out in outpatients are described. PMID:6337611

Weight changes in obese adults 6-months after discontinuation of double-blind zonisamide or placebo treatment

PubMed Central

Shin, J.H.; Gadde, K.M.; Øtbye, T.; Bray, Bray

2014-01-01

We evaluated weight changes in obese patients at 6-months after they ended participation in a 12-month randomized controlled trial in which they received daily placebo, zonisamide 200 mg, or zonisamide 400 mg, in addition to lifestyle counseling. Of the originally randomized 225 patients, 218 completed month-12 when study interventions were discontinued. For the 154 patients who returned for 6-month follow-up off-treatment, weight changes between month-12 and month-18 for placebo (n=53), zonisamide 200 mg (n=49), and zonisamide 400 mg groups (n=52) were 0.5 kg (95% CI, −0.8 to 1.8; 0.7%), 1.5 kg (0.2 to 2.8; 1.6%; p=0.26 vs placebo) and 2.4 kg (1.1 to 3.7; 2.6%; p=0.04 vs placebo), respectively. Our results suggest that although zonisamide 400 mg daily for 12-months resulted in greater weight loss than with placebo, weight regain after discontinuation of interventions was greater in the zonisamide 400 mg group than placebo group. PMID:25123600

Placebo response in binge eating disorder: a pooled analysis of 10 clinical trials from one research group.

PubMed

Blom, Thomas J; Mingione, Carolyn J; Guerdjikova, Anna I; Keck, Paul E; Welge, Jeffrey A; McElroy, Susan L

2014-03-01

The aim of this study was to gain further understanding of placebo response in binge eating disorder. We pooled participant-level data from 10 double-blind, placebo-controlled, randomized trials of medications for binge eating disorder. The primary outcomes were response (75% reduction in binge eating episodes), cessation of binge eating episodes, change in mean weekly binge eating episodes and binge eating episodes per week. Of 234 participants receiving placebo, 89 (38%) were responders and 59 (26%) attained cessation. Placebo-treated participants significantly reduced their binge eating. The mean (SD) binge eating episodes per week at baseline was 5.2 (3.2) and at endpoint was 2.2 (2.6). Lower baseline binge eating episode frequency and longer study participation were significantly associated with response and cessation. Less severe eating pathology at baseline was associated with higher placebo response and cessation rates. Future clinical trials may want to stipulate that participants exceed a threshold of illness severity, which may lead to better placebo and drug separation. Copyright © 2014 John Wiley & Sons, Ltd and Eating Disorders Association.

Tofacitinib or Adalimumab versus Placebo for Psoriatic Arthritis.

PubMed

Mease, Philip; Hall, Stephen; FitzGerald, Oliver; van der Heijde, Désirée; Merola, Joseph F; Avila-Zapata, Francisco; Cieślak, Dorota; Graham, Daniela; Wang, Cunshan; Menon, Sujatha; Hendrikx, Thijs; Kanik, Keith S

2017-10-19

Tofacitinib is an oral Janus kinase inhibitor that is under investigation for the treatment of psoriatic arthritis. We evaluated tofacitinib in patients with active psoriatic arthritis who previously had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs). In this 12-month, double-blind, active-controlled and placebo-controlled, phase 3 trial, we randomly assigned patients in a 2:2:2:1:1 ratio to receive one of the following regimens: tofacitinib at a 5-mg dose taken orally twice daily (107 patients), tofacitinib at a 10-mg dose taken orally twice daily (104), adalimumab at a 40-mg dose administered subcutaneously once every 2 weeks (106), placebo with a blinded switch to the 5-mg tofacitinib dose at 3 months (52), or placebo with a blinded switch to the 10-mg tofacitinib dose at 3 months (53). Placebo groups were pooled for analyses up to month 3. Primary end points were the proportion of patients who had an American College of Rheumatology 20 (ACR20) response (≥20% improvement from baseline in the number of tender and swollen joints and at least three of five other important domains) at month 3 and the change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) score (scores range from 0 to 3, with higher scores indicating greater disability) at month 3. ACR20 response rates at month 3 were 50% in the 5-mg tofacitinib group and 61% in the 10-mg tofacitinib group, as compared with 33% in the placebo group (P=0.01 for the comparison of the 5-mg dose with placebo; P<0.001 for the comparison of the 10-mg dose with placebo); the rate was 52% in the adalimumab group. The mean change in the HAQ-DI score was -0.35 in the 5-mg tofacitinib group and -0.40 in the 10-mg tofacitinib group, as compared with -0.18 in the placebo group (P=0.006 for the comparison of the 5-mg dose with placebo; P<0.001 for the comparison of the 10-mg dose with placebo); the score change was -0.38 in the adalimumab group. The rate of adverse events through month 12 was 66% in the 5-mg tofacitinib group, 71% in the 10-mg tofacitinib group, 72% in the adalimumab group, 69% in the placebo group that switched to the 5-mg tofacitinib dose, and 64% in the placebo group that switched to the 10-mg tofacitinib dose. There were four cases of cancer, three serious infections, and four cases of herpes zoster in patients who received tofacitinib during the trial. The efficacy of tofacitinib was superior to that of placebo at month 3 in patients with psoriatic arthritis who had previously had an inadequate response to conventional synthetic DMARDs. Adverse events were more frequent with tofacitinib than with placebo. (Funded by Pfizer; OPAL Broaden ClinicalTrials.gov number, NCT01877668 .).

Semiotics and the placebo effect.

PubMed

Miller, Franklin G; Colloca, Luana

2010-01-01

Despite substantial progress in elucidating its neurobiological mechanisms, theoretical understanding of the placebo effect is poorly developed. Application of the semiotic theory developed by the American philosopher Charles Peirce offers a promising account of placebo effects as involving the apprehension and response to signs. The semiotic approach dovetails with the various psychological mechanisms invoked to account for placebo effects, such as conditioning and expectation, and bridges the biological and cultural dimensions of this fascinating phenomenon.

Levodopa, placebo and rotigotine change biomarker levels for oxidative stress.

PubMed

Muhlack, Siegfried; Kinkel, Manuel; Herrman, Lennard; Müller, Thomas

2017-05-01

Homocysteine increase and glutathione derivative cysteinyl-glycine fall are indirect biomarkers for oxidative stress, for instance due to dopamine D 1 receptor stimulation. To investigate the influence of the D 1 receptor agonists levodopa and rotigotine compared with placebo on homocysteine and cysteinyl-glycine in plasma of patients with Parkinson's disease. Patients received 100 mg levodopa, 4 mg rotigotine or placebo. Cysteinyl-glycine and homocysteine were measured every 30 min over three hours. Homocysteine rose during levodopa- and placebo administration. Rotigotine had no effect. Cysteine-glycine only increased after placebo- but not after levodopa- or rotigotine. Homocysteine elevation results from hepatic and gastrointestinal methylation processes. Transdermal rotigotine circumvents these methylation locations. Turnover of segregated alkyl residuals from rotigotine serves as methyl group donors, which counteract homocysteine increment. The placebo-related cysteinyl-glycine increase results from reduced free radical exposure. Low levodopa dosing and antioxidants in the rotigotine patch matrix prevented cysteinyl-glycine fall.

COMBINED TREATMENT WITH SAXAGLIPTIN PLUS DAPAGLIFLOZIN REDUCES INSULIN LEVELS BY INCREASED INSULIN CLEARANCE AND IMPROVES β-CELL FUNCTION.

PubMed

Ekholm, Ella; Hansen, Lars; Johnsson, Eva; Iqbal, Nayyar; Carlsson, Björn; Chen, Hungta; Hirshberg, Boaz

2017-03-01

To determine if reduction in serum insulin with dapagliflozin plus saxagliptin or dapagliflozin add-on to metformin contributed to increased insulin clearance and to assess the effects of these treatments on β-cell function. Patients (glycated hemoglobin, 8 to 12%; 64 to 108 mmol/mol) were randomized to 24-week, double-blind treatment with saxagliptin 5 mg/day plus dapagliflozin 10 mg/day (n = 179), saxagliptin 5 mg/day plus placebo (n = 176), or dapagliflozin 10 mg/day plus placebo (n = 179) added to metformin. C-peptide to insulin ratio was used as an index of insulin clearance during a meal tolerance test, and β-cell function was evaluated by Homeostasis Model Assessment 2. At 24 weeks, compared with baseline, saxagliptin + dapagliflozin and saxagliptin + placebo increased mean (95% confidence interval [CI]) C-peptide area under the curve (AUC 0-180 min ) (40.2 [9.2 to 71.3] ng/mL and 95.4 [63.4 to 127.4] ng/mL, respectively); no change was noted with dapagliflozin + placebo (14.5 [-17.6 to 46.8] ng/mL). Insulin AUC was reduced from baseline with saxagliptin + dapagliflozin (-1,120.4 [-1,633.9 to -606.9] μU/mL) and dapagliflozin + placebo (-1,018.6 [-1550.5 to -486.8] μU/mL) but increased with saxagliptin + placebo (661.2 [131.1 to 1,191.3] μU/mL). C-peptide to insulin ratio did not change versus baseline with saxagliptin + placebo but increased after saxagliptin + dapagliflozin and dapagliflozin + placebo, largely due to decreased insulin AUC with dapagliflozin. All treatments improved β-cell function (mean change [95% CI] from baseline, saxagliptin+dapagliflozin: 20.6% [16.5% to 24.8%]; dapagliflozin + placebo: 17.0% [12.7% to 21.4%]; saxagliptin + placebo: 11.0% [6.6% to 15.5%]). Increased C-peptide to insulin ratio with saxagliptin + dapagliflozin and dapagliflozin + placebo add-on to metformin compared with saxagliptin + placebo add-on to metformin suggests that dapagliflozin increases insulin clearance and may contribute to lower circulating insulin. All treatments improved β-cell function, with the greatest improvements with saxagliptin + dapagliflozin and dapagliflozin + placebo. A1c = glycated hemoglobin AUC 0-180 min = area under the curve from 0 to 180 minutes HOMA-2β = homeostasis model assessment-2 β-cell function SGLT-2 = sodium-glucose cotransporter-2 T2D = type 2 diabetes.

Differing antidepressant maintenance methodologies.

PubMed

Safer, Daniel J

2017-10-01

The principle evidence that antidepressant medication (ADM) is an effective maintenance treatment for adults with major depressive disorder (MDD) is from placebo substitution trials. These trials enter responders from ADM efficacy trials into randomized, double-blind placebo-controlled (RDBPC) effectiveness trials to measure the rate of MDD relapse over time. However, other randomized maintenance trial methodologies merit consideration and comparison. A systematic review of ADM randomized maintenance trials included research reports from multiple databases. Relapse rate was the main effectiveness outcome assessed. Five ADM randomized maintenance methodologies for MDD responders are described and compared for outcome. These effectiveness trials include: placebo-substitution, ADM/placebo extension, ADM extension, ADM vs. psychotherapy, and treatment as usual. The placebo-substitution trials for those abruptly switched to placebo resulted in unusually high (46%) rates of relapse over 6-12months, twice the continuing ADM rate. These trials were characterized by selective screening, high attrition, an anxious anticipation of a switch to placebo, and a risk of drug withdrawal symptoms. Selectively screened ADM efficacy responders who entered into 4-12month extension trials experienced relapse rates averaging ~10% with a low attrition rate. Non-industry sponsored randomized trials of adults with multiple prior MDD episodes who were treated with ADM maintenance for 1-2years experienced relapse rates averaging 40%. Placebo substitution trial methodology represents only one approach to assess ADM maintenance. Antidepressant maintenance research for adults with MDD should be evaluated for industry sponsorship, attrition, the impact of the switch to placebo, and major relapse differences in MDD subpopulations. Copyright © 2017. Published by Elsevier Inc.

A Brief History of Placebos and Clinical Trials in Psychiatry

PubMed Central

Shorter, Edward

2013-01-01

The history of placebos in psychiatry can be understood only in the context of randomized controlled trials (RCTs). Placebo treatments are as old as medicine itself, and are particularly effective in dealing with psychosomatic symptoms. In psychiatry, placebos have mainly been featured in clinical drug trials. The earliest controlled trial in psychiatry (not involving drugs) occurred in 1922, followed by the first crossover studies during the 1930s. Meanwhile the concept of randomization was developed during the interwar years by British statistician Ronald A Fisher, and introduced in 3 trials of tuberculosis drugs between 1947 and 1951. These classic studies established the RCT as the gold standard in pharmaceutical trials, and its status was cemented during the mid-1950s. Nevertheless, while the placebo became established as a standard measure of drug action, placebo treatments became stigmatized as unethical. This is unfortunate, as they constitute one of the most powerful therapies in psychiatry. In recent years, moreover, the dogma of the placebo-controlled trial as the only acceptable data for drug licensing is also being increasingly discredited. This backlash has had 2 sources: one is the recognition that the US Food and Drug Administration has been too lax in permitting trials controlled with placebos alone, rather than also using an active agent as a test of comparative efficacy. In addition, there is evidence that in the hands of the pharmaceutical industry, the scientific integrity of RCTs themselves has been degraded into a marketing device. The once-powerful placebo is thus threatened with extinction. PMID:21507275

A randomized, placebo-controlled trial of an amino acid preparation on timing and quality of sleep.

PubMed

Shell, William; Bullias, Debbie; Charuvastra, Elizabeth; May, Lawrence A; Silver, David S

2010-01-01

This study was an outpatient, randomized, double-blind, placebo-controlled trial of a combination amino acid formula (Gabadone) in patients with sleep disorders. Eighteen patients with sleep disorders were randomized to either placebo or active treatment group. Sleep latency and duration of sleep were measured by daily questionnaires. Sleep quality was measured using a visual analog scale. Autonomic nervous system function was measured by heart rate variability analysis using 24-hour electrocardiographic recordings. In the active group, the baseline time to fall asleep was 32.3 minutes, which was reduced to 19.1 after Gabadone administration (P = 0.01, n = 9). In the placebo group, the baseline latency time was 34.8 minutes compared with 33.1 minutes after placebo (P = nonsignificant, n = 9). The difference was statistically significant (P = 0.02). In the active group, the baseline duration of sleep was 5.0 hours (mean), whereas after Gabadone, the duration of sleep increased to 6.83 (P = 0.01, n = 9). In the placebo group, the baseline sleep duration was 7.17 +/- 7.6 compared with 7.11 +/- 3.67 after placebo (P = nonsignificant, n = 9). The difference between the active and placebo groups was significant (P = 0.01). Ease of falling asleep, awakenings, and am grogginess improved. Objective measurement of parasympathetic function as measured by 24-hour heart rate variability improved in the active group compared with placebo. An amino acid preparation containing both GABA and 5-hydroxytryptophan reduced time to fall asleep, decreased sleep latency, increased the duration of sleep, and improved quality of sleep.

Efficacy of desvenlafaxine 50 mg compared with placebo in patients with moderate or severe major depressive disorder: a pooled analysis of six randomized, double-blind, placebo-controlled studies.

PubMed

Papakostas, George I; Culpepper, Larry; Fayyad, Rana S; Musgnung, Jeff; Guico-Pabia, Christine J

2013-11-01

This study assessed the efficacy of desvenlafaxine 50 mg/day compared with placebo for treating moderate or severe major depressive disorder (MDD). Data were pooled from six double-blind, placebo-controlled, desvenlafaxine 50 mg/day fixed-dose studies in adults with MDD. The primary endpoint was improvement in 17-item Hamilton Rating Scale for Depression (HAM-D17) scores from baseline at week 8. HAM-D17 changes were evaluated in patients with moderate (18

Placebo effect of medication cost in Parkinson disease: a randomized double-blind study.

PubMed

Espay, Alberto J; Norris, Matthew M; Eliassen, James C; Dwivedi, Alok; Smith, Matthew S; Banks, Christi; Allendorfer, Jane B; Lang, Anthony E; Fleck, David E; Linke, Michael J; Szaflarski, Jerzy P

2015-02-24

To examine the effect of cost, a traditionally "inactive" trait of intervention, as contributor to the response to therapeutic interventions. We conducted a prospective double-blind study in 12 patients with moderate to severe Parkinson disease and motor fluctuations (mean age 62.4 ± 7.9 years; mean disease duration 11 ± 6 years) who were randomized to a "cheap" or "expensive" subcutaneous "novel injectable dopamine agonist" placebo (normal saline). Patients were crossed over to the alternate arm approximately 4 hours later. Blinded motor assessments in the "practically defined off" state, before and after each intervention, included the Unified Parkinson's Disease Rating Scale motor subscale, the Purdue Pegboard Test, and a tapping task. Measurements of brain activity were performed using a feedback-based visual-motor associative learning functional MRI task. Order effect was examined using stratified analysis. Although both placebos improved motor function, benefit was greater when patients were randomized first to expensive placebo, with a magnitude halfway between that of cheap placebo and levodopa. Brain activation was greater upon first-given cheap but not upon first-given expensive placebo or by levodopa. Regardless of order of administration, only cheap placebo increased activation in the left lateral sensorimotor cortex and other regions. Expensive placebo significantly improved motor function and decreased brain activation in a direction and magnitude comparable to, albeit less than, levodopa. Perceptions of cost are capable of altering the placebo response in clinical studies. This study provides Class III evidence that perception of cost is capable of influencing motor function and brain activation in Parkinson disease. © 2015 American Academy of Neurology.

Olanzapine versus Placebo in Adolescents with Schizophrenia; a 6-Week, Randomized Double-Blind, Placebo-Controlled Trial

ERIC Educational Resources Information Center

Kryzhanovskaya, Ludmila; Schulz, Charles; McDougle, Christopher; Frazier, Jean; Dittman, Ralf; Robertson-Plouch, Carol; Bauer, Theresa; Xu, Wen; Wang, Wei; Carlson, Janice; Tohen, Mauricio

2009-01-01

The efficacy of olanzapine in treating schizophrenia was tested through a placebo-controlled trial involving one hundred seven inpatient and outpatients adolescents. Patients who took olanzapine experienced significant symptom improvement.

Preventing Second Cancers in Colon Cancer Survivors

Cancer.gov

In this phase III trial, people who have had curative surgery for colon cancer will be randomly assigned to take sulindac and a placebo, eflornithine and a placebo, both sulindac and eflornithine, or two placebo pills for 36 months.

Placebo Effect

MedlinePlus

... de- signed to investigate how a placebo produces benefit. The patients with PD who thought that they were receiving the real treatment but who really received a placebo had the same changes in their brains on PET scans as those who received the medication. It ...

Enhancing Placebo Effects: Insights From Social Psychology

PubMed Central

SLIWINSKI, JIM; ELKINS, GARY R.

2012-01-01

Placebo effects are widely recognized as having a potent impact upon treatment outcomes in both medical and psychological interventions, including hypnosis. In research utilizing randomized clinical trials, there is usually an effort to minimize or control placebo effects. However, in clinical practice there may be significant benefits in enhancing placebo effects. Prior research from the field of social psychology has identified three factors that may enhance placebo effects, namely: priming, client perceptions, and the theory of planned behavior. These factors are reviewed and illustrated via a case example. The consideration of social-psychological factors to enhance positive expectancies and beliefs has implications for clinical practice as well as future research into hypnotic interventions. PMID:23488251

Metformin does not enhance ovulation induction in clomiphene resistant polycystic ovary syndrome in clinical practice

PubMed Central

Sturrock, N D C; Lannon, B; Fay, T N

2002-01-01

Aims To determine whether metformin pretreatment has beneficial effects in clomiphene resistant infertile women with polycystic ovary syndrome (PCOS) in an infertility clinic. Methods This was a randomized placebo controlled double-blind crossover study of 3 months metformin (1500 mg day−1)/placebo, followed by 3 months metformin/placebo together with clomiphene (50–100 mg for 5 days) for three cycles in clomiphene resistant women with PCOS. The primary outcomes were restoration of spontaneous menses, ovulation induction (spontaneous or clomiphene induced) and pregnancy. Secondary endpoints were changes in biochemical parameters related to androgens and insulin. Results Twelve women completed the metformin arm and 14 the placebo arm. Spontaneous menstruation resumed in five metformin treated patients and in six placebo treated women, P = 0.63. No women given metformin spontaneously ovulated, although one patient given placebo did, P = 0.30. There was no difference in the efficacy of clomiphene between the two groups with ovulation being induced in five (out of 12) metformin treated women and four (out of 14) placebo treated women, P = 0.63. Pregnancy occurred in three (out of 12) women given metformin and two (out of 14) women given placebo, P = 0.59. Conclusions Metformin is not always beneficial when given to clomiphene resistant infertile women with PCOS in clinical practice. PMID:11994052

Auricular Acupuncture for Exam Anxiety in Medical Students—A Randomized Crossover Investigation

PubMed Central

Klausenitz, Catharina; Hacker, Henriette; Hesse, Thomas; Kohlmann, Thomas; Endlich, Karlhans; Hahnenkamp, Klaus; Usichenko, Taras

2016-01-01

Auricular acupuncture (AA) is effective in the treatment of preoperative anxiety. The aim was to investigate whether AA can reduce exam anxiety as compared to placebo and no intervention. Forty-four medical students were randomized to receive AA, placebo, or no intervention in a crossover manner and subsequently completed three comparable oral anatomy exams with an interval of 1 month between the exams/interventions. AA was applied using indwelling fixed needles bilaterally at points MA-IC1, MA-TF1, MA-SC, MA-AT1 and MA-TG one day prior to each exam. Placebo needles were used as control. Levels of anxiety were measured using a visual analogue scale before and after each intervention as well as before each exam. Additional measures included the State-Trait-Anxiety Inventory, duration of sleep at night, blood pressure, heart rate and the extent of participant blinding. All included participants finished the study. Anxiety levels were reduced after AA and placebo intervention compared to baseline and the no intervention condition (p < 0.003). AA was better at reducing anxiety than placebo in the evening before the exam (p = 0.018). Participants were able to distinguish between AA and placebo intervention. Both AA and placebo interventions reduced exam anxiety in medical students. The superiority of AA over placebo may be due to insufficient blinding of participants. PMID:28033320

On Suggestibility and Placebo: A Follow-Up Study.

PubMed

Lifshitz, Michael; Sheiner, Eli O; Olson, Jay A; Thériault, Rémi; Raz, Amir

2017-04-01

Identifying what makes some people respond well to placebos remains a major challenge. Here, we attempt to replicate an earlier study in which we found a relationship between hypnotic suggestibility and subjective ratings of relaxation following the ingestion of a placebo sedative (Sheiner, Lifshitz, & Raz, 2016). To assess the reliability of this effect, we tested 34 participants using a similar design. Participants ingested a placebo capsule in one of two conditions: (1) relaxation, wherein we described the capsule as a herbal sedative, or (2) control, wherein we described the capsule as inert. To index placebo response, we collected measures of blood pressure and heart rate, as well as self-report ratings of relaxation and drowsiness. Despite using a similar experimental design as in our earlier study, we were unable to replicate the correlation between hypnotic suggestibility and placebo response. Furthermore, whereas in our former experiment we observed a change in subjective ratings of relaxation but no change in physiological measures, here we found that heart rate dropped in the relaxation condition while subjective ratings remained unchanged. Even within a consistent context of relaxation, therefore, our present results indicate that placebos may induce effects that are fickle, tenuous, and unreliable. Although we had low statistical power, our findings tentatively accord with the notion that placebo response likely involves a complex, multifaceted interaction between traits, expectancies, and contexts.

["Placebo effect", from personal convictions to collective representations: A psychosocial reading of a pharmacodynamic phenomenon].

PubMed

Balez, R; Couturaud, F; Touffet, L

2015-11-01

After starting with a brief historical account of the placebo effect organized around the elaboration of clinical trials and around sham therapy as a method, we will offer a psychosocial point of view on the placebo phenomenon. The placebo effect is at the heart of medicine and particularly of therapeutic trials from theoretical research on a drug to its acceptance and its use in every-day clinical practice. The placebo effect intermingles biology, relationships and the context of therapeutic interactions. This type of phenomenon originates as much from biology as from human psychology. Our article puts more precisely into question the part that psychology has in the placebo phenomenon and suggests a chart to address it. This chart refers both to the pharmacodynamic effect given to drugs in a subjective way, and to the collective representations and social interactions depending on them. What can we say about the psychosociological dimensions of the placebo effect? How is it possible to organize the scope of these dimensions to base systematic studies on them in the field of clinical trials? We try to give elements of response to these questions by suggesting the study of the placebo effect as an original field of study by necessarily mobilizing both health sciences and the human and social sciences. Copyright © 2015 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

Therapeutic effects of nandrolone and testosterone in adult male HIV patients with AIDS wasting syndrome (AWS): a randomized, double-blind, placebo-controlled trial.

PubMed

Sardar, Partha; Jha, Ayan; Roy, Deeptarka; Majumdar, Uddalak; Guha, Pradipta; Roy, Sabyasachi; Banerjee, Ramtanu; Banerjee, Amit Kumar; Bandyopadhyay, Dipanjan

2010-01-01

We aimed to compare therapeutic effects of intramuscular (IM) nandrolone decanoate and IM testosterone enanthate in male HIV patients with AIDS wasting syndrome (AWS) with placebo control. In this randomized, double-blind, placebo-controlled, 12-week trial, 104 patients with AWS who satisfied our inclusion criteria were randomly allotted in a 2:2:1 ratio to the 3 intervention groups: nandrolone, testosterone, and placebo. We administered 150 mg nandrolone and 250 mg testosterone (both IM, biweekly). The primary outcome measure was a comparison of absolute change in weight at 12 weeks between the nandrolone decanoate, testosterone, and placebo groups. Intent-to-treat analysis was done. The nandrolone group recorded maximum mean increase in weight (3.20 kg; post hoc P < .01 compared to placebo). Body mass index (BMI) of subjects in the nandrolone group had a significantly greater increase (mean = 1.28) compared to both testosterone (post hoc P < .05) and placebo (post hoc P < .01). Waist circumference and triceps skinfold thickness of patients on nandrolone showed similar results. Nandrolone also ensured a better quality of life. Patients with low testosterone level (<3 ng/mL) benefited immensely from nandrolone therapy, which increased their weight and BMI significantly compared to placebo (P < .05). Our trial demonstrates the superior therapeutic effects of nandrolone in male AWS patients, including the androgen deficient.

Exploring the Effect of Lactium™ and Zizyphus Complex on Sleep Quality: A Double-Blind, Randomized Placebo-Controlled Trial

PubMed Central

Scholey, Andrew; Benson, Sarah; Gibbs, Amy; Perry, Naomi; Sarris, Jerome; Murray, Greg

2017-01-01

Acute, non-clinical insomnia is not uncommon. Sufferers commonly turn to short-term use of herbal supplements to alleviate the symptoms. This placebo-controlled, double-blind study investigated the efficacy of LZComplex3 (lactium™, Zizyphus, Humulus lupulus, magnesium and vitamin B6), in otherwise healthy adults with mild insomnia. After a 7-day single-blind placebo run-in, eligible volunteers (n = 171) were randomized (1:1) to receive daily treatment for 2 weeks with LZComplex3 or placebo. Results revealed that sleep quality measured by change in Pittsburgh Sleep Quality Index (PSQI) score improved in both the LZComplex3 and placebo groups. There were no significant between group differences between baseline and endpoint on the primary outcome. The majority of secondary outcomes, which included daytime functioning and physical fatigue, mood and anxiety, cognitive performance, and stress reactivity, showed similar improvements in the LZComplex3 and placebo groups. A similar proportion of participants reported adverse events (AEs) in both groups, with two of four treatment-related AEs in the LZComplex3 group resulting in permanent discontinuation. It currently cannot be concluded that administration of LZComplex3 for 2 weeks improves sleep quality, however, a marked placebo response (despite placebo run-in) and/or short duration of treatment may have masked a potential beneficial effect on sleep quality. PMID:28218661

Treatment for premenstrual syndrome with Vitex agnus castus: A prospective, randomized, multi-center placebo controlled study in China.

PubMed

He, Zhong; Chen, Rong; Zhou, Yingfang; Geng, Li; Zhang, Zhenyu; Chen, Shuling; Yao, Yanjun; Lu, Junli; Lin, Shouqing

2009-05-20

To investigate the efficacy and safety of VAC BNO 1095 extract in Chinese women suffering from moderate to severe premenstrual syndrome (PMS). Prospective, double-blind, placebo controlled, parallel-group, multi-center clinical trial design was employed. After screening and preparation phase lasting three cycles, Eligible patients were randomly assigned into treatment or placebo groups and had treatment with VAC extract or placebo for up to three cycles. Efficacy was assessed using the Chinese version PMS-diary (PMSD) and PMTS. Two hundred and seventeen women were eligible to enter the treatment phase (TP) and were randomly assigned into the treatment group (108) or the placebo group (109), 208 provided the efficacy data (treatment 104, placebo 104), and 202 completed the treatment phase (treatment 101, placebo 101). The mean total PMSD score decreased from 29.23 at baseline (0 cycle) to 6.41 at the termination (3rd cycle) for the treatment group and from 28.14 at baseline (0 cycle) to 12.64 at the termination (3rd cycle) for the placebo group. The total PMSD score of 3rd cycle was significantly lower than the baseline in both groups (p<0.0001). The difference in the mean scores from the baseline to the 3rd cycle in the treatment group (22.71+/-10.33) was significantly lower than the difference in the placebo group (15.50+/-12.94, p<0.0001). Results of PMTS were similar, the total scores for PMTS were significantly lower between the two groups (p<0.01) and within each group (p<0.01). The score was decreased from 26.17+/-4.79 to 9.92+/-9.01 for the treatment group, and from 27.10+/-4.76 to 14.59+/-10.69 for the placebo group. A placebo effect of 50% was found in the present study. No serious adverse event (SAE) occurred in both groups. Vitex agnus castus (VAC BNO 1095 corresponding to 40mg herbal drug) is a safe, well tolerated and effective drug of the treatment for Chinese women with the moderate to severe PMS.

A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: the Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) trial.

PubMed

Binkley, Neil; Bolognese, Michael; Sidorowicz-Bialynicka, Anna; Vally, Tasneem; Trout, Richard; Miller, Colin; Buben, Christine E; Gilligan, James P; Krause, David S

2012-08-01

The Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) study was a randomized, double-blind, double-dummy, active- and placebo-controlled, multiple-dose, phase 3 study to assess the efficacy and safety of oral recombinant calcitonin for treatment of postmenopausal osteoporosis. A total of 565 women age 46 to 86 (mean 66.5) years were randomized (4:3:2) to receive oral recombinant salmon calcitonin (rsCT) tablets (0.2  mg/d) plus placebo nasal spray, synthetic salmon calcitonin (ssCT) nasal spray (200 IU/d) plus placebo tablets, or placebo (placebo tablets plus placebo nasal spray), respectively for 48 weeks. All women received calcium (≥1000  mg/d) and vitamin D (800 IU/d). Women randomized to oral rsCT had a mean ± SD percent increase from baseline in lumbar spine bone mineral density (BMD) (1.5% ± 3.2%) that was greater than those randomized to ssCT nasal spray (0.78% ± 2.9%) or placebo (0.5% ± 3.2%). Lumbar spine BMD change in those receiving nasal calcitonin did not differ from placebo. Oral rsCT treatment also resulted in greater improvements in trochanteric and total proximal femur BMD than ssCT nasal spray. Reductions in bone resorption markers with oral rsCT were greater than those observed in ssCT nasal spray or placebo recipients. Approximately 80% of subjects in each treatment group experienced an adverse event, the majority of which were mild or moderate in intensity. Gastrointestinal system adverse events were reported by nearly one-half of women in all treatment groups and were the principal reason for premature withdrawals. Less than 10% of women experienced a serious adverse event and no deaths occurred. Overall, oral rsCT was superior to nasal ssCT and placebo for increasing BMD and reducing bone turnover. Oral rsCT was safe and as well tolerated as ssCT nasal spray or placebo. Oral calcitonin may provide an additional treatment alternative for women with postmenopausal osteoporosis. Copyright © 2012 American Society for Bone and Mineral Research.

Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials

PubMed Central

Panés, Julian; Sandborn, William J; Schreiber, Stefan; Sands, Bruce E; Vermeire, Séverine; D'Haens, Geert; Panaccione, Remo; Higgins, Peter D R; Colombel, Jean-Frederic; Feagan, Brian G; Chan, Gary; Moscariello, Michele; Wang, Wenjin; Niezychowski, Wojciech; Marren, Amy; Healey, Paul; Maller, Eric

2017-01-01

Objective Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for IBD. We evaluated the efficacy and safety of tofacitinib for induction and maintenance treatment in patients with moderate-to-severe Crohn's disease (CD). Design We conducted two randomised, double-blind, placebo-controlled, multicentre phase IIb studies. Adult patients with moderate-to-severe CD were randomised to receive induction treatment with placebo, tofacitinib 5 or 10 mg twice daily for 8 weeks. Those achieving clinical response-100 or remission were re-randomised to maintenance treatment with placebo, tofacitinib 5 or 10 mg twice daily for 26 weeks. Primary endpoints were clinical remission at the end of the induction study, and clinical response-100 or remission at the end of the maintenance study. Results 180/280 patients randomised in the induction study were enrolled in the maintenance study. At week 8 of induction, the proportion of patients with clinical remission was 43.5% and 43.0% with 5 and 10 mg twice daily, respectively, compared with 36.7% in the placebo group (p=0.325 and 0.392 for 5 and 10 mg twice daily vs placebo). At week 26 of maintenance, the proportion of patients with clinical response-100 or remission was 55.8% with tofacitinib 10 mg twice daily compared with 39.5% with tofacitinib 5 mg twice daily and 38.1% with placebo (p=0.130 for 10 mg twice daily vs placebo). Compared with placebo, the change in C-reactive protein from baseline was statistically significant (p<0.0001) with 10 mg twice daily after both induction and maintenance treatments. Conclusions Primary efficacy endpoints were not significantly different from placebo, although there was evidence of a minor treatment effect. No new safety signals were observed for tofacitinib. Trial registration numbers NCT01393626 and NCT01393899. PMID:28209624

Consistent and significant improvement of nighttime voiding frequency (nocturia) with silodosin in men with LUTS suggestive of BPH: pooled analysis of three randomized, placebo-controlled, double-blind phase III studies.

PubMed

Eisenhardt, Andreas; Schneider, Tim; Cruz, Francisco; Oelke, Matthias

2014-10-01

Nocturia is prevalent and bothersome in men with lower urinary tract symptoms suggestive of BPH (LUTS/BPH). α-Adrenoceptor antagonists without subtype selectivity have inconsistently shown significant effects on nocturia in these patients. We explored the effects of the α1A-adrenoceptor subtype-selective antagonist silodosin on nocturia by analyzing three placebo-controlled registration studies. Responses to question 7 of the IPSS questionnaire were analyzed for the entire study population and patients with ≥ 2 voids/night at baseline. Improvement/worsening rates for nocturia were calculated for once-daily silodosin 8 mg and placebo. Silodosin effects on the mean number of nocturnal voids were compared with placebo, and the number of patients in whom nocturia was reduced to <2 times was calculated. In total, 1,479 men were treated with silodosin or placebo; 1,266 men (85 %) had ≥ 2 voids/night at baseline. Compared to placebo, more men treated with silodosin reported about nocturia improvement (53.4 vs. 42.8 %, p < 0.0001) and fewer patients about worsening (9.0 vs. 14.3 %, p < 0.0001). Silodosin significantly reduced nocturia within each study and pooled cohort compared to placebo (p < 0.001). In men with ≥ 2 nocturnal voids at baseline, 61 and 49 % of patients with silodosin and placebo had reductions of ≥ 1 voids/night, respectively (p = 0.0003), and significantly more patients with silodosin had <2 nocturia episodes at study end compared to placebo (29.3 vs. 19.0 %; p = 0.0002). Although a weak impact on nocturia is already known from α-adrenoceptor antagonists without subtype selectivity, the individual placebo-controlled studies and the pooled data analysis showed that the α1A-adrenoceptor subtype-selective antagonist silodosin consistently and significantly improves nocturia in men with LUTS/BPH.

Estimated medical cost reductions for paliperidone palmitate vs placebo in a randomized, double-blind relapse-prevention trial of patients with schizoaffective disorder.

PubMed

Joshi, K; Lin, J; Lingohr-Smith, M; Fu, D J

2015-01-01

The objective of this economic model was to estimate the difference in medical costs among patients treated with paliperidone palmitate once-monthly injectable antipsychotic (PP1M) vs placebo, based on clinical event rates reported in the 15-month randomized, double-blind, placebo-controlled, parallel-group study of paliperidone palmitate evaluating time to relapse in subjects with schizoaffective disorder. Rates of psychotic, depressive, and/or manic relapses and serious and non-serious treatment-emergent adverse events (TEAEs) were obtained from the long-term paliperidone palmitate vs placebo relapse prevention study. The total annual medical cost for a relapse from a US payer perspective was obtained from published literature and the costs for serious and non-serious TEAEs were based on Common Procedure Terminology codes. Total annual medical cost differences for patients treated with PP1M vs placebo were then estimated. Additionally, one-way and Monte Carlo sensitivity analyses were conducted. Lower rates of relapse (-18.3%) and serious TEAEs (-3.9%) were associated with use of PP1M vs placebo as reported in the long-term paliperidone palmitate vs placebo relapse prevention study. As a result of the reduction in these clinical event rates, the total annual medical cost was reduced by $7140 per patient treated with PP1M vs placebo. One-way sensitivity analysis showed that variations in relapse rates had the greatest impact on the estimated medical cost differences (range: -$9786, -$4670). Of the 10,000 random cycles of Monte Carlo simulations, 100% showed a medical cost difference <$0 (reduction) for patients using PPIM vs placebo. The average total annual medical differences per patient were -$8321 for PP1M monotherapy and -$6031 for PPIM adjunctive therapy. Use of PP1M for treatment of patients with schizoaffective disorder was associated with a significantly lower rate of relapse and a reduction in medical costs compared to placebo. Further evaluation in the real-world setting is warranted.

Patient attitudes about the clinical use of placebo: qualitative perspectives from a telephone survey.

PubMed

Ortiz, Robin; Chandros Hull, Sara; Colloca, Luana

2016-04-04

To examine qualitative responses regarding the use of placebo treatments in medical care in a sample of US patients.Survey studies suggest a deliberate clinical use of placebos by physicians, and prior research has found that although most US patients find placebo use acceptable, the rationale for these beliefs is largely unknown. Members of the Outpatient Clinic at the Kaiser Permanente Northern California interviewed research participants who had been seen for a chronic health problem at least once in the prior 6 months. 853 women (61%) and men, white (58%) and non-white participants aged 18-75 years. Qualitative responses on perceptions of placebo use from one-time telephone surveys were analysed for common themes and associations with demographic variables. Prior results indicated that a majority of respondents felt it acceptable for doctors to recommend placebo treatments. Our study found that a lack of harm (n=291, 46.1%) and potential benefit (n=250, 39.6%) were the most common themes to justify acceptability of placebo use. Responses citing potential benefit were associated with higher education (r=0.787; p<0.024). Of the minority of respondents who judged it never acceptable for doctors to recommend placebo treatments, the most often referenced rationale was obligation of the doctor to do more (n=102, 48.3%). Additional themes emerged around the issue of whether a doctor was transparent about placebo use, including honesty, patient's right to know and power of the mind. Older age was associated with likelihood to cite overall physician, as opposed to treatment, related themes (r=0.753; p<0.002). Participants seem to appreciate and understand the lack of harm and potential benefit associated with placebo treatments, while valuing the role of the physician and the patient in its implementation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Chemotherapy following radium‐223 dichloride treatment in ALSYMPCA

PubMed Central

Hoskin, Peter; Coleman, Robert E.; Nilsson, Sten; Vogelzang, Nicholas J.; Petrenciuc, Oana; Staudacher, Karin; Thuresson, Marcus; Parker, Christopher

2016-01-01

BACKGROUND Radium‐223 prolongs overall survival in patients with castration‐resistant prostate cancer (CRPC) and symptomatic bone metastases, regardless of prior docetaxel. Whether or not chemotherapy can be safely administered following radium‐223 treatment is of clinical importance. An exploratory analysis of prospectively collected data, from the ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) patient subgroup who received chemotherapy after radium‐223 or placebo treatment, was conducted to evaluate the safety and efficacy of chemotherapy following radium‐223. METHODS In ALSYMPCA, CRPC patients with symptomatic bone metastases and no visceral metastases were randomized 2:1 to receive six injections of radium‐223 (50 kBq/kg IV) or placebo plus best standard of care, stratified by prior docetaxel, baseline alkaline phosphatase, and current bisphosphonate use. In this exploratory analysis, chemotherapy agents administered following study treatment were identified; timing and duration were calculated. Hematologic safety was reviewed, and overall survival analyzed. RESULTS Overall, 142 radium‐223 and 64 placebo patients received subsequent chemotherapy; most common were docetaxel (70% radium‐223, 72% placebo) and mitoxantrone (16% radium‐223, 20% placebo). The majority of patients (61% radium‐223, 58% placebo) had received prior docetaxel. Radium‐223 patients started subsequent chemotherapy later than placebo patients; chemotherapy duration was similar between groups. In radium‐223 and placebo patients receiving subsequent chemotherapy, median hematologic values (hemoglobin, neutrophils, and platelets) remained nearly constant up to 18 months following start of chemotherapy, regardless of prior docetaxel treatment. A low percentage of patients in both groups had grades 3–4 hematologic values (<10%). Platelet count decline, from last measurement before chemotherapy, was numerically greater in radium‐223 versus placebo patients. Median overall survivals from start of chemotherapy were 16.0 and 15.8 months following radium‐223 and placebo, respectively. CONCLUSIONS Chemotherapy following radium‐223, regardless of prior docetaxel, is feasible and appears to be well tolerated in patients with CRPC and symptomatic bone metastases. Prostate 76:905–916, 2016. © 2016 The Authors. The Prostate published by Wiley Periodicals, Inc. PMID:27004570

Amiodarone prophylaxis for tachycardias after coronary artery surgery: a randomised, double blind, placebo controlled trial.

PubMed Central

Butler, J; Harriss, D R; Sinclair, M; Westaby, S

1993-01-01

BACKGROUND--Arrhythmias are a common cause of morbidity after cardiac surgery. This study assessed the efficacy of prophylactic amiodarone in reducing the incidence of atrial fibrillation or flutter and ventricular arrhythmias after coronary artery surgery. METHODS--A double blind, randomised, placebo controlled trial. 60 patients received a 24 hour intravenous infusion of amiodarone (15 mg/kg started after removal of the aortic cross clamp) followed by 200 mg orally three times daily for 5 days, and 60 patients received placebo. RESULTS--6 patients (10%) in the amiodarone group and 14 (23%) in the placebo group needed treatment for arrhythmias (95% confidence interval (95% CI) for the difference between groups was 0 to 26%, p = 0.05). The incidence of supraventricular tachycardia detected clinically and requiring treatment was lower in the amiodarone group (8% amiodarone v 20% placebo, 95% CI 0 to 24%, p = 0.07). The incidence detected by 24 hour Holter monitoring was similar (17% amiodarone v 20% placebo). Untreated arrhythmias in the amiodarone group were either clinically benign and undetected (n = 3) or the ventricular response rate was slow (n = 2). Age > 60 years was a positive risk factor for the development of supraventricular tachycardia in the amiodarone group but not in the placebo group. Fewer patients had episodes of ventricular tachycardia or fibrillation recorded on Holter monitoring in the amiodarone group (15% amiodarone v 33% placebo, 95% CI 3 to 33%, p = 0.02). Bradycardia (78% amiodarone v 48% placebo, 95% CI 14% to 46%, p < 0.005) and pauses (7% amiodarone v 0% placebo) occurred in more amiodarone treated patients. Bradycardia warranted discontinuation of treatment in one patient treated with amiodarone. CONCLUSIONS--The incidence of clinically significant tachycardia was reduced by amiodarone. The ventricular response rate was slowed in supraventricular tachycardia, but the induction of bradycardia may preclude the routine use of amiodarone for prophylaxis. PMID:8038000

A Randomized Study of Lubiprostone for Opioid-Induced Constipation in Patients with Chronic Noncancer Pain

PubMed Central

Cryer, Byron; Katz, Seymour; Vallejo, Ricardo; Popescu, Anca; Ueno, Ryuji

2014-01-01

Objective To evaluate the efficacy and safety of oral lubiprostone for relieving symptoms of opioid-induced constipation (OIC) in patients with chronic noncancer pain. Design Prospective, randomized, double-blind, placebo-controlled trial. Setting Seventy-nine US and Canadian centers. Subjects Patients aged ≥18 years with OIC, defined as <3 spontaneous bowel movements (SBMs) per week. Methods Patients received lubiprostone 24 mcg or placebo twice daily for 12 weeks. The primary endpoint was change from baseline in SBM frequency at week 8. Results Among randomized patients (N = 418; lubiprostone, N = 210; placebo, N = 208), most completed the study (lubiprostone, 67.1%; placebo, 69.7%). The safety and efficacy (intent-to-treat) populations included 414 (lubiprostone, N = 208; placebo, N = 206) and 413 (lubiprostone, N = 209; placebo, N = 204) patients, respectively. The mean (standard deviation) age was 50.4 (10.9) years; most patients were female (64.4%) and white (77.7%). Changes from baseline in SBM frequency rates were significantly higher at week 8 (P = 0.005) and overall (P = 0.004) in patients treated with lubiprostone compared with placebo. Pairwise comparisons showed significantly greater overall improvement for abdominal discomfort (P = 0.047), straining (P < 0.001), constipation severity (P = 0.007), and stool consistency (P < 0.001) with lubiprostone compared with placebo. Moreover, patients rated the effectiveness of lubiprostone as significantly (P < 0.05) better than placebo for 11 of 12 weeks. The most common treatment-related adverse events (AEs) with lubiprostone and placebo were nausea (16.8% vs 5.8%, respectively), diarrhea (9.6% vs 2.9%), and abdominal distention (8.2% vs 2.4%). No lubiprostone-related serious AEs occurred. Conclusion Lubiprostone effectively relieved OIC and associated signs and symptoms and was well tolerated in patients with chronic noncancer pain (http://clinicaltrials.gov/ct2/show/NCT00595946). PMID:24716835

Cardiovascular safety of empagliflozin in patients with type 2 diabetes: a meta-analysis of data from randomized placebo-controlled trials.

PubMed

Salsali, A; Kim, G; Woerle, H J; Broedl, U C; Hantel, S

2016-10-01

To assess the effect of empagliflozin on cardiovascular (CV) risk in patients with type 2 diabetes (T2DM) through a meta-analysis of data from eight placebo-controlled trials. Data were analysed from eight randomized placebo-controlled trials undertaken to investigate the efficacy and safety of empagliflozin 10 and 25 mg once daily in patients with T2DM, comprising patients at low/medium and high CV risk. Suspected CV events were prospectively adjudicated. The empagliflozin 10 and 25 mg groups were pooled for the primary analysis. The primary endpoint was a composite of CV death, non-fatal myocardial infarction (MI), non-fatal stroke and hospitalization for unstable angina [4-point major adverse CV events (MACE)]. The secondary endpoint was a composite of CV death, non-fatal MI and non-fatal stroke (3-point MACE). Risk estimates were calculated using Cox regression analysis. A total of 3835 patients received placebo and 7457 received empagliflozin. Total exposure was 7448.3 years for placebo and 15482.1 years for empagliflozin. Four-point MACE occurred in 365 (9.5%) patients receiving placebo and 635 (8.5%) patients receiving empagliflozin [hazard ratio for empagliflozin vs. placebo 0.86 (95% CI 0.76, 0.98)]. Three-point MACE occurred in 307 (8.0%) patients receiving placebo and 522 (7.0%) patients receiving empagliflozin [hazard ratio for empagliflozin vs. placebo 0.84 (95% CI 0.73, 0.96)]. In a meta-analysis of data from eight randomized trials involving 11 292 patients with T2DM at low/medium or high CV risk, empagliflozin was associated with a reduced risk of 4-point MACE and 3-point MACE compared with placebo. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Nizatidine versus placebo in active benign gastric ulcer disease: an eight-week, multicenter, randomized, double-blind comparison. The Nizatidine Benign Gastric Ulcer Disease Study Group.

PubMed

Cloud, M L; Enas, N; Offen, W W

1992-09-01

To determine if 150 mg nizatidine twice daily or 300 mg nizatidine at bedtime are similarly effective and to compare each dose with placebo in healing benign gastric ulcers and relieving peptic ulcer symptoms. This study was a randomized, double-blind, placebo-controlled parallel comparison. The study was conducted at 74 gastroenterology and internal medicine clinics in the United States and Canada. Four hundred fifty-six patients with active benign gastric ulcer documented by endoscopy participated in the study. On the basis of a computer-generated randomization list, patients were assigned sequentially to receive either 150 mg nizatidine twice daily (n = 151), 300 mg nizatidine once daily at bedtime and identically appearing placebo capsules in the morning (n = 153), or placebo capsules twice daily (n = 152). Treatment lasted for 8 weeks unless healing was documented by endoscopy after 4 weeks. Antacid tablets (aluminum hydroxide, magnesium hydroxide, simethicone combination) were supplied for relief of symptoms. Both doses of nizatidine significantly improved healing rates at 8 weeks compared with placebo. Daytime and nighttime symptom severity was improved by both nizatidine regimens at end point (p less than 0.015 versus placebo, two-tailed test). Antacid use was similar for all groups in the end point analysis. Patient well-being was significantly better in patients treated with nizatidine than in patients in the placebo group ((p less than 0.04, two-tailed test). No clinically significant differences in the incidence of adverse clinical or laboratory events were noted. Nizatidine, 300 mg at bedtime and 150 mg twice daily, resulted in greater healing of benign gastric ulcers than placebo treatment after 8 weeks. Relief of the symptoms of gastric ulcer was significantly better in the patients receiving nizatidine treatment versus placebo treatment.

A randomized study of lubiprostone for opioid-induced constipation in patients with chronic noncancer pain.

PubMed

Cryer, Byron; Katz, Seymour; Vallejo, Ricardo; Popescu, Anca; Ueno, Ryuji

2014-11-01

To evaluate the efficacy and safety of oral lubiprostone for relieving symptoms of opioid-induced constipation (OIC) in patients with chronic noncancer pain. Prospective, randomized, double-blind, placebo-controlled trial. Seventy-nine US and Canadian centers. Patients aged ≥ 18 years with OIC, defined as <3 spontaneous bowel movements (SBMs) per week. Patients received lubiprostone 24 mcg or placebo twice daily for 12 weeks. The primary endpoint was change from baseline in SBM frequency at week 8. Among randomized patients (N=418; lubiprostone, N=210; placebo, N=208), most completed the study (lubiprostone, 67.1%; placebo, 69.7%). The safety and efficacy (intent-to-treat) populations included 414 (lubiprostone, N=208; placebo, N=206) and 413 (lubiprostone, N=209; placebo, N=204) patients, respectively. The mean (standard deviation) age was 50.4 (10.9) years; most patients were female (64.4%) and white (77.7%). Changes from baseline in SBM frequency rates were significantly higher at week 8 (P=0.005) and overall (P=0.004) in patients treated with lubiprostone compared with placebo. Pairwise comparisons showed significantly greater overall improvement for abdominal discomfort (P=0.047), straining (P<0.001), constipation severity (P=0.007), and stool consistency (P<0.001) with lubiprostone compared with placebo. Moreover, patients rated the effectiveness of lubiprostone as significantly (P<0.05) better than placebo for 11 of 12 weeks. The most common treatment-related adverse events (AEs) with lubiprostone and placebo were nausea (16.8% vs 5.8%, respectively), diarrhea (9.6% vs 2.9%), and abdominal distention (8.2% vs 2.4%). No lubiprostone-related serious AEs occurred. Lubiprostone effectively relieved OIC and associated signs and symptoms and was well tolerated in patients with chronic noncancer pain (http://clinicaltrials.gov/ct2/show/NCT00595946). © 2014 The Authors. Pain Medicine published by Wiley Periodicals, Inc. on behalf of American Academy of Pain Medicine.

Effects of plasma rich in growth factors (PRGF) on biomechanical properties of Achilles tendon repair.

PubMed

López-Nájera, Diego; Rubio-Zaragoza, Mónica; Sopena-Juncosa, Joaquín J; Alentorn-Geli, Eduard; Cugat-Bertomeu, Ramón; Fernández-Sarmiento, J Andrés; Domínguez-Pérez, Juan M; García-Balletbó, Montserrat; Primo-Capella, Víctor J; Carrillo-Poveda, José M

2016-12-01

To assess the biomechanical effects of intra-tendinous injections of PRGF on the healing Achilles tendon after repair in a sheep model. Thirty sheep were randomly assigned into one of the six groups depending on the type of treatment received (PRGF or placebo) and survival time (2, 4 and 8 weeks). The Achilles tendon injury was repaired by suturing the tendinous edges employing a three-loop pulley pattern. A trans-articular external fixation system was then used for immobilization. The PRGF or placebo was administered on a weekly basis completing a maximum of three infiltrations. The force, section and tension values were compared between the operated and healthy Achilles tendons across all groups. The PRGF-treated tendons had higher force at 8 weeks compared with the placebo group (p = 0.007). Between 2 and 4 weeks, a significant increase in force in both the PRGF-treated tendon (p = 0.0027) and placebo group (p = 0.0095) occurred. No significant differences were found for section ratio between PRGF-treated tendons and the placebo group for any of the time periods evaluated. At 2 weeks, PRGF-treated tendons had higher tension ratio compared with placebo group tendons (p = 0.0143). Both PRGF and placebo treatments significantly improved the force (p < 0.001 and p = 0.0095, respectively) and tension (p = 0.009 and p = 0.0039, respectively) ratios at 8 weeks compared with 2 weeks. The application of PRGF increases Achilles tendon repair strength at 8 weeks compared with the use of placebo. The use of PRGF does not modify section and tension ratios compared with placebo at 8 weeks. The tension ratio progressively increases between 2 and 8 weeks compared with the placebo.

EDTA chelation therapy alone and in combination with oral high-dose multivitamins and minerals for coronary disease: The factorial group results of the Trial to Assess Chelation Therapy.

PubMed

Lamas, Gervasio A; Boineau, Robin; Goertz, Christine; Mark, Daniel B; Rosenberg, Yves; Stylianou, Mario; Rozema, Theodore; Nahin, Richard L; Terry Chappell, L; Lindblad, Lauren; Lewis, Eldrin F; Drisko, Jeanne; Lee, Kerry L

2014-07-01

Disodium ethylenediaminetetraacetic acid (EDTA) reduced adverse cardiac outcomes in a factorial trial also testing oral vitamins. This report describes the intent-to-treat comparison of the 4 factorial groups overall and in patients with diabetes. This was a double-blind, placebo-controlled, 2 × 2 factorial multicenter randomized trial of 1,708 post-myocardial infarction (MI) patients ≥50 years of age and with creatinine ≤2.0 mg/dL randomized to receive 40 EDTA chelation or placebo infusions plus 6 caplets daily of a 28-component multivitamin-multimineral mixture or placebo. The primary end point was a composite of total mortality, MI, stroke, coronary revascularization, or hospitalization for angina. Median age was 65 years, 18% were female, 94% were Caucasian, 37% were diabetic, 83% had prior coronary revascularization, and 73% were on statins. Five-year Kaplan-Meier estimates for the primary end point was 31.9% in the chelation + high-dose vitamin group, 33.7% in the chelation + placebo vitamin group, 36.6% in the placebo infusion + active vitamin group, and 40.2% in the placebo infusions + placebo vitamin group. The reduction in primary end point by double active treatment compared with double placebo was significant (hazard ratio 0.74, 95% CI 0.57-0.95, P = .016). In patients with diabetes, the primary end point reduction of double active compared with double placebo was more pronounced (hazard ratio 0.49, 95% CI 0.33-0.75, P < .001). In stable post-MI patients on evidence-based medical therapy, the combination of oral high-dose vitamins and chelation therapy compared with double placebo reduced clinically important cardiovascular events to an extent that was both statistically significant and of potential clinical relevance. Copyright © 2014 The Authors. Published by Mosby, Inc. All rights reserved.

The Placebo Effect in Clinical Trials for Alcohol Dependence: An Exploratory Analysis of 51 Naltrexone and Acamprosate Studies

PubMed Central

Litten, Raye Z.; Castle, I-Jen P.; Falk, Daniel; Ryan, Megan; Fertig, Joanne; Chen, Chiung M.; Yi, Hsiao-ye

2013-01-01

Background The placebo effect often undermines efforts to determine treatment effectiveness in clinical trials. A significant placebo response occurs in alcohol trials, but it is not well understood. The purpose of this study was to characterize the placebo response across multiple naltrexone and acamprosate studies. Methods Fifty-one trials, 3 with a naltrexone and an acamprosate arm, 31 with at least 1 naltrexone arm, and 17 with at least 1 acamprosate arm, were identified from Cochrane reviews and PubMed search. To be included in this study, patients had to be at least 18 years old, abstinent from alcohol before randomization, and meet a diagnosis of alcohol dependence. Pearson correlation coefficients (rp) and simple linear regression were used to describe the strength of linear relationships between placebo response and treatment effect size. Spearman’s rank correlation coefficients (rs) were used to examine the strength of associations between study characteristics and placebo response. Results For the end-point measures of percent days abstinent and total abstinence, a negative relationship was evident between placebo response and treatment effect size in the naltrexone trials (rp = −0.55, p < 0.01 and rp = −0.20, p = 0.35, respectively) as well as in the acamprosate trials (rp = −0.45, p = 0.09 and rp = −0.56, p = 0.01, respectively). The placebo response for percent days abstinent was negatively correlated with mean age of participants (rs = −0.42, p = 0.05) across naltrexone trials and positively correlated with publication year (rs = 0.57, p = 0.03) across acamprosate trials. However, these two study characteristics were not significantly correlated with treatment effect size. Conclusion The placebo response varied considerably across trials and was negatively correlated with the treatment effect size. Additional studies are required to fully understand the complex nature of the placebo response and to evaluate approaches to minimize its effects. PMID:23889231

Placebo and Nocebo Effects in Sexual Medicine: An Experimental Approach.

PubMed

Kruger, Tillmann H C; Grob, Carolin; de Boer, Claas; Peschel, Thomas; Hartmann, Uwe; Tenbergen, Gilian; Schedlowski, Manfred

2016-11-16

Few studies have investigated placebo and nocebo effects in a human sexuality context. Studying placebo and nocebo responses in this context may provide insight into their potential to modulate sexual drive and function. To examine such effects in sexual medicine, 48 healthy, male heterosexual participants were divided into four groups. Each group received instruction to expect stimulating effects, no effect, or an inhibitory effect on sexual functions. Only one group received the dopamine agonist cabergoline; all other groups received placebo or nocebo. Modulations in sexual experience were examined through an established experimental paradigm of sexual arousal and masturbation-induced orgasm during erotic film sequences with instruction to induce placebo or nocebo effects. Endocrine data, appetitive, consummatory, and refractory sexual behavior parameters were assessed using the Arizona Sexual Experience Scale (ASEX) and the Acute Sexual Experience Scale (ASES). Results showed increased levels of sexual function after administration of cabergoline with significant effects for several parameters. Placebo effects were induced only to a small degree. No negative effects on sexual parameters in the nocebo condition were noted. This paradigm could induce only small placebo and nocebo effects. This supports the view that healthy male sexual function seems relatively resistant to negative external influences.

Reconsidering the Placebo Response from a Broad Anthropological Perspective

PubMed Central

Thompson, Jennifer Jo; Ritenbaugh, Cheryl; Nichter, Mark

2009-01-01

This paper considers how the full range of human experience may catalyze a placebo response. The placebo effect has been characterized as something to control in clinical research, something to cultivate in clinical practice, and something present in all healing encounters. We examine domains in which the term ‘placebo’ is used in discourse: clinical research, clinical practice, media representations of treatment efficacy, and lay interpretations of placebo—an under-researched topic. We briefly review major theoretical frameworks proposed to explain the placebo effect: classical conditioning, expectancy, the therapeutic relationship, and sociocultural ‘meaning.’ As a corrective to what we see as an over-emphasis on conscious cognitive approaches to understanding placebo, we reorient the discussion to argue that direct embodied experience may take precedence over meaning-making in the healing encounter. As an example, we examine the neurobiology of rehearsing or visualizing wellness as a mode of directly (performatively) producing an outcome often dismissed as a ‘placebo response.’ Given body/mind/emotional resonance, we suggest that the placebo response is an evolutionarily adaptive trait and part of healing mechanisms operating across many levels—from genetic and cellular to social and cultural. PMID:19107582

A placebo-controlled, fixed-dose study of aripiprazole in children and adolescents with irritability associated with autistic disorder.

PubMed

Marcus, Ronald N; Owen, Randall; Kamen, Lisa; Manos, George; McQuade, Robert D; Carson, William H; Aman, Michael G

2009-11-01

To evaluate the short-term efficacy and safety of aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Two hundred eighteen children and adolescents (aged 6-17 years) with a diagnosis of autistic disorder, and with behaviors such as tantrums, aggression, self-injurious behavior, or a combination of these symptoms, were randomized 1:1:1:1 to aripiprazole (5, 10, or 15 mg/day) or placebo in this 8-week double-blind, randomized, placebo-controlled, parallel-group study. Efficacy was evaluated using the caregiver-rated Aberrant Behavior Checklist Irritability subscale (primary efficacy measure) and the clinician-rated Clinical Global Impressions-Improvement score. Safety and tolerability were also assessed. At week 8, all aripiprazole doses produced significantly greater improvement than placebo in mean Aberrant Behavior Checklist Irritability subscale scores (5 mg/day, -12.4; 10 mg/day, -13.2; 15 mg/day, -14.4; versus placebo, -8.4; all p < .05). All aripiprazole doses demonstrated significantly greater improvements in mean Clinical Global Impressions-Improvement score than placebo at week 8. Discontinuation rates due to adverse events were as follows: placebo 7.7%, aripiprazole 5 mg/day 9.4%, 10 mg/day 13.6%, and 15 mg/day 7.4%. The most common adverse event leading to discontinuation was sedation. There were two serious adverse events: presyncope (5 mg/day) and aggression (10 mg/day). At week 8, mean weight change (last observation carried forward) was as follows: placebo +0.3 kg, aripiprazole 5 mg/day +1.3 kg, 10 mg/day +1.3 kg, and 15 mg/day +1.5 kg; all p < .05 versus placebo. Aripiprazole was efficacious and generally safe and well tolerated in the treatment of children and adolescents with irritability associated with autistic disorder.

Pregabalin versus pramipexole: effects on sleep disturbance in restless legs syndrome.

PubMed

Garcia-Borreguero, Diego; Patrick, Jeffrey; DuBrava, Sarah; Becker, Philip M; Lankford, Alan; Chen, Crystal; Miceli, Jeffrey; Knapp, Lloyd; Allen, Richard P

2014-04-01

To compare pregabalin versus placebo and pramipexole for reducing restless legs syndrome (RLS)-related sleep disturbance. Randomized, double-blinded, crossover trial. Twenty-three US sleep centers. Eighty-five individuals with moderate to severe idiopathic RLS and associated sleep disturbance. Participants were randomized across 6 treatment sequences comprising three 4-week periods on pregabalin 300 mg/day (n = 75), pramipexole 0.5 mg/day (n = 76), or placebo (n = 73). Polysomnography was conducted over 2 nights at the end of each period. Primary (wake after sleep onset [WASO], pregabalin vs placebo) and key secondary endpoints were analyzed for statistical significance, with descriptive statistics for other endpoints. Pregabalin improved sleep maintenance, demonstrated by reductions in WASO (-27.1 min vs placebo [P < 0.0001]; -26.9 vs pramipexole) and number of awakenings after sleep onset (-2.7 vs placebo; -7.9 vs pramipexole [P < 0.0001]) by polysomnography, and an increase in subjective total sleep time (30.8 min vs placebo [P < 0.0001]; 26.8 vs pramipexole). Pregabalin also increased slow wave sleep duration (20.9 min vs placebo; 32.1 vs pramipexole [P < 0.0001]). Reduction in periodic limb movement arousal index (PLMAI) with pregabalin was similar to pramipexole and greater than placebo (-3.7 PLMA/h [P < 0.0001]), although reduction in total PLM in sleep was less than for pramipexole. This study demonstrated improvements in objective and subjective measures of sleep maintenance and sleep architecture with pregabalin compared with placebo and pramipexole. Effects of pregabalin on periodic limb movement arousal index were comparable to pramipexole. ClinicalTrials.gov identifier, NCT00991276; http://clinicaltrials.gov/show/NCT00991276.

A randomized, double-blind, placebo-controlled trial of safinamide as add-on therapy in early Parkinson's disease patients.

PubMed

Stocchi, Fabrizio; Borgohain, Rupam; Onofrj, Marco; Schapira, Anthony H V; Bhatt, Mohit; Lucini, Valentina; Giuliani, Rodolfo; Anand, Ravi

2012-01-01

Safinamide is an α-aminoamide with both dopaminergic and nondopaminergic mechanisms of action evaluated as an add-on to dopamine agonist (DA) therapy in early-stage PD. In this 24-week, double-blind study, patients with early PD receiving a stable dose of a single DA were randomized to once-daily safinamide 100 mg, safinamide 200 mg, or placebo. The primary efficacy variable was UPDRS part III (motor examination) total score. Analysis was hierarchical: 200 mg of safinamide versus placebo was tested first; the success of safinamide 100 mg versus placebo was contingent on this. Two hundred sixty-nine patients received safinamide 100 mg (n = 90), safinamide 200 mg (n = 89), or placebo (n = 90); 70, 81, and 81 patients, respectively, completed the study. Mean improvements from baseline to week 24 in UPDRS III total scores were -3.90 for safinamide 200 mg, -6.0 for safinamide 100 mg and -3.60 for placebo. The difference between safinamide 200 mg and placebo was not significant [point estimate: -0.4; 95% confidence interval (CI): -2.3-1.4; P = 0.6504]. Although the difference between 100 mg/day and placebo was significant (point estimate: -1.9; 95% CI: -3.7 to -0.1; P = 0.0419), these results are considered exploratory. No clinically meaningful differences from placebo were observed for any safety variables. This study did not demonstrate a significant improvement of the primary endpoint for safinamide 200 mg/day. Exploratory analysis of the primary endpoint for 100 mg/day demonstrated that the addition of safinamide to a stable dose of DA improves motor symptoms in early PD and warrants further investigation. Copyright © 2011 Movement Disorder Society.

No evidence for differential dose effects of hydrocortisone on intrusive memories in female patients with complex post-traumatic stress disorder--a randomized, double-blind, placebo-controlled, crossover study.

PubMed

Ludäscher, Petra; Schmahl, Christian; Feldmann, Robert E; Kleindienst, Nikolaus; Schneider, Miriam; Bohus, Martin

2015-10-01

Post-traumatic stress disorder is characterized by intrusive traumatic memories. Presently, a controversial debate is ongoing regarding whether reduced cortisol secretion in post-traumatic stress disorder promotes an automatic retrieval of trauma-associated memories. Hence, a pharmacological elevation of cortisol was proposed to decrease post-traumatic stress disorder symptoms, particularly intrusions. The present study investigated the impact of two different doses of hydrocortisone on automatic memory retrieval using a randomized, double-blind, placebo-controlled, crossover study in 30 inpatients with post-traumatic stress disorder. All participants were female and received various psychotropic medications. They were randomly assigned to one of two groups within a crossover design: they received either 1 week placebo followed by 1 week hydrocortisone 10/d, followed by 1 week placebo, followed by hydrocortisone 30 mg/d (15 participants) or 1 week hydrocortisone 30 mg/d, followed by 1 week placebo, followed by 1 week hydrocortisone 10 mg/d, followed by 1 week placebo (15 participants). The outcome measures were the frequency and the intensity of intrusions, the overall symptomatology of post-traumatic stress disorder and the general psychopathology. We did not find any differences in the frequency and the intensity of post-traumatic stress disorder-related intrusions between the 10 mg hydrocortisone, the 30 mg hydrocortisone and the placebo condition. All effect sizes for the hydrocortisone condition vs. placebo were very small. Additionally, the overall symptomatology of post-traumatic stress disorder and the general psychopathology did not differ between the hydrocortisone therapies and placebo. Our results do not show any effect of the hydrocortisone administration on intrusions in complex post-traumatic stress disorder. © The Author(s) 2015.

Effect of silodosin on specific urinary symptoms associated with benign prostatic hyperplasia: analysis of international prostate symptom scores in 2 phase III clinical studies.

PubMed

Gittelman, Marc C; Marks, Leonard S; Hill, Lawrence A; Volinn, Weining; Hoel, Gary

2010-01-01

Pooled results from 2 randomized, placebo-controlled, US phase III studies (NCT00224107, NCT00224120) showed that silodosin, a uroselective α-blocker, significantly improved International Prostate Symptom Scores (IPSS) in men with symptomatic benign prostatic hyperplasia (BPH). This analysis evaluated the effect of silodosin on each symptom assessed by IPSS questionnaire. Study participants (N = 923) were men aged ≥50 years with IPSS ≥13 and Qmax 4-15 mL/s. They received silodosin 8 mg or placebo once daily for 12 weeks. Patient responses to 7 IPSS questions were collected at weeks 0 (baseline), 0.5, 1, 2, 4, and 12 and scored on a 6-point scale. Efficacy of silodosin versus placebo was assessed by analysis of covariance. For each symptom, the 2 treatment groups had similar mean baseline scores. Decrease in score from baseline (mean ± standard deviation) to last observation was significantly greater with silodosin than with placebo for all symptoms (P < 0.005); symptom improvement with silodosin (versus placebo) was greatest for weak stream (silodosin, -1.1 ± 1.4 versus placebo, -0.5 ± 1.2; P < 0.0001) and smallest for nocturia (silodosin, -0.6 ± 1.1 versus placebo, -0.4 ± 1.2; P = 0.0037). Compared with placebo, silodosin significantly improved nocturia within 1 week (silodosin, -0.5 ± 1.07 versus placebo, -0.3 ± 1.05; P = 0.009) and all other symptoms within 3 to 4 days (P < 0.01). Silodosin significantly improved all BPH-associated symptoms assessed by IPSS questionnaire within the first week of treatment. All improvements were maintained over the 12-week study period.

Effect of silodosin on specific urinary symptoms associated with benign prostatic hyperplasia: analysis of international prostate symptom scores in 2 phase III clinical studies

PubMed Central

Gittelman, Marc C; Marks, Leonard S; Hill, Lawrence A; Volinn, Weining; Hoel, Gary

2011-01-01

Purpose Pooled results from 2 randomized, placebo-controlled, US phase III studies (NCT00224107, NCT00224120) showed that silodosin, a uroselective α-blocker, significantly improved International Prostate Symptom Scores (IPSS) in men with symptomatic benign prostatic hyperplasia (BPH). This analysis evaluated the effect of silodosin on each symptom assessed by IPSS questionnaire. Materials and methods Study participants (N = 923) were men aged ≥50 years with IPSS ≥13 and Qmax 4–15 mL/s. They received silodosin 8 mg or placebo once daily for 12 weeks. Patient responses to 7 IPSS questions were collected at weeks 0 (baseline), 0.5, 1, 2, 4, and 12 and scored on a 6-point scale. Efficacy of silodosin versus placebo was assessed by analysis of covariance. Results For each symptom, the 2 treatment groups had similar mean baseline scores. Decrease in score from baseline (mean ± standard deviation) to last observation was significantly greater with silodosin than with placebo for all symptoms (P < 0.005); symptom improvement with silodosin (versus placebo) was greatest for weak stream (silodosin, −1.1 ± 1.4 versus placebo, −0.5 ± 1.2; P < 0.0001) and smallest for nocturia (silodosin, −0.6 ± 1.1 versus placebo, −0.4 ± 1.2; P = 0.0037). Compared with placebo, silodosin significantly improved nocturia within 1 week (silodosin, −0.5 ± 1.07 versus placebo, −0.3 ± 1.05; P = 0.009) and all other symptoms within 3 to 4 days (P < 0.01). Conclusions Silodosin significantly improved all BPH-associated symptoms assessed by IPSS questionnaire within the first week of treatment. All improvements were maintained over the 12-week study period. PMID:24198629

Randomised clinical trial: evaluation of the efficacy of mesalazine (mesalamine) suppositories in patients with ulcerative colitis and active rectal inflammation -- a placebo-controlled study.

PubMed

Watanabe, M; Nishino, H; Sameshima, Y; Ota, A; Nakamura, S; Hibi, T

2013-08-01

Mesalazine suppositories are recommended and widely used as the standard therapy in induction and maintenance of remission for proctitis. To evaluate the efficacy of mesalazine suppositories in patients with ulcerative colitis (UC) and rectal inflammation; and in patient groups categorised by the extent of lesions. This study was a phase III multicentre, randomised, double-blind, placebo-controlled, parallel-group study. Mild-to-moderate UC patients with rectal inflammation were randomly assigned either a 1 g mesalazine or placebo suppository. The suppository was administered in the rectum once daily for 4 weeks. The primary efficacy end point was the rate of endoscopic remission (mucosal score of 0 or 1) after 4 weeks. The endoscopic remission rates after 4 weeks in the mesalazine and placebo suppository groups were 81.5% and 29.7%, respectively, and the superiority of mesalazine to placebo was confirmed (P < 0.0001, chi-squared test). For proctitis, the endoscopic remission rates after 4 weeks were 83.8% and 36.1% in the mesalazine and placebo suppository groups, respectively, and the corresponding rates for all other types of UC were 78.6% and 21.4%, respectively. The superiority of mesalazine to placebo was confirmed in both subgroups (P < 0.0001, Fisher's exact test). The percentage of patients without bleeding was significantly higher in the mesalazine group than the placebo group from Day 3 of treatment (P = 0.0001, Fisher's exact test). The effectiveness of mesalazine suppositories in all types of UC patients with rectal inflammation was confirmed for the first time in a double-blind, placebo-controlled, parallel-group study (JapicCTI- 111421). © 2013 John Wiley & Sons Ltd.

Nursing knowledge: hints from the placebo effect.

PubMed

Zanotti, Renzo; Chiffi, Daniele

2017-07-01

Nursing knowledge stems from a dynamic interplay between population-based scientific knowledge (the general) and specific clinical cases (the particular). We compared the 'cascade model of knowledge translation', also known as 'classical biomedical model' in clinical practice (in which knowledge gained at population level may be applied directly to a specific clinical context), with an emergentist model of knowledge translation. The structure and dynamics of nursing knowledge are outlined, adopting the distinction between epistemic and non-epistemic values. Then, a (moderately) emergentist approach to nursing knowledge is proposed, based on the assumption of a two-way flow from the general to the particular and vice versa. The case of the 'placebo effect' is analysed as an example of emergentist knowledge. The placebo effect is usually considered difficult to be explained within the classical biomedical model, and we underscore its importance in shaping nursing knowledge. In fact, nurses are primarily responsible for administering placebo in the clinical setting and have an essential role in promoting the placebo effect and reducing the nocebo effect. The beliefs responsible for the placebo effect are as follows: (1) interactive, because they depend on the relationship between patients and health care professionals; (2) situated, because they occur in a given clinical context related to certain rituals; and (3) grounded on higher order beliefs concerning what an individual thinks about the beliefs of others. It is essential to know the clinical context and to understand other people's beliefs to make sense of the placebo effect. The placebo effect only works when the (higher order) beliefs of doctors, nurses and patients interact in a given setting. Finally, we argue for a close relationship between placebo effect and nursing knowledge. © 2016 John Wiley & Sons Ltd.

Saccharomyces boulardii for the prevention of antibiotic-associated diarrhea in adult hospitalized patients: a single-center, randomized, double-blind, placebo-controlled trial.

PubMed

Pozzoni, Pietro; Riva, Alessia; Bellatorre, Alessandro Giacco; Amigoni, Maria; Redaelli, Elena; Ronchetti, Anna; Stefani, Mariangela; Tironi, Rosangela; Molteni, Edoardo Ennio; Conte, Dario; Casazza, Giovanni; Colli, Agostino

2012-06-01

Antibiotic-associated diarrhea (AAD) and Clostridium difficile-associated diarrhea (CDAD) are common complications of antibiotic use. Probiotics were effective in preventing AAD and CDAD in several randomized controlled trials. This study was aimed at testing the effect of Saccharomyces boulardii on the occurrence of AAD and CDAD in hospitalized patients. A single-center, randomized, double-blind, placebo-controlled, parallel-group trial was performed. Patients being prescribed antibiotics or on antibiotic therapy for <48 h were eligible. Exclusion criteria were ongoing diarrhea, recent assumption of probiotics, lack of informed consent, inability to ingest capsules, and severe pancreatitis. Patients received a capsule containing S. boulardii or an indistinguishable placebo twice daily within 48 h of beginning antibiotic therapy, continued treatment for 7 days after antibiotic withdrawal, and were followed for 12 weeks after ending antibiotic treatment. Of 562 consecutive eligible patients, 275 patients aged 79.2 ± 9.8 years (134 on placebo) were randomized and 204 aged 78.4 ± 10.0 years (98 on placebo) completed the follow-up. AAD developed in 13.3% (13/98) of the patients receiving placebo and in 15.1% (16/106) of those receiving S. boulardii (odds ratio for S. boulardii vs. placebo, 1.16; 95% confidence interval (CI), 0.53-2.56). Five cases of CDAD occurred, 2 in the placebo group (2.0%) and 3 in the probiotic group (2.8%; odds ratio for S. boulardii vs. placebo, 1.40; 95% CI, 0.23-8.55). There was no difference in mortality rates (12.7% vs. 15.6%, P=0.60). In elderly hospitalized patients, S. boulardii was not effective in preventing the development of AAD.

A double-blind, placebo-controlled trial of epsilon-aminocaproic acid for reducing blood loss in coronary artery bypass grafting surgery.

PubMed

Kikura, Mutsuhito; Levy, Jerrold H; Tanaka, Kenichi A; Ramsay, James G

2006-02-01

Epsilon-aminocaproic acid is a plasmin inhibitor that potentially reduces perioperative bleeding when administered prophylactically to cardiac surgery patients. To evaluate the efficacy of epsilon-aminocaproic acid, a prospective placebo-controlled trial was conducted in patients undergoing primary coronary artery bypass grafting surgery. One hundred patients were randomly assigned to receive either epsilon-aminocaproic acid (100 mg/kg before skin incision followed by 1 g/hour continuous infusion until chest closure, 10 g in cardiopulmonary bypass circuit) or placebo, and the efficacy of epsilon-aminocaproic acid was evaluated by the reduction in postoperative thoracic-drainage volume and in donor-blood transfusion up to postoperative day 12. Postoperative thoracic-drainage volume was significantly lower in the epsilon-aminocaproic acid group compared with the placebo group (epsilon-aminocaproic acid, 649 +/- 261 mL; versus placebo, 940 +/- 626 mL; p=0.003). There were no significant differences between the epsilon-aminocaproic acid and placebo groups in the percentage of patients requiring donor red blood cell transfusions (epsilon-aminocaproic acid, 24%; versus placebo, 18%; p=0.62) or in the number of units of donor red blood cells transfused (epsilon-aminocaproic acid, 2.2 +/- 0.8 U; versus placebo, 1.9 +/- 0.8 U; p=0.29). Epsilon-aminocaproic acid did not reduce the risk of donor red blood cell transfusions compared with placebo (odds ratio: 1.2, 95% confidence interval; 0.4 to 3.2, p=0.63). Prophylactic administration of epsilon-aminocaproic acid reduces postoperative thoracic-drainage volume by 30%, but it may not be potent enough to reduce the requirement and the risk for donor blood transfusion in cardiac surgery patients. This information is useful for deciding on a therapy for hemostasis in cardiac surgery.

Erlotinib, erlotinib-sulindac versus placebo: a randomized, double-blind, placebo-controlled window trial in operable head and neck cancer.

PubMed

Gross, Neil D; Bauman, Julie E; Gooding, William E; Denq, William; Thomas, Sufi M; Wang, Lin; Chiosea, Simion; Hood, Brian L; Flint, Melanie S; Sun, Mai; Conrads, Thomas P; Ferris, Robert L; Johnson, Jonas T; Kim, Seungwon; Argiris, Athanassios; Wirth, Lori; Nikiforova, Marina N; Siegfried, Jill M; Grandis, Jennifer R

2014-06-15

The EGF receptor (EGFR) and COX2 pathways are upregulated in head and neck squamous cell carcinoma (HNSCC). Preclinical models indicate synergistic antitumor activity from dual blockade. We conducted a randomized, double-blind, placebo-controlled window trial of erlotinib, an EGFR inhibitor; erlotinib plus sulindac, a nonselective COX inhibitor; versus placebo. Patients with untreated, operable stage II-IVb HNSCC were randomized 5:5:3 to erlotinib, erlotinib-sulindac, or placebo. Tumor specimens were collected before and after seven to 14 days of treatment. The primary endpoint was change in Ki67 proliferation index. We hypothesized an ordering effect in Ki67 reduction: erlotinib-sulindac > erlotinib > placebo. We evaluated tissue microarrays by immunohistochemistry for pharmacodynamic modulation of EGFR and COX2 signaling intermediates. From 2005-2009, 47 patients were randomized for the target 39 evaluable patients. Thirty-four tumor pairs were of sufficient quality to assess biomarker modulation. Ki67 was significantly decreased by erlotinib or erlotinib-sulindac (omnibus comparison, two-sided Kruskal-Wallis, P = 0.04). Wilcoxon pairwise contrasts confirmed greater Ki67 effect in both erlotinib groups (erlotinib-sulindac vs. placebo, P = 0.043; erlotinib vs. placebo, P = 0.027). There was a significant trend in ordering of Ki67 reduction: erlotinib-sulindac > erlotinib > placebo (two-sided exact Jonckheere-Terpstra, P = 0.0185). Low baseline pSrc correlated with greater Ki67 reduction (R(2) = 0.312, P = 0.024). Brief treatment with erlotinib significantly decreased proliferation in HNSCC, with additive effect from sulindac. Efficacy studies of dual EGFR-COX inhibition are justified. pSrc is a potential resistance biomarker for anti-EGFR therapy, and warrants investigation as a molecular target. ©2014 American Association for Cancer Research.

Erlotinib, erlotinib-sulindac vs. placebo: a randomized, double-blind, placebo-controlled window trial in operable head and neck cancer

PubMed Central

Gross, Neil D.; Bauman, Julie E.; Gooding, William E.; Denq, William; Thomas, Sufi M.; Wang, Lin; Chiosea, Simion; Hood, Brian L.; Flint, Melanie S.; Sun, Mai; Conrads, Thomas P.; Ferris, Robert L.; Johnson, Jonas T.; Kim, Seungwon; Argiris, Athanassios; Wirth, Lori; Nikiforova, Marina N.; Siegfried, Jill M.; Grandis, Jennifer R.

2014-01-01

Purpose The epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) pathways are upregulated in head and neck squamous cell carcinoma (HNSCC). Preclinical models indicate synergistic anti-tumor activity from dual blockade. We conducted a randomized, double-blind, placebo-controlled window trial of erlotinib, an EGFR inhibitor; erlotinib plus sulindac, a non-selective COX inhibitor, vs. placebo. Experimental Design Patients with untreated, operable Stage II-IVb HNSCC were randomized 5:5:3 to erlotinib, erlotinib-sulindac, or placebo. Tumor specimens were collected before and after 7-14 days of treatment. The primary endpoint was change in Ki-67 proliferation index. We hypothesized an ordering effect in Ki-67 reduction: erlotinib-sulindac > erlotinib > placebo. We evaluated tissue microarrays by immunohistochemistry for pharmacodynamic modulation of EGFR and COX-2 signaling intermediates. Results From 2005-2009, 47 patients were randomized for the target 39 evaluable patients. Thirty-four tumor pairs were of sufficient quality to assess biomarker modulation. Ki-67 was significantly decreased by erlotinib or erlotinib-sulindac (omnibus comparison, two-sided Kruskal-Wallis, p=0.04). Wilcoxon pairwise contrasts confirmed greater Ki-67 effect in both erlotinib groups (erlotinib-sulindac vs. placebo p=0.043; erlobinib vs. placebo, p=0.027). There was a significant trend in ordering of Ki-67 reduction: erlotinib-sulindac > erlotinib > placebo (two-sided exact Jonckheere-Terpstra, p =0.0185). Low baseline pSrc correlated with greater Ki-67 reduction (R2 = .312, p = 0.024). Conclusions Brief treatment with erlotinib significantly decreased proliferation in HNSCC, with additive effect from sulindac. Efficacy studies of dual EGFR-COX inhibition are justified. pSrc is a potential resistance biomarker for anti-EGFR therapy, and warrants investigation as a molecular target. PMID:24727329

Effect of red yeast rice combined with antioxidants on lipid pattern, hs-CRP level, and endothelial function in moderately hypercholesterolemic subjects.

PubMed

Cicero, Arrigo F G; Morbini, Martino; Parini, Angelo; Urso, Riccardo; Rosticci, Martina; Grandi, Elisa; Borghi, Claudio

2016-01-01

Our aim was to test, through a crossover, double-blind, placebo-controlled randomized clinical trial, if a short-term treatment with 10 mg monacolins combined with antioxidants could improve lipid pattern, high-sensitivity C-reactive protein (hs-CRP), and endothelial function in a small cohort of moderately hypercholesterolemic subjects. Thus, 25 healthy, moderately hypercholesterolemic subjects were consecutively enrolled and, after 4 weeks of stabilization diet, were randomized to the sequence placebo followed by a washout, monacolins or monacolins followed by a washout, placebo, with each period being 4 weeks long. At each study step, a complete lipid pattern, safety parameters, hs-CRP, and endothelial function have been measured. When compared to the placebo phase, during monacolin treatment, patients experienced a more favorable percentage change in total cholesterol (TC) (TC after monacolin treatment, -18.35%; TC after placebo treatment, -5.39%), low-density lipoprotein cholesterol (LDL-C) (LDL after monacolin treatment, -22.36%; LDL after placebo treatment, -1.38%), non-high-density lipoprotein cholesterol (HDL-C) (non-HDL after monacolin treatment, -22.83%; non-HDL after placebo treatment: -7.15%), hs-CRP (hs-CRP after monacolin treatment: -2.33%; hs-CRP after placebo treatment, 2.11%), and endothelial function (pulse volume displacement after monacolin treatment, 18.59%; pulse volume displacement after placebo treatment, -6.69%). No significant difference was observed with regard to triglycerides, HDL-cholesterol, and safety parameters. On the basis of our data, we could demonstrate that a 10 mg monacolin nutraceutical treatment appears to safely reduce cholesterolemia, hs-CRP, and markers of vascular remodeling in moderately hypercholesterolemic subjects. These results need to be confirmed in larger patient samples and in studies with longer duration.

A randomized, double-blind, placebo-controlled clinical trial of megestrol acetate as an appetite stimulant in children with weight loss due to cancer and/or cancer therapy.

PubMed

Cuvelier, Geoff D E; Baker, Tina J; Peddie, Elaine F; Casey, Linda M; Lambert, Pascal J; Distefano, Dianne S; Wardle, Marlene G; Mychajlunow, Beth A; Romanick, Marcel A; Dix, David B; Wilson, Beverly A

2014-04-01

Megestrol acetate (MA) is an appetite stimulant with efficacy in promoting weight gain in adults with cancer-associated anorexia-cachexia. Studies documenting MA efficacy in children, however, are limited. We present the first randomized, double-blind, placebo-controlled clinical trial of MA versus placebo in children with cancer and weight loss. Subjects <18 years of age with weight loss (minimum 5% from highest previous weight; or %ideal body weight <90%) due to cancer and/or cancer therapy were randomized to either MA (7.5 mg/kg/day) or placebo for a planned study duration of 90 days. Primary outcome was the difference between groups in mean percent weight change from beginning to end of the study period. Secondary outcomes included effects on anthropometrics, body composition, need for tube feeding or parenteral nutrition, and toxicities. Twenty-six patients were randomly assigned (13 MA, 13 placebo). The MA group experienced a mean weight gain of +19.7% compared to a mean weight loss of -1.2% in the placebo group, for a difference of +20.9% (95%CI: +11.3% to +30.5%, P = 0.003) in favor of MA over placebo. MA subjects experienced significant increases in weight for age z-scores, body mass index z-scores, and mid upper arm circumference compared to placebo. DXA scanning suggested disproportionate increases in fat accrual. Adrenal suppression was the main toxicity of MA. In children with high-risk malignancies, MA resulted in significant increases in mean percent weight change compared to placebo. Further studies of MA should be pursued to better delineate the effect on nutritional status. © 2013 Wiley Periodicals, Inc.

[Effect of Xinling Wan in treatment of stable angina pectoris: a randomized, double-blinded, placebo parallel-controlled, multicenter trial].

PubMed

Gao, Jian-Wei; Gao, Xue-Min; Zou, Ting; Zhao, Tian-Meng; Wang, Dong-Hua; Wu, Zong-Gui; Ren, Chang-Jie; Wang, Xing; Geng, Nai-Zhi; Zhao, Ming-Jun; Liang, Qiu-Ming; Feng, Xing; Yang, Bai-Song; Shi, Jun-Ling; Hua, Qi

2018-03-01

To evaluate the effectiveness and safety of Xinling Wan on patients with stable angina pectoris, a randomized, double-blinded, placebo parallel-controlled, multicenter clinical trial was conducted. A total of 232 subjects were enrolled and randomly divided into experiment group and placebo group. The experiment group was treated with Xinling Wan (two pills each time, three times daily) for 4 weeks, and the placebo group was treated with placebo. The effectiveness evaluation showed that Xinling Wan could significantly increase the total duration of treadmill exercise among patients with stable angina pectoris. FAS analysis showed that the difference value of the total exercise duration was between experiment group (72.11±139.32) s and placebo group (31.25±108.32) s. Xinling Wan could remarkably increase the total effective rate of angina pectoris symptom score, and the analysis showed that the total effective rate was 78.95% in experiment group and 42.61% in placebo group. The reduction of nitroglycerin dose was (2.45±2.41) tablets in experiment group and (0.50±2.24) tablets in placebo group on the basis of FAS analysis. The decrease of symptom integral was (4.68±3.49) in experiment group and (3.19±3.31) in placebo group based on FAS analysis. Besides, Xinling Wan could decrease the weekly attack time and the duration of angina pectoris. PPS analysis results were similar to those of FAS analysis. In conclusion, Xinling Wan has an obvious therapeutic effect in treating stable angina pectoris, with a good safety and a low incidence of adverse event and adverse reaction in experiment group. Copyright© by the Chinese Pharmaceutical Association.

What Is the Role of the Placebo Effect for Pain Relief in Neurorehabilitation? Clinical Implications From the Italian Consensus Conference on Pain in Neurorehabilitation.

PubMed

Castelnuovo, Gianluca; Giusti, Emanuele Maria; Manzoni, Gian Mauro; Saviola, Donatella; Gabrielli, Samantha; Lacerenza, Marco; Pietrabissa, Giada; Cattivelli, Roberto; Spatola, Chiara Anna Maria; Rossi, Alessandro; Varallo, Giorgia; Novelli, Margherita; Villa, Valentina; Luzzati, Francesca; Cottini, Andrea; Lai, Carlo; Volpato, Eleonora; Cavalera, Cesare; Pagnini, Francesco; Tesio, Valentina; Castelli, Lorys; Tavola, Mario; Torta, Riccardo; Arreghini, Marco; Zanini, Loredana; Brunani, Amelia; Seitanidis, Ionathan; Ventura, Giuseppe; Capodaglio, Paolo; D'Aniello, Guido Edoardo; Scarpina, Federica; Brioschi, Andrea; Bigoni, Matteo; Priano, Lorenzo; Mauro, Alessandro; Riva, Giuseppe; Di Lernia, Daniele; Repetto, Claudia; Regalia, Camillo; Molinari, Enrico; Notaro, Paolo; Paolucci, Stefano; Sandrini, Giorgio; Simpson, Susan; Wiederhold, Brenda Kay; Gaudio, Santino; Jackson, Jeffrey B; Tamburin, Stefano; Benedetti, Fabrizio

2018-01-01

It is increasingly acknowledged that the outcomes of medical treatments are influenced by the context of the clinical encounter through the mechanisms of the placebo effect. The phenomenon of placebo analgesia might be exploited to maximize the efficacy of neurorehabilitation treatments. Since its intensity varies across neurological disorders, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCP) summarized the studies on this field to provide guidance on its use. A review of the existing reviews and meta-analyses was performed to assess the magnitude of the placebo effect in disorders that may undergo neurorehabilitation treatment. The search was performed on Pubmed using placebo, pain, and the names of neurological disorders as keywords. Methodological quality was assessed using a pre-existing checklist. Data about the magnitude of the placebo effect were extracted from the included reviews and were commented in a narrative form. 11 articles were included in this review. Placebo treatments showed weak effects in central neuropathic pain (pain reduction from 0.44 to 0.66 on a 0-10 scale) and moderate effects in postherpetic neuralgia (1.16), in diabetic peripheral neuropathy (1.45), and in pain associated to HIV (1.82). Moderate effects were also found on pain due to fibromyalgia and migraine; only weak short-term effects were found in complex regional pain syndrome. Confounding variables might have influenced these results. These estimates should be interpreted with caution, but underscore that the placebo effect can be exploited in neurorehabilitation programs. It is not necessary to conceal its use from the patient. Knowledge of placebo mechanisms can be used to shape the doctor-patient relationship, to reduce the use of analgesic drugs and to train the patient to become an active agent of the therapy.

Efficient assessment of efficacy in post-traumatic peripheral neuropathic pain patients: pregabalin in a randomized, placebo-controlled, crossover study

PubMed Central

Jenkins, Tim M; Smart, Trevor S; Hackman, Frances; Cooke, Carol; Tan, Keith KC

2012-01-01

Background: Detecting the efficacy of novel analgesic agents in neuropathic pain is challenging. There is a critical need for study designs with the desirable characteristics of assay sensitivity, low placebo response, reliable pain recordings, low cost, short duration of exposure to test drug and placebo, and relevant and recruitable population. Methods: We designed a proof-of-concept, double-blind, randomized, placebo-controlled, crossover study in patients with post-traumatic peripheral neuropathic pain (PTNP) to evaluate whether such a study design had the potential to detect efficacious agents. Pregabalin, known to be efficacious in neuropathic pain, was used as the active analgesic. We also assessed physical activity throughout the study. Results: Twenty-five adults (20–70 years of age) with PTNP for ≥3 months entered a screening week and were then randomized to one of the two following treatment sequences: (1) pregabalin followed by placebo or (2) placebo followed by pregabalin. These 2-week treatment periods were separated by a 2-week washout period. Patients on pregabalin treatment received escalating doses to a final dosage of 300 mg/day (days 5–15). In an attempt to minimize placebo response, patients received placebo treatment during the screening week and the 2-week washout period. Average daily pain scores (primary endpoint) were significantly reduced for pregabalin versus placebo, with a mean treatment difference of −0.81 (95% confidence interval: −1.45 to −0.17; P = 0.015). Conclusion: The efficacy of pregabalin was similar to that identified in a large, parallel group trial in PTNP. Therefore, this efficient crossover study design has potential utility for future proof-of-concept studies in neuropathic pain. PMID:22888270

A diet containing whey protein, glutamine, and TGFbeta modulates gut protein metabolism during chemotherapy-induced mucositis in rats.

PubMed

Boukhettala, Nabile; Ibrahim, Ayman; Claeyssens, Sophie; Faure, Magali; Le Pessot, Florence; Vuichoud, Jacques; Lavoinne, Alain; Breuillé, Denis; Déchelotte, Pierre; Coëffier, Moïse

2010-08-01

Mucositis, a common side effect of chemotherapy, is characterized by compromised digestive function, barrier integrity and immune competence. Our aim was to evaluate the impact of a specifically designed diet Clinutren Protect (CP), which contains whey proteins, TGFbeta-rich casein, and free glutamine, on mucositis in rats. Mucositis was induced by three consecutive injections (day 0, day 1, day 2) of methotrexate (2.5 mg/kg). Rats had free access to CP or placebo diets from days -7 to 9. In the placebo diet, whey proteins and TGFbeta-rich casein were replaced by TGFbeta-free casein and glutamine by alanine. Intestinal parameters were assessed at day 3 and 9. Values, expressed as mean +/- SEM, were compared using two-way ANOVA. At day 3, villus height was markedly decreased in the placebo (296 +/- 11 microm) and CP groups (360 +/- 10 microm) compared with controls (464 +/- 27 microm), but more markedly in the placebo as compared to CP group. The intestinal damage score was also reduced in the CP compared with the placebo group. Glutathione content increased in the CP compared with the placebo group (2.2 +/- 0.2 vs. 1.7 +/- 0.2 micromol/g tissue). Gut protein metabolism was more affected in the placebo than in the CP group. The fractional synthesis rate was decreased in the placebo group (93.8 +/- 4.9%/day) compared with controls (121.5 +/- 12.1, P < 0.05), but not in the CP group (106.0 +/- 13.1). In addition, at day 9, rats exhibited improved body weight and food intake recovery in the CP compared to the placebo group. Clinutren Protect feeding reduces intestinal injury in the acute phase of methotrexate-induced mucositis in rats and improves recovery.

Knowledge, attitude and practice among Chinese acupuncturists receiving sham and/or placebo acupuncture: a cross-sectional survey.

PubMed

Jin, Chunlan; Zhou, Xinyao; Pang, Ran

2015-06-01

Placebo and sham acupuncture are common control strategies in acupuncture studies. However, the perception and practice of these approaches in acupuncturists are poorly documented. To investigate knowledge of, attitude towards and practice of sham and/or placebo acupuncture among Chinese acupuncturists. A cross-sectional survey conducted in six different tertiary care hospitals of traditional Chinese medicine in Beijing, China. A total of 92 licensed acupuncturists were asked to complete a predesigned and structured questionnaire on-site. A response rate of 92.4% (n=85) was achieved. Almost all participants (99%, n=84) had moderate knowledge about sham and/or placebo acupuncture, but only a minority (27%, n=23) reported an excellent understanding. The general attitude towards sham and/or placebo acupuncture was positive. Most respondents (99%, n=84) thought such controls were necessary and the majority (81%, n=69) believed they were feasible in acupuncture research. More than two-thirds of participants (71%, n=60) had applied sham and/or placebo acupuncture, but only a few (8%, 5/60) used it as the most common control strategy in clinical trials. The result of our survey suggests that Chinese acupuncturists have a moderate knowledge of, and a positive attitude towards, sham and/or placebo acupuncture. Research into sham and/or placebo acupuncture is limited in comparison with other control strategies. Therefore, an in-service education programme for acupuncturists and standardisation of sham and/or placebo acupuncture need to be developed. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Effect of opicapone multiple‐dose regimens on levodopa pharmacokinetics

PubMed Central

Rocha, José‐Francisco; Sicard, Éric; Fauchoux, Nicolas; Falcão, Amílcar; Santos, Ana; Loureiro, Ana I.; Pinto, Roberto; Bonifácio, Maria João; Nunes, Teresa; Almeida, Luís

2016-01-01

Aims To compare the levodopa/carbidopa (LC) and levodopa/benserazide (LB) pharmacokinetic profiles following repeated doses of opicapone (OPC) administered apart from levodopa. Methods Two randomized, double blind, sex‐balanced, placebo‐controlled studies in four groups of 12 or 18 healthy subjects each. In each group, enrolled subjects received a once‐daily morning (5, 15 and 30 mg) or evening (5, 15 and 50 mg) administration of OPC or placebo for up to 28 days. On the morning of Day 11, 12 h after the OPC or placebo evening dose, or the morning of Day 21, 1 h after the OPC or placebo dose, a single dose of immediate‐release 100/25 mg LC was administered. Similarly, on Day 18 morning, 12 h after the OPC or placebo evening dose, or Day 28 morning, 1 h after the OPC or placebo dose, a single dose of immediate‐release 100/25 mg LB was administered. Results All OPC treatments, in relation to the placebo group, presented a higher extent of exposure (AUC) to levodopa following either LC or LB doses. A relevant but not dose‐dependent increase in the levodopa AUC occurred with all OPC dose groups in relation to placebo. All active treatments significantly inhibited both peak (Emax) and extent (AUEC) of the catechol‐O‐methyltransferase activity in relation to placebo. The tolerability profile was favourable. Conclusion Opicapone, as once‐daily oral evening regimen and/or 1 h apart from levodopa therapy, increases the bioavailability of levodopa associated with its pronounced, long‐lasting and sustained catechol‐O‐methyltransferase inhibition. The tolerability profile was favourable and similar between OPC and placebo. PMID:27763682

A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, FIXED-DOSE PHASE III STUDY OF VILAZODONE IN PATIENTS WITH GENERALIZED ANXIETY DISORDER

PubMed Central

Gommoll, Carl; Durgam, Suresh; Mathews, Maju; Forero, Giovanna; Nunez, Rene; Tang, Xiongwen; Thase, Michael E

2015-01-01

Background Vilazodone, a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist, is approved for treating major depressive disorder in adults. This study (NCT01629966 ClinicalTrials.gov) evaluated the efficacy and safety of vilazodone in adults with generalized anxiety disorder (GAD). Methods A multicenter, double-blind, parallel-group, placebo-controlled, fixed-dose study in patients with GAD randomized (1:1:1) to placebo (n = 223), or vilazodone 20 mg/day (n = 230) or 40 mg/day (n = 227). Primary and secondary efficacy parameters were total score change from baseline to week 8 on the Hamilton Rating Scale for Anxiety (HAMA) and Sheehan Disability Scale (SDS), respectively, analyzed using a predefined mixed-effect model for repeated measures (MMRM). Safety outcomes were presented by descriptive statistics. Results The least squares mean difference (95% confidence interval) in HAMA total score change from baseline (MMRM) was statistically significant for vilazodone 40 mg/day versus placebo (–1.80 [–3.26, –0.34]; P = .0312 [adjusted for multiple comparisons]), but not for vilazodone 20 mg/day versus placebo. Mean change from baseline in SDS total score was not significantly different for either dose of vilazodone versus placebo when adjusted for multiplicity; significant improvement versus placebo was noted for vilazodone 40 mg/day without adjustment for multiplicity (P = .0349). The incidence of adverse events was similar for vilazodone 20 and 40 mg/day (∼71%) and slightly lower for placebo (62%). Nausea, diarrhea, dizziness, vomiting, and fatigue were reported in ≥5% of patients in either vilazodone group and at least twice the rate of placebo. Conclusions Vilazodone was effective in treating anxiety symptoms of GAD. No new safety concerns were identified. PMID:25891440

Effect of cessation of GH treatment on cognition during transition phase in Prader-Willi syndrome: results of a 2-year crossover GH trial.

PubMed

Kuppens, R J; Mahabier, E F; Bakker, N E; Siemensma, E P C; Donze, S H; Hokken-Koelega, A C S

2016-11-16

Patients with Prader-Willi syndrome (PWS) have a cognitive impairment. Growth hormone (GH) treatment during childhood improves cognitive functioning, while cognition deteriorates in GH-untreated children with PWS. Cessation of GH treatment at attainment of adult height (AH) might deteriorate their GH-induced improved cognition, while continuation might benefit them. We, therefore, investigated the effects of placebo versus GH administration on cognition in young adults with PWS who were GH-treated for many years during childhood and had attained AH. Two-year, randomized, double-blind, placebo-controlled cross-over study in 25 young adults with PWS. Cross-over intervention with placebo and GH (0.67 mg/m 2 /day), both during 1 year. Total (TIQ), verbal (VIQ) and performance IQ (PIQ) did not deteriorate during 1 year of placebo, compared to GH treatment (p > 0.322). Young adults with a lower TIQ had significantly more loss of TIQ points during placebo versus GH, in particular VIQ decreased more in those with a lower VIQ. The effect of placebo versus GH on TIQ, VIQ and PIQ was not different for gender or genotype. Compared to GH treatment, 1 year of placebo did not deteriorate cognitive functioning of GH-treated young adults with PWS who have attained AH. However, patients with a lower cognitive functioning had more loss in IQ points during placebo versus GH treatment. The reassuring finding that 1 year of placebo does not deteriorate cognitive functioning does, however, not exclude a gradual deterioration of cognitive functioning on the long term. ISRCTN24648386 , NTR1038 , Dutch Trial Register, www.trialregister.nl . Registered 16 August 2007.

Lansoprazole 15 mg once daily for 14 days is effective for treatment of frequent heartburn: results of 2 randomized, placebo-controlled, double-blind studies.

PubMed

Kushner, Pamela R; Snoddy, Andrew M; Gilderman, Larry; Peura, David A

2009-07-01

To investigate the efficacy and safety of a 14-day treatment period with lansoprazole 15 mg for frequent heartburn in patients who are likely to select a nonprescription medication before consulting a prescriber. Adults with untreated frequent heartburn > or = 2 days a week over the past month were recruited for 2 identical multicenter, double-blind studies conducted with a 1-week screening and heartburn medication washout, a 1-week placebo run-in, a 2-week placebo-controlled treatment, and a 1-week placebo follow-up. After the washout and placebo run-in, subjects were randomly assigned to receive lansoprazole 15 mg or placebo once daily for 14 days in a double-blind fashion. Antacid tablets were permitted as rescue medication. Endpoints included percentage of 24-hour days without heartburn (primary), percentage of night-times without heartburn, and percentage of subjects without heartburn during day 1 of treatment (secondary endpoints). Data were collected daily via an interactive voice response system. In studies 1 and 2, 282 and 288 subjects, respectively, were randomly assigned to lansoprazole, and 282 in each study received placebo. The mean percentage of days without heartburn was greater among lansoprazole recipients compared with placebo recipients (P < 0.0001). Significantly more subjects treated with lansoprazole also reported no night-time heartburn and no heartburn during day 1 of the 14-day treatment. Adverse events were infrequent and were similar for lansoprazole and placebo groups. During the 14-day treatment period in a population with frequent heartburn who were likely to select a medication without consulting a prescriber, lansoprazole 15 mg once daily showed rapid and sustained effectiveness throughout a 24-hour period and was well tolerated.

Randomized clinical trial: macrogol/PEG 3350 plus electrolytes for treatment of patients with constipation associated with irritable bowel syndrome.

PubMed

Chapman, R W; Stanghellini, V; Geraint, M; Halphen, M

2013-09-01

Polyethylene glycol (PEG) 3350 plus electrolytes (PEG 3350+E) is an established treatment for constipation and has been proposed as a treatment option for constipation associated with irritable bowel syndrome (IBS-C). This study aimed to compare the efficacy and safety of PEG 3350+E vs. placebo in adult patients with IBS-C. Following a 14-day run-in period without study medication, patients with confirmed IBS-C were randomized to receive PEG 3350+E (N=68) or placebo (N=71) for 28 days. The primary endpoint was the mean number of spontaneous bowel movements (SBMs) per day in the last treatment week. In both groups, mean weekly number of SBMs (±s.d.) increased from run-in. The difference between the groups in week 4 (PEG 3350+E, 4.40±2.581; placebo, 3.11±1.937) was statistically significant (95% confidence interval: 1.17, 1.95; P<0.0001). Although mean severity score for abdominal discomfort/pain was significantly reduced compared with run-in with PEG 3350+E, there was no difference vs. placebo. Spontaneous complete bowel movements, responder rates, stool consistency, and severity of straining also showed superior improvement in the PEG 3350+E group over placebo in week 4. The most common drug related treatment-emergent adverse events were abdominal pain (PEG 3350+E, 4.5%; placebo, 0%) and diarrhoea (PEG 3350+E, 4.5%; placebo, 4.3%). In IBS-C, PEG 3350+E was superior to placebo for relief of constipation, and although a statistically significant improvement in abdominal discomfort/pain was observed compared with baseline, there was no associated improvement compared with placebo. PEG 3350+E is a well-established and effective treatment that should be considered suitable for use in IBS-C.

Midazolam as an active placebo in 3 fentanyl-validated nociceptive pain models.

PubMed

Prosenz, Julian; Gustorff, Burkhard

2017-07-01

The use of inactive placebos in early translational trials of potentially analgesic compounds is discouraged because of the side-effect profiles of centrally acting analgesics. Therefore, benzodiazepines are used, although their use has not been validated in this context. Whether benzodiazepines confound the results of acute pain tests is unknown. Midazolam (0.06 mg/kg) as an active placebo was investigated in 3 nociceptive models that included contact heat, electrical pain, and pressure pain thresholds in 24 healthy volunteers. Fentanyl (1 μg/kg) served as an internal validator in this randomized, placebo (saline) controlled, 3-way cross-over trial. The primary outcome parameter (contact heat pain) was analyzed using a one-way, repeated measures analysis of variance and Tukey's post test. Midazolam did not reduce pain ([numeric rating scale], 0-100) in a statistically significant manner compared with placebo for the contact heat (mean difference -1.7, 95% confidence interval -10.6 to 7.3; P = 0.89) or electrical pain (4.3, -5.1 to 13.7; P = 0.51) test, nor did it raise the pressure pain thresholds (-28 kPa, -122; 64 kPa, P = 0.73). The width of the confidence intervals suggested that there were no clinically meaningful analgesic effects compared with the placebo. In contrast, the analgesic efficacy of fentanyl was effectively demonstrated in all 3 models (P < 0.01 vs midazolam and placebo). The findings of this study show that midazolam can be used as an active placebo in analgesic drug trials. Furthermore, the proposed models were simple to implement and very effective in detecting analgesia. The test battery can be used in translational trials for new compounds and comes with an active placebo and an optional active comparator.

A double-blind, randomized, placebo-controlled, fixed-dose phase III study of vilazodone in patients with generalized anxiety disorder.

PubMed

Gommoll, Carl; Durgam, Suresh; Mathews, Maju; Forero, Giovanna; Nunez, Rene; Tang, Xiongwen; Thase, Michael E

2015-06-01

Vilazodone, a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist, is approved for treating major depressive disorder in adults. This study (NCT01629966 ClinicalTrials.gov) evaluated the efficacy and safety of vilazodone in adults with generalized anxiety disorder (GAD). A multicenter, double-blind, parallel-group, placebo-controlled, fixed-dose study in patients with GAD randomized (1:1:1) to placebo (n = 223), or vilazodone 20 mg/day (n = 230) or 40 mg/day (n = 227). Primary and secondary efficacy parameters were total score change from baseline to week 8 on the Hamilton Rating Scale for Anxiety (HAMA) and Sheehan Disability Scale (SDS), respectively, analyzed using a predefined mixed-effect model for repeated measures (MMRM). Safety outcomes were presented by descriptive statistics. The least squares mean difference (95% confidence interval) in HAMA total score change from baseline (MMRM) was statistically significant for vilazodone 40 mg/day versus placebo (-1.80 [-3.26, -0.34]; P = .0312 [adjusted for multiple comparisons]), but not for vilazodone 20 mg/day versus placebo. Mean change from baseline in SDS total score was not significantly different for either dose of vilazodone versus placebo when adjusted for multiplicity; significant improvement versus placebo was noted for vilazodone 40 mg/day without adjustment for multiplicity (P = .0349). The incidence of adverse events was similar for vilazodone 20 and 40 mg/day (∼71%) and slightly lower for placebo (62%). Nausea, diarrhea, dizziness, vomiting, and fatigue were reported in ≥5% of patients in either vilazodone group and at least twice the rate of placebo. Vilazodone was effective in treating anxiety symptoms of GAD. No new safety concerns were identified. © 2015 The Authors. Depression and Anxiety published by Wiley Periodicals, Inc.

M16. Valbenazine (NBI-98854) for the Treatment of Tardive Dyskinesia: Analysis by Underlying Psychiatric Diagnosis in Phase III KINECT 3 Study

PubMed Central

Josiassen, Richard; Kane, John; Burke, Joshua; Jimenez, Roland; Siegert, Scott; Liang, Grace

2017-01-01

Abstract Background: Valbenazine is a novel and highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor that is being evaluated for the treatment of tardive dyskinesia (TD), a persistent movement disorder resulting from exposure to antipsychotics or other dopamine receptor blocking agents (DRBAs). The efficacy of valbenazine in treating TD was demonstrated in a Phase 3 clinical trial (KINECT 3; NCT02274558), which included subjects with underlying schizophrenia/schizoaffective disorder or mood disorder. Further analyses of data from that trial were conducted to explore the efficacy of valbenazine across diagnostic subgroups. Methods: Subjects in this 6-week, double-blind, placebo-controlled trial were randomized 1:1:1 to once-daily valbenazine 80 mg, valbenazine 40 mg, or placebo. The primary endpoint was change from baseline to Week 6 on the Abnormal Involuntary Movement Scale (AIMS) total score (items 1–7) for valbenazine 80 mg vs placebo in the intent-to-treat (ITT) population. AIMs were videotaped and ratings were conducted by central raters blind to study visit and group. Additional outcomes included AIMS total score change (40 mg vs placebo) and Clinical Global Impression of Change-Tardive Dyskinesia (CGI TD) score (80 and 40 mg vs placebo) at Week 6. In addition to being evaluated in the ITT population, these outcomes were analyzed in subgroups categorized by underlying psychiatric diagnosis (schizophrenia/schizoaffective disorder or mood disorder). Results: At Week 6 in the ITT population (N = 225), AIMS score improvement was significantly greater with valbenazine 80 mg than placebo (least squares [LS] mean change from baseline: 80 mg, 3.2; placebo, −0.1; P < .0001). AIMS score change at Week 6 for valbenazine 40 mg (1.9) was also greater than placebo (P = .0021). Statistical testing was not conducted in the subgroups, but the magnitude of AIMS improvement in these patients was comparable to results in the overall ITT population: schizophrenia/schizoaffective disorder (n = 148; mean change from baseline: 80 mg, −3.1; 40 mg, −1.5; placebo, +0.4); mood disorder (n = 77; 80 mg, 3.6; 40 mg, −2.5; placebo, −0.7). CGI-TD scores at Week 6 in the ITT population indicated greater global improvement with valbenazine than placebo, but between-group differences were not statistically significant (LS mean scores: 80 mg, 2.9; 40 mg, 2.9; placebo, 3.2). CGI-TD outcomes in the subgroups were as follows: schizophrenia/schizoaffective disorder (mean scores: 80 mg, 3.0; 40 mg, 2.9; placebo, 3.1); mood disorder (80 mg, 2.7; 40 mg, 2.9; placebo, 3.2). Psychiatric status remained stable during the 6-week double-blind treatment period. Conclusion: Once-daily treatment with valbenazine improved TD regardless of underlying psychiatric diagnosis.

Placebo Effects and Informed Consent.

PubMed

Alfano, Mark

2015-01-01

The concepts of placebos and placebo effects refer to extremely diverse phenomena. I recommend dissolving the concepts of placebos and placebo effects into loosely related groups of specific mechanisms, including (potentially among others) expectation-fulfillment, classical conditioning, and attentional-somatic feedback loops. If this approach is on the right track, it has three main implications for the ethics of informed consent. First, because of the expectation-fulfillment mechanism, the process of informing cannot be considered independently from the potential effects of treatment. Obtaining informed consent influences the effects of treatment. This provides support for the authorized concealment and authorized deception paradigms, and perhaps even for outright deceptive placebo use. Second, doctors may easily fail to consider the potential benefits of conditioning, leading them to misjudge the trade-off between beneficence and autonomy. Third, how attentional-somatic feedback loops play out depends not only on the content of the informing process but also on its framing. This suggests a role for libertarian paternalism in clinical practice.

You Can't Always Get What You Want: The Influence of Choice on Nocebo and Placebo Responding.

PubMed

Bartley, Hannah; Faasse, Kate; Horne, Rob; Petrie, Keith J

2016-06-01

Choice may be an important influence on the effectiveness and side effects of medical treatments. We investigated the impact of having a choice of medication compared to no choice on both nocebo and placebo responding. Sixty-one participants were randomly assigned to either choose between or be assigned to one of the two equivalent beta-blocker medications (actually placebos) for pre-examination anxiety. There was a greater nocebo response in the no choice group and an increased placebo response in the choice group. Participants in the no choice group attributed significantly more side effects to the tablet than the choice group (p = 0.045), particularly at the 24-h follow-up (p = 0.002). The choice group showed a stronger placebo response in heart rate than the non-choice group. Not being given a choice of medication increased the nocebo effect and reduced the placebo response to the treatment.

Paroxetine in the treatment of dysthymic disorder without co-morbidities: A double-blind, placebo-controlled, flexible-dose study.

PubMed

Ravindran, Arun V; Cameron, Colin; Bhatla, Raj; Ravindran, Lakshmi N; da Silva, Tricia L

2013-04-01

Few published studies have evaluated selective serotonin reuptake inhibitors in dysthymia without current co-morbid major depression. In this 12-week study, 40 dysthymic patients were randomly assigned to either placebo (n=19) or 20-40 mg/day of paroxetine (n=21). At endpoint, the paroxetine group showed significantly greater improvement on the Clinical Global Impression Scale, Beck Depression Inventory, and Quality of Life Enjoyment and Satisfaction Questionnaire (p<0.05), and a trend to superiority over placebo on the Hamilton Depression Rating Scale. Response and remission were significantly higher with paroxetine than placebo (p<0.05). There were no significant differences in drop out rates or frequency of adverse effects, except for excessive sweating (greater with paroxetine, p=0.04). Reporting of multiple side effects was also higher with paroxetine than with placebo (p=0.02). Paroxetine is more effective than placebo in improving symptoms and quality of life in dysthymia, and is generally tolerable. Copyright © 2012 Elsevier B.V. All rights reserved.

Bronchodilator efficacy of tiotropium in patients with mild to moderate COPD.

PubMed

Johansson, Gunnar; Lindberg, Anne; Romberg, Kerstin; Nordström, Lars; Gerken, Fronke; Roquet, Annika

2008-09-01

Evaluation of tiotropium efficacy in patients with mild chronic obstructive pulmonary disease (COPD) defined by the 2003 Swedish Society of Respiratory Medicine guidelines (post-bronchodilator FEV1/FVC <70%; FEV1 >60% predicted). In this 12-week, randomised, double-blind, placebo-controlled study of tiotropium 18 mcg once daily versus placebo, respiratory function was assessed on Days 1, 15 and 85 (baseline: pre-dose Day 1). Mean+/-SD baseline FEV1 (% predicted) was 73.4+/-12.5 (tiotropium, n=107; placebo, n=117). Tiotropium significantly improved change from baseline in area under the curve from pre-dose to 2 hours post-dose (AUC0-2 h) FEV1 versus placebo, by 166+/-26 mL (mean+/-SE) at study end (p<0.0001). With tiotropium, there were significant increases in the change in AUC0-2 h FVC versus baseline, and trough FEV1 and FVC, versus placebo, on all test days (p<0.01). Adverse event rates were similar. Compared with placebo, tiotropium improved lung function in patients with mild COPD.

Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomised, placebo controlled study

PubMed Central

Schellenberg, R

2001-01-01

Objectives To compare the efficacy and tolerability of agnus castus fruit (Vitex agnus castus L extract Ze 440) with placebo for women with the premenstrual syndrome. Design Randomised, double blind, placebo controlled, parallel group comparison over three menstrual cycles. Setting General medicine community clinics. Participants 178 women were screened and 170 were evaluated (active 86; placebo 84). Mean age was 36 years, mean cycle length was 28 days, mean duration of menses was 4.5 days. Interventions Agnus castus (dry extract tablets) one tablet daily or matching placebo, given for three consecutive cycles. Main outcome measures Main efficacy variable: change from baseline to end point (end of third cycle) in women's self assessment of irritability, mood alteration, anger, headache, breast fullness, and other menstrual symptoms including bloating. Secondary efficacy variables: changes in clinical global impression (severity of condition, global improvement, and risk or benefit) and responder rate (50% reduction in symptoms). Results Improvement in the main variable was greater in the active group compared with placebo group (P<0.001). Analysis of the secondary variables showed significant (P<0.001) superiority of active treatment in each of the three global impression items. Responder rates were 52% and 24% for active and placebo, respectively. Seven women reported mild adverse events (four active; three placebo), none of which caused discontinuation of treatment. Conclusions Dry extract of agnus castus fruit is an effective and well tolerated treatment for the relief of symptoms of the premenstrual syndrome. PMID:11159568

Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomised, placebo controlled study.

PubMed

Schellenberg, R

2001-01-20

To compare the efficacy and tolerability of agnus castus fruit (Vitex agnus castus L extract Ze 440) with placebo for women with the premenstrual syndrome. Randomised, double blind, placebo controlled, parallel group comparison over three menstrual cycles. General medicine community clinics. 178 women were screened and 170 were evaluated (active 86; placebo 84). Mean age was 36 years, mean cycle length was 28 days, mean duration of menses was 4.5 days. Agnus castus (dry extract tablets) one tablet daily or matching placebo, given for three consecutive cycles. Main efficacy variable: change from baseline to end point (end of third cycle) in women's self assessment of irritability, mood alteration, anger, headache, breast fullness, and other menstrual symptoms including bloating. Secondary efficacy variables: changes in clinical global impression (severity of condition, global improvement, and risk or benefit) and responder rate (50% reduction in symptoms). Improvement in the main variable was greater in the active group compared with placebo group (P<0.001). Analysis of the secondary variables showed significant (P<0.001) superiority of active treatment in each of the three global impression items. Responder rates were 52% and 24% for active and placebo, respectively. Seven women reported mild adverse events (four active; three placebo), none of which caused discontinuation of treatment. Dry extract of agnus castus fruit is an effective and well tolerated treatment for the relief of symptoms of the premenstrual syndrome.

The ethics of placebo-controlled trials: a comparison of inert and active placebo controls.

PubMed

Edward, Sarah J L; Stevens, Andrew J; Braunholtz, David A; Lilford, Richard J; Swift, Teresa

2005-05-01

Because of the recent and controversial example of sham surgery for the evaluation of fetal tissue transplants for Parkinson's disease, there is renewed interest in the ethics of using "active" placebos in surgical trials, where otherwise there are no inert procedures available, and in pharmacological trials, where there are inert substances, but where patients may guess to which arm they have been allocated. This paper seeks to clarify the ethical arguments surrounding the use of active placebos in trials, and to set up a notation for assessing the ethics of trials more generally. We first establish an framework by which ethics committees can analyze such trials. We examine (1) the scientific value of the research; (2) the expected risks and benefits to individual patients, and (3) the voluntary nature of consent. We then contrast the implications of this framework for inert and active placebo-controlled trials, respectively. In particular, we analyze their relative expected utility using three main utility factors, namely, treatment effects, placebo effects, and altruism. We conclude that, when the intervention is already widely available, active placebo trials rely more heavily on altruism than do inert placebo trials and, when the intervention is restricted, this excess reliance may not be needed. What our analysis provides is the explicit justification for the apparent caution of Institutional Review Boards or ethics committees when reviewing sham operations, especially when the expected harm is not trivial and the risk of exploitation is high.

A randomized placebo-controlled trial to evaluate a novel noninjectable anesthetic gel with thermosetting agent during scaling and root planing in chronic periodontitis patients.

PubMed

Dayakar, M M; Akbar, S M

2016-01-01

To study the efficacy of a noninjectable anesthetic gel with a thermosetting agent in the reduction of pain during scaling and root planing (SRP) in untreated chronic periodontitis patients. This study is a randomized, double-masked, split-mouth, placebo-controlled trial. Thirty patients were enrolled who underwent SRP in a split-mouth (right side/left side) manner. Before commencement of SRP, both quadrants on each side were isolated and had a randomized gel (either placebo or test gel) placed in the periodontal pockets for 30 s. The pain was measured using numerical rating scale (NRS) and verbal rating scale (VRS). The median NRS pain score for the patients treated with the anesthetic test gel was 1 (range: 0-4) as opposed to 5 (range: 3-7) in the placebo treated patients. The mean rank of pain score using NRS in test gel was 16.18 as compared to 44.82 in placebo treated sites. Hence, significant reduction in pain was found in test gel as compared to placebo using NRS (P < 0.001). The VRS showed that the majority of patients reported no pain or mild pain with a median of 1 as compared to placebo treated sites with a median of 2 suggestive of moderate pain. The NRS and VRS pain scores showed that the side treated with anesthetic gel was statistically more effective than the placebo in reducing pain during SRP.

Designing a placebo device: involving service users in clinical trial design.

PubMed

Gooberman-Hill, Rachael; Jinks, Clare; Bouças, Sofia Barbosa; Hislop, Kelly; Dziedzic, Krysia S; Rhodes, Carol; Burston, Amanda; Adams, Jo

2013-12-01

Service users are increasingly involved in the design of clinical trials and in product and device development. Service user involvement in placebo development is crucial to a credible and acceptable placebo for clinical trials, but such involvement has not yet been reported. To enhance the design of a future clinical trial of hand splints for thumb-base osteoarthritis (OA), service users were involved in splint selection and design of a placebo splint. This article describes and reflects on this process. Two fora of service users were convened in 2011. Service users who had been prescribed a thumb splint for thumb-base OA were approached about involvement by Occupational Therapy (OT) practitioners. A total of eight service users took part in the fora. Service users discussed their experience of OA and their own splints and then tried a variety of alternative splints. Through this they identified the active features of splints alongside acceptable and unacceptable design features. Service users focused on wearability and support with or without immobilization. Fora discussed whether a placebo group ('arm') was an acceptable feature of a future trial, and service users developed a potential design for a placebo splint. This is the first project that to involve service users in placebo design. Service users are increasingly involved in product and device design and are ideally placed to identify features to make a placebo credible yet lacking key active ingredients. The future trial will include research into its acceptability. © 2013 John Wiley & Sons Ltd.

The Effects of Haloperidol on Learning and Behavior in Autistic Children.

ERIC Educational Resources Information Center

Campbell, Magda; And Others

1982-01-01

Statistically, haloperidol was significantly superior to placebo in reducing behavioral symptoms. In a discrimination learning paradigm, autistic children receiving haloperidol learned the discrimination while those on placebo did not. Discrimination attained on haloperidol was retained when the children were switched to placebo. (Author)

When is the best moment to apply photobiomodulation therapy (PBMT) when associated to a treadmill endurance-training program? A randomized, triple-blinded, placebo-controlled clinical trial.

PubMed

Miranda, Eduardo Foschini; Tomazoni, Shaiane Silva; de Paiva, Paulo Roberto Vicente; Pinto, Henrique Dantas; Smith, Denis; Santos, Larissa Aline; de Tarso Camillo de Carvalho, Paulo; Leal-Junior, Ernesto Cesar Pinto

2018-05-01

Photobiomodulation therapy (PBMT) employing low-level laser therapy (LLLT) and/or light emitting diode therapy (LEDT) has emerged as an electrophysical intervention that could be associated with aerobic training to enhance beneficial effects of aerobic exercise. However, the best moment to perform irradiation with PBMT in aerobic training has not been elucidated. The aim of this study was to assess the effects of PBMT applied before and/or after each training session and to evaluate outcomes of the endurance-training program associated with PBMT. Seventy-seven healthy volunteers completed the treadmill-training protocol performed for 12 weeks, with 3 sessions per week. PBMT was performed before and/or after each training session (17 sites on each lower limb, using a cluster of 12 diodes: 4 × 905 nm super-pulsed laser diodes, 4 × 875 nm infrared LEDs, and 4 × 640 nm red LEDs, dose of 30 J per site). Volunteers were randomized in four groups according to the treatment they would receive before and after each training session: PBMT before + PBMT after, PBMT before + placebo after, placebo before + PBMT after, and placebo before + placebo after. Assessments were performed before the start of the protocol and after 4, 8, and 12 weeks of training. Primary outcome was time until exhaustion; secondary outcome measures were oxygen uptake and body fat. PBMT applied before and after aerobic exercise training sessions (PBMT before + PBMT after group) significantly increased (p < 0.05) the percentage of change of time until exhaustion and oxygen uptake compared to the group treated with placebo before and after aerobic exercise training sessions (placebo before + placebo after group) at 4th, 8th, and 12th week. PBMT applied before and after aerobic exercise training sessions (PBMT before + PBMT after group) also significantly improved (p < 0.05) the percentage of change of body fat compared to the group treated with placebo before and after aerobic exercise training sessions (placebo before + placebo after group) at 8th and 12th week. PBMT applied before and after sessions of aerobic training during 12 weeks can increase the time-to-exhaustion and oxygen uptake and also decrease the body fat in healthy volunteers when compared to placebo irradiation before and after exercise sessions. Our outcomes show that PBMT applied before and after endurance-training exercise sessions lead to improvement of endurance three times faster than exercise only.

Psychiatric and cognitive adverse events: A pooled analysis of three phase III trials of adjunctive eslicarbazepine acetate for partial-onset seizures.

PubMed

Andermann, Eva; Biton, Victor; Benbadis, Selim R; Shneker, Bassel; Shah, Aashit K; Carreño, Mar; Trinka, Eugen; Ben-Menachem, Elinor; Biraben, Arnaud; Rocha, Francisco; Gama, Helena; Cheng, Hailong; Blum, David

2018-05-01

To evaluate the nature and incidence of psychiatric and cognitive adverse events (AEs) reported with eslicarbazepine acetate (ESL) used as adjunctive treatment for refractory partial-onset seizures (POS) in adults. This was a post-hoc analysis of data pooled from three randomized double-blind, placebo-controlled trials (BIA-2093-301, -302, -304). After an 8-week baseline period, patients received placebo or adjunctive ESL 400mg (studies 301 and 302 only), 800mg, or 1200mg once daily (QD) for 14weeks (2-week titration period, 12-week maintenance period). Psychiatric and cognitive AEs were identified from individual patient data. Suicidality was also evaluated using the Columbia-Classification Algorithm of Suicide Assessment (C-CASA), or the Columbia-Suicide Severity Rating Scale (C-SSRS). P-values were obtained using the chi-square test of independence or Fisher's exact test, without correcting for multiplicity. The analysis population included 1447 patients (ESL, n=1021; placebo, n = 426). Psychiatric treatment-emergent AEs (TEAEs) occurred in 10.8% of patients receiving ESL, and in a comparable proportion (10.3%) of patients receiving placebo (p=0.802). The incidence of depression and suicidality-related TEAEs was higher for ESL (7.4%) vs. placebo (3.8%) (p=0.009). The occurrence of these TEAEs differed between treatment groups (p = 0.010), but there was no notable trend between increasing ESL dose and increasing incidence of depression and suicidality-related TEAEs. Aggression/hostility-related TEAEs occurred in <0.1% of patients taking ESL vs. 0.9% taking placebo. The incidence of cognitive TEAEs was higher for ESL (7.1%) vs. placebo (4.0%) (p=0.023); incidences of memory impairment, attention disturbance, apathy, and aphasia were higher for ESL 1200mg than for other treatment groups. Incidences of psychiatric and cognitive serious AEs (SAEs) were 0.6% and 0.2% with ESL, and 0.5% and 0% with placebo, respectively. Psychiatric and cognitive TEAEs leading to discontinuation occurred in 1.9% and 1.4% of patients taking ESL, and 0.7% and 0.5% taking placebo, respectively. In phase III clinical trials of adjunctive ESL for treatment-refractory POS, psychiatric and cognitive TEAEs were reported infrequently with ESL and placebo. The incidences of depression and suicidality-related TEAEs and of cognitive TEAEs were higher for patients taking ESL vs. placebo. Incidences of psychiatric and cognitive SAEs, and TEAEs leading to discontinuation, were low with ESL and placebo. Copyright © 2017. Published by Elsevier Inc.

Mindfulness Meditation-Based Pain Relief Employs Different Neural Mechanisms Than Placebo and Sham Mindfulness Meditation-Induced Analgesia.

PubMed

Zeidan, Fadel; Emerson, Nichole M; Farris, Suzan R; Ray, Jenna N; Jung, Youngkyoo; McHaffie, John G; Coghill, Robert C

2015-11-18

Mindfulness meditation reduces pain in experimental and clinical settings. However, it remains unknown whether mindfulness meditation engages pain-relieving mechanisms other than those associated with the placebo effect (e.g., conditioning, psychosocial context, beliefs). To determine whether the analgesic mechanisms of mindfulness meditation are different from placebo, we randomly assigned 75 healthy, human volunteers to 4 d of the following: (1) mindfulness meditation, (2) placebo conditioning, (3) sham mindfulness meditation, or (4) book-listening control intervention. We assessed intervention efficacy using psychophysical evaluation of experimental pain and functional neuroimaging. Importantly, all cognitive manipulations (i.e., mindfulness meditation, placebo conditioning, sham mindfulness meditation) significantly attenuated pain intensity and unpleasantness ratings when compared to rest and the control condition (p < 0.05). Mindfulness meditation reduced pain intensity (p = 0.032) and pain unpleasantness (p < 0.001) ratings more than placebo analgesia. Mindfulness meditation also reduced pain intensity (p = 0.030) and pain unpleasantness (p = 0.043) ratings more than sham mindfulness meditation. Mindfulness-meditation-related pain relief was associated with greater activation in brain regions associated with the cognitive modulation of pain, including the orbitofrontal, subgenual anterior cingulate, and anterior insular cortex. In contrast, placebo analgesia was associated with activation of the dorsolateral prefrontal cortex and deactivation of sensory processing regions (secondary somatosensory cortex). Sham mindfulness meditation-induced analgesia was not correlated with significant neural activity, but rather by greater reductions in respiration rate. This study is the first to demonstrate that mindfulness-related pain relief is mechanistically distinct from placebo analgesia. The elucidation of this distinction confirms the existence of multiple, cognitively driven, supraspinal mechanisms for pain modulation. Recent findings have demonstrated that mindfulness meditation significantly reduces pain. Given that the "gold standard" for evaluating the efficacy of behavioral interventions is based on appropriate placebo comparisons, it is imperative that we establish whether there is an effect supporting meditation-related pain relief above and beyond the effects of placebo. Here, we provide novel evidence demonstrating that mindfulness meditation produces greater pain relief and employs distinct neural mechanisms than placebo cream and sham mindfulness meditation. Specifically, mindfulness meditation-induced pain relief activated higher-order brain regions, including the orbitofrontal and cingulate cortices. In contrast, placebo analgesia was associated with decreased pain-related brain activation. These findings demonstrate that mindfulness meditation reduces pain through unique mechanisms and may foster greater acceptance of meditation as an adjunct pain therapy. Copyright © 2015 the authors 0270-6474/15/3515308-19$15.00/0.

Formulation and characterization of a compacted multiparticulate system for modified release of water-soluble drugs--part 1--acetaminophen.

PubMed

Cantor, Stuart L; Hoag, Stephen W; Augsburger, Larry L

2009-03-01

The aim of this study was to characterize and evaluate a modified release, multiparticulate tablet formulation consisting of placebo beads and drug-loaded beads. Acetaminophen (APAP) bead formulations containing ethylcellulose (EC) from 40-60% and placebo beads containing 30% calcium silicate and prepared using 0-20% alcohol were developed using extrusion-spheronization and studied using a central composite experimental design. Particle size and true density of beads were measured. Segregation testing was performed using the novel ASTM D6940-04 method on a 50:50 blend of uncoated APAP beads (60%EC) : calcium silicate placebo beads (10% alcohol). Tablets were prepared using an instrumented Stokes-B2 rotary tablet press and evaluated for crushing strength and dissolution rate. Compared with drug beads (60%EC), placebo beads (10% alcohol) were smaller but had higher true densities: 864.8 mum and 1.27 g/cm(3), and 787.1 mum and 1.73 g/cm(3), respectively. Segregation testing revealed that there was approximately a 20% difference in drug content (as measured by the coefficient of variation) between initial and final blend samples. Although calcium silicate-based placebo beads were shown to be ineffective cushioning agents in blends with Surelease(R)-coated APAP beads, they were found to be very compactibile when used alone and gave tablet crushing strength values between 14 and 17 kP. The EC in the APAP bead matrix minimally suppressed the drug release from uncoated beads (t(100%) = 2 h). However, while tablets containing placebo beads reformulated with glycerol monostearate (GMS) showed a slower release rate (t(60%)= 5 h) compared with calcium silicate-based placebos, some coating damage ( approximately 30%) still occurred on compression as release was faster than coated APAP beads alone. While tablets containing coated drug beads can be produced with practical crushing strengths (>8 kP) and low compression pressures (10-35 MPa), dissolution studies revealed that calcium silicate-based placebos are ineffective as cushioning agents. Blend segregation was likely observed due to the particle size and the density differences between APAP beads and calcium silicate-based placebo beads; placebo bead percolation can perhaps be minimized by increasing their size during the extrusion-spheronization process. The GMS- based placebos offer greater promise as cushioning agents for compacted, coated drug beads; however, this requires an optimized compression pressure range and drug bead : placebo bead ratio (i.e., 50:50).

Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis.

PubMed

Sandborn, William J; Su, Chinyu; Sands, Bruce E; D'Haens, Geert R; Vermeire, Séverine; Schreiber, Stefan; Danese, Silvio; Feagan, Brian G; Reinisch, Walter; Niezychowski, Wojciech; Friedman, Gary; Lawendy, Nervin; Yu, Dahong; Woodworth, Deborah; Mukherjee, Arnab; Zhang, Haiying; Healey, Paul; Panés, Julian

2017-05-04

Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy. We conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks. In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels. In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo. (Funded by Pfizer; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain ClinicalTrials.gov numbers, NCT01465763 , NCT01458951 , and NCT01458574 , respectively.).

Developing a placebo-controlled trial in surgery: issues of design, acceptability and feasibility.

PubMed

Campbell, M K; Entwistle, V A; Cuthbertson, B H; Skea, Z C; Sutherland, A G; McDonald, A M; Norrie, J D; Carlson, R V; Bridgman, S

2011-02-21

Surgical placebos are controversial. This in-depth study explored the design, acceptability, and feasibility issues relevant to designing a surgical placebo-controlled trial for the evaluation of the clinical and cost effectiveness of arthroscopic lavage for the management of people with osteoarthritis of the knee in the UK. Two surgeon focus groups at a UK national meeting for orthopaedic surgeons and one regional surgeon focus group (41 surgeons); plenary discussion at a UK national meeting for orthopaedic anaesthetists (130 anaesthetists); three focus groups with anaesthetists (one national, two regional; 58 anaesthetists); two focus groups with members of the patient organisation Arthritis Care (7 participants); telephone interviews with people on consultant waiting lists from two UK regional centres (15 participants); interviews with Chairs of UK ethics committees (6 individuals); postal surveys of members of the British Association of Surgeons of the Knee (382 surgeons) and members of the British Society of Orthopaedic Anaesthetists (398 anaesthetists); two centre pilot (49 patients assessed). There was widespread acceptance that evaluation of arthroscopic lavage had to be conducted with a placebo control if scientific rigour was not to be compromised. The choice of placebo surgical procedure (three small incisions) proved easier than the method of anaesthesia (general anaesthesia). General anaesthesia, while an excellent mimic, was more intrusive and raised concerns among some stakeholders and caused extensive discussion with local decision-makers when seeking formal approval for the pilot.Patients were willing to participate in a pilot with a placebo arm; although some patients when allocated to surgery became apprehensive about the possibility of receiving placebo, and withdrew. Placebo surgery was undertaken successfully. Our study illustrated the opposing and often strongly held opinions about surgical placebos, the ethical issues underpinning this controversy, and the challenges that exist even when ethics committee approval has been granted. It showed that a placebo-controlled trial could be conducted in principle, albeit with difficulty. It also highlighted that not only does a placebo-controlled trial in surgery have to be ethically and scientifically acceptable but that it also must be a feasible course of action. The place of placebo-controlled surgical trials more generally is likely to be limited and require specific circumstances to be met. Suggested criteria are presented. The trial was assigned ISRCTN02328576 through http://controlled-trials.com/ in June 2006. The first patient was randomised to the pilot in July 2007.

Mindfulness Meditation-Based Pain Relief Employs Different Neural Mechanisms Than Placebo and Sham Mindfulness Meditation-Induced Analgesia

PubMed Central

Emerson, Nichole M.; Farris, Suzan R.; Ray, Jenna N.; Jung, Youngkyoo; McHaffie, John G.; Coghill, Robert C.

2015-01-01

Mindfulness meditation reduces pain in experimental and clinical settings. However, it remains unknown whether mindfulness meditation engages pain-relieving mechanisms other than those associated with the placebo effect (e.g., conditioning, psychosocial context, beliefs). To determine whether the analgesic mechanisms of mindfulness meditation are different from placebo, we randomly assigned 75 healthy, human volunteers to 4 d of the following: (1) mindfulness meditation, (2) placebo conditioning, (3) sham mindfulness meditation, or (4) book-listening control intervention. We assessed intervention efficacy using psychophysical evaluation of experimental pain and functional neuroimaging. Importantly, all cognitive manipulations (i.e., mindfulness meditation, placebo conditioning, sham mindfulness meditation) significantly attenuated pain intensity and unpleasantness ratings when compared to rest and the control condition (p < 0.05). Mindfulness meditation reduced pain intensity (p = 0.032) and pain unpleasantness (p < 0.001) ratings more than placebo analgesia. Mindfulness meditation also reduced pain intensity (p = 0.030) and pain unpleasantness (p = 0.043) ratings more than sham mindfulness meditation. Mindfulness-meditation-related pain relief was associated with greater activation in brain regions associated with the cognitive modulation of pain, including the orbitofrontal, subgenual anterior cingulate, and anterior insular cortex. In contrast, placebo analgesia was associated with activation of the dorsolateral prefrontal cortex and deactivation of sensory processing regions (secondary somatosensory cortex). Sham mindfulness meditation-induced analgesia was not correlated with significant neural activity, but rather by greater reductions in respiration rate. This study is the first to demonstrate that mindfulness-related pain relief is mechanistically distinct from placebo analgesia. The elucidation of this distinction confirms the existence of multiple, cognitively driven, supraspinal mechanisms for pain modulation. SIGNIFICANCE STATEMENT Recent findings have demonstrated that mindfulness meditation significantly reduces pain. Given that the “gold standard” for evaluating the efficacy of behavioral interventions is based on appropriate placebo comparisons, it is imperative that we establish whether there is an effect supporting meditation-related pain relief above and beyond the effects of placebo. Here, we provide novel evidence demonstrating that mindfulness meditation produces greater pain relief and employs distinct neural mechanisms than placebo cream and sham mindfulness meditation. Specifically, mindfulness meditation-induced pain relief activated higher-order brain regions, including the orbitofrontal and cingulate cortices. In contrast, placebo analgesia was associated with decreased pain-related brain activation. These findings demonstrate that mindfulness meditation reduces pain through unique mechanisms and may foster greater acceptance of meditation as an adjunct pain therapy. PMID:26586819

Developing a placebo-controlled trial in surgery: Issues of design, acceptability and feasibility

PubMed Central

2011-01-01

Background Surgical placebos are controversial. This in-depth study explored the design, acceptability, and feasibility issues relevant to designing a surgical placebo-controlled trial for the evaluation of the clinical and cost effectiveness of arthroscopic lavage for the management of people with osteoarthritis of the knee in the UK. Methods Two surgeon focus groups at a UK national meeting for orthopaedic surgeons and one regional surgeon focus group (41 surgeons); plenary discussion at a UK national meeting for orthopaedic anaesthetists (130 anaesthetists); three focus groups with anaesthetists (one national, two regional; 58 anaesthetists); two focus groups with members of the patient organisation Arthritis Care (7 participants); telephone interviews with people on consultant waiting lists from two UK regional centres (15 participants); interviews with Chairs of UK ethics committees (6 individuals); postal surveys of members of the British Association of Surgeons of the Knee (382 surgeons) and members of the British Society of Orthopaedic Anaesthetists (398 anaesthetists); two centre pilot (49 patients assessed). Results There was widespread acceptance that evaluation of arthroscopic lavage had to be conducted with a placebo control if scientific rigour was not to be compromised. The choice of placebo surgical procedure (three small incisions) proved easier than the method of anaesthesia (general anaesthesia). General anaesthesia, while an excellent mimic, was more intrusive and raised concerns among some stakeholders and caused extensive discussion with local decision-makers when seeking formal approval for the pilot. Patients were willing to participate in a pilot with a placebo arm; although some patients when allocated to surgery became apprehensive about the possibility of receiving placebo, and withdrew. Placebo surgery was undertaken successfully. Conclusions Our study illustrated the opposing and often strongly held opinions about surgical placebos, the ethical issues underpinning this controversy, and the challenges that exist even when ethics committee approval has been granted. It showed that a placebo-controlled trial could be conducted in principle, albeit with difficulty. It also highlighted that not only does a placebo-controlled trial in surgery have to be ethically and scientifically acceptable but that it also must be a feasible course of action. The place of placebo-controlled surgical trials more generally is likely to be limited and require specific circumstances to be met. Suggested criteria are presented. Trial registration number The trial was assigned ISRCTN02328576 through http://controlled-trials.com/ in June 2006. The first patient was randomised to the pilot in July 2007. PMID:21338481

Characteristics of Placebo Responders in Pediatric Clinical Trials of Attention-Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Newcorn, Jeffrey H.; Sutton, Virginia K.; Zhang, Shuyu; Wilens, Timothy; Kratochvil, Christopher; Emslie, Graham J.; D'Souza, Deborah N.; Schuh, Leslie M.; Allen, Albert J.

2009-01-01

Objective: Understanding placebo response is a prerequisite to improving clinical trial methodology. Data from placebo-controlled trials of atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder (ADHD) were analyzed to identify demographic and clinical characteristics that might predict placebo…

Design Dilemma: The Debate over Using Placebos in Cancer Clinical Trials

Cancer.gov

Many patients and researchers assert that in cancer clinical trials, placebos are inappropriate and that all participants should receive active treatment. But with the emergence of molecularly targeted anticancer agents, some cancer researchers believe placebo-controlled trials are now feasible and, in some cases, necessary.

Double-blind trial of recombinant gamma-interferon versus placebo in the treatment of rheumatoid arthritis. 1989.

PubMed

Cannon, Grant W; Pincus, Seth H; Emkey, Ronald D; Denes, Alex; Cohen, Selwyn A; Wolfe, Frederick; Saway, P Anthony; Jaffer, Adrian M; Weaver, Arthur L; Cogen, Lewis; Schindler, John D

2008-02-01

One hundred five patients were enrolled in a 12-week, randomized, prospective, double-blind, placebo-controlled trial of recombinant human gamma-interferon (rHu gamma-IFN) for the treatment of rheumatoid arthritis. Fifty-four patients received rHu gamma-IFN and 51 received placebo. Forty-two patients in each group completed the 12-week trial. Some clinical improvement occurred in both groups of patients. Although the improvement with rHu gamma-IFN was greater than that with placebo, the differences were generally not statistically significant.

The neuroscience of placebo effects: connecting context, learning and health

PubMed Central

Wager, Tor D.; Atlas, Lauren Y.

2018-01-01

Placebo effects are beneficial effects that are attributable to the brain–mind responses to the context in which a treatment is delivered rather than to the specific actions of the drug. They are mediated by diverse processes — including learning, expectations and social cognition — and can influence various clinical and physiological outcomes related to health. Emerging neuroscience evidence implicates multiple brain systems and neurochemical mediators, including opioids and dopamine. We present an empirical review of the brain systems that are involved in placebo effects, focusing on placebo analgesia, and a conceptual framework linking these findings to the mind–brain processes that mediate them. This framework suggests that the neuropsychological processes that mediate placebo effects may be crucial for a wide array of therapeutic approaches, including many drugs. PMID:26087681

Treatment of acute cerebral infarction with a choline precursor in a multicenter double-blind placebo-controlled study.

PubMed

Tazaki, Y; Sakai, F; Otomo, E; Kutsuzawa, T; Kameyama, M; Omae, T; Fujishima, M; Sakuma, A

1988-02-01

A multicenter double-blind placebo-controlled study of cytidine 5'-diphosphocholine (CDP-choline) was conducted to evaluate possible clinical benefits of the drug in patients with acute, moderate to severe cerebral infarction. The patients included also suffered from moderate to mild disturbances of consciousness, and all were admitted within 14 days of the ictus. Patients were allocated randomly to treatment with either CDP-choline (1,000 mg/day i.v. once daily for 14 days) or with placebo (physiological saline). One hundred thirty-three patients received CDP-choline treatment, and 139 received placebo. The group treated with CDP-choline showed significant improvements in level of consciousness compared with the placebo-treated group, and CDP-choline was an entirely safe treatment.

Clinical trial: efficacy and safety of dexlansoprazole MR 60 and 90 mg in healed erosive oesophagitis - maintenance of healing and symptom relief.

PubMed

Howden, C W; Larsen, L M; Perez, M C; Palmer, R; Atkinson, S N

2009-11-01

Dexlansoprazole MR, a modified-release formulation of dexlansoprazole, an enantiomer of lansoprazole, effectively heals erosive oesophagitis. To assess dexlansoprazole MR in maintaining healed erosive oesophagitis. Patients (n = 451) with erosive oesophagitis healed in either of two dexlansoprazole MR healing trials randomly received dexlansoprazole MR 60 or 90 mg or placebo once daily in this double-blind trial. The percentage of patients who maintained healing at month 6 was analysed using life table and crude rate methods. Secondary endpoints were percentages of nights and of 24-h days without heartburn based on daily diaries. Dexlansoprazole MR 60 and 90 mg were superior to placebo for maintaining healing (P < 0.0025). Maintenance rates were 87% and 82% for the 60 and 90 mg doses, respectively, vs. 26% for placebo (life table), and 66% and 65% vs. 14%, respectively (crude rate). Both doses were superior to placebo for the percentage of 24-h heartburn-free days (60 mg, 96%; 90 mg, 94%; placebo, 19%) and nights (98%, 97%, and 50%, respectively). Diarrhoea, flatulence, gastritis (symptoms) and abdominal pain occurred more frequently with dexlansoprazole MR than placebo, but were not dose-related. Dexlansoprazole MR effectively maintained healed erosive oesophagitis and symptom relief compared with placebo, and was well tolerated.

Spinal Manipulative Therapy Specific Changes In Pain Sensitivity In Individuals With Low Back Pain (NCT01168999)

PubMed Central

Bialosky, Joel E; George, Steven Z; Horn, Maggie E; Price, Donald D; Staud, Roland; Robinson, Michael E

2013-01-01

Spinal Manipulative Therapy (SMT) is effective for some individuals experiencing low back pain (LBP); however, the mechanisms are not established regarding the role of placebo. SMT is associated with changes in pain sensitivity suggesting related altered central nervous system response or processing of afferent nociceptive input. Placebo is also associated with changes in pain sensitivity and the efficacy of SMT for changes in pain sensitivity beyond placebo has not been adequately considered. We randomly assigned 110 participants with LBP to receive SMT, placebo SMT, placebo SMT with the instructional set, “The manual therapy technique you will receive has been shown to significantly reduce low back pain in some people”, or no intervention. Participants receiving the SMT and placebo SMT received their assigned intervention 6 times over two weeks. Pain sensitivity was assessed prior to and immediately following the assigned intervention during the first session. Clinical outcomes were assessed at baseline and following two weeks of participation in the study. Immediate attenuation of suprathreshold heat response was greatest following SMT (p= 0.05, partial η2= 0.07). Group dependent differences were not observed for changes in pain intensity and disability at two week. Participant satisfaction was greatest following the enhanced placebo SMT. PMID:24361109

Ondansetron or droperidol for prophylaxis of nausea and vomiting after intrathecal morphine.

PubMed

Peixoto, A J; Celich, M F; Zardo, L; Peixoto Filho, A J

2006-08-01

There is a controversy regarding the best drug for prevention of nausea and vomiting in patients receiving intrathecal morphine. The aim of this study was to examine efficacy and tolerability of droperidol compared with ondansetron for the prevention of morphine-induced nausea and vomiting. In a randomized, placebo-controlled trial, 120 women undergoing Caesarean section under spinal anaesthesia with intrathecal morphine 0.1 mg received intravenous ondansetron 4 mg (n = 40), droperidol 1.25 mg (n = 40) or saline (n = 40) immediately after umbilical-cord clamping. Nausea and vomiting were graded according to intensity at 1, 2, 4, 6, 12 and 24 h. Nausea or vomiting occurred in 14 patients (35%) in the placebo group, 4 (10%) in the ondansetron group and 10 (25%) in the droperidol group; the difference between ondansetron and placebo was statistically significant (P = 0.007). Eleven of the 14 placebo patients (27.5%) vomited, compared with none of the 4 ondansetron patients (vs. placebo, P = 0.0004) and 5 of the droperidol patients (vs. placebo, P = 0.18). Three of the 14 placebo patients (7.5%) were nauseous, compared with 4 (10%) receiving ondansetron and 5 (12.5%) receiving droperidol. Ondansetron was effective in reducing the incidence of nausea and vomiting in patients receiving intrathecal morphine for Caesarean section.

Rostral Anterior Cingulate Cortex Theta Current Density and Response to Antidepressants and Placebo in Major Depression

PubMed Central

Korb, Alexander S.; Hunter, Aimee M.; Cook, Ian A.; Leuchter, Andrew F.

2009-01-01

Objective To assess whether pretreatment theta current density in the rostral anterior cingulate (rACC) and medial orbitofrontal cortex (mOFC) differentiates responders from non-responders to antidepressant medication or placebo in a double-blinded study. Methods Pretreatment EEGs were collected from 72 subjects with Major Depressive Disorder (MDD) who participated in one of three placebo-controlled trials. Subjects were randomized to receive treatment with fluoxetine, venlafaxine, or placebo. Low-resolution brain electromagnetic tomography (LORETA) was used to assess theta current density in the rACC and mOFC. Results Medication responders showed elevated rACC and mOFC theta current density compared to medication non-responders (rACC: p=0.042; mOFC: p=0.039). There was no significant difference in either brain region between placebo responders and placebo non-responders. Conclusions Theta current density in the rACC and mOFC may be useful as a biomarker for prediction of response to antidepressant medication. Significance This is the first double-blinded treatment study to examine pretreatment rACC and mOFC theta current density in relation to antidepressant response and placebo response. Results support the potential clinical utility of this approach for predicting clinical outcome to antidepressant treatments in MDD. PMID:19539524

A double-blind, placebo-controlled study of the safety and efficacy of ipratropium bromide nasal spray versus placebo in patients with the common cold.

PubMed

Dockhorn, R; Grossman, J; Posner, M; Zinny, M; Tinkleman, D

1992-12-01

Ipratropium bromide (IB) has been found to reduce secretions in the upper respiratory tract; this is accomplished through competitive inhibition of acetylcholine at muscarinic receptors that control rhinorrhea production. This study compared the safety and efficacy of IB with placebo in the symptomatic relief of rhinorrhea in patients with the common cold. Human subjects with symptoms of a common cold, primarily rhinorrhea, were enrolled and treated with either IB (84 micrograms/nostril) or placebo; each was administered as two sprays per nostril, four times a day, for 4 days. Primary efficacy analyses were in-clinic measurements of nasal discharge weights over a 3-hour period after administration on days 1 and 2 and assessment of rhinorrhea symptoms by use of a subjective patient-completed visual analog rating scale. IB significantly reduced rhinorrhea an average of 18% over placebo for days 1 and 2 (p = 0.01). Visual analog scale scores showed an average improvement in rhinorrhea of 22% over placebo (p = 0.001). When patients with relatively minor rhinorrhea (baseline weight of nasal discharge < or = 1.0 gm) were excluded, IB produced an average reduction in nasal discharge of 23% over placebo for days 1 and 2 (p = 0.003).

Lubiprostone plus PEG electrolytes versus placebo plus PEG electrolytes for outpatient colonoscopy preparation: a randomized, double-blind placebo-controlled trial.

PubMed

Sofi, Aijaz A; Nawras, Ali T; Pai, Chetan; Samuels, Qiana; Silverman, Ann L

2015-01-01

Bowel preparation using large volume of polyethylene glycol (PEG) solutions is often poorly tolerated. Therefore, there are ongoing efforts to develop an alternative bowel cleansing regimen that should be equally effective and better tolerated. The aim of this study was to assess the efficacy of lubiprostone (versus placebo) plus PEG as a bowel cleansing preparation for colonoscopy. Our study was a randomized, double-blind placebo-controlled design. Patients scheduled for screening colonoscopy were randomized 1:1 to lubiprostone (group 1) or placebo (group 2) plus 1 gallon of PEG. The primary endpoints were patient's tolerability and endoscopist's evaluation of the preparation quality. The secondary endpoint was to determine any reduction in the amount of PEG consumed in the lubiprostone group compared with the placebo group. One hundred twenty-three patients completed the study and were included in the analysis. There was no difference in overall cleanliness. The volume of PEG was similar in both the groups. The volume of PEG approached significance as a predictor of improved score for both the groups (P = 0.054). Lubiprostone plus PEG was similar to placebo plus PEG in colon cleansing and volume of PEG consumed. The volume of PEG consumed showed a trend toward improving the quality of the colon cleansing.

Pharmacological interventions for self-injurious behaviour in adults with intellectual disabilities: Abridged republication of a Cochrane systematic review.

PubMed

Gormez, A; Rana, F; Varghese, S

2014-07-01

We aimed to determine clinical effectiveness of pharmacological interventions for self-injurious behaviour in adults with intellectual disability. We searched the following databases: CENTRAL; MEDLINE; EMBASE; PsycINFO; CINAHL; SCI; SSCI; Conference Proceedings Citation Index - Science; Conference Proceedings Citation Index - Social Science and Humanities; ZETOC; World Cat .We also searched ClinicalTrials.gov,ICTRP and the reference lists of included trials. We included randomised controlled trials that examined drug interventions versus placebo for self-injurious behaviour. We found five double-blind, placebo-controlled trials, which included a total of 50 people. Four trials compared the effects of naltrexone versus placebo and one trial clomipramine versus placebo. We did not identify any relevant placebo-controlled trials for other drugs. We presented a narrative summary, as meta-analysis was not appropriate due to differences in study designs, differences between interventions and heterogeneous outcome measures. There was weak evidence in included trials that any active drug was more effective than placebo for people with intellectual disability demonstrating self-injurious behaviour. Due to sparse data, an absence of power and statistical significance, and high risk of bias for four of the included trials, we are unable to reach any definite conclusions about the relative benefits of naltrexone or clomipramine compared to placebo. © The Author(s) 2014.

An adaptogenic role for omega-3 fatty acids in stress; a randomised placebo controlled double blind intervention study (pilot) [ISRCTN22569553

PubMed Central

Bradbury, Joanne; Myers, Stephen P; Oliver, Chris

2004-01-01

Background There is evidence for an adaptive role of the omega -3 fatty acid, docosahexaenoic acid (DHA) during stress. Mechanisms of action may involve regulation of stress mediators, such as the catecholamines and proinflammatory cytokines. Prevention of stress-induced aggression and hostility were demonstrated in a series of clinical trials. This study investigates whether perceived stress is ameliorated by DHA in stressed university staff. Methods Subjects that scored ≥ 17 on the Perceived Stress Scale were randomised into a 6-week pilot intervention study. The diet reactive group was supplemented with 6 g of fish oil containing 1.5 g per day DHA, while the placebo group was supplemented with 6 g a day of olive oil. The groups were compared with each other and a wider cross sectional study population that did not receive either active or placebo intervention. Results There was a significant reduction in perceived stress in both the fish oil and the placebo group from baseline. There was also a significant between-group difference between the fish oil group and the no-treatment controls in the rate of stress reduction (p < 0.05). However, there was not a significant between-group difference between the fish oil and the placebo group, nor the placebo group and the control group. These results are discussed in the context of several methodological limitations. The significant stress reductions in both the fish oil and the placebo group are considered in view of statistical regression, an effect likely to have been exaggerated by the time course of the study, a large placebo effect and the possibility of an active effect from the placebo. Conclusion There were significant differences (p < 0.05) in the fish oil group compared with no-treatment controls. This effect was not demonstrated in the placebo group. As a pilot study, it was not sufficiently powered to find the difference between the fish oil group and the placebo group significant. Further work needs to be undertaken to conclusively demonstrate these data trends. However, the findings from this research support the literature in finding a protective or 'adaptogenic' role for omega-3 fatty acids in stress. PMID:15566625

Proof-of-Concept Study to Assess the Nociceptin Receptor Antagonist LY2940094 as a New Treatment for Alcohol Dependence.

PubMed

Post, Anke; Smart, Trevor S; Jackson, Kimberley; Mann, Joanne; Mohs, Richard; Rorick-Kehn, Linda; Statnick, Michael; Anton, Raymond; O'Malley, Stephanie S; Wong, Conrad J

2016-09-01

This was a proof-of-concept study to evaluate the efficacy of LY2940094, a nociceptin/orphanin FQ peptide receptor antagonist, in reducing alcohol consumption in actively alcohol-drinking patients with alcohol dependence. Eighty-eight patients, 21 to 66 years of age, diagnosed with alcohol dependence, reporting 3 to 6 heavy drinking days per week, were randomized (1:1) to 8 weeks of treatment with once-daily oral placebo (N = 44) or 40 mg/d of LY2940094 (N = 44). The primary efficacy analysis was the change from baseline in number of drinks per day (NDD) utilizing mixed-model repeated measures comparing LY2940094 and placebo in Month 2 of the 8-week double-blind treatment period. The probability that the difference relative to placebo in NDD was ≤0 at endpoint was calculated, and a probability ≥80% was considered to be evidence that LY2940094 was associated with the reduction in NDD. After 8 weeks of treatment, reduction in mean NDD did not differ between LY2940094 versus placebo (-1.4 vs. -1.5, respectively, 44% probability of greater reduction relative to placebo), but there was a greater reduction in the mean percentage of heavy drinking days in a month with LY2940094 versus placebo (-24.5 vs. -15.7%, respectively, 93% probability of a greater reduction relative to placebo), and an increase in the mean percentage of abstinent days in a month compared to placebo (9.1 vs. 1.9%, respectively, 91% probability of a greater increase relative to placebo). Patients who were treated with LY2940094 showed decreased plasma levels of gamma-glutamyl transferase with probabilities ≥98% for greater reduction compared with placebo at Weeks 1, 4, 6, and 8. Treatment-emergent adverse events in ≥5% of patients treated with LY2940094 included insomnia, vomiting, and anxiety. There were no serious adverse events or significant changes in laboratory assessments or vital signs with LY2940094. Although not reducing the NDD, LY2940094, compared to placebo, did reduce heavy drinking days and increased abstinence days in patients with alcohol dependence. Copyright © 2016 by the Research Society on Alcoholism.

Lisdexamfetamine dimesylate augmentation for adults with major depressive disorder and inadequate response to antidepressant monotherapy: Results from 2 phase 3, multicenter, randomized, double-blind, placebo-controlled studies.

PubMed

Richards, Cynthia; McIntyre, Roger S; Weisler, Richard; Sambunaris, Angelo; Brawman-Mintzer, Olga; Gao, Joseph; Geibel, Brooke; Dauphin, Matthew; Madhoo, Manisha

2016-12-01

The efficacy, safety, and tolerability of lisdexamfetamine dimesylate (LDX) augmentation of antidepressant monotherapy in adults with major depressive disorder (MDD) from two phase 3 studies are reported. Across study 1 (placebo, n=201; LDX, n=201) and study 2 (placebo, n=213; LDX, n=211), most participants (placebo and LDX) in the safety analysis set were female (study 1: 66.2% and 64.2%; study 2: 67.1% and 66.8%); mean±SD ages were 41.8±12.04 with placebo and 42.2±12.32 with LDX in study 1 and 42.6±11.41 with placebo and 42.0±11.63 with LDX in study 2. Participants (18-65 y) had DSM-IV-TR-diagnosed MDD and lead-in baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total scores ≥24. Eight-week antidepressant lead-in phases prospectively assessed antidepressant response. Then, 8 weeks of randomized (1:1), double-blind treatment with dose-optimized LDX (20-70mg) or placebo in participants exhibiting inadequate antidepressant monotherapy responses (augmentation baseline MADRS total scores ≥18 and <50% MADRS total score reductions from lead-in baseline to augmentation baseline) was initiated. The primary endpoint was MADRS total score change from augmentation baseline to week 16. Safety and tolerability measures included the occurrence of treatment-emergent adverse events (TEAEs). Least squares mean (95% CI) treatment differences (LDX-placebo) for MADRS total score changes from augmentation baseline to week 16 were not statistically significant in study 1 (0.1 [-1.7, 2.0], P=0.883) or study 2 (-0.5 [-2.3, 1.3], P=0.583). The only TEAE reported by >5% of LDX participants at twice the placebo rate in both studies was dry mouth. Limitations include the exclusion of participants with psychiatric comorbidities/active medical disorders, the inability to assess specific MDD symptom domains (eg, anhedonia, cognition) or subtypes, the use of telephone-based depression assessments, and the potential influence of placebo response. Contrary to expectations, LDX augmentation was not superior to placebo in reducing depressive symptoms in individuals with MDD exhibiting inadequate responses to antidepressant monotherapy. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Urtica dioica for treatment of benign prostatic hyperplasia: a prospective, randomized, double-blind, placebo-controlled, crossover study.

PubMed

Safarinejad, Mohammad Reza

2005-01-01

To determine the effects of therapy with Urtica dioica for symptomatic relief of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). A 6-month, double-blind, placebo-controlled, randomized, partial crossover, comparative trial of Urtica dioica with placebo in 620 patients was conducted. Patients were evaluated using the International Prostate Symptom Score (IPSS), the maximum urinary flow rate (Qmax), postvoid residual urine volume (PVR), Serum Prostatic- Specific Antigen (PSA), testosterone levels, and prostate size. At the end of 6-month trial, unblinding revealed that patients who initially received the placebo were switched to Urtica dioica. Both groups continued the medication up to 18 months. 558 patients (90%) completed the study (287/305, 91% in the Urtica dioica group, and 271/315, 86% in the placebo group). By intention- to-treat analysis, at the end of 6-month trial, 232 (81%) of 287 patients in the Urtica dioica group reported improved LUTS compared with 43 (16%) of 271 patients in the placebo group (P < 0.001). Both IPSS and Qmax showed greater improvement with drug than with placebo. The IPSS went from 19.8 down to 11.8 with Urtica dioica and from 19.2 to 17.7 with placebo (P = 0.002). Peak flow rates improved by 3.4 mL/s for placebo recipients and by 8.2 mL/s for treated patients (P < 0.05). In Urtica dioica group, PVR decreased from an initial value of 73 to 36 mL (P < 0.05). No appreciable change was seen in the placebo group. Serum PSA and testosterone levels were unchanged in both groups. A modest decrease in prostate size as measured by transrectal ultrasonography (TRUS) was seen in Urtica dioica group (from 40.1 cc initially to 36.3 cc; P < 0.001). There was no change in the prostate volume at the end of study with placebo. At 18-month follow-up, only patients who continued therapy, had a favorable treatment variables value. No side effects were identified in either group. In the present study, Urtica dioica have beneficial effects in the treatment of symptomatic BPH. Further clinical trials should be conducted to confirm these results before concluding that Urtica dioica is effective.

A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure

PubMed Central

McMurray, John; Packer, Milton; Desai, Akshay; Gong, Jianjian; Greenlaw, Nicola; Lefkowitz, Martin; Rizkala, Adel; Shi, Victor; Rouleau, Jean; Solomon, Scott; Swedberg, Karl; Zile, Michael R.; Andersen, Karl; Arango, Juan Luis; Arnold, Malcolm; Be˘lohlávek, Jan; Böhm, Michael; Boytsov, Sergey; Burgess, Lesley; Cabrera, Walter; Chen, Chen-Huan; Erglis, Andrejs; Fu, Michael; Gomez, Efrain; Gonzalez, Angel; Hagege, Albert-Alain; Katova, Tzvetana; Kiatchoosakun, Songsak; Kim, Kee-Sik; Bayram, Edmundo; Martinez, Felipe; Merkely, Bela; Mendoza, Iván; Mosterd, Arend; Negrusz-Kawecka, Marta; Peuhkurinen, Keijo; Ramires, Felix; Refsgaard, Jens; Senni, Michele; Sibulo, Antonio S.; Silva-Cardoso, José; Squire, Iain; Starling, Randall C.; Vinereanu, Dragos; Teerlink, John R.; Wong, Raymond

2015-01-01

Aims Although active-controlled trials with renin–angiotensin inhibitors are ethically mandated in heart failure with reduced ejection fraction, clinicians and regulators often want to know how the experimental therapy would perform compared with placebo. The angiotensin receptor-neprilysin inhibitor LCZ696 was compared with enalapril in PARADIGM-HF. We made indirect comparisons of the effects of LCZ696 with putative placebos. Methods and results We used the treatment-arm of the Studies Of Left Ventricular Dysfunction (SOLVD-T) as the reference trial for comparison of an ACE inhibitor to placebo and the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (CHARM-Alternative) as the reference trial for comparison of an ARB to placebo. The hazard ratio of LCZ696 vs. a putative placebo was estimated through the product of the hazard ratio of LCZ696 vs. enalapril (active-control) and that of the historical active-control (enalapril or candesartan) vs. placebo. For the primary composite outcome of cardiovascular death or heart failure hospitalization in PARADIGM-HF, the relative risk reduction with LCZ696 vs. a putative placebo from SOLVD-T was 43% (95%CI 34–50%; P < 0.0001) with similarly large effects on cardiovascular death (34%, 21–44%; P < 0.0001) and heart failure hospitalization (49%, 39–58%; P < 0.0001). For all-cause mortality, the reduction compared with a putative placebo was 28% (95%CI 15–39%; P < 0.0001). Putative placebo analyses based on CHARM-Alternative gave relative risk reductions of 39% (95%CI 27–48%; P < 0.0001) for the composite outcome of cardiovascular death or heart failure hospitalization, 32% (95%CI 16–45%; P < 0.0001) for cardiovascular death, 46% (33–56%; P < 0.0001) for heart failure hospitalization, and 26% (95%CI 11–39%; P < 0.0001) for all-cause mortality. Conclusion These indirect comparisons of LCZ696 with a putative placebo show that the strategy of combined angiotensin receptor blockade and neprilysin inhibition led to striking reductions in cardiovascular and all-cause mortality, as well as heart failure hospitalization. These benefits were obtained even though LCZ696 was added to comprehensive background beta-blocker and mineralocorticoid receptor antagonist therapy. PMID:25416329

A Double-Blind, Placebo-Controlled Study of Selegiline Transdermal System in Depressed Adolescents

PubMed Central

Hochadel, Thomas J.; Portland, Kimberly Blanchard; Azzaro, Albert J.; Katic, Alain; Khan, Arif; Emslie, Graham

2014-01-01

Abstract Objective: A randomized, double-blind, placebo-controlled flexible-dose, parallel group trial was conducted at 26 clinical investigational sites in the United States to examine the safety and efficacy of the selegiline transdermal system (STS) (EMSAM®) in adolescents (ages 12–17 years) meeting American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for moderate to severe major depressive disorder (MDD) without psychotic features. Methods: Adolescents (n=308) with moderate to severe MDD were randomized to either STS (n=152) or placebo (n=156). Two hundred and fifteen (69.8%) subjects completed the study and 17 (5.5%) reported discontinuation because of adverse events (AEs). The primary efficacy outcome measure was the mean change from baseline to end of study (week 12 last observation carried forward [LOCF]) in the Children's Depression Rating Scale-Revised (CDRS-R) total score. Secondary outcome measures included end-point Clinical Global Impressions – Severity (CGI-S) and Clinical Global Impressions – Improvement (CGI-I). Results: Patients on STS or placebo had a significant decline from baseline (p<0.001) on their CDRS-R total score with mean reductions±SD as follows: STS 21.4±16.6; placebo 21.5±16.5. Both groups had similar response rates (58.6% vs. 59.3%) defined as CGI-I of 1 or 2 at study end. However, these between-group efficacy findings were without statistical significance. The overall incidence of reported AEs was 62.5% for STS-treated patients and 57.7% for placebo-treated patients. Most commonly reported AEs in STS or placebo groups were application site reactions (STS=24.3%; placebo=21.8%), headache (STS=17.1%; placebo=16.7%), and nausea (STS=7.2%; placebo=7.7%). Treatment groups did not differ on any laboratory parameters, vital signs, or electrocardiogram (ECG) findings. No suspected hypertensive crises were reported in the trial. Conclusions: These data demonstrated that the STS was safe and well tolerated in this adolescent sample. However, both STS-treated and placebo-treated subjects demonstrated a decline from baseline in depressive symptoms (CDRS-R total score) over the length of the study, without statistical superiority by either group. PMID:24955812

First-dose analgesic effect of the cyclo-oxygenase-2 selective inhibitor lumiracoxib in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled comparison with celecoxib [NCT00267215

PubMed Central

Wittenberg, Ralf H; Schell, Ernest; Krehan, Gerhard; Maeumbaed, Roland; Runge, Hans; Schlüter, Peter; Fashola, Taiwo OA; Thurston, Helen J; Burger, Klaus J; Trechsel, Ulrich

2006-01-01

Cyclo-oxygenase-2 selective inhibitors are frequently used to manage osteoarthritis. We compared the analgesic efficacy of the novel cyclo-oxygenase-2 selective inhibitor lumiracoxib (Prexige®) versus placebo and celecoxib in patients with knee osteoarthritis. This seven day, double-blind, placebo and active comparator controlled, parallel group study included 364 patients aged ≥50 years with moderate-to-severe symptomatic knee osteoarthritis. Patients received lumiracoxib 400 mg/day (four times the recommended chronic dose in osteoarthritis; n = 144), placebo (n = 75), or celecoxib 200 mg twice daily (n = 145). The primary variable was actual pain intensity difference (100 mm visual–analogue scale) between baseline and the mean of three hour and five hour assessments after the first dose. Actual pain intensity difference, average and worst pain, pain relief and functional status (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC™]) were measured over seven days. Patients also completed a global evaluation of treatment effect at study end or premature discontinuation. For the primary variable, the superiority of lumiracoxib versus placebo, the noninferiority of lumiracoxib versus celecoxib, and the superiority of lumiracoxib versus celecoxib were assessed by closed test procedure adjusting for multiplicity, thereby maintaining the overall 5% significance level. In addition, celecoxib was assessed versus placebo in a predefined exploratory manner to assess trial sensitivity. Lumiracoxib provided better analgesia than placebo 3–5 hours after the first dose (P = 0.004) through to study end. The estimated difference between lumiracoxib and celecoxib 3–5 hours after the first dose was not significant (P = 0.185). Celecoxib was not significantly different from placebo in this analysis (P = 0.069). At study end 13.9% of lumiracoxib-treated patients reported complete pain relief versus 5.5% and 5.3% of celecoxib and placebo recipients, respectively. WOMAC™ total and subscales improved for both active treatments versus placebo except for difficulty in performing daily activities, for which celecoxib just failed to achieve significance (P = 0.056). In the patient's global evaluation of treatment effect, 58.1% of patients receiving lumiracoxib rated treatment as 'excellent' or 'good', versus 48.6% of celecoxib and 25.3% of placebo patients. Lumiracoxib was well tolerated. The overall incidence of adverse events was similar across treatment groups. PMID:16469112

Incidence of seizure exacerbation and seizures reported as adverse events during adjunctive treatment with eslicarbazepine acetate: A pooled analysis of three Phase III controlled trials.

PubMed

Carreño, Mar; Benbadis, Selim; Rocha, Francisco; Blum, David; Cheng, Hailong

2017-12-01

To investigate whether adjunctive eslicarbazepine acetate (ESL) could lead to exacerbation of seizures in some patients. Post-hoc analysis of data pooled from three Phase III trials of adjunctive ESL (studies 301, 302, and 304) for refractory partial-onset seizures (POS). Following an 8-week baseline period, patients were randomized to receive placebo or ESL 400, 800, or 1,200 mg once daily (2-week titration, 12-week maintenance, 2-4 week tapering-off periods). Patient seizure diary data and seizure treatment-emergent adverse event (TEAE) reports were pooled for analysis. The modified intent-to-treat and safety populations comprised 1,410 patients and 1,447 patients, respectively. Titration period : Compared with placebo (32/21%), significantly smaller proportions of patients taking ESL 800 mg (20/15%) and 1,200 mg (22/12%) had a ≥25/≥50% increase in standardized seizure frequency (SSF) from baseline; there was no significant difference between placebo and ESL 400 mg. Maintenance period : Compared with placebo (20%), significantly smaller proportions of patients taking ESL (400 mg, 12%; 800 mg, 12%; 1,200 mg, 14%) had an increase in SSF ≥25%. When evaluating ≥50% increases in SSF, only ESL 800 mg (7%) was significantly different from placebo (12%). Some patients had no secondarily generalized tonic-clonic (sGTC) seizures during baseline but had ≥1 sGTC seizure during maintenance treatment (placebo, 11%; ESL 400 mg, 5%; 800 mg, 10%; 1,200 mg, 5%). Fewer patients had a ≥25% increase in sGTC seizure frequency with ESL (400 mg, 11%; 800 mg, 9%; 1,200 mg, 14%) versus placebo (19%). The incidence of seizures reported as TEAEs was low in all treatment groups; incidences were generally lower with ESL versus placebo. Tapering-off period : Similar proportions of patients taking ESL and placebo had a ≥25/≥50% increase in SSF. Seizure TEAE incidence was numerically higher with ESL versus placebo. Treatment with adjunctive ESL does not appear to aggravate POS or sGTC seizures.

Acupuncture versus paroxetine for the treatment of premature ejaculation: a randomized, placebo-controlled clinical trial.

PubMed

Sunay, Didem; Sunay, Melih; Aydoğmuş, Yasin; Bağbancı, Sahin; Arslan, Hüseyin; Karabulut, Ayhan; Emir, Levent

2011-05-01

Acupuncture therapy has been used by many researchers in both male and female sexual dysfunction studies. To determine whether acupuncture is effective as a premature ejaculation (PE) treatment compared with paroxetine and placebo. The study was conducted with methodologic rigor based on Consolidated Standards of Reporting Trials (CONSORT) criteria. Ninety patients referred to the urology clinic at a tertiary training and research hospital with PE were included in this randomized controlled trial and randomly assigned into paroxetine, acupuncture, and placebo groups. Heterosexual, sexually active men aged between 28 and 50 yr were included. Men with other sexual disorders, including erectile dysfunction; with chronic psychiatric or systemic diseases; with alcohol or substance abuse; or who used any medications were excluded. The medicated group received paroxetine 20 mg/d; the acupuncture or sham-acupuncture (placebo) groups were treated twice a week for 4 wk. Intravaginal ejaculation latency times (IELTs) and the Premature Ejaculation Diagnostic Tool (PEDT) were used to assess PE. IELTs were calculated by using a partner-held stopwatch. Data were analyzed statistically. Median PEDT scores of paroxetine, acupuncture, and placebo groups were 17.0, 16.0, and 15.5 before treatment, and 10.5, 11.0, and 16.0 after treatment, respectively (p=0.001, p=0.001, and p=0.314, respectively). Subscores after treatment were significantly lower than subscores before treatment in the paroxetine and acupuncture groups but remained the same in the placebo group. Significant differences were found between mean-rank IELTs of the paroxetine and placebo groups (p=0.001) and the acupuncture and placebo groups (p=0.001) after treatment. Increases of IELTs with paroxetine, acupuncture, and placebo acupuncture were 82.7, 65.7, and 33.1 s, respectively. Extent of ejaculation delay induced by paroxetine was significantly higher than that of acupuncture (p=0.001). The most important limitation of the study was the lack of follow-up. Although less effective than daily paroxetine, acupuncture had a significant stronger ejaculation-delaying effect than placebo. Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Supplementation of standard antibiotic therapy with oral probiotics for bacterial vaginosis and aerobic vaginitis: a randomised, double-blind, placebo-controlled trial.

PubMed

Heczko, Piotr B; Tomusiak, Anna; Adamski, Paweł; Jakimiuk, Artur J; Stefański, Grzegorz; Mikołajczyk-Cichońska, Aleksandra; Suda-Szczurek, Magdalena; Strus, Magdalena

2015-12-03

This multicentre, randomised, double-blind, placebo-controlled trial was performed to determine whether the use of oral probiotic preparation (prOVag®) containing three Lactobacillus strains together with standard metronidazole treatment and also targeted antibiotic treatment (following the failure of metronidazole therapy) could reduce the recurrence rates of bacterial vaginosis (BV) and aerobic vaginitis (AV). Patients at private gynaecological clinics in Poland with histories of recurrent BV/AV and current symptoms were randomly allocated to receive metronidazole and probiotic or placebo, and assessed monthly on visits II and III-V. The total number of study visits was 5-6 (I, II, II bis - if applicable, III, IV, V). One probiotic or placebo capsule was administered with metronidazole/targeted antibiotic twice daily for 10 days; during follow up, patients took one capsule daily for 10 days perimenstrually. Clinical examination and vaginal swabbing were performed at each visit. Primary outcomes were clinical or microbiological BV/AV recurrence and probiotic safety. Secondary outcomes were vaginal pH, Nugent score, and Lactobacillus counts in the vaginal microbiota. Safety analysis was performed in 578 (probiotic, n = 285; placebo, n = 293) 18-50-year-old women who were randomised. BV/AV was confirmed microbiologically in 241 (probiotic, n = 118; placebo, n = 123) participants, who continued the trial. Data from 154 (probiotic, n = 73; placebo, n = 81) participants who completed the study were analysed to determine the efficacy of prOVag. Additional analyses included 37 (probiotic, n = 22; placebo, n = 15) participants who received targeted antibiotics and probiotics or placebo. prOVag lengthened the time to clinical relapse of BV/AV symptoms up to 51 % (p < 0.05) compared with placebo; AV relapse was delayed by up to 76 % (p < 0.05). Probiotic use also reduced and maintained low vaginal pH and Nugent score, and increased vaginal Lactobacillus counts following standard treatment. This study demonstrated that oral probiotics lengthened remission in patients with recurrent BV/AV and improved clinical and microbiological parameters. NCT01993524 ; 20 November 2013.

Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials.

PubMed

Panés, Julian; Sandborn, William J; Schreiber, Stefan; Sands, Bruce E; Vermeire, Séverine; D'Haens, Geert; Panaccione, Remo; Higgins, Peter D R; Colombel, Jean-Frederic; Feagan, Brian G; Chan, Gary; Moscariello, Michele; Wang, Wenjin; Niezychowski, Wojciech; Marren, Amy; Healey, Paul; Maller, Eric

2017-06-01

Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for IBD. We evaluated the efficacy and safety of tofacitinib for induction and maintenance treatment in patients with moderate-to-severe Crohn's disease (CD). We conducted two randomised, double-blind, placebo-controlled, multicentre phase IIb studies. Adult patients with moderate-to-severe CD were randomised to receive induction treatment with placebo, tofacitinib 5 or 10 mg twice daily for 8 weeks. Those achieving clinical response-100 or remission were re-randomised to maintenance treatment with placebo, tofacitinib 5 or 10 mg twice daily for 26 weeks. Primary endpoints were clinical remission at the end of the induction study, and clinical response-100 or remission at the end of the maintenance study. 180/280 patients randomised in the induction study were enrolled in the maintenance study. At week 8 of induction, the proportion of patients with clinical remission was 43.5% and 43.0% with 5 and 10 mg twice daily, respectively, compared with 36.7% in the placebo group (p=0.325 and 0.392 for 5 and 10 mg twice daily vs placebo). At week 26 of maintenance, the proportion of patients with clinical response-100 or remission was 55.8% with tofacitinib 10 mg twice daily compared with 39.5% with tofacitinib 5 mg twice daily and 38.1% with placebo (p=0.130 for 10 mg twice daily vs placebo). Compared with placebo, the change in C-reactive protein from baseline was statistically significant (p<0.0001) with 10 mg twice daily after both induction and maintenance treatments. Primary efficacy endpoints were not significantly different from placebo, although there was evidence of a minor treatment effect. No new safety signals were observed for tofacitinib. NCT01393626 and NCT01393899. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Heavy Resistance Training in Hypoxia Enhances 1RM Squat Performance

PubMed Central

Inness, Mathew W. H.; Billaut, François; Walker, Emily J.; Petersen, Aaron C.; Sweeting, Alice J.; Aughey, Robert J.

2016-01-01

Purpose: To determine if heavy resistance training in hypoxia (IHRT) is more effective at improving strength, power, and increasing lean mass than the same training in normoxia. Methods: A pair-matched, placebo-controlled study design included 20 resistance-trained participants assigned to IHRT (FIO2 0.143) or placebo (FIO2 0.20), (n = 10 per group). Participants were matched for strength and training. Both groups performed 20 sessions over 7 weeks either with IHRT or placebo. All participants were tested for 1RM, 20-m sprint, body composition, and countermovement jump pre-, mid-, and post-training and compared via magnitude-based inferences. Presentation of Results: Groups were not clearly different for any test at baseline. Training improved both absolute (IHRT: 13.1 ± 3.9%, effect size (ES) 0.60, placebo 9.8 ± 4.7%, ES 0.31) and relative 1RM (IHRT: 13.4 ± 5.1%, ES 0.76, placebo 9.7 ± 5.3%, ES 0.48) at mid. Similarly, at post both groups increased absolute (IHRT: 20.7 ± 7.6%, ES 0.74, placebo 14.1 ± 6.0%, ES 0.58) and relative 1RM (IHRT: 21.6 ± 8.5%, ES 1.08, placebo 13.2 ± 6.4%, ES 0.78). Importantly, the change in IHRT was greater than placebo at mid for both absolute [4.4% greater change, 90% Confidence Interval (CI) 1.0:8.0%, ES 0.21, and relative strength (5.6% greater change, 90% CI 1.0:9.4%, ES 0.31 (relative)]. There was also a greater change for IHRT at post for both absolute (7.0% greater change, 90% CI 1.3:13%, ES 0.33), and relative 1RM (9.2% greater change, 90% CI 1.6:14.9%, ES 0.49). Only IHRT increased countermovement jump peak power at Post (4.9%, ES 0.35), however the difference between IHRT and placebo was unclear (2.7, 90% CI –2.0:7.6%, ES 0.20) with no clear differences in speed or body composition throughout. Conclusion: Heavy resistance training in hypoxia is more effective than placebo for improving absolute and relative strength. PMID:27857693

Anti-inflammatory effects of salmeterol/fluticasone propionate 50/250 mcg combination therapy in Japanese patients with chronic obstructive pulmonary disease

PubMed Central

Asai, Kazuhisa; Kobayashi, Akihiro; Makihara, Yukio; Johnson, Malcolm

2015-01-01

Purpose Using sputum neutrophils as the primary measure, and other inflammation biomarkers, this study evaluated the anti-inflammatory effects of the combination salmeterol 50 mcg and fluticasone propionate 250 mcg (SFC 250) in Japanese patients with chronic obstructive pulmonary disease (COPD). Patients and methods Patients were treated in a randomized, double-blind, parallel group, placebo-controlled trial with SFC 250 twice daily (n=26) or placebo (n=26) for 12 weeks. At the start and end of treatment, inflammation biomarkers (sputum and serum), lung function, and health status (COPD Assessment Test [CAT] questionnaire) were measured. Results Although a numerical decrease in differential neutrophil count was observed from baseline, SFC 250 did not significantly reduce sputum neutrophils compared with placebo, nor were there significant changes from baseline in the other biomarkers (sputum or serum), lung function, or CAT, versus placebo. Squamous epithelial cell contamination in some sputum samples rendered them unacceptable for analysis, which reduced the sample size to n=19 (SFC 250) and n=10 (placebo). However, inclusion of contaminated samples did not affect the overall trend of the outcome. Ad hoc bootstrap statistical analysis showed a 27.9% (SFC 250) and 1.3% (placebo) decrease in sputum neutrophils. Sputum IL-8 decreased by 43.2% after SFC 250 but increased by 48.3% with placebo. Responder analyses showed 42% of patients had ≥20% decrease in neutrophils from baseline; and 47% of patients had a ≥200 pg/mL change in sputum IL-8 following SFC 250 versus 20% after placebo; both changes are considered clinically relevant. Conclusion This study provides additional information about inflammation in Japanese COPD patients and is the first to study the anti-inflammatory effects of SFC 250 in this context and population. In the primary analysis, SFC 250 did not produce significant changes from baseline in sputum neutrophil levels or other sputum or serum inflammatory markers compared with placebo. Secondary ad hoc statistical analysis showed that SFC 250 reduced the number of sputum neutrophils and IL-8 compared with placebo. PMID:25945045

Placebo and Nocebo Effects: The Advantage of Measuring Expectations and Psychological Factors

PubMed Central

Corsi, Nicole; Colloca, Luana

2017-01-01

Several studies have explored the predictability of placebo and nocebo individual responses by investigating personality factors and expectations of pain decreases and increases. Psychological factors such as optimism, suggestibility, empathy and neuroticism have been linked to placebo effects, while pessimism, anxiety and catastrophizing have been associated to nocebo effects. We aimed to investigate the interplay between psychological factors, expectations of low and high pain and placebo hypoalgesia and nocebo hyperalgesia. We studied 46 healthy participants using a well-validated conditioning paradigm with contact heat thermal stimulations. Visual cues were presented to alert participants about the level of intensity of an upcoming thermal pain. We delivered high, medium and low levels of pain associated with red, yellow and green cues, respectively, during the conditioning phase. During the testing phase, the level of painful stimulations was surreptitiously set at the medium control level with all the three cues to measure placebo and nocebo effects. We found both robust placebo hypolagesic and nocebo hyperalgesic responses that were highly correlated with expectancy of low and high pain. Simple linear regression analyses showed that placebo responses were negatively correlated with anxiety severity and different aspects of fear of pain (e.g., medical pain, severe pain). Nocebo responses were positively correlated with anxiety sensitivity and physiological suggestibility with a trend toward catastrophizing. Step-wise regression analyses indicated that an aggregate score of motivation (value/utility and pressure/tense subscales) and suggestibility (physiological reactivity and persuadability subscales), accounted for the 51% of the variance in the placebo responsiveness. When considered together, anxiety severity, NEO openness-extraversion and depression accounted for the 49.1% of the variance of the nocebo responses. Psychological factors per se did not influence expectations. In fact, mediation analyses including expectations, personality factors and placebo and nocebo responses, revealed that expectations were not influenced by personality factors. These findings highlight the potential advantage of considering batteries of personality factors and measurements of expectation in predicting placebo and nocebo effects related to experimental acute pain. PMID:28321201

Eight weeks of supplementation with a multi-ingredient weight loss product enhances body composition, reduces hip and waist girth, and increases energy levels in overweight men and women.

PubMed

Lopez, Hector L; Ziegenfuss, Tim N; Hofheins, Jennifer E; Habowski, Scott M; Arent, Shawn M; Weir, Joseph P; Ferrando, Arny A

2013-04-19

Numerous natural products are marketed and sold claiming to decrease body weight and fat, but few undergo finished product-specific research demonstrating their safety and efficacy. To determine the safety and efficacy of a multi-ingredient supplement containing primarily raspberry ketone, caffeine, capsaicin, garlic, ginger and Citrus aurantium (Prograde Metabolism™ [METABO]) as an adjunct to an eight-week weight loss program. Using a randomized, placebo-controlled, double-blind design, 70 obese but otherwise healthy subjects were randomly assigned to METABO or a placebo and underwent 8 weeks of daily supplementation, a calorie restricted diet, and exercise training. Subjects were tested for changes in body composition, serum adipocytokines (adiponectin, resistin, leptin, TNF-α, IL-6) and markers of health including heart rate and blood pressure. Of the 45 subjects who completed the study, significant differences were observed in: body weight (METABO -2.0% vs. placebo -0.5%, P < 0.01), fat mass (METABO -7.8 vs. placebo -2.8%, P < 0.001), lean mass (METABO +3.4% vs. placebo +0.8%, P < 0.03), waist girth (METABO -2.0% vs. placebo -0.2%, P < 0.0007), hip girth (METABO -1.7% vs. placebo -0.4%, P < 0.003), and energy levels per anchored visual analogue scale (VAS) (METABO +29.3% vs. placebo +5.1%, P < 0.04). During the first 4 weeks, effects/trends for maintaining elevated serum leptin (P < 0.03) and decreased serum resistin (P < 0.08) in the METABO group vs. placebo were also observed. No changes in systemic hemodynamics, clinical blood chemistries, adverse events, or dietary intake were noted between groups. METABO administration is a safe and effective adjunct to an eight-week diet and exercise weight loss program by augmenting improvements in body composition, waist and hip girth. Adherence to the eight-week weight loss program also led to beneficial changes in body fat in placebo. Ongoing studies to confirm these results and clarify the mechanisms (i.e., biochemical and neuroendocrine mediators) by which METABO exerts the observed salutary effects are being conducted.

Anti-inflammatory effects of salmeterol/fluticasone propionate 50/250 mcg combination therapy in Japanese patients with chronic obstructive pulmonary disease.

PubMed

Asai, Kazuhisa; Kobayashi, Akihiro; Makihara, Yukio; Johnson, Malcolm

2015-01-01

Using sputum neutrophils as the primary measure, and other inflammation biomarkers, this study evaluated the anti-inflammatory effects of the combination salmeterol 50 mcg and fluticasone propionate 250 mcg (SFC 250) in Japanese patients with chronic obstructive pulmonary disease (COPD). Patients were treated in a randomized, double-blind, parallel group, placebo-controlled trial with SFC 250 twice daily (n=26) or placebo (n=26) for 12 weeks. At the start and end of treatment, inflammation biomarkers (sputum and serum), lung function, and health status (COPD Assessment Test [CAT] questionnaire) were measured. Although a numerical decrease in differential neutrophil count was observed from baseline, SFC 250 did not significantly reduce sputum neutrophils compared with placebo, nor were there significant changes from baseline in the other biomarkers (sputum or serum), lung function, or CAT, versus placebo. Squamous epithelial cell contamination in some sputum samples rendered them unacceptable for analysis, which reduced the sample size to n=19 (SFC 250) and n=10 (placebo). However, inclusion of contaminated samples did not affect the overall trend of the outcome. Ad hoc bootstrap statistical analysis showed a 27.9% (SFC 250) and 1.3% (placebo) decrease in sputum neutrophils. Sputum IL-8 decreased by 43.2% after SFC 250 but increased by 48.3% with placebo. Responder analyses showed 42% of patients had ≥20% decrease in neutrophils from baseline; and 47% of patients had a ≥200 pg/mL change in sputum IL-8 following SFC 250 versus 20% after placebo; both changes are considered clinically relevant. This study provides additional information about inflammation in Japanese COPD patients and is the first to study the anti-inflammatory effects of SFC 250 in this context and population. In the primary analysis, SFC 250 did not produce significant changes from baseline in sputum neutrophil levels or other sputum or serum inflammatory markers compared with placebo. Secondary ad hoc statistical analysis showed that SFC 250 reduced the number of sputum neutrophils and IL-8 compared with placebo.

A randomized, placebo-controlled trial of lubiprostone for opioid-induced constipation in chronic noncancer pain.

PubMed

Jamal, M Mazen; Adams, Atoya B; Jansen, Jan-Peter; Webster, Lynn R

2015-05-01

This multicenter, phase 3 trial evaluated oral lubiprostone for constipation associated with non-methadone opioids in patients with chronic noncancer-related pain. Adults with opioid-induced constipation (OIC; <3 spontaneous bowel movements [SBMs] per week) were randomized 1:1 to double-blind lubiprostone 24 μg or placebo twice daily for 12 weeks. The primary end point was the overall SBM response rate. Responders had at least moderate response (≥1 SBM improvement over baseline frequency) in all treatment weeks with available observed data, as well as full response (≥3 SBMs per week) for at least 9 of the 12 treatment weeks. In total, 431 patients were randomized; 212 each received lubiprostone and placebo, and 7 were not treated. Overall, the SBM response rate was significantly higher for patients treated with lubiprostone vs. placebo (27.1 vs. 18.9%, respectively; P=0.030). Overall mean change from baseline in SBM frequency was significantly greater with lubiprostone vs. placebo (3.2 vs. 2.4, respectively; P=0.001). The median time to first SBM was significantly shorter with lubiprostone vs. placebo (23.5 vs. 37.7 h, respectively; P=0.004). Compared with placebo, the patients treated with lubiprostone exhibited significant improvements in straining (P=0.004), stool consistency (P<0.001), and constipation severity (P=0.010). No significant differences were observed in quality-of-life measures or the use of rescue medication; however, the percentage of patients who used rescue medication was consistently lower in the lubiprostone group than in the placebo group at months 1 (34.9 vs. 37.7%), 2 (23.4 vs. 26.6%), and 3 (20.5 vs. 22.0%). Adverse events (AEs) >5% were diarrhea, nausea, vomiting, and abdominal pain (lubiprostone: 11.3, 9.9, 4.2, and 7.1%, respectively; placebo, 3.8, 4.7, 5.2, and 0%, respectively). None of the serious AEs (lubiprostone, 3.3%; placebo, 2.8%) were related to lubiprostone. Lubiprostone significantly improved symptoms of OIC and was well tolerated in patients with chronic noncancer pain.

A Randomized, Placebo-Controlled Trial of Lubiprostone for Opioid-Induced Constipation in Chronic Noncancer Pain

PubMed Central

Jamal, M Mazen; Adams, Atoya B; Jansen, Jan-Peter; Webster, Lynn R

2015-01-01

OBJECTIVES: This multicenter, phase 3 trial evaluated oral lubiprostone for constipation associated with non-methadone opioids in patients with chronic noncancer-related pain. METHODS: Adults with opioid-induced constipation (OIC; <3 spontaneous bowel movements [SBMs] per week) were randomized 1:1 to double-blind lubiprostone 24 μg or placebo twice daily for 12 weeks. The primary end point was the overall SBM response rate. Responders had at least moderate response (≥1 SBM improvement over baseline frequency) in all treatment weeks with available observed data, as well as full response (≥3 SBMs per week) for at least 9 of the 12 treatment weeks. RESULTS: In total, 431 patients were randomized; 212 each received lubiprostone and placebo, and 7 were not treated. Overall, the SBM response rate was significantly higher for patients treated with lubiprostone vs. placebo (27.1 vs. 18.9%, respectively; P=0.030). Overall mean change from baseline in SBM frequency was significantly greater with lubiprostone vs. placebo (3.2 vs. 2.4, respectively; P=0.001). The median time to first SBM was significantly shorter with lubiprostone vs. placebo (23.5 vs. 37.7 h, respectively; P=0.004). Compared with placebo, the patients treated with lubiprostone exhibited significant improvements in straining (P=0.004), stool consistency (P<0.001), and constipation severity (P=0.010). No significant differences were observed in quality-of-life measures or the use of rescue medication; however, the percentage of patients who used rescue medication was consistently lower in the lubiprostone group than in the placebo group at months 1 (34.9 vs. 37.7%), 2 (23.4 vs. 26.6%), and 3 (20.5 vs. 22.0%). Adverse events (AEs) >5% were diarrhea, nausea, vomiting, and abdominal pain (lubiprostone: 11.3, 9.9, 4.2, and 7.1%, respectively; placebo, 3.8, 4.7, 5.2, and 0%, respectively). None of the serious AEs (lubiprostone, 3.3% placebo, 2.8%) were related to lubiprostone. CONCLUSIONS: Lubiprostone significantly improved symptoms of OIC and was well tolerated in patients with chronic noncancer pain. PMID:25916220

Atomoxetine treatment of attention-deficit/hyperactivity disorder in young adults with assessment of functional outcomes: a randomized, double-blind, placebo-controlled clinical trial.

PubMed

Durell, Todd M; Adler, Lenard A; Williams, Dave W; Deldar, Ahmed; McGough, James J; Glaser, Paul E; Rubin, Richard L; Pigott, Teresa A; Sarkis, Elias H; Fox, Bethany K

2013-02-01

Attention-deficit/hyperactivity disorder (ADHD) is associated with significant impairment in multiple functional domains. This trial evaluated efficacy in ADHD symptoms and functional outcomes in young adults treated with atomoxetine. Young adults (18-30 years old) with ADHD were randomized to 12 weeks of double-blind treatment with atomoxetine (n = 220) or placebo (n = 225). The primary efficacy measure of ADHD symptom change was Conners' Adult ADHD Rating Scale (CAARS): Investigator-Rated: Screening Version Total ADHD Symptoms score with adult prompts. Secondary outcomes scales included the Adult ADHD Quality of Life-29, Clinical Global Impression-ADHD-Severity, Patient Global Impression-Improvement, CAARS Self-Report, Behavior Rating Inventory of Executive Function-Adult Version Self-Report, and assessments of depression, anxiety, sleepiness, driving behaviors, social adaptation, and substance use. Atomoxetine was superior to placebo on CAARS: Investigator-Rated: Screening Version (atomoxetine [least-squares mean ± SE, -13.6 ± 0.8] vs placebo [-9.3 ± 0.8], 95% confidence interval [-6.35 to -2.37], P < 0.001), Clinical Global Impression-ADHD-Severity (atomoxetine [-1.1 ± 0.1] vs placebo [-0.7 ± 0.1], 95% confidence interval [-0.63 to -0.24], P < 0.001), and CAARS Self-Report (atomoxetine [-11.9 ± 0.8] vs placebo [-7.8 ± 0.7], 95% confidence interval [-5.94 to -2.15], P < 0.001) but not on Patient Global Impression-Improvement. In addition, atomoxetine was superior to placebo on Adult ADHD Quality of Life-29 and Behavior Rating Inventory of Executive Function-Adult Version Self-Report. Additional assessments failed to detect significant differences (P ≥ 0.05) between atomoxetine and placebo. The adverse event profile was similar to that observed in other atomoxetine studies. Nausea, decreased appetite, insomnia, dry mouth, irritability, dizziness, and dyspepsia were reported significantly more often with atomoxetine than with placebo. Atomoxetine reduced ADHD symptoms and improved quality of life and executive functioning deficits in young adults compared with placebo. Atomoxetine was also generally well tolerated.

Healthcare resource utilization with ixazomib or placebo plus lenalidomide-dexamethasone in the randomized, double-blind, phase 3 TOURMALINE-MM1 study in relapsed/refractory multiple myeloma.

PubMed

Hari, Parameswaran; Lin, Huamao Mark; Zhu, Yanyan; Berg, Deborah; Richardson, Paul G; Moreau, Philippe

2018-05-29

The aim of this analysis was to assess healthcare resource utilization in the pivotal phase 3 TOURMALINE-MM1 study of the oral proteasome inhibitor ixazomib or placebo plus lenalidomide and dexamethasone (Rd) in relapsed and/or refractory multiple myeloma (RRMM). In this double-blind, placebo-controlled, randomized study (NCT01564537), 722 patients with RRMM following 1-3 prior lines of therapy received Rd plus ixazomib (ixazomib-Rd; n = 360) or matching placebo (placebo-Rd; n = 362) until disease progression or unacceptable toxicity. Healthcare resource utilization data were captured on Day 1 of each 28-day cycle, every 4 weeks during follow-up for progression-free survival, and every 12 weeks during subsequent follow-up, and included medical encounters (length of stay, inpatient, outpatient, and reason) and number of missing days from work or other activities for patients and caregivers. Exposure-adjusted rates of hospitalization were similar between the ixazomib-Rd and placebo-Rd arms, at 0.530 and 0.564 per patient year (ppy), respectively, as were outpatient visit rates (3.305 and 3.355 ppy). Mean length of hospitalization per patient was 10.0 and 10.8 days, respectively. In both arms, hospitalization and outpatient visit rates were higher in patients with two or three prior lines of treatment (ixazomib-Rd: 0.632 and 3.909 ppy; placebo-Rd: 0.774 and 3.539 ppy) compared with patients with one prior line (ixazomib-Rd: 0.460 and 2.888 ppy; placebo-Rd: 0.436 and 3.243 ppy). Patients and their caregivers who missed any work or other activity missed a median of 7 and 5 days in the ixazomib-Rd arm, respectively, vs 8 and 4 days with placebo-Rd. The study was not powered for a statistical comparison of healthcare resource utilization between treatment arms, nor did it capture costs associated with utilization of the identified healthcare resources. This pre-specified analysis demonstrated that the all-oral triplet regimen of ixazomib added to Rd did not increase healthcare resource utilization compared with placebo-Rd.

Raloxifene Plus Antipsychotics Versus Placebo Plus Antipsychotics in Severely Ill Decompensated Postmenopausal Women With Schizophrenia or Schizoaffective Disorder: A Randomized Controlled Trial.

PubMed

Weiser, Mark; Levi, Linda; Burshtein, Shimon; Hagin, Michal; Matei, Valentin P; Podea, Delia; Micluția, Ioana; Tiugan, Alexandru; Păcală, Bogdan; Grecu, Iosif Gabos; Noy, Adam; Zamora, Daisy; Davis, John M

2017-07-01

Several single-center studies have found raloxifene, an estrogen agonist, to be effective in ameliorating symptoms of schizophrenia in stable patients as augmentation of antipsychotics. This multicenter study assessed whether raloxifene plus antipsychotic treatment, in comparison to placebo plus antipsychotics, improves symptoms or cognition in severely ill decompensated schizophrenia patients. In this 16-week, double-blind, randomized, placebo-controlled study, 200 severely ill, decompensated postmenopausal women who met DSM-IV-TR criteria for schizophrenia or schizoaffective disorder were recruited from January 2011 to December 2012 and were randomized to receive either raloxifene 120 mg/d plus antipsychotics or placebo plus antipsychotics. The primary outcome measure was Positive and Negative Syndrome Scale (PANSS) total score at the end of the trial. The placebo plus antipsychotics group experienced statistically significant improvement in PANSS total score (P < .001) compared to the raloxifene plus antipsychotics group, using mixed models for repeated measures, with results favoring placebo by 4.5 points (95% CI, 2.3-6.7). These results were clearly outside the 95% confidence interval. This negative effect was more pronounced in patients who had more frequent relapses and in those with baseline PANSS scores of 100 or higher. There were no differences between groups in Clinical Global Impression Scale-Severity scores or Composite Brief Assessment of Cognition in Schizophrenia scores at 16 weeks (P > .3). Baseline follicle-stimulating hormone and estradiol levels did not alter the drug-placebo differences. Individuals in the active treatment arm showed worse outcome than those in the placebo arm, most likely as a result of chance variation, but the results unequivocally show no benefit of antipsychotics plus raloxifene versus antipsychotics plus placebo in this large randomized, double-blind, placebo-controlled trial in postmenopausal women. These data do not support the use of raloxifene in severely decompensated schizophrenia patients until reliable research identifies what subgroup of patients or domain of outcome is benefited. ClinicalTrials.gov identifier: NCT01280305. © Copyright 2017 Physicians Postgraduate Press, Inc.

Bromelain and cardiovascular risk factors in diabetes: An exploratory randomized, placebo controlled, double blind clinical trial.

PubMed

Ley, Chit Moy; Ni, Qing; Liao, Xing; Gao, Huai-Lin; Robinson, Nicola

2016-10-01

To assess whether the dietary supplement (bromelain) has the potential to reduce plasma fibrinogen and other cardiovascular disease (CVD) risk factors in patients with diabetes. This randomized placebo controlled, double blind, parallel design, efficacy study was carried out in China and investigated the effect of 12 weeks of bromelain (1,050 mg/day) on plasma fibrinogen. This randomized controlled trial (RCT) recruited 68 Chinese diabetic patients [32 males and 36 females; Han origin, mean age of 61.26 years (standard deviation (SD), 12.62 years)] with at least one CVD risk factor. Patients were randomized into either bromelain or placebo group. While bromelain group received bromelain capsule, the placebo group received placebo capsule which consisted inert ingredient and has no treatment effect. Subjects were required to take 1,050 mg (3×350 mg) of either bromelain or starch-filled placebo capsules, two to be taken (2×350 mg) after breakfast and another (350 mg) after dinner, daily for 12 weeks. Plasma fibrinogen, CVD risk factors and anthropometric indicators were determined at baseline and at 12 weeks. The change in the fibrinogen level in the bromelain group at the end of the study showed a mean reduction of 0.13 g/L (standard deviation (SD) 0.86g/L) compared with the mean reduction of 0.36 g/L (SD 0.96 g/L) for the placebo group. However, there was no significant difference in the mean change in fibrinogen between the placebo and bromelain groups (mean difference=0.23g/L (SD 0.22 g/L), =0.291). Similarly, the difference in mean change in other CVD risk factors (blood lipids, blood pressure), blood glucose, C-reactive protein and anthropometric measures between the bromelain and placebo groups was also not statistically significant. Statistical differences in fibrinogen between bromelain and placebo groups before the trial despite randomization may have influenced the results of this study. This RCT failed to show a beneficial effect in reducing fibrinogen or influencing other selected CVD risk factors but suggests other avenues for subsequent research on bromelain.

Neurodevelopmental outcome and growth at 18 to 22 months' corrected age in extremely low birth weight infants treated with early erythropoietin and iron.

PubMed

Ohls, Robin K; Ehrenkranz, Richard A; Das, Abhik; Dusick, Anna M; Yolton, Kimberly; Romano, Elaine; Delaney-Black, Virginia; Papile, Lu-Ann; Simon, Neal P; Steichen, Jean J; Lee, Kimberly G

2004-11-01

Clinical trials evaluating the use of erythropoietin (Epo) have demonstrated a limited reduction in transfusions; however, long-term developmental follow-up data are scarce. We compared anthropometric measurements, postdischarge events, need for transfusions, and developmental outcomes at 18 to 22 months' corrected age in extremely low birth weight (ELBW) infants treated with early Epo and supplemental iron therapy with that of placebo/control infants treated with supplemental iron alone. The National Institute of Child Health and Human Development Neonatal Research Network completed a randomized, controlled trial of early Epo and iron therapy in preterm infants < or =1250 g. A total of 172 ELBW (< or =1000-g birth weight) infants were enrolled (87 Epo and 85 placebo/control). Of the 72 Epo-treated and 70 placebo/control ELBW infants surviving to discharge, follow-up data (growth, development, rehospitalization, transfusions) at 18 to 22 months' corrected age were collected on 51 of 72 Epo-treated infants (71%) and 51 of 70 placebo/controls (73%) by certified examiners masked to the treatment group. Statistical significance was determined using chi2 analysis. There were no significant differences between treatment groups in weight or length or in the percentage of infants weighing <10th percentile either at the time of discharge or at follow-up, and no difference was found in the mean head circumference between groups. A similar percentage of infants in each group was rehospitalized (38% Epo and 35% placebo/control) for similar reasons. There were no differences between groups with respect to the percentage of infants with Bayley-II Mental Developmental Index <70 (34% Epo and 36% placebo/control), blindness (0% Epo and 2% placebo/control), deafness or hearing loss requiring amplification (2% Epo and 2% placebo/control), moderate to severe cerebral palsy (16% Epo and 18% placebo/control) or the percentage of infants with any of the above-described neurodevelopmental impairments (42% Epo and 44% placebo/control). Treatment of ELBW infants with early Epo and iron does not significantly influence anthropometric measurements, need for rehospitalization, transfusions after discharge, or developmental outcome at 18 to 22 months' corrected age.

Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder.

PubMed

Owen, Randall; Sikich, Linmarie; Marcus, Ronald N; Corey-Lisle, Patricia; Manos, George; McQuade, Robert D; Carson, William H; Findling, Robert L

2009-12-01

The objective of this study was to evaluate short-term efficacy and safety of aripiprazole in the treatment of irritability in children and adolescents with autistic disorder who were manifesting behaviors such as tantrums, aggression, self-injurious behavior, or a combination of these. This 8-week, double-blind, randomized, placebo-controlled, parallel-group study was conducted of children and adolescents (aged 6-17 years) with autistic disorder. Patients were randomly assigned (1:1) to flexibly dosed aripiprazole (target dosage: 5, 10, or 15 mg/day) or placebo. Efficacy outcome measures included the Aberrant Behavior Checklist irritability subscale and the Clinical Global Impression-Improvement score (CGI-I). Safety and tolerability were also assessed. Ninety-eight patients were randomly assigned to receive placebo (n = 51) or aripiprazole (n = 47). Mean improvement in Aberrant Behavior Checklist irritability subscale score was significantly greater with aripiprazole than with placebo from week 1 through week 8. Aripiprazole demonstrated significantly greater global improvements than placebo, as assessed by the mean CGI-I score from week 1 through week 8; however, clinically significant residual symptoms may still persist for some patients. Discontinuation rates as a result of adverse events (AEs) were 10.6% for aripiprazole and 5.9% for placebo. Extrapyramidal symptom-related AE rates were 14.9% for aripiprazole and 8.0% for placebo. No serious AEs were reported. Mean weight gain was 2.0 kg on aripiprazole and 0.8 kg on placebo at week 8. Aripiprazole was efficacious in children and adolescents with irritability associated with autistic disorder and was generally safe and well tolerated.

Is TENS purely a placebo effect? A controlled study on chronic low back pain.

PubMed

Marchand, S; Charest, J; Li, J; Chenard, J R; Lavignolle, B; Laurencelle, L

1993-07-01

Although high-frequency low-intensity transcutaneous electric nerve stimulation (TENS) has been extensively used to relieve low back pain, experimental studies of its effectiveness have yielded contradictory findings mainly due to methodological problems in pain evaluation and placebo control. In the present study, separate visual analog scales (VAS) were used to measure the sensory-discriminative and motivational-affective components of low back pain. Forty-two subjects were randomly assigned to 1 of 3 groups: TENS, placebo-TENS, and no treatment (control). In order to measure the short-term effect of TENS, VAS pain ratings were taken before and after each treatment session. Also, to measure long-term effects, patients rated their pain at home every 2 h throughout a 3-day period before and 1 week, 3 months and 6 months after the treatment sessions. In comparing the pain evaluations made immediately before and after each treatment session, TENS and placebo-TENS significantly reduced both the intensity and unpleasantness of chronic low back pain. TENS was significantly more efficient than placebo-TENS in reducing pain intensity but not pain unpleasantness. TENS also produced a significant additive effect over repetitive treatment sessions for pain intensity and relative pain unpleasantness. This additive effect was not found for placebo-TENS. When evaluated at home, pain intensity was significantly reduced more by TENS than placebo-TENS 1 week after the end of treatment, but not 3 months and 6 months later. At home evaluation of pain unpleasantness in the TENS group was never different from the placebo-TENS group.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolonged remission from hepatic encephalopathy with rifaximin: results of a placebo crossover analysis

PubMed Central

Bajaj, J S; Barrett, A C; Bortey, E; Paterson, C; Forbes, W P

2015-01-01

Background Rifaximin therapy reduced risk of hepatic encephalopathy (HE) recurrence and HE-related hospitalisations during a 6-month, randomised, placebo-controlled trial (RCT) and a 24-month open-label maintenance (OLM) study. However, the impact of crossover from placebo to rifaximin therapy is unclear. Aim To study the impact of crossing over from placebo to rifaximin treatment on breakthrough HE and hospitalisation rates using a within-subjects design. Methods Adults with cirrhosis and history of overt HE episodes, currently in HE remission, received placebo during the RCT and crossed over to rifaximin 550 mg twice daily during the OLM study. Rate of breakthrough overt HE episodes, hospitalisations and incidence and rate of adverse events (AEs) were analysed during RCT and first 6 months of OLM. Results Of 82 patients randomised to placebo in the RCT who crossed over to the OLM study, 39 experienced an HE episode during the RCT compared with 14 during the OLM study (P < 0.0001). Significantly lower rates of HE events were observed with rifaximin treatment compared with placebo treatment (P < 0.0001). Rates of HE-related hospitalisation were numerically lower during rifaximin treatment compared with placebo treatment, although not significant. Rates of most common AEs, serious AEs and infection-related AEs were similar between the two treatments. Conclusions This analysis confirms the repeatability of results from the RCT on safety and efficacy of rifaximin 550 mg twice daily in reducing the risk of hepatic encephalopathy recurrence, and suggests these findings are translatable outside of a rigorous, controlled trial setting. PMID:25339518

RESPIRE 1: a phase III placebo-controlled randomised trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis.

PubMed

De Soyza, Anthony; Aksamit, Timothy; Bandel, Tiemo-Joerg; Criollo, Margarita; Elborn, J Stuart; Operschall, Elisabeth; Polverino, Eva; Roth, Katrin; Winthrop, Kevin L; Wilson, Robert

2018-01-01

We evaluated the efficacy and safety of ciprofloxacin dry powder for inhalation (DPI) in patients with non-cystic fibrosis bronchiectasis, two or more exacerbations in the previous year and pre-defined bacteria in sputum.In this phase III, double-blind, placebo-controlled trial, patients were randomised 2:1 to twice-daily ciprofloxacin DPI 32.5 mg or placebo in two treatment regimens consisting of on/off treatment cycles of 14 or 28 days for 48 weeks. The primary end-points were time to first exacerbation and frequency of exacerbations.A total of 416 patients were randomised to the 14-day on/off regimen (ciprofloxacin DPI (n=137) and placebo (n=68)) or the 28-day on/off regimen (ciprofloxacin DPI (n=141) and placebo (n=70)). Ciprofloxacin DPI 14 days on/off significantly prolonged time to first exacerbation versus pooled placebo (median time >336 versus 186 days; hazard ratio 0.53, 97.5% CI 0.36-0.80; p=0.0005) and reduced the frequency of exacerbations compared with matching placebo by 39% (mean number of exacerbations 0.6 versus 1.0; incidence rate ratio 0.61, 97.5% CI 0.40-0.91; p=0.0061). Outcomes for ciprofloxacin DPI 28 days on/off were not statistically significantly different from placebo. The safety profile of ciprofloxacin DPI was favourable.Ciprofloxacin DPI was well tolerated and has the potential to be an effective treatment option in non-cystic fibrosis bronchiectasis. Copyright ©ERS 2018.

A randomized placebo-controlled trial to evaluate a novel noninjectable anesthetic gel with thermosetting agent during scaling and root planing in chronic periodontitis patients

PubMed Central

Dayakar, MM; Akbar, SM

2016-01-01

Aim: To study the efficacy of a noninjectable anesthetic gel with a thermosetting agent in the reduction of pain during scaling and root planing (SRP) in untreated chronic periodontitis patients. Materials and Methods: This study is a randomized, double-masked, split-mouth, placebo-controlled trial. Thirty patients were enrolled who underwent SRP in a split-mouth (right side/left side) manner. Before commencement of SRP, both quadrants on each side were isolated and had a randomized gel (either placebo or test gel) placed in the periodontal pockets for 30 s. The pain was measured using numerical rating scale (NRS) and verbal rating scale (VRS). Results: The median NRS pain score for the patients treated with the anesthetic test gel was 1 (range: 0-4) as opposed to 5 (range: 3-7) in the placebo treated patients. The mean rank of pain score using NRS in test gel was 16.18 as compared to 44.82 in placebo treated sites. Hence, significant reduction in pain was found in test gel as compared to placebo using NRS (P < 0.001). The VRS showed that the majority of patients reported no pain or mild pain with a median of 1 as compared to placebo treated sites with a median of 2 suggestive of moderate pain. Conclusions: The NRS and VRS pain scores showed that the side treated with anesthetic gel was statistically more effective than the placebo in reducing pain during SRP. PMID:27051372

A Comparison of Cilostazol and Pentoxifylline for Treating Intermittent Claudication

NASA Technical Reports Server (NTRS)

Dawson, David L.; Cutler, Bruce S.; Hiatt, William R.; Hobson, Robert W., II; Martin, John D.; Bortey, Enoch B.; Forbes, William P.; Strandness, D. Eugene, Jr.; Homick, Jerry L. (Technical Monitor)

1999-01-01

A randomized, double-blind, placebo-controlled, parallel-group, phase III multicenter trial was performed to evaluate the relative efficacy and safety of cilostazol and pentoxifylline. The study included 54 outpatient vascular clinics, including sites at Air Force, Veterans Affairs, tertiary care, and university hospitals in the United States. Of 922 consenting patients, 698 met the inclusion criteria, were randomized, and received treatment with either cilostazol 100 mg P0 twice a day, pentoxifylline 400 mg PO 3 times a day, or placebo. Treatment was double-dummy to ensure study blindness. Efficacy was primarily established by maximal walking distance (MWD), measured with constant-speed, variable-grade treadmill testing, assessed at baseline and at 4, 8, 12, 16, 20, and 24 weeks. Mean MWD of cilostazol-treated patients (n=227) was significantly improved at every visit compared with patients who received pentoxifylline (n=232) or placebo (n=239). After 24 weeks of cilostazol, mean MWD increased 53.9% (107.3 m) from baseline, and the effect had not plateaued. This was better (P < 0.001) than the 30.4% (64.4 m) MWD improvement with pentoxifylline. MWD improvement with pentoxifylline was similar (P = 0.82) to that of placebo (64.7 m). Deaths and serious adverse event rates were similar in each group. Common side effects included headache (27.8% with cilostazol, 11.2% with pentoxifylline, 11.7% with placebo), palpitations (17.2% with cilostazol, 2.2% with pentoxifylllne, 1.3% with placebo), and abnormal stools. Cilostazol was significantly better than pentoxifylline or placebo for increasing walking distances; pentoxifylline was no better than placebo.

True rate of mineralocorticoid receptor antagonists-related hyperkalemia in placebo-controlled trials: A meta-analysis.

PubMed

Vukadinović, Davor; Lavall, Daniel; Vukadinović, Aleksandra Nikolovska; Pitt, Bertram; Wagenpfeil, Stefan; Böhm, Michael

2017-06-01

Mineralocorticoid receptor antagonists (MRA) improve survival in heart failure with reduced ejection fraction but are often underused, mostly due to concerns of hyperkalemia. Because hyperkalemia occurs also on placebo, we aimed to determine the truly MRA-related rate of hyperkalemia. We performed a meta-analysis including randomized, placebo-controlled trials reporting hyperkalemia on MRAs in patients after myocardial infarction or with chronic heart failure. We evaluated the truly MRA-related rate of hyperkalemia that represents hyperkalemia on MRA, corrected for hyperkalemia on placebo (Pla), according to the equation: True MRA (%)=(MRA (%) - Pla (%))/MRA (%). A total number of 16,065 patients from 7 trials were analyzed. Hyperkalemia was more frequently observed on MRA (9.3%) vs placebo (4.3%) (risk ratio 2.17, 95% CI 1.92-2.45, P<.0001). Truly MRA-related hyperkalemia was 54%, whereas 46% were non-MRA related. In trials using eplerenone, hyperkalemia was documented in 5.0% on eplerenone and in 2.6% on placebo (P<.0001). In spironolactone trials, hyperkalemia was documented in 17.5% and in 7.5% of patients on placebo (P=.0001). Hypokalemia occurred less frequently in patients on MRA (9.3%) compared with placebo (14.8%) (risk ratio 0.58, CI 0.47-0.72, P<.0001). This meta-analysis shows that in clinical trials, 54% of hyperkalemia cases were specifically related to the MRA treatment and 46% to other reasons. Therefore, non-MRA-related rises in potassium levels might be underestimated and should be rigorously explored before cessation of the evidence-based therapy with MRAs. Copyright © 2017 Elsevier Inc. All rights reserved.

A pilot study of chromium picolinate for weight loss.

PubMed

Yazaki, Yuka; Faridi, Zubaida; Ma, Yingying; Ali, Ather; Northrup, Veronika; Njike, Valentine Yanchou; Liberti, Lauren; Katz, David L

2010-03-01

Chromium is an essential trace element and nutritional supplement that has garnered interest for use as a weight loss aid. This trial assesses the effects of chromium picolinate supplementation, alone and combined with nutritional education, on weight loss in apparently healthy overweight adults. This was a randomized, double-blind, placebo-controlled trial of 80 otherwise healthy, overweight adults assessed at baseline for central adiposity measured by computerized tomography. Subjects were randomly assigned to daily ingestion of 1000 microg of chromium picolinate or placebo for 24 weeks. All subjects received passive nutritional education at the 12-week point in both the intervention and control groups. Outcomes include weight, height, blood pressure, percent body fat, serum, and urinary biomarkers. At baseline, both the chromium and placebo groups had similar mean body mass index (BMI) (chromium = 36 +/- 6.7 kg/m(2) versus placebo = 36.1 +/- 7.6 kg/m(2); p = 0.98). After 12 weeks, no change was seen in BMI in the intervention as compared to placebo (chromium = 0.3 +/- 0.8 kg/m(2) versus placebo = 0.0 +/- 0.4 kg/m(2); p = 0.07). No change was seen in BMI after 24 weeks in the intervention as compared to placebo (chromium = 0.1 +/- 0.2 kg/m(2) versus placebo = 0.0 +/- 0.5 kg/m(2); p = 0.81). Variation in central adiposity did not affect any outcome measures. Supplementation of 1000 microg of chromium picolinate alone, and in combination with nutritional education, did not affect weight loss in this population of overweight adults. Response to chromium did not vary with central adiposity.

The Influence of Nicotine Dose and Nicotine Dose Expectancy on the Cognitive and Subjective Effects of Cigarette Smoking

PubMed Central

Juliano, Laura M.; Fucito, Lisa M.; Harrell, Paul T.

2013-01-01

This study investigated the independent and interactive effects of nicotine dose and nicotine dose expectancy on smoking outcomes using a 2 (given nicotine vs. placebo) × 2 (told nicotine vs. placebo) Balanced Placebo Design (BPD). Smokers (N = 148) completed the Rapid Visual Information Processing Task (RVIP) and measures of smoking urge, mood, and cigarette ratings (e.g., satisfying) after smoking a nicotine or placebo cigarette crossed with instructions that the cigarette contained either nicotine or no nicotine. Nicotine cigarettes (0.6 mg nicotine) produced better sustained attention performance than placebos as indicated by RVIP reaction time, hits, and sensitivity (A′). Nicotine cigarettes also produced better mood and greater rewarding subjective effects of the cigarettes on 11 of 11 dimensions compared to placebos. Nicotine instructions resulted in fewer RVIP false alarms, better mood, and greater rewarding subjective effects of the cigarettes on 9 of 11 dimensions compared to placebo instructions. Nicotine dose by nicotine dose expectancy interactions were also observed for urge and tension-anxiety, such that the dose expectancy manipulation produced differential effects only among those who smoked placebo cigarettes. In contrast a significant interaction for self-reported vigor-activity demonstrated that the dose expectancy manipulation produced effects only among those who smoked nicotine cigarettes. This study provides additional evidence that nicotine improves cognitive performance, and provides initial evidence that denicotinized cigarettes smoked under the guise that they contain nicotine influence cognitive performance, albeit with less robust effects than nicotine. These data may inform the development of expectancy-based interventions for tobacco dependence. PMID:21463067

Biofeedback for anismus: has placebo effect been overlooked?

PubMed

Meagher; Sun; Kennedy; Smart; Lubowski

1999-03-01

Multiple uncontrolled studies have concluded that biofeedback is successful in treating anismus. This study's objective was to assess the physiological effects of placebo and biofeedback treatment on patients with anismus and to correlate changes with clinical improvement. Twelve patients with symptoms and electrophysiological findings of anismus were studied. Initial assessment included a detailed history, symptom assessment by linear analogue scales, anorectal manometric and electrophysiological studies, colon transit scintigraphy, and scintigraphic proctography. Patients underwent 5 days of placebo treatment, followed 1 week later by re-assessment of symptoms and physiological studies. Five days of biofeedback was then given followed by another complete re-assessment 1 week later. A final interview was performed 2 months later. All assessments were by an independent observer who was not responsible for the treatments. Seven patients reported an overall improvement in symptoms following placebo treatment. A total of seven patients reported improvement following biofeedback, three of whom had already reported an improvement with placebo. One patient who reported improvement following placebo had worsening of symptoms following biofeedback. The only symptoms or tests which changed more with biofeedback than placebo were anal pressure and electromyographic activity on attempted defaecation in the left lateral position. There was no demonstrable correlation between change in symptoms and change in physiological tests. The scintigraphic 'ejection fraction' of the rectum was unchanged by treatment. Clinical improvement in previous studies may in part be due to placebo effect and observer bias. Improvement with biofeedback may be due to physiological changes which are not detected with conventional anorectal physiological tests.

A placebo-controlled study of the nasal decongestant effect of phenylephrine and pseudoephedrine in the Vienna Challenge Chamber.

PubMed

Horak, Friedrich; Zieglmayer, Petra; Zieglmayer, René; Lemell, Patrick; Yao, Ruji; Staudinger, Heribert; Danzig, Melvyn

2009-02-01

Studies on the efficacy of phenylephrine in the treatment of nasal congestion have yielded inconsistent results, notwithstanding its approval for this indication. To evaluate and compare the decongestant effect of a single dose of phenylephrine to placebo and pseudoephedrine in patients with seasonal allergic rhinitis. This randomized, placebo-controlled, 3-way crossover study evaluated patient-scored nasal congestion, peak nasal inspiratory flow, and rhinomanometry at more than 6 hours in 39 grass-sensitive patients exposed to grass pollen in the Vienna Challenge Chamber. Patients were dosed with immediate-release formulations of phenylephrine, 12 mg, pseudoephedrine, 60 mg, as a control, or placebo. Phenylephrine was not significantly different from placebo in the primary end point, mean change in nasal congestion score at more than 6 hours (P = .56), whereas pseudoephedrine was significantly more effective than both placebo (P < .01) and phenylephrine (P = .01). Phase 1 results showed a difference between phenylephrine and placebo that was 64% of the difference between pseudoephedrine and placebo, substantially greater than the 17% difference observed for all phases. Carryover bias due to patient recall of the pseudoephedrine effect may have influenced these results. Rhinomanometry and peak nasal inspiratory flow results were consistent with these data. Neither phenylephrine nor pseudoephedrine had an effect on the nonnasal symptoms. No adverse events were reported in this study. During a 6-hour observation period, a single dose of pseudoephedrine but not phenylephrine resulted in significant improvement in measures of nasal congestion. Neither phenylephrine nor pseudoephedrine had an effect on nonnasal symptoms.

Randomised controlled trial of homoeopathy versus placebo in perennial allergic rhinitis with overview of four trial series.

PubMed

Taylor, M A; Reilly, D; Llewellyn-Jones, R H; McSharry, C; Aitchison, T C

To test the hypothesis that homoeopathy is a placebo by examining its effect in patients with allergic rhinitis and so contest the evidence from three previous trials in this series. Randomised, double blind, placebo controlled, parallel group, multicentre study. Four general practices and a hospital ear, nose, and throat outpatient department. 51 patients with perennial allergic rhinitis. Random assignment to an oral 30c homoeopathic preparation of principal inhalant allergen or to placebo. Changes from baseline in nasal inspiratory peak flow and symptom visual analogue scale score over third and fourth weeks after randomisation. Fifty patients completed the study. The homoeopathy group had a significant objective improvement in nasal airflow compared with the placebo group (mean difference 19.8 l/min, 95% confidence interval 10.4 to 29.1, P=0.0001). Both groups reported improvement in symptoms, with patients taking homoeopathy reporting more improvement in all but one of the centres, which had more patients with aggravations. On average no significant difference between the groups was seen on visual analogue scale scores. Initial aggravations of rhinitis symptoms were more common with homoeopathy than placebo (7 (30%) v 2 (7%), P=0.04). Addition of these results to those of three previous trials (n=253) showed a mean symptom reduction on visual analogue scores of 28% (10.9 mm) for homoeopathy compared with 3% (1.1 mm) for placebo (95% confidence interval 4.2 to 15.4, P=0.0007). The objective results reinforce earlier evidence that homoeopathic dilutions differ from placebo.

Combining rigour with relevance: a novel methodology for testing Chinese herbal medicine.

PubMed

Flower, Andrew; Lewith, George; Little, Paul

2011-03-24

There is a need to develop an evidence base for Chinese herbal medicine (CHM) that is both rigorous and reflective of good practice. This paper proposes a novel methodology to test individualised herbal decoctions using a randomised, double blinded, placebo controlled clinical trial. A feasibility study was conducted to explore the role of CHM in the treatment of endometriosis. Herbal formulae were pre-cooked and dispensed as individual doses in sealed plastic sachets. This permitted the development and testing of a plausible placebo decoction. Participants were randomised at a distant pharmacy to receive either an individualised herbal prescription or a placebo. The trial met the predetermined criteria for good practice. Neither the participants nor the practitioner-researcher could reliably identify group allocation. Of the 28 women who completed the trial, in the placebo group (n=15) 3 women (20%) correctly guessed they were on placebo, 8 (53%) thought they were on herbs and 4 (27%) did not know which group they had been allocated to. In the active group (n=13) 2 (15%) though they were on placebo, 8 (62%) thought they were on herbs and 3 (23%) did not know. Randomisation, double blinding and allocation concealment were successful and the study model appeared to be feasible and effective. It is now possible to subject CHM to rigorous scientific scrutiny without compromising model validity. Improvement in the design of the placebo using food colourings and flavourings instead of dried food will help guarantee the therapeutic inertia of the placebo decoction. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Placebo Response in Repetitive Transcranial Magnetic Stimulation Trials of Treatment of Auditory Hallucinations in Schizophrenia: A Meta-Analysis

PubMed Central

Dollfus, Sonia; Lecardeur, Laurent; Morello, Rémy; Etard, Olivier

2016-01-01

Several meta-analyses have assessed the response of patients with schizophrenia with auditory verbal hallucinations (AVH) to treatment with repetitive transcranial magnetic stimulation (rTMS); however, the placebo response has never been explored. Typically observed in a therapeutic trial, the placebo effect may have a major influence on the effectiveness of rTMS. The purpose of this meta-analysis is to evaluate the magnitude of the placebo effect observed in controlled studies of rTMS treatment of AVH, and to determine factors that can impact the magnitude of this placebo effect, such as study design considerations and the type of sham used. The study included twenty-one articles concerning 303 patients treated by sham rTMS. A meta-analytic method was applied to obtain a combined, weighted effect size, Hedges’s g. The mean weighted effect size of the placebo effect across these 21 studies was 0.29 (P < .001). Comparison of the parallel and crossover studies revealed distinct results for each study design; placebo has a significant effect size in the 13 parallel studies (g = 0.44, P < 10−4), but not in the 8 crossover studies (g = 0.06, P = .52). In meta-analysis of the 13 parallel studies, the 45° position coil showed the highest effect size. Our results demonstrate that placebo effect should be considered a major source of bias in the assessment of rTMS efficacy. These results fundamentally inform the design of further controlled studies, particularly with respect to studies of rTMS treatment in psychiatry. PMID:26089351

Cutaneous irritancy of an ibuprofen medicated plaster in healthy volunteers.

PubMed

Maganji, Manisha; Connolly, Mark P; Bhatt, Aomesh

2018-01-01

Ibuprofen is a commonly used non-steroidal anti-inflammatory drug administered to treat injuries, joint pain, and recurrent muscular skeletal pain. The aim of this study was to determine the cutaneous irritancy of a medicated ibuprofen plaster compared with a placebo plaster in healthy volunteers. Healthy volunteers (N = 31) were treated at the same time with one ibuprofen and one placebo plaster. The ibuprofen and placebo plaster were applied in a randomized fashion to sites on the left or right side of subjects' lower backs. At each scheduled visit, the plasters and applications sites were assessed for degree of adhesion and skin irritancy, respectively. The plasters were applied on study Days 1, 2, 3, 5, 8, 10, 12, 15, 17, and 19, with final plaster removal on Day 22. The ibuprofen medicated plaster compared with placebo had a lower percentage of Grade 1 (23.3% vs. 46.7%, respectively), Grade 2 (10% vs. 20%), and ≥Grade 3 (3% vs. 16.1%) irritancy scores after 21 days of application. The mean irritation score across the study was 0.40 for the ibuprofen medicated plaster and 1.18 for the placebo plaster. The irritation score on Day 22 of the study was 0.53 for the ibuprofen medicated plaster and 1.50 for placebo. The placebo plaster was associated with a higher number of stopped applications due to Grade 3 or above skin reactions compared with the ibuprofen medicated plaster (5 vs. 1, respectively). The ibuprofen medicated plaster was well tolerated and was associated with lower irritancy than the placebo plaster.

Teacher Response to the Methylphenidate (Ritalin) versus Placebo Status of Hyperactive Boys in the Classroom.

ERIC Educational Resources Information Center

Whalen, Carol K.; And Others

1981-01-01

Teacher behaviors toward hyperactive boys on methylphenidate (ritalin), toward hyperactive boys on placebo, and toward normal comparison peers were compared. Teachers were more intense and controlling toward hyperactive boys on placebo, but no differences emerged between comparison and medicated groups. Need for broader monitoring of treatment…

Lithium Treatment of Acute Mania in Adolescents: A Placebo-Controlled Discontinuation Study

ERIC Educational Resources Information Center

Kafantaris, Vivian; Coletti, Daniel J.; Dicker, Robert; Padula, Gina; Pleak, Richard R.; Alvir, Jose Ma. J.; Kane, John M.

2004-01-01

Objective: There are no published placebo-controlled studies of any agent in the treatment of acute mania in children or adolescents. This is the first placebo-controlled study of lithium's efficacy in the treatment of acute mania in adolescents. Method: In this discontinuation study, participants received open treatment with lithium at…

The Placebo Effect and Learning: Implications for Counsellors

ERIC Educational Resources Information Center

Hagen, Brad; Gunn, Thelma

2006-01-01

The placebo effect is a fascinating and complex phenomenon, and may well account for much of the effectiveness of many medical therapies, such as pain medications and antidepressants. While health professionals have long debated the role that placebos may play in health care, the counselling profession has devoted less attention to the placebo…

A double-blind, placebo-controlled, ascending-dose, randomized study to evaluate the safety, tolerability and effects on cognition of AL-108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment.

PubMed

Morimoto, Bruce H; Schmechel, Don; Hirman, Joe; Blackwell, Andrew; Keith, Julian; Gold, Michael

2013-01-01

AL-108-211 was a placebo-controlled, ascending-dose study that explored the safety, tolerability and efficacy of 12 weeks of treatment with AL-108 in subjects with amnestic mild cognitive impairment. A total of 144 subjects were randomized in a 2:1 drug:placebo ratio. Subjects were enrolled into the low-dose group or placebo and then to the high-dose group or placebo. Pooling of the placebo groups yielded 3 groups (approx. 48/group) whose baseline demographics and disease characteristics were well matched. AL-108 was generally safe and well tolerated. Analyses of efficacy data failed to detect a statistically significant difference between the treatment groups on the composite cognitive memory score. Analyses of the individual cognitive tasks identified signals of potential efficacy in 2 tests of memory and attention. These data suggest that AL-108 was generally safe, well tolerated and merits additional investigation as a treatment for Alzheimer's disease. Copyright © 2013 S. Karger AG, Basel.

Ethics of placebo-controlled clinical trials in multiple sclerosis: a reassessment.

PubMed

Polman, C H; Reingold, S C; Barkhof, F; Calabresi, P A; Clanet, M; Cohen, J A; Cutter, G R; Freedman, M S; Kappos, L; Lublin, F D; McFarland, H F; Metz, L M; Miller, A E; Montalban, X; O'Connor, P W; Panitch, H; Richert, J R; Petkau, J; Schwid, S R; Sormani, M P; Thompson, A J; Weinshenker, B G; Wolinsky, J S

2008-03-25

The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in "resource-restricted" environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes.

Elagolix treatment for endometriosis-associated pain: results from a phase 2, randomized, double-blind, placebo-controlled study.

PubMed

Diamond, Michael P; Carr, Bruce; Dmowski, W Paul; Koltun, William; O'Brien, Chris; Jiang, Ping; Burke, Joshua; Jimenez, Roland; Garner, Elizabeth; Chwalisz, Kristof

2014-03-01

This Phase 2 study evaluated the safety and efficacy of elagolix for treating endometriosis-associated pain. A total of 155 women with laparoscopically confirmed endometriosis were randomized to placebo, elagolix 150 mg, or elagolix 250 mg once daily for 12 weeks. Placebo patients were rerandomized to elagolix and elagolix patients continued their dosing assignment for 12 additional weeks; the primary efficacy measure was changed from baseline in the monthly mean numerical rating scale for pain at week 12. Monthly mean (standard error of the mean) reductions were greater with elagolix versus placebo (-1.19 ± 0.18, -1.25 ± 0.18, and -0.88 ± 0.18 for elagolix 150 mg, 250 mg, and placebo, respectively); differences were not statistically significant. Monthly mean dysmenorrhea and nonmenstrual pelvic pain scores were reduced with elagolix, with significant differences for dysmenorrhea at weeks 8 and 12 versus placebo (P < .05). Minimal bone mineral density changes were observed with elagolix treatment. In women with endometriosis-associated pain, elagolix demonstrated an acceptable efficacy and safety profile in this Phase 2 study.

Placebo effects in spider phobia: an eye-tracking experiment.

PubMed

Gremsl, Andreas; Schwab, Daniela; Höfler, Carina; Schienle, Anne

2018-01-05

Several eye-tracking studies have revealed that spider phobic patients show a typical hypervigilance-avoidance pattern when confronted with images of spiders. The present experiment investigated if this pattern can be changed via placebo treatment. We conducted an eye-tracking experiment with 37 women with spider phobia. They looked at picture pairs (a spider paired with a neutral picture) for 7 s each in a retest design: once with and once without a placebo pill presented along with the verbal suggestion that it can reduce phobic symptoms. The placebo was labelled as Propranolol, a beta-blocker that has been successfully used to treat spider phobia. In the placebo condition, both the fixation count and the dwell time on the spider pictures increased, especially in the second half of the presentation time. This was associated with a slight decrease in self-reported symptom severity. In summary, we were able to show that a placebo was able to positively influence visual avoidance in spider phobia. This effect might help to overcome apprehension about engaging in exposure therapy, which is present in many phobic patients.

A double-blind, placebo-controlled, multicenter study with alprazolam and extended-release alprazolam in the treatment of panic disorder.

PubMed

Pecknold, J; Luthe, L; Munjack, D; Alexander, P

1994-10-01

This is a double-blind, placebo-controlled, flexible-dose, multicenter, 6-week study comparing regular alprazolam (compressed tablet, CT), given four times per day, and extended release alprazolam (XR), given once in the morning. The aim of the XR preparation is to offer less frequent dosing and to reduce interdose anxiety. Of the intent-to-treat group of 209 patients, 184 completed 3 weeks of medication and were evaluated according to protocol. There was a completer rate for the 6 weeks of 94% (CT), 97% (XR), and 87% (placebo). On global measures, Hamilton Rating Scale for Anxiety, phobia rating, and work disability measures, both active treatment groups were equally effective and significantly more efficacious than the placebo cell on endpoint MANOVA analysis. On analysis of the panic factor with endpoint data, both active treatment groups were equally effective throughout the 6-week trial and significantly more efficacious than the placebo group. Drowsiness occurred more frequently with CT alprazolam (86% of patients) than with the XR preparation (79%) or placebo (49%).

Escitalopram treatment of depression in human immunodeficiency virus/acquired immunodeficiency syndrome: a randomized, double-blind, placebo-controlled study.

PubMed

Hoare, Jacqueline; Carey, Paul; Joska, John A; Carrara, Henri; Sorsdahl, Katherine; Stein, Dan J

2014-02-01

Depression can be a chronic and impairing illness in people with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. Large randomized studies of newer selective serotonin reuptake inhibitors such as escitalopram in the treatment of depression in HIV, examining comparative treatment efficacy and safety, have yet to be done in HIV-positive patients. This was a fixed-dose, placebo-controlled, randomized, double-blind study to investigate the efficacy of escitalopram in HIV-seropositive subjects with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, major depressive disorder. One hundred two participants were randomly assigned to either 10 mg of escitalopram or placebo for 6 weeks. An analysis of covariance of the completers found that there was no advantage for escitalopram over placebo on the Montgomery-Asberg Depression Rating Scale (p = 0.93). Sixty-two percent responded to escitalopram and 59% responded to placebo on the Clinical Global Impression Scale. Given the relatively high placebo response, future trials in this area need to be selective in participant recruitment and to be adequately powered.

A review of the ethics of the use of placebo in clinical trials for relapsing-remitting multiple sclerosis therapeutics.

PubMed

Solomon, Andrew J; Bernat, James L

2016-05-01

Randomized placebo-controlled clinical trials have been considered the most rigorous method of evaluating the efficacy of novel treatment interventions. The first effective disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) were approved in the 1990s after a number of pivotal placebo-controlled trials. Since then, the ethics of the continued use of placebo in clinical trials of new DMTs for RRMS has been the subject of repeated policy statements and recommendations by international committees. As further data have accumulated demonstrating a reduction in long-term morbidity and mortality with early initiation of DMT, a growing consensus has emerged that further inclusion of placebo arms in clinical trials of novel RRMS therapies is no longer ethical. Copyright © 2016 Elsevier B.V. All rights reserved.

Combined caffeine and carbohydrate ingestion: effects on nocturnal sleep and exercise performance in athletes.

PubMed

Miller, Ben; O'Connor, Helen; Orr, Rhonda; Ruell, Patricia; Cheng, Hoi Lun; Chow, Chin Moi

2014-12-01

In athletes, caffeine use is common although its effects on sleep have not been widely studied. This randomised, double-blind, placebo-controlled crossover trial investigated the effects of late-afternoon caffeine and carbohydrate-electrolyte (CEB) co-ingestion on cycling performance and nocturnal sleep. Six male cyclists/triathletes (age 27.5 ± 6.9 years) completed an afternoon training session (TS; cycling 80 min; 65% VO₂max) followed by a 5 kJ kg(-1) cycling time trial (TT). Caffeine (split dose 2 × 3 mg kg(-1)) or placebo was administered 1 h prior and 40 min into the TS. A 7.4% CEB (3 ml kg(-1) every 15 min) was administered during the TS, followed 30 min after by a standardised evening meal. Participants retired at their usual bedtime and indices of sleep duration and quality were monitored via polysomnography. mean ± SD. All participants performed better in the caffeine TT (caffeine 19.7 ± 3.3; placebo 20.5 ± 3.5 min; p = 0.006), while ratings of perceived exertion (caffeine 12.0 ± 0.6; placebo 12.9 ± 0.7; p = 0.004) and heart rate (caffeine 175 ± 6; placebo 167 ± 11 bpm; p = 0.085) were lower in the caffeine TS. Caffeine intake induced significant disruptions to a number of sleep indices including increased sleep onset latency (caffeine 51.1 ± 34.7; placebo 10.2 ± 4.2 min; p = 0.028) and decreased sleep efficiency (caffeine 76.1 ± 19.6; placebo 91.5 ± 4.2%; p = 0.028), rapid eye movement sleep (caffeine 62.1 ± 19.6; placebo 85.8 ± 24.7 min; p = 0.028) and total sleep time (caffeine 391 ± 97; placebo 464 ± 49 min; p = 0.028). This study supports a performance-enhancing effect of caffeine, although athletes (especially those using caffeine for late-afternoon/evening training and competition) should consider its deleterious effects on sleep.

The effect of topical arnica on muscle pain.

PubMed

Adkison, Julie D; Bauer, David W; Chang, Terence

2010-10-01

The herb Arnica montana, in topical formulations, has been reputed to decrease bruising and muscle pain. This claim has been inadequately and incompletely addressed. To determine whether topical A. montana cream could decrease subjective leg pain following calf raises. Secondary outcomes were effects on ankle range of motion and muscle tenderness. A randomized, double-blind, placebo-controlled trial was conducted in 53 subjects. Active range of motion was measured in both ankles, and then a series of calf-raises were completed according to a standardized protocol. Each participant received 2 tubes of cream, 1 with active arnica and 1 with placebo. The creams were applied to the lower legs immediately after the exercise, and again at 24 and 48 hours postexercise according to the "RIGHT" or "LEFT" labels. At 48 hours postexercise, subjects had their ankle range of motion and muscle tenderness measured. Subjects used the analog scale to rate pain in each leg at baseline, 24 hours, 48 hours, and 72 hours. No significant differences in pain scores were seen before exercise (arnica: 0.07 vs placebo: 0.09, p = 0.32). Pain scores on legs treated with arnica were higher than scores on those receiving placebo 24 hours after exercise (3.04 vs 2.36, respectively; p < 0.005). Pain scores on day 3 (arnica: 3.44 vs placebo: 3.20, p = 0.66) and day 4 (arnica: 2.36 vs placebo: 2.31, p = 0.62) were not significantly different. There was no difference in muscle tenderness (arnica: 1.05 vs placebo: 1.05, p = 1.0). Ankle range of motion did not differ significantly on either day 1 (arnica: 64.70 degrees vs placebo: 66.15, p = 0.352 or day 3 (arnica: 63.32 degrees vs placebo: 65.94, p = 0.058). Rather than decreasing leg pain, arnica was found to increase leg pain 24 hours after eccentric calf exercises. This effect did not extend to the 48-hour measurement.

Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer.

PubMed

Beer, Tomasz M; Kwon, Eugene D; Drake, Charles G; Fizazi, Karim; Logothetis, Christopher; Gravis, Gwenaelle; Ganju, Vinod; Polikoff, Jonathan; Saad, Fred; Humanski, Piotr; Piulats, Josep M; Gonzalez Mella, Pablo; Ng, Siobhan S; Jaeger, Dirk; Parnis, Francis X; Franke, Fabio A; Puente, Javier; Carvajal, Roman; Sengeløv, Lisa; McHenry, M Brent; Varma, Arvind; van den Eertwegh, Alfonsus J; Gerritsen, Winald

2017-01-01

Purpose Ipilimumab increases antitumor T-cell responses by binding to cytotoxic T-lymphocyte antigen 4. We evaluated treatment with ipilimumab in asymptomatic or minimally symptomatic patients with chemotherapy-naive metastatic castration-resistant prostate cancer without visceral metastases. Patients and Methods In this multicenter, double-blind, phase III trial, patients were randomly assigned (2:1) to ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Ipilimumab 10 mg/kg or placebo maintenance therapy was administered to nonprogressing patients every 3 months. The primary end point was overall survival (OS). Results Four hundred patients were randomly assigned to ipilimumab and 202 to placebo; 399 were treated with ipilimumab and 199 with placebo. Median OS was 28.7 months (95% CI, 24.5 to 32.5 months) in the ipilimumab arm versus 29.7 months (95% CI, 26.1 to 34.2 months) in the placebo arm (hazard ratio, 1.11; 95.87% CI, 0.88 to 1.39; P = .3667). Median progression-free survival was 5.6 months in the ipilimumab arm versus 3.8 with placebo arm (hazard ratio, 0.67; 95.87% CI, 0.55 to 0.81). Exploratory analyses showed a higher prostate-specific antigen response rate with ipilimumab (23%) than with placebo (8%). Diarrhea (15%) was the only grade 3 to 4 treatment-related adverse event (AE) reported in ≥ 10% of ipilimumab-treated patients. Nine (2%) deaths occurred in the ipilimumab arm due to treatment-related AEs; no deaths occurred in the placebo arm. Immune-related grade 3 to 4 AEs occurred in 31% and 2% of patients, respectively. Conclusion Ipilimumab did not improve OS in patients with metastatic castration-resistant prostate cancer. The observed increases in progression-free survival and prostate-specific antigen response rates suggest antitumor activity in a patient subset.

Nitroglycerin 0.4% ointment vs placebo in the treatment of pain resulting from chronic anal fissure: a randomized, double-blind, placebo-controlled study

PubMed Central

2013-01-01

Background Complications of chronic anal fissure (CAF) treatments are prompting interest in lower-risk therapies. This study was conducted to compare nitroglycerin (NTG) 0.4% ointment with placebo for pain associated with CAF. Methods In this randomized, double-blind, placebo-controlled trial, patients with one CAF and moderate-to-severe pain (≥50 mm on a 100 mm visual analog scale [VAS]) received 375 mg NTG 0.4% (1.5 mg active ingredient) or 375 mg placebo ointment applied anally every 12 hours for 21 days. The primary end point was change from baseline VAS score in 24-hour pain averaged over days 14–18. Review of data from patients who withdrew early was blinded to treatment. To control for the confounding effects of analgesics, all patients received 650 mg acetaminophen for headache prophylaxis before each application. Results A total of 247 patients were enrolled (NTG, n = 123; placebo, n = 124). The prespecified baseline observation carried forward (BOCF) analysis found no significant difference between groups; however, a last observation carried forward (LOCF) analysis showed a significant advantage for NTG. A post hoc analysis (LOCF/BOCF hybrid) demonstrated a significant adjusted mean difference of −7.0 mm in favor of NTG 0.4% (95% CI −13.6, –0.4; P = .038). Headache was the most common adverse event in the NTG (69.9%) and placebo (47.6%) groups. Conclusions This was the first placebo-controlled study that also controlled for the confounding effects of analgesics used to treat NTG-induced headache. In patients with moderate-to-severe CAF pain, NTG 0.4% ointment effectively reduced CAF pain compared with placebo. Trial registration ClinicalTrials.gov, NCT00522041 PMID:23815124

The safety and tolerability of vortioxetine: Analysis of data from randomized placebo-controlled trials and open-label extension studies

PubMed Central

Baldwin, David S; Chrones, Lambros; Florea, Ioana; Nielsen, Rebecca; Nomikos, George G; Palo, William; Reines, Elin

2016-01-01

The safety and tolerability of vortioxetine in adults with major depressive disorder was assessed. Tolerability was based on the nature, incidence and severity of treatment-emergent adverse events (TEAEs) during acute (6/8) week treatment in 11 randomized, double-blind placebo-controlled short-term studies in major depressive disorder: six with an active reference. Symptoms following discontinuation were assessed through the Discontinuation-Emergent Signs and Symptoms checklist in three studies. Long-term (⩽52 weeks) tolerability was evaluated in five open-label extension studies. Patients (n =5701) were acutely treated with either placebo (n=1817), vortioxetine (5–20mg/day; n=3018), venlafaxine XR (225mg/day; n=113) or duloxetine (60mg/day; n=753). The withdrawal rate due to TEAEs during treatment with vortioxetine (5–20mg/day) was 4.5–7.8%, compared with placebo (3.6%), venlafaxine XR (14.2%) or duloxetine (8.8%). Common TEAEs (incidence ⩾5% and >2 × placebo) with vortioxetine (5–20mg/day) were nausea (20.9–31.2%) and vomiting (2.9–6.5%). For vortioxetine (5–20mg/day), the incidence of TEAEs associated with insomnia was 2.0–5.1% versus 4.0% for placebo, and with sexual dysfunction 1.6–1.8% versus 1.0% for placebo. Discontinuation symptoms as assessed by the mean Discontinuation-Emergent Signs and Symptoms total score after abrupt discontinuation were comparable to placebo in the first and second week. Vortioxetine had no effect relative to placebo on clinical laboratory parameters, body weight, heart rate or blood pressure. Vortioxetine showed no clinically relevant effect on ECG parameters, including the QTcF interval. In long-term treatment, no new types of TEAEs were seen; the mean weight gain was 0.7–0.8kg. Thus, vortioxetine (5–20mg/day) appears safe and generally well tolerated in the treatment of major depressive disorder. PMID:26864543

The safety and tolerability of vortioxetine: Analysis of data from randomized placebo-controlled trials and open-label extension studies.

PubMed

Baldwin, David S; Chrones, Lambros; Florea, Ioana; Nielsen, Rebecca; Nomikos, George G; Palo, William; Reines, Elin

2016-03-01

The safety and tolerability of vortioxetine in adults with major depressive disorder was assessed. Tolerability was based on the nature, incidence and severity of treatment-emergent adverse events (TEAEs) during acute (6/8) week treatment in 11 randomized, double-blind placebo-controlled short-term studies in major depressive disorder: six with an active reference. Symptoms following discontinuation were assessed through the Discontinuation-Emergent Signs and Symptoms checklist in three studies. Long-term (⩽52 weeks) tolerability was evaluated in five open-label extension studies. Patients (n =5701) were acutely treated with either placebo (n=1817), vortioxetine (5-20mg/day; n=3018), venlafaxine XR (225mg/day; n=113) or duloxetine (60mg/day; n=753). The withdrawal rate due to TEAEs during treatment with vortioxetine (5-20mg/day) was 4.5-7.8%, compared with placebo (3.6%), venlafaxine XR (14.2%) or duloxetine (8.8%). Common TEAEs (incidence ⩾5% and >2 × placebo) with vortioxetine (5-20mg/day) were nausea (20.9-31.2%) and vomiting (2.9-6.5%). For vortioxetine (5-20mg/day), the incidence of TEAEs associated with insomnia was 2.0-5.1% versus 4.0% for placebo, and with sexual dysfunction 1.6-1.8% versus 1.0% for placebo. Discontinuation symptoms as assessed by the mean Discontinuation-Emergent Signs and Symptoms total score after abrupt discontinuation were comparable to placebo in the first and second week. Vortioxetine had no effect relative to placebo on clinical laboratory parameters, body weight, heart rate or blood pressure. Vortioxetine showed no clinically relevant effect on ECG parameters, including the QTcF interval. In long-term treatment, no new types of TEAEs were seen; the mean weight gain was 0.7-0.8kg. Thus, vortioxetine (5-20mg/day) appears safe and generally well tolerated in the treatment of major depressive disorder. © The Author(s) 2016.

WITHDRAWN: Transcutaneous electrical nerve stimulation and acupuncture-like transcutaneous electrical nerve stimulation for chronic low back pain.

PubMed

Gadsby, J G; Flowerdew, M W

2007-07-18

In view of the claims and counter-claims of the effectiveness of transcutaneous electrical nerve stimulation, it would seem appropriate to systematically review the literature. To determine the effectiveness of transcutaneous electrical nerve stimulation in reducing pain and improving range of movement in patients with chronic low back pain. Electronic searches of EMBASE, MEDLINE, CISCOM, AMED for all studies of TENS in the English language, identifying those treating chronic low back pain and hand searching their references. The inclusion criterion for studies included in this review, 6 of 68 identified, was comparisons of TENS/ALTENS versus placebo in patients with chronic low back pain. Outcome data on pain reduction, range of movement, functional status and work was extracted by two independent reviewers together with trial design qualities to construct a Quality Index. The ratio of odds of improvement in pain for each comparison was calculated: TENS vs. placebo at 1.62 (95% CI 0.90, 2.68); ALTENS vs. placebo at 7.22 (95% CI 2.60, 20.01) and TENS/ALTENS vs. placebo at 2.11 (95% CI 1.32, 3.38) times that of placebo. An improvement in pain reduction was seen in 45.80% (CI 37.00%, 55.00%) of TENS; 86.70% (CI 80.00%, 93.00%) of ALTENS; 54.00% (CI 46.20%, 61.80%) of TENS/ ALTENS and 36.40% (95%CI 28.40%, 44.40%) of placebo subjects. The odds of improvement in range of movement on ALTENS vs. placebo was 6.61 times (95% CI 2.36, 18.55) that of placebo. Transcutaneous electrical nerve stimulation appears to reduce pain and improve the range of movement in chronic low back pain subjects. A definitive randomised controlled study of ALTENS, TENS, placebo/no treatment controls, of sufficient power, is needed to confirm these findings.

A randomized, double-blind, placebo-controlled study of escitalopram in patients with social anxiety disorder in Japan.

PubMed

Asakura, Satoshi; Hayano, Taiji; Hagino, Atsushi; Koyama, Tsukasa

2016-01-01

This randomized, double-blind placebo-controlled study compared the efficacy and tolerability of escitalopram (10 and 20 mg/day) in Japanese patients with social anxiety disorder (SAD). Patients aged 18-64 years with a primary diagnosis of DSM-IV-TR defined SAD, a Liebowitz Social Anxiety Scale Japanese version (LSAS-J) total score ≥60 and a Clinical Global Impression-Severity (CGI-S) score ≥4 at baseline were randomly assigned (1:1:1) to placebo, escitalopram 10 mg or escitalopram 20 mg. The primary endpoint was change from baseline to Week 12 in the LSAS-J total score for both escitalopram 10 mg and 20 mg versus placebo (ANCOVA, FAS, LOCF), using a hierarchical testing procedure. Pre-specified secondary endpoints included LSAS-J sensitivity analyses. This study has the www.japic.or.jp identifier: JapicCTI-121842. For the primary efficacy endpoint, the difference from placebo in the LSAS-J was -3.9 (p = 0.089) for escitalopram 10 mg. Since the superiority of escitalopram 10 mg over placebo was not confirmed, an analysis without multiplicity adjustment was made, which showed a difference for escitalopram 20 mg versus placebo of -9.8 (p < 0.001). In pre-specified sensitivity analyses, the difference versus placebo was -4.9 (p = 0.035) (ANCOVA, FAS, OC) and -5.0 (p = 0.028) (MMRM, FAS) (escitalopram 10 mg) and -10.1 (p < 0.001) (ANCOVA, FAS, OC) and -10.6 (p < 0.001) (MMRM, FAS) (escitalopram 20 mg). Common adverse events (incidence ≥5% and significantly different from placebo) were somnolence, nausea and ejaculation disorder. Escitalopram was efficacious, safe and well tolerated by patients with SAD in Japan. Study limitations are discussed including patient characteristics.

Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial

PubMed Central

Smith, Ellen M. Lavoie; Pang, Herbert; Cirrincione, Constance; Fleishman, Stewart; Paskett, Electra D.; Ahles, Tim; Bressler, Linda R.; Fadul, Camilo E.; Knox, Chetaye; Le-Lindqwister, Nguyet; Gilman, Paul B.; Shapiro, Charles L.

2013-01-01

Context There are no known effective treatments for painful chemotherapy-induced peripheral neuropathy (CIPN). Objective The primary objective was to determine the effect of duloxetine 60 mg daily on CIPN “average” pain severity Design Randomized, double-blind, placebo-controlled crossover Setting Eight National Cancer Institute (NCI)-funded cooperative research networks recruited patients from community and academic settings between April 2008 and March 2011. Study follow-up was completed July 2012. Patients 231 patients ≥ 25 years of age were randomized (stratified by chemotherapy drug and CIPN comorbid risk) to receive either duloxetine followed by placebo or placebo followed by duloxetine. Eligible patients reported ≥ Grade 1 sensory CIPN per the NCI Common Toxicity Criteria for Adverse Events and ≥ 4/10 average CIPN-related pain following paclitaxel or oxaliplatin treatment. 81% completed the initial treatment period. Intervention The initial treatment consisted of duloxetine/placebo 30mg/one capsule daily for the first week, then 60mg/two capsules for four additional weeks Outcome Measure The primary hypothesis was that duloxetine would be more effective than placebo in decreasing CIPN pain. Pain severity was assessed using the Brief Pain Inventory-Short Form “average pain” item [0 (no pain) – 10 (as bad as can imagine)]. Results Individuals receiving duloxetine as initial treatment (weeks 1–5) reported a larger mean decrease in average pain (1.06; 95% CI: 0.72, 1.40) compared to placebo-treated patients (0.34; 95% CI: 0.01, 0.66) (p = 0.003) (effect size = 0.513). The observed mean difference in the average pain score between the duloxetine and placebo groups was 0.73 (95% CI: 0.26, 1.20). 59% of duloxetine-treated patients compared to 38% of placebo-treated patients reported decreased pain of any amount. Conclusions Among patients with painful CIPN, the use of duloxetine compared with placebo for 5 weeks resulted in a greater reduction in pain. PMID:23549581

Does the increasing placebo response impact outcomes of adult and pediatric ADHD clinical trials? Data from the US Food and Drug Administration 2000-2009.

PubMed

Khan, Arif; Fahl Mar, Kaysee; Brown, Walter A

2017-11-01

In a study of recent antidepressant clinical trial data, it was found placebo response had grown significantly over time and that contrary to expectations, trial outcome measures and success rate were not impacted. The aim of this paper was to evaluate if this trend of increasing placebo response and stable outcome measures could be seen in clinical trial data for Attention-Deficit Hyperactivity Disorder, a different psychiatric condition with susceptibility to placebo response. For this reason, we evaluated efficacy data reported in the FDA Medical and Statistical reviews for 10 ADHD medication programs (4917 patients, 17 trials, 29 treatment arms). Placebo and medication response were measured as percent symptom reduction and effect sizes and drug-placebo differences were calculated for each treatment arm and analyzed in relation to year of approval. We also investigated the potential role of age and medication class on trends and outcomes. Results showed a similar pattern to antidepressants wherein the placebo response is rising significantly over time (r = 0.636, p = 0.006) and effect size (r < 0.0001, p = 1.0), drug-placebo difference (r = -0.238, p = 0.214), and success rate (28/29 97%) have remained unaffected, likely due to a parallel, although not statistically significant increase in medication response (r = 0.326, p = 0.085). Age and medication class did not alter these observed time trends but pediatric trials and stimulants were found to have more robust treatment effects than adult trials and non-stimulants. The results of this study suggest that like antidepressants, the relationship between placebo response and the outcomes of ADHD clinical trials is weak at best. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Effects of a standardized Bacopa monnieri extract on cognitive performance, anxiety, and depression in the elderly: a randomized, double-blind, placebo-controlled trial.

PubMed

Calabrese, Carlo; Gregory, William L; Leo, Michael; Kraemer, Dale; Bone, Kerry; Oken, Barry

2008-07-01

Study aims were to evaluate effects of Bacopa monnieri whole plant standardized dry extract on cognitive function and affect and its safety and tolerability in healthy elderly study participants. The study was a randomized, double-blind, placebo-controlled clinical trial with a placebo run-in of 6 weeks and a treatment period of 12 weeks. Volunteers were recruited from the community to a clinic in Portland, Oregon by public notification. Fifty-four (54) participants, 65 or older (mean 73.5 years), without clinical signs of dementia, were recruited and randomized to Bacopa or placebo. Forty-eight (48) completed the study with 24 in each group. Standardized B. monnieri extract 300 mg/day or a similar placebo tablet orally for 12 weeks. The primary outcome variable was the delayed recall score from the Rey Auditory Verbal Learning Test (AVLT). Other cognitive measures were the Stroop Task assessing the ability to ignore irrelevant information, the Divided Attention Task (DAT), and the Wechsler Adult Intelligence Scale (WAIS) letter-digit test of immediate working memory. Affective measures were the State-Trait Anxiety Inventory, Center for Epidemiologic Studies Depression scale (CESD)-10 depression scale, and the Profile of Mood States. Vital signs were also monitored. Controlling for baseline cognitive deficit using the Blessed Orientation-Memory-Concentration test, Bacopa participants had enhanced AVLT delayed word recall memory scores relative to placebo. Stroop results were similarly significant, with the Bacopa group improving and the placebo group unchanged. CESD-10 depression scores, combined state plus trait anxiety scores, and heart rate decreased over time for the Bacopa group but increased for the placebo group. No effects were found on the DAT, WAIS digit task, mood, or blood pressure. The dose was well tolerated with few adverse events (Bacopa n = 9, placebo n = 10), primarily stomach upset. This study provides further evidence that B. monnieri has potential for safely enhancing cognitive performance in the aging.

Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4-week, randomized, placebo-controlled trial (EASE-1).

PubMed

Pieber, T R; Famulla, S; Eilbracht, J; Cescutti, J; Soleymanlou, N; Johansen, O E; Woerle, H J; Broedl, U C; Kaspers, S

2015-10-01

To investigate the pharmacodynamics, efficacy and safety of empagliflozin as adjunct to insulin in patients with type 1 diabetes. A total of 75 patients with glycated haemoglobin (HbA1c) concentrations of ≥7.5 to ≤10.5% (≥58 to ≤91 mmol/mol) were randomized to receive once-daily empagliflozin 2.5 mg, empagliflozin 10 mg, empagliflozin 25 mg, or placebo as adjunct to insulin for 28 days. Insulin dose was to be kept as stable as possible for 7 days then adjusted, at the investigator's discretion, to achieve optimum glycaemic control. The primary exploratory endpoint was change from baseline in 24-h urinary glucose excretion (UGE) on day 7. Empagliflozin significantly increased 24-h UGE versus placebo on days 7 and 28. On day 28, adjusted mean differences with empagliflozin versus placebo in changes from baseline in: HbA1c were -0.35 to -0.49% (-3.8 to -5.4 mmol/mol; all p < 0.05 vs. placebo); total daily insulin dose -0.07 to -0.09 U/kg (all p<0.05 vs placebo); and weight were -1.5 to -1.9 kg (all p < 0.001 vs. placebo). In the placebo, empagliflozin 2.5, 10 and 25 mg groups, respectively, adverse events were reported in 94.7, 89.5, 78.9 and 100.0% of patients, and the rate of symptomatic hypoglycaemic episodes with glucose ≤3.0 mmol/l not requiring assistance was 1.0, 0.4, 0.5 and 0.8 episodes per 30 days. In patients with type 1 diabetes, empagliflozin for 28 days as adjunct to insulin increased UGE, improved HbA1c and reduced weight with lower insulin doses compared with placebo and without increasing hypoglycaemia. © 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

The Placebo Response in Pediatric Abdominal Pain-Related Functional Gastrointestinal Disorders: A Systematic Review and Meta-Analysis.

PubMed

Hoekman, Daniël R; Zeevenhooven, Judith; van Etten-Jamaludin, Faridi S; Douwes Dekker, Iuke; Benninga, Marc A; Tabbers, Merit M; Vlieger, Arine M

2017-03-01

To investigate the magnitude and determinants of the placebo response in studies with pediatric abdominal pain-related functional gastrointestinal disorders. The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL were searched for systematic reviews and randomized placebo-controlled trials concerning children 4-18 years of age with an abdominal pain-related functional gastrointestinal disorder. The primary outcome was the pooled proportion of subjects assigned to placebo with improvement as defined by the authors. The effect of trial characteristics on the magnitude of the placebo response was investigated using univariate meta-regression analysis. Twenty-one trials were identified. The pooled proportion of subjects with improvement was 41% (95% CI, 34%-49%; 17 studies) and with no pain was 17% (95% CI, 8%-32%; 7 studies). The pooled standardized mean difference on the Faces Pain Scales compared with baseline was -0.73 (95% CI, -1.04 to -0.42; 8 studies). There was significant heterogeneity across studies with respect to both outcomes. Lower dosing frequency (P = .04), positive study (P = .03), longer duration of treatment (P < .001), and higher placebo dropout (P < .001) were associated with higher report of no pain. Response on Faces Pain Scales was greater in studies conducted in the Middle East (P = .002), in studies that did not report the randomization schedule (P = .02), and in studies with a higher percentage of females (P = .04). Approximately 41% of children with abdominal pain-related functional gastrointestinal disorders improve on placebo. Several trial characteristics are correlated significantly with the proportion of patients with no pain on placebo and with the magnitude of the placebo response on Faces Pain Scales. These data could be valuable for the design of future studies. Copyright © 2016 Elsevier Inc. All rights reserved.

Randomized, Double-Blind, Placebo-Controlled, Phase III Chemoprevention Trial of Selenium Supplementation in Patients With Resected Stage I Non–Small-Cell Lung Cancer: ECOG 5597

PubMed Central

Karp, Daniel D.; Lee, Sandra J.; Keller, Steven M.; Wright, Gail Shaw; Aisner, Seena; Belinsky, Steven Alan; Johnson, David H.; Johnston, Michael R.; Goodman, Gary; Clamon, Gerald; Okawara, Gordon; Marks, Randolph; Frechette, Eric; McCaskill-Stevens, Worta; Lippman, Scott M.; Ruckdeschel, John; Khuri, Fadlo R.

2013-01-01

Purpose Selenium has been reported to have chemopreventive benefits in lung cancer. We conducted a double-blind, placebo-controlled trial to evaluate the incidence of second primary tumors (SPTs) in patients with resected non–small-cell lung cancer (NSCLC) receiving selenium supplementation. Patients and Methods Patients with completely resected stage I NSCLC were randomly assigned to take selenized yeast 200 μg versus placebo daily for 48 months. Participation was 6 to 36 months postoperatively and required a negative mediastinal node biopsy, no excessive vitamin intake, normal liver function, negative chest x-ray, and no other evidence of recurrence. Results The first interim analysis in October 2009, with 46% of the projected end points accumulated, showed a trend in favor of the placebo group with a low likelihood that the trial would become positive; thus, the study was stopped. One thousand seven hundred seventy-two participants were enrolled, with 1,561 patients randomly assigned. Analysis was updated in June 2011 with the maturation of 54% of the planned end points. Two hundred fifty-two SPTs (from 224 patients) developed, of which 98 (from 97 patients) were lung cancer (38.9%). Lung and overall SPT incidence were 1.62 and 3.54 per 100 person-years, respectively, for selenium versus 1.30 and 3.39 per 100 person-years, respectively, for placebo (P = .294). Five-year disease-free survival was 74.4% for selenium recipients versus 79.6% for placebo recipients. Grade 1 to 2 toxicity occurred in 31% of selenium recipients and 26% of placebo recipients, and grade ≥ 3 toxicity occurred in less than 2% of selenium recipients versus 3% of placebo recipients. Compliance was excellent. No increase in diabetes mellitus or skin cancer was detected. Conclusion Selenium was safe but conferred no benefit over placebo in the prevention of SPT in patients with resected NSCLC. PMID:24002495

Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease.

PubMed

Yale, J-F; Bakris, G; Cariou, B; Nieto, J; David-Neto, E; Yue, D; Wajs, E; Figueroa, K; Jiang, J; Law, G; Usiskin, K; Meininger, G

2014-10-01

This study evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) and within a subset of Stage 3 chronic kidney disease (CKD; estimated glomerular filtration rate [eGFR] ≥ 30 and <50 ml/min/1.73 m(2)). In this 52-week, randomized, double-blind, placebo-controlled study, patients (N = 269; mean eGFR, 39.4 ml/min/1.73 m(2)) received canagliflozin 100 or 300 mg and placebo once daily. Efficacy endpoints included changes in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight and systolic blood pressure (BP); adverse events (AEs) were also recorded. At week 52, canagliflozin 100 and 300 mg reduced HbA1c compared with placebo (-0.19, -0.33 and 0.07%, respectively); placebo-subtracted differences (95% confidence interval) were -0.27% (-0.53, 0.001) and -0.41% (-0.68, -0.14). Canagliflozin also lowered FPG, body weight and BP versus placebo. Overall AE incidence was 85.6, 80.9, and 86.7% with canagliflozin 100 and 300 mg and placebo, respectively. Osmotic diuresis-related AEs were more common with both canagliflozin doses, and incidences of urinary tract infections and volume depletion-related AEs were higher with canagliflozin 300 mg versus placebo. Decreases in eGFR (-2.1, -4.0 and -1.6 ml/min/1.73 m(2)) were seen with canagliflozin 100 and 300 mg compared with placebo. Canagliflozin 100 and 300 mg provided median percent reductions in urine albumin to creatinine ratio versus placebo (-16.4, -28.0 and 19.7%). Canagliflozin improved glycaemic control and was generally well tolerated in patients with T2DM and within a subset of Stage 3 CKD over 52 weeks. © 2014 John Wiley & Sons Ltd.

Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial.

PubMed

Taylor, Jerome H; Landeros-Weisenberger, Angeli; Coughlin, Catherine; Mulqueen, Jilian; Johnson, Jessica A; Gabriel, Daniel; Reed, Margot O; Jakubovski, Ewgeni; Bloch, Michael H

2018-01-01

Many patients with social anxiety disorder (SAD) experience inadequate symptom relief from available treatments. Ketamine is a potent N-methyl-D-aspartate receptor antagonist with a potentially novel mechanism of action for the treatment of anxiety disorders. Therefore, we conducted a double-blind, randomized, placebo-controlled crossover trial in 18 adults with DSM-5 SAD and compared the effects between intravenous ketamine (0.5 mg/kg over 40 min) and placebo (normal saline) on social phobia symptoms. Ketamine and placebo infusions were administered in a random order with a 28-day washout period between infusions. Ratings of anxiety were assessed 3-h post-infusion and followed for 14 days. We used linear mixed models to assess the impact of ketamine and placebo on anxiety symptoms. Outcomes were blinded ratings on the Liebowitz Social Anxiety Scale (LSAS) and self-reported anxiety on a visual analog scale (VAS-Anxiety). We also used the Wilcoxon signed-rank test to compare the proportion of treatment responders. Based on prior studies, we defined response as a greater than 35% LSAS reduction and 50% VAS-Anxiety reduction. We found ketamine resulted in a significantly greater reduction in anxiety relative to placebo on the LSAS (Time × Treatment: F 9,115 =2.6, p=0.01) but not the VAS-Anxiety (Time × Treatment: F 10,141 =0.4, p=0.95). Participants were significantly more likely to exhibit a treatment response after ketamine infusion relative to placebo in the first 2 weeks following infusion measured on the LSAS (33.33% response ketamine vs 0% response placebo, Wilcoxon signed-rank test z=2.24, p=0.025) and VAS (88.89% response ketamine vs 52.94% response placebo, Wilcoxon signed-rank test z=2.12, p=0.034). In conclusion, this proof-of-concept trial provides initial evidence that ketamine may be effective in reducing anxiety.

Rofecoxib versus ibuprofen for acute treatment of migraine: a randomised placebo controlled trial

PubMed Central

Misra, U; Jose, M; Kalita, J

2004-01-01

Background: Rofecoxib is a potent cyclo-oxygenase-2 inhibitor with a long duration of action. Its role in migraine has not been systematically evaluated. Aim: To study the efficacy of rofecoxib in migraine. Method: In a randomised placebo controlled trial rofecoxib 25 mg, ibuprofen 400 mg, and placebo were compared regarding their efficacy in relieving acute migraine attack. Migraine patients with 2–6 attacks per month were recruited. Headache severity, functional disability, and severity of associated symptoms were graded on a 0–3 scale. The primary endpoint was pain relief at two hours. Relief of associated symptoms and sustained pain relief for 24 hours were also noted. Result: One hundred and twenty four patients were randomised into rofecoxib (42), ibuprofen (40), and placebo (42) groups. One hundred and one patients were followed up: 33 on rofecoxib, 35 ibuprofen, and 33 placebo. Patients' ages ranged from 16–62 (mean 31.4) years, and 83 were females. Pain relief at two hours was noted in 45.5% on rofecoxib, 55.6% on ibuprofen, and 9.1% in the placebo group. The associated symptoms at two hours were reduced in 39.4% on rofecoxib, 50% on ibuprofen, and 9.1% in the placebo group. Sustained 24 hour pain relief was noted in 36.4% on rofecoxib, 41% on ibuprofen, and 6.1% in the placebo group. In the ibuprofen group, five patients had abdominal pain but there were no side effects in those on rofecoxib or in the control group. Both rofecoxib and ibuprofen were significantly effective in relieving pain, associated symptoms at two hours, and in sustained pain relief. There was no significant difference between rofecoxib and ibuprofen in aborting acute migraine attacks. Conclusions: Both ibuprofen and rofecoxib were superior to placebo in aborting an acute migraine attack, and there was no significant difference in their efficacy in an acute migraine attack. PMID:15579612

A polysomnographic placebo-controlled evaluation of the efficacy and safety of eszopiclone relative to placebo and zolpidem in the treatment of primary insomnia.

PubMed

Erman, Milton K; Zammit, Gary; Rubens, Robert; Schaefer, Kendyl; Wessel, Thomas; Amato, David; Caron, Judy; Walsh, James K

2008-06-15

To evaluate the polysomnographic efficacy and the safety of a range of doses of eszopiclone relative to placebo in patients with primary insomnia. Zolpidem 10 mg was included as an active control. This multicenter, randomized, crossover study enrolled patients aged 21-64 years meeting the DSM-IV criteria for primary insomnia (n = 65). Patients received 2 nights treatment each with placebo, eszopiclone 1 mg, 2 mg, 2.5 mg, or 3 mg, and zolpidem 10 mg after randomization to one of 6 treatment sequences. Visits were separated by a 3-7 day washout. Objective efficacy was assessed by polysomnography (PSG). The primary endpoint was latency to persistent sleep (LPS); key secondary endpoints were sleep efficiency (SE) and wake time after sleep onset (WASO); other endpoints included wake time during sleep (WTDS) and number of awakenings (NAW), as well as patient-reported variables. LPS and SE were significantly different than placebo for all active treatments (p < 0.05 for all). Significant differences from placebo were noted in the 3 objective sleep maintenance measures (WASO, WTDS, and NAW) for eszopiclone 3 mg (p < 0.05), which was not the case for zolpidem 10 mg or the other eszopiclone doses. The incidence of central nervous system adverse events was 23.4% for zolpidem 10 mg, 6.2% to 12.5% for the eszopiclone doses, and 7.9% for placebo. Relative to placebo, all active treatments were effective in reducing LPS and increasing SE. Eszopiclone 3 mg was significantly different from placebo on the 3 PSG measures of sleep maintenance (WASO, WTDS, and NAW). Significant differences between zolpidem 10 mg and eszopiclone (2 mg or 3 mg) were not observed for PSG-measured outcomes, although the study was not powered to detect differences between the active drug conditions.

Efficacy and safety of epicutaneous ketoprofen in Transfersome (IDEA‐033) versus oral celecoxib and placebo in osteoarthritis of the knee: multicentre randomised controlled trial

PubMed Central

Rother, Matthias; Lavins, Bernard J; Kneer, Werner; Lehnhardt, Klaus; Seidel, Egbert J; Mazgareanu, Stefan

2007-01-01

Objective To compare epicutaneous ketoprofen in Transfersome (ultra‐deformable vesicles, IDEA‐033) versus oral celecoxib and placebo for relief of signs and symptoms in knee osteoarthritis. Methods This was a multicentre, randomised, double‐blind, controlled trial; 397 patients with knee osteoarthritis participated and 324 completed the trial. They were randomly assigned 110 mg epicutaneous ketoprofen in 4.8 g Transfersome plus oral placebo (n = 138), 100 mg oral celecoxib plus placebo gel (n = 132), or both placebo formulations (n = 127) twice daily for 6 weeks. Primary efficacy outcome measures were the changes from baseline to end of the study on the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index pain subscale, physical function subscale and patient global assessment (PGA) of response. Results The mean WOMAC pain subscale scores in the intent to treat population were reduced by 18.2 (95% confidence interval −22.1 to −14.3), 20.3 (−24.3 to −16.2) and 9.9 (−13.9 to −5.8) in the IDEA‐033, celecoxib and placebo groups, respectively, and the physical function subscale score by 14.6 (−18.1 to −11.0), 16.6 (−20.2 to −13.0) and 10.2 (−13.8 to −6.6), respectively. The mean PGA of response scores were 1.8 (1.6 to 2.1), 1.7 (1.5 to 1.9) and 1.3 (1.1 to 1.5), respectively. The differences in change between IDEA‐033 and placebo were statistically significant for pain subscale (p<0.01) and PGA of response (p<0.01). Gastrointestinal adverse events for IDEA‐033 were similar to placebo. Conclusion IDEA‐033 is superior to placebo and comparable with celecoxib in relieving pain associated with an acute flare of knee osteoarthritis. PMID:17363401

Cardiovascular Profile of Valbenazine: Analysis of Pooled Data from Three Randomized, Double-Blind, Placebo-Controlled Trials.

PubMed

Thai-Cuarto, Dao; O'Brien, Christopher F; Jimenez, Roland; Liang, Grace S; Burke, Joshua

2018-04-01

Valbenazine is a novel vesicular monoamine transporter 2 inhibitor approved for the treatment of tardive dyskinesia in adults. Using data from double-blind, placebo-controlled trials, analyses were conducted to evaluate the cardiovascular effects of once-daily valbenazine in patients with a psychiatric disorder who developed tardive dyskinesia after exposure to a dopamine-blocking medication. Data were pooled from three 6-week, double-blind, placebo-controlled trials: KINECT (NCT01688037), KINECT 2 (NCT01733121), and KINECT 3 (NCT02274558). Data from the 42-week valbenazine extension period of KINECT 3 were also analyzed. Outcomes of interest included cardiovascular-related treatment-emergent adverse events, vital sign measurements, and electrocardiogram parameters. The pooled safety population included 400 participants (placebo, n = 178; valbenazine 40 mg/day, n = 110; valbenazine 80 mg/day, n = 112). A history of cardiac disorders was present in 11.8% of participants, and 74.3% were taking a concomitant medication with known potential for QT prolongation. Mean changes from baseline to week 6 in supine vital signs and QTcF (Fridericia correction) were as follows for placebo, valbenazine 40 mg/day, and valbenazine 80 mg/day, respectively: systolic blood pressure (0.2, - 2.1, - 1.8 mmHg), diastolic blood pressure (- 0.1, - 1.6, - 1.2 mmHg), heart rate (- 1.7, - 2.2, - 1.7 bpm), QTcF interval (1.2, 1.1, 2.1 ms); all p > 0.05 for valbenazine vs. placebo. No statistically significant differences were observed between placebo and valbenazine in cardiovascular-related, treatment-emergent adverse events. No notable additional effects on cardiovascular outcomes were found with up to 48 weeks of valbenazine treatment. Results from double-blind, placebo-controlled trials showed no apparent difference between valbenazine and placebo on cardiovascular outcomes. No additional cardiovascular risk was detected during a longer extension study with valbenazine.

Pregabalin Versus Pramipexole: Effects on Sleep Disturbance in Restless Legs Syndrome

PubMed Central

Garcia-Borreguero, Diego; Patrick, Jeffrey; DuBrava, Sarah; Becker, Philip M.; Lankford, Alan; Chen, Crystal; Miceli, Jeffrey; Knapp, Lloyd; Allen, Richard P.

2014-01-01

Study Objectives: To compare pregabalin versus placebo and pramipexole for reducing restless legs syndrome (RLS)-related sleep disturbance. Design: Randomized, double-blinded, crossover trial. Setting: Twenty-three US sleep centers. Participants: Eighty-five individuals with moderate to severe idiopathic RLS and associated sleep disturbance. Interventions: Participants were randomized across 6 treatment sequences comprising three 4-week periods on pregabalin 300 mg/day (n = 75), pramipexole 0.5 mg/day (n = 76), or placebo (n = 73). Measurements and Results: Polysomnography was conducted over 2 nights at the end of each period. Primary (wake after sleep onset [WASO], pregabalin vs placebo) and key secondary endpoints were analyzed for statistical significance, with descriptive statistics for other endpoints. Pregabalin improved sleep maintenance, demonstrated by reductions in WASO (-27.1 min vs placebo [P < 0.0001]; -26.9 vs pramipexole) and number of awakenings after sleep onset (-2.7 vs placebo; -7.9 vs pramipexole [P < 0.0001]) by polysomnography, and an increase in subjective total sleep time (30.8 min vs placebo [P < 0.0001]; 26.8 vs pramipexole). Pregabalin also increased slow wave sleep duration (20.9 min vs placebo; 32.1 vs pramipexole [P < 0.0001]). Reduction in periodic limb movement arousal index (PLMAI) with pregabalin was similar to pramipexole and greater than placebo (-3.7 PLMA/h [P < 0.0001]), although reduction in total PLM in sleep was less than for pramipexole. Conclusions: This study demonstrated improvements in objective and subjective measures of sleep maintenance and sleep architecture with pregabalin compared with placebo and pramipexole. Effects of pregabalin on periodic limb movement arousal index were comparable to pramipexole. Trial Registration: ClinicalTrials.gov identifier, NCT00991276; http://clinicaltrials.gov/show/NCT00991276 Citation: Garcia-Borreguero D; Patrick J; DuBrava S; Becker PM; Lankford A; Chen C; Miceli J; Knapp L; Allen RP. Pregabalin versus pramipexole: effects on sleep disturbance in restless legs syndrome. SLEEP 2014;37(4):635-643. PMID:24899755

Randomised clinical trial: the clinical efficacy and safety of an alginate-antacid (Gaviscon Double Action) versus placebo, for decreasing upper gastrointestinal symptoms in symptomatic gastroesophageal reflux disease (GERD) in China.

PubMed

Sun, J; Yang, C; Zhao, H; Zheng, P; Wilkinson, J; Ng, B; Yuan, Y

2015-10-01

There is a paucity of large-scale studies evaluating the clinical benefit of the Gaviscon Double Action (DA) alginate-antacid formulation for treating gastroesophageal reflux disease (GERD) symptoms. Randomised double-blind placebo-controlled parallel-group study to evaluate efficacy and safety of Gaviscon DA in reducing heartburn, regurgitation and dyspepsia symptoms in individuals with mild-to-moderate GERD in China. Participants with symptomatic GERD (n = 1107) were randomised to receive Gaviscon DA or placebo (two tablets four times daily) for seven consecutive days. The primary endpoint compared the change in Reflux Disease Questionnaire (RDQ) score for the GERD (heartburn + regurgitation) dimension between Gaviscon DA and placebo. Secondary endpoints compared the change in RDQ scores for individual heartburn, regurgitation and dyspepsia dimensions, overall treatment evaluation (OTE) scores and incidence of adverse events (AEs). Mean RDQ GERD scores: 2.51 for Gaviscon DA and 2.50 for placebo at baseline; 1.25 for Gaviscon DA and 1.46 for placebo post treatment. Gaviscon DA was statistically superior to placebo in reducing GERD and dyspepsia RDQ scores [least-squares mean (LSM) difference: GERD -0.21, P < 0.0001; dyspepsia -0.18, P = 0.0004], despite a substantial placebo response. The Gaviscon DA group reported more favourable overall treatment responses than the placebo group across all OTE categories (P < 0.0001). Superior relief of GERD symptoms was observed both in those with non-erosive and those with erosive reflux disease (LSM difference -0.14 [P = 0.038] and -0.29 [P < 0.0001] respectively). Incidence of AEs was similar in both groups. Gaviscon DA tablets provide effective and safe reduction in acid reflux and dyspepsia symptoms in Chinese individuals with mild-to-moderate GERD. ClinicalTrials.gov: NCT01869491. © 2015 The Authors. Alimentary Pharmacology & Therapeutics Published by John Wiley & Sons Ltd.

Placebos and painkillers: is mind as real as matter?

PubMed

Colloca, Luana; Benedetti, Fabrizio

2005-07-01

Considerable progress has been made in our understanding of the neurobiological mechanisms of the placebo effect, and most of our knowledge originates from the field of pain and analgesia. Today, the placebo effect represents a promising model that could allow us to shed new light on mind-body interactions. The mental events induced by placebo administration can activate mechanisms that are similar to those activated by drugs, which indicates a similarity between psychosocial and pharmacodynamic effects. These new neurobiological advances are already changing our conception of how clinical trials and medical practice must be viewed and conducted.

A double-blind placebo-controlled trial of maca root as treatment for antidepressant-induced sexual dysfunction in women.

PubMed

Dording, Christina M; Schettler, Pamela J; Dalton, Elizabeth D; Parkin, Susannah R; Walker, Rosemary S W; Fehling, Kara B; Fava, Maurizio; Mischoulon, David

2015-01-01

Objective. We sought to demonstrate that maca root may be an effective treatment for antidepressant-induced sexual dysfunction (AISD) in women. Method. We conducted a 12-week, double-blind, placebo-controlled trial of maca root (3.0 g/day) in 45 female outpatients (mean age of 41.5 ± 12.5 years) with SSRI/SNRI-induced sexual dysfunction whose depression remitted. Endpoints were improvement in sexual functioning as per the Arizona Sexual Experience Scale (ASEX) and the Massachusetts General Hospital Sexual Function Questionnaire (MGH-SFQ). Results. 45 of 57 consented females were randomized, and 42 (30 premenopausal and 12 postmenopausal women) were eligible for a modified intent-to-treat analysis based on having had at least one postmedication visit. Remission rates by the end of treatment were higher for the maca than the placebo group, based on attainment of an ASEX total score ≤ 10 (9.5% for maca versus 4.8% for placebo), attaining an MGH-SFQ score ≤ 12 (30.0% for maca versus 20.0% for placebo) and reaching an MGH-SFQ score ≤ 8 (9.5% for maca versus 5.0% for placebo). Higher remission rates for the maca versus placebo group were associated with postmenopausal status. Maca was well tolerated. Conclusion. Maca root may alleviate SSRI-induced sexual dysfunction in postmenopausal women. This trial is registered with NCT00568126.

Safety and Efficacy of Black Cohosh and Red Clover for the Management of Vasomotor Symptoms: A Randomized Controlled Trial

PubMed Central

Geller, Stacie E.; Shulman, Lee P.; van Breemen, Richard B.; Banuvar, Suzanne; Zhou, Ying; Epstein, Geena; Hedayat, Samad; Nikolic, Dejan; Krause, Elizabeth C.; Piersen, Colleen E.; Bolton, Judy L.; Pauli, Guido F.; Farnsworth, Norman R.

2009-01-01

Objective The aim of this study was to evaluate the safety and efficacy of black cohosh and red clover compared with placebo for the relief of menopausal vasomotor symptoms. Design This study was a randomized, four-arm, double-blind clinical trial of standardized black cohosh, red clover, placebo and 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (CEE/MPA; n = 89). Primary outcome measures were reduction in vasomotor symptoms (hot flashes and night sweats) by black cohosh and red clover compared with placebo; secondary outcomes included safety evaluation, reduction of somatic symptoms, relief of sexual dysfunction, and overall improvement in quality of life. Results Reductions in number of vasomotor symptoms after 12-month intervention were as follows: black cohosh (34%), red clover (57%), placebo (63%), and CEE/MPA (94%), with only CEE/MPA differing significantly from placebo. Black cohosh and red clover did not significantly reduce the frequency of vasomotor symptoms as compared with placebo. Secondary measures indicated that both botanicals were safe as administered. In general, there were no improvements in other menopausal symptoms. Conclusions Compared with placebo, black cohosh and red clover did not reduce the number of vasomotor symptoms. Safety monitoring indicated that chemically and biologically standardized extracts of black cohosh and red clover were safe during daily administration for 12 months. PMID:19609225

Effect of long-term intranasal oxytocin on sexual dysfunction in premenopausal and postmenopausal women: a randomized trial.

PubMed

Muin, Dana A; Wolzt, Michael; Marculescu, Rodrig; Sheikh Rezaei, Safoura; Salama, Mohamed; Fuchs, Carola; Luger, Anton; Bragagna, Elia; Litschauer, Brigitte; Bayerle-Eder, Michaela

2015-09-01

To assess the effect of on-demand intranasal oxytocin administration on female sexual function and activity. Randomized, prospective, double-blind, placebo-controlled, crossover trial with duration of 22 weeks. Academic medical center. Thirty pre-and postmenopausal women with sexual dysfunction. Over 8 weeks, intranasal oxytocin (32 IU) or placebo self-administered by women within 50 minutes before sexual intercourse; after a washout period of 2 weeks, crossover with patients switched to the alternate group for another 8 weeks. Primary outcome parameter: Female Sexual Function Index (FSFI); secondary outcome parameters: Female Sexual Distress Scale (FSDS), Sexual Quality of Life-Female (SQOL-F), Sexual Interest and Desire Inventory-Female (SIDI-F), and Hamilton depression scale (HDS). After oxytocin and placebo, the FSFI score increased by 26% and 31%, SQOL-F score by 144% and 125%, and SIDI-F score by 29% and 23%, respectively (repeated measures analysis of variance between groups). After oxytocin and placebo, the FSDS score decreased by 36% and 45%, respectively (repeated measures analysis of variance between groups). There was no statistically significant treatment, sequence (placebo first/second), or interaction effect. Long-term intranasal oxytocin and placebo administration both improved sexual function and symptoms of depression in women over time with no treatment, sequence (placebo first/second), or interaction effect. NCT02229721. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Therapeutic effect of Vitex agnus castus in patients with premenstrual syndrome.

PubMed

Zamani, Mehrangiz; Neghab, Nosrat; Torabian, Saadat

2012-01-01

Medical therapies have been widely used for premenstrual syndrome (PMS), but in all of them side effects are predominant. Herbal remedies rarely have side effects and people have more tendencies toward them than chemical therapies. In this study the therapeutic effect of Vitex agnus castus on women who had the PMS, in comparison with placebo, were investigated. In this randomized, placebo-controlled, double-blind study, from 134 selected patients 128 women suffered from PMS were evaluated (active 62, placebo 66). All patients answered to a self assessment questionnaire about their headache, anger, irritability, depression, breast fullness and bloating and tympani during the premenstrual period before the study. Forty drops of Vitex agnus extract or matching placebo, administrated for 6 days before menses for 6 consecutive cycles. Patients answered the self-assessment questionnaires after 6 menstrual cycles, again. Each item rated using a visual analogue scale (VAS). The mean age was 30.77 (SD=4.37) years in the active group and 30.89 (SD=4.02) years in the placebo group.Rank of variables had significantly difference in active and placebo group before and after the study (P<0.0001) also we noticed significant differences on the use of Vitex agnus in comparison with placebo (P<0.0001). Vitex agnus can be considered as an effective and well tolerated treatment for the relief of symptoms of mild and moderate PMS.

Efficacy of betamethasone valerate medicated plaster on painful chronic elbow tendinopathy: a double-blind, randomized, placebo-controlled trial

PubMed Central

Frizziero, Antonio; Causero, Araldo; Bernasconi, Stefano; Papalia, Rocco; Longo, Mario; Sessa, Vincenzo; Sadile, Francesco; Greco, Pasquale; Tarantino, Umberto; Masiero, Stefano; Rovati, Stefano; Frangione, Valeria

2016-01-01

Summary Objective to investigate the efficacy and safety of a medicated plaster containing betamethasone valerate (BMV) 2.25 mg in patients with chronic elbow tendinopathy. Methods randomized, double-blind, placebo-controlled study with assignment 2:2:1:1 to BMV medicated plaster applied daily for 12 hours, daily for 24 hours or matched placebo. 62 patients aged ≥18 years with chronic lateral elbow tendinopathy were randomized. The primary efficacy variable was pain reduction (VAS) at day 28. Secondary objectives included summed pain intensity differences (SPID), overall treatment efficacy and tolerability. Results mean reduction in VAS pain score at day 28 was greater in both BMV medicated plaster groups, −39.35±27.69 mm for BMV12-h and −36.91±32.50 mm for BMV24-h, than with placebo, −20.20±27.32 mm. Considering the adjusted mean decreases, there was a statistically significant difference between BMV12-h and placebo (p=0.0110). Global pain relief (SPID) and overall treatment efficacy were significantly better with BMV. BMV and placebo plasters had similar local tolerability and there were few treatment-related adverse events. Conclusions BMV plaster was significantly more effective than placebo at reducing pain in patients with chronic elbow tendinopathies. The BMV plaster was safe and well tolerated. PMID:27331041

Z-drug for schizophrenia: A systematic review and meta-analysis.

PubMed

Kishi, Taro; Inada, Ken; Matsui, Yuki; Iwata, Nakao

2017-10-01

No systematic reviews and meta-analyses on the use of Z-drug for schizophrenia are available. Randomized, placebo-controlled, or non-pharmacological intervention-controlled trials published before 03/20/2017 were retrieved from major healthcare databases and clinical trial registries. A meta-analysis including only randomized, placebo-controlled trials was performed. Efficacy outcomes were measured as improvement in overall schizophrenia symptoms, total sleep time, and wake after sleep onset. Safety/acceptability outcomes were discontinuation rate and individual adverse events. Four trials [1 alpidem placebo-controlled study (n=66), 2 eszopiclone placebo-controlled studies (n=60), and 1 eszopiclone, shallow needling-controlled study (n=96)] were identified. The meta-analysis showed no significant differences in any outcome between pooled Z-drug and placebo treatment groups. For individual studies, alpidem was superior to placebo in improving the overall schizophrenia symptoms. One of the eszopiclone studies showed that eszopiclone was superior to placebo in improving the Insomnia Severity Index scores. Another eszopiclone study showed that eszopiclone did not differ from shallow needling therapy in improving both schizophrenia- and insomnia-related symptoms. Although this study failed to show significant benefits for the use of Z-drug in the treatment of schizophrenia, it showed that short-term use of eszopiclone is an acceptable method for treating persistent insomnia among these patients. Copyright © 2017 Elsevier B.V. All rights reserved.

A Double-Blind Placebo-Controlled Trial of Maca Root as Treatment for Antidepressant-Induced Sexual Dysfunction in Women

PubMed Central

Dording, Christina M.; Schettler, Pamela J.; Dalton, Elizabeth D.; Parkin, Susannah R.; Walker, Rosemary S. W.; Fehling, Kara B.; Fava, Maurizio

2015-01-01

Objective. We sought to demonstrate that maca root may be an effective treatment for antidepressant-induced sexual dysfunction (AISD) in women. Method. We conducted a 12-week, double-blind, placebo-controlled trial of maca root (3.0 g/day) in 45 female outpatients (mean age of 41.5 ± 12.5 years) with SSRI/SNRI-induced sexual dysfunction whose depression remitted. Endpoints were improvement in sexual functioning as per the Arizona Sexual Experience Scale (ASEX) and the Massachusetts General Hospital Sexual Function Questionnaire (MGH-SFQ). Results. 45 of 57 consented females were randomized, and 42 (30 premenopausal and 12 postmenopausal women) were eligible for a modified intent-to-treat analysis based on having had at least one postmedication visit. Remission rates by the end of treatment were higher for the maca than the placebo group, based on attainment of an ASEX total score ≤ 10 (9.5% for maca versus 4.8% for placebo), attaining an MGH-SFQ score ≤ 12 (30.0% for maca versus 20.0% for placebo) and reaching an MGH-SFQ score ≤ 8 (9.5% for maca versus 5.0% for placebo). Higher remission rates for the maca versus placebo group were associated with postmenopausal status. Maca was well tolerated. Conclusion. Maca root may alleviate SSRI-induced sexual dysfunction in postmenopausal women. This trial is registered with NCT00568126. PMID:25954318

Reducing placebo exposure in trials: Considerations from the Research Roundtable in Epilepsy.

PubMed

Fureman, Brandy E; Friedman, Daniel; Baulac, Michel; Glauser, Tracy; Moreno, Jonathan; Dixon-Salazar, Tracy; Bagiella, Emilia; Connor, Jason; Ferry, Jim; Farrell, Kathleen; Fountain, Nathan B; French, Jacqueline A

2017-10-03

The randomized controlled trial is the unequivocal gold standard for demonstrating clinical efficacy and safety of investigational therapies. Recently there have been concerns raised about prolonged exposure to placebo and ineffective therapy during the course of an add-on regulatory trial for new antiepileptic drug approval (typically ∼6 months in duration), due to the potential risks of continued uncontrolled epilepsy for that period. The first meeting of the Research Roundtable in Epilepsy on May 19-20, 2016, focused on "Reducing placebo exposure in epilepsy clinical trials," with a goal of considering new designs for epilepsy regulatory trials that may be added to the overall development plan to make it, as a whole, safer for participants while still providing rigorous evidence of effect. This topic was motivated in part by data from a meta-analysis showing a 3- to 5-fold increased rate of sudden unexpected death in epilepsy in participants randomized to placebo or ineffective doses of new antiepileptic drugs. The meeting agenda included rationale and discussion of different trial designs, including active-control add-on trials, placebo add-on to background therapy with adjustment, time to event designs, adaptive designs, platform trials with pooled placebo control, a pharmacokinetic/pharmacodynamic approach to reducing placebo exposure, and shorter trials when drug tolerance has been ruled out. The merits and limitations of each design were discussed and are reviewed here. © 2017 American Academy of Neurology.

The challenges of control groups, placebos and blinding in clinical trials of dietary interventions.

PubMed

Staudacher, Heidi M; Irving, Peter M; Lomer, Miranda C E; Whelan, Kevin

2017-08-01

High-quality placebo-controlled evidence for food, nutrient or dietary advice interventions is vital for verifying the role of diet in optimising health or for the management of disease. This could be argued to be especially important where the benefits of dietary intervention are coupled with potential risks such as compromising nutrient intake, particularly in the case of exclusion diets. The objective of the present paper is to explore the challenges associated with clinical trials in dietary research, review the types of controls used and present the advantages and disadvantages of each, including issues regarding placebos and blinding. Placebo-controlled trials in nutrient interventions are relatively straightforward, as in general placebos can be easily produced. However, the challenges associated with conducting placebo-controlled food interventions and dietary advice interventions are protean, and this has led to a paucity of placebo-controlled food and dietary advice trials compared with drug trials. This review appraises the types of controls used in dietary intervention trials and provides recommendations and nine essential criteria for the design and development of sham diets for use in studies evaluating the effect of dietary advice, along with practical guidance regarding their evaluation. The rationale for these criteria predominantly relate to avoiding altering the outcome of interest in those delivered the sham intervention in these types of studies, while not compromising blinding.

A double-blind, randomized, placebo-controlled, single-dose study of the cyclooxygenase-2 inhibitor, GW406381, as a treatment for acute migraine.

PubMed

Wentz, A L; Jimenez, T B; Dixon, R M; Aurora, S K; Gold, M

2008-04-01

The objective of the present study was to explore the clinical efficacy and tolerability of GW406381, a cyclooxygenase-2 (COX-2) inhibitor with relatively high CNS penetration, in acute migraine. This was a double-blind, single-dose study of GW406381 compared with placebo and naproxen sodium compared with placebo (protocol number CXA20008). Three hundred and thirty-seven subjects were randomized 1:1:1 to GW406381 (70 mg), naproxen sodium (825 mg), or placebo for the treatment of one migraine headache of moderate or severe intensity in a potential 8-week period. The primary end-point was the proportion of subjects with headache relief [reduction in headache severity score from pre-dose 2 (moderate) or 3 (severe) to 0 (no pain) or 1 (mild)] at 2 h post-dose for GW406381 compared with placebo. Significantly higher proportions of subjects treated with GW406381 (50%, P = 0.032) or naproxen sodium (56%, P = 0.005) than with placebo (35%) reported headache relief at 2 h post-dose. Additional significant benefits were observed on many secondary outcomes, including proportions of subjects pain-free, for both GW406381 and naproxen sodium treatment compared with placebo. Both active treatments were well tolerated. Single-dose GW406381 (70 mg) and naproxen sodium (825 mg) were effective and well tolerated in the treatment of acute migraine.

Randomized, double-blind, placebo-controlled trial of saw palmetto in men with lower urinary tract symptoms.

PubMed

Gerber, G S; Kuznetsov, D; Johnson, B C; Burstein, J D

2001-12-01

To assess the effects of saw palmetto on urinary symptoms, sexual function, and urinary flow rate in men with lower urinary tract symptoms using a double-blind, randomized, placebo-controlled trial. The eligible patients were 45 years of age or older and had an International Prostate Symptom Score of 8 or greater. After a 1-month placebo run-in period, 85 men were randomized to receive saw palmetto or placebo for 6 months. Patients were evaluated using the International Prostate Symptom Score, a sexual function questionnaire, and by measurement of the urinary flow rate. The mean symptom score decreased from 16.7 to 12.3 in the saw palmetto group compared with 15.8 to 13.6 in the placebo group (P = 0.038). The quality-of-life score improved to a greater degree in the saw palmetto group, but this difference was not statistically significant. No change occurred in the sexual function questionnaire results in either group. The peak flow rate increased by 1.0 mL/s and 1.4 mL/s in the saw palmetto and placebo groups, respectively (P = 0.73). Saw palmetto led to a statistically significant improvement in urinary symptoms in men with lower urinary tract symptoms compared with placebo. Saw palmetto had no measurable effect on the urinary flow rates. The mechanism by which saw palmetto improves urinary symptoms remains unknown.

Clinical efficacies of shampoos containing ciclopirox olamine (1.5%) and ketoconazole (2.0%) in the treatment of seborrhoeic dermatitis.

PubMed

Ratnavel, Ravi C; Squire, Ruth A; Boorman, Graham C

2007-01-01

Ciclopirox olamine (CPO) is a broad-spectrum antifungal with anti-inflammatory properties effective against the yeast implicated in seborrhoeic dermatitis, Malassezia spp. This study compared 1.5% CPO shampoo with 2.0% ketoconazole shampoo and placebo in scalp seborrhoeic dermatitis. A randomized, double-blind, 4-week treatment period was preceded by a 2-week run-in period and followed by a 2-week run-out period. A total of 350 patients (150 CPO, 150 ketoconazole, 50 placebo) were enrolled. Assessments included scalp area affected, the severity of scaling, erythema, itching and scaling, and overall signs and symptoms. Both shampoos were significantly more effective than placebo in reducing the area affected. The mean reduction from baseline to end of treatment was 48.2 cm(2) with CPO, 41.4 cm(2) with ketoconazole and 20.0 cm(2) with placebo. Patients rated the CPO shampoo as superior to placebo (p<0.001) and ketoconazole shampoo (p<0.05) on the basis of overall signs and symptoms. Assessments of itching and scaling were also significantly in favour of the CPO shampoo over placebo at the end of treatment. All three shampoos were well tolerated. CPO shampoo was superior to placebo and at least as effective as ketoconazole shampoo in treating scalp seborrhoeic dermatitis. Patients rated the overall improvement as better with CPO than with ketoconazole shampoo.

Changes in visceral adiposity and serum cholesterol with a novel viscous polysaccharide in Japanese adults with abdominal obesity.

PubMed

Reimer, Raylene A; Yamaguchi, Hideyo; Eller, Lindsay K; Lyon, Michael R; Gahler, Roland J; Kacinik, Veronica; Juneja, Prateek; Wood, Simon

2013-09-01

Evidence supports the role of dietary fiber in improving metabolic health. PolyGlycopleX (PGX), a viscous functional polysaccharide improves lipidemia and glycemia in healthy adults. Our objective was to examine the effects of PGX on risk factors associated with the metabolic syndrome in Japanese adults with abdominal obesity. Sixty four subjects assigned to 14 weeks of 15 g day(-1) of PGX or placebo were assessed in a randomized, double-blind, placebo-controlled, parallel group trial. At week 0 and 14, primary outcome measures were serum lipids, abdominal adiposity, glucose tolerance and blood pressure. Total and LDL cholesterol were reduced at week 14 with PGX but not placebo (P < 0.05). The reduction in waist circumference at week 14 was greater with PGX versus placebo (P < 0.05). In females, abdominal visceral fat was decreased to a greater extent with PGX versus placebo (P < 0.05). While glucose tolerance worsened with placebo over time, PGX reduced glucose total area under the curve from week 0 to 6 (P = 0.039). Serum concentrations of resistin and IL6 increased slightly in placebo and decreased slightly with PGX . PGX is a functional fiber that shows promise in reducing risk factors related to the metabolic syndrome in Japanese adults with abdominal obesity. Copyright © 2013 The Obesity Society.

Nicergoline in mild to moderate dementia. A multicenter, double-blind, placebo-controlled study.

PubMed

Battaglia, A; Bruni, G; Ardia, A; Sacchetti, G

1989-04-01

In view of some controversies still existing about the real efficacy of ergot derivatives in the management of dementia, a double-blind, randomized, parallel group trial extending up to 6 months was carried out to compare the effects of nicergoline, 60 mg daily, and placebo in 315 patients suffering from mild to moderate dementia. Clinical evaluation was performed by the SCAG scale. The trial, which included a 1-month placebo run-in period, showed that both placebo and nicergoline were associated with some degree of improvement. The effect of nicergoline, however, was significantly greater and more sustained, steadily increasing with time. In particular, the difference between nicergoline and placebo in mean total SCAG score was 5.5 at 3 months (95% confidence interval: 3.6-7.4) and increased to 9.8 at 6 months (95% confidence interval: 7.8-11.8). A comparison of nicergoline versus placebo in the frequencies of changes in each item of the SCAG showed also a significant difference at 6 months, the percent of patients displaying an improvement by at least 2 points ranging from 13.5 (bothersome) to 30.2 (disorientation) in nicergoline group, against 4.1 (self-care) to 14.3 (fatigue) in placebo group. The safety of nicergoline, as judged by hemodynamic changes and drug-related adverse reactions, was quite satisfactory.

A Randomized, Placebo-Controlled Study of Once-Daily Atomoxetine in the School Setting in Children with ADHD

ERIC Educational Resources Information Center

Weiss, Margaret; Tannock, Rosemary; Kratochvil, Christopher; Dunn, David; Velez-Borras, Jesus; Thomason, Christine; Tamura, Roy; Kelsey, Douglas; Stevens, Linda; Allen, Albert J.

2005-01-01

Objective: Five studies have demonstrated the effectiveness of atomoxetine compared with placebo in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD) based on parent reports. The primary objective of this clinical trial was to assess the efficacy of once-daily atomoxetine compared with placebo using teacher reports. Method: One…

Nicotine Gum and Behavioral Treatment: A Placebo Controlled Trial.

ERIC Educational Resources Information Center

Hall, Sharon M.; And Others

1987-01-01

Assigned 139 subjects to intensive behavioral or to low-contact smoking treatment and to 2-milligram nicotine gum or to placebo gum in a 2x2 factorial design. Nicotine gum produced higher abstinence rates than did placebo. Subjects receiving low-contact condition plus nicotine gum had excellent abstinence rates at both 26 weeks and 52 weeks.…

A Randomized Placebo-Controlled Trial of a School-Based Depression Prevention Program.

ERIC Educational Resources Information Center

Merry, Sally; McDowell, Heather; Wild, Chris J.; Bir, Julliet; Cunliffe, Rachel

2004-01-01

Objective: To conduct a placebo-controlled study of the effectiveness of a universal school-based depression prevention program. Method: Three hundred ninety-two students age 13 to 15 from two schools were randomized to intervention (RAP-Kiwi) and placebo programs run by teachers. RAP-Kiwi was an 11-session manual-based program derived from…

Atomoxetine for Hyperactivity in Autism Spectrum Disorders: Placebo-Controlled Crossover Pilot Trial

ERIC Educational Resources Information Center

Arnold, L. Eugene; Aman, Michael G.; Cook, Amelia M.; Witwer, Andrea N.; Hall, Kristy L.; Thompson, Susan; Ramadan, Yaser

2006-01-01

Objective: To explore placebo-controlled efficacy and safety of atomoxetine (ATX) for attention-deficit/hyperactivity disorder (ADHD) symptoms in children with autism spectrum disorders (ASD). Method: Children ages 5 to 15 with ASD and prominent ADHD symptoms were randomly assigned to order in a crossover of clinically titrated ATX and placebo, 6…

Differential Effectiveness of Electromyograph Feedback, Verbal Relaxation Instructions, and Medication Placebo with Tension Headaches

ERIC Educational Resources Information Center

Cox, Daniel J.; And Others

1975-01-01

Adults with chronic tension headaches were assigned to auditory electromyograph (EMG) feedback (N=9), to progressive relaxation (N=9), and to placebo treatment (N=9). Data indicated that biofeedback and verbal relaxation instructions were equally superior to the medicine placebo on all measured variables in the direction of clinical improvement,…

Naldemedine versus placebo for opioid-induced constipation (COMPOSE-1 and COMPOSE-2): two multicentre, phase 3, double-blind, randomised, parallel-group trials.

PubMed

Hale, Martin; Wild, James; Reddy, Jyotsna; Yamada, Tadaaki; Arjona Ferreira, Juan Camilo

2017-08-01

Opioid-induced constipation is a frequent side-effect of opioid treatment, and standard interventions have limited or inconsistent efficacy. This study assessed the efficacy and safety of naldemedine, a peripherally acting μ-opioid receptor antagonist, for the treatment of opioid-induced constipation in patients with chronic non-cancer pain. We report two double-blind, randomised, placebo-controlled trials in adults with chronic non-cancer pain and opioid-induced constipation. The first (COMPOSE-1) was done in 68 outpatient sites in seven countries and the second (COMPOSE-2) at 69 outpatient sites in six countries; both studies were done in Europe and the USA. Eligible patients were aged 18-80 years, did not use laxatives, and had a stable opioid regimen for treatment of chronic non-cancer pain with a total daily dose averaging at least 30 mg (morphine equivalent) for at least 1 month before screening. Patients were randomly assigned (1:1) to receive either oral naldemedine 0·2 mg or matching placebo once a day for 12 weeks. Randomisation was stratified by average total daily opioid dose (30-100 mg and >100 mg equivalents of oral morphine sulphate). The primary endpoint was proportion of responders. A responder had at least three spontaneous bowel movements (SBMs) per week with an increase from baseline of at least one SBM per week for at least 9 weeks of the 12-week treatment period including at least three of the last 4 weeks. Efficacy endpoints were analysed by intention to treat and the safety population included all patients who received at least one dose of study drug. These trials have both been completed and are registered with ClinicalTrials.gov, numbers NCT01965158 and NCT01993940. In COMPOSE-1, 547 patients were recruited between Aug 29, 2013, and Jan 22, 2015, and were randomly assigned to receive naldemedine (n=274) or placebo (n=273). Patients for COMPOSE-2 were recruited between Nov 4, 2013, and June 9, 2015; 553 patients were randomly assigned to receive naldemedine (n=277) or placebo (n=276). Five patients were enrolled at more than one site, so were excluded from the intention-to-treat population (COMPOSE-1: one per group; COMPOSE-2: one in the naldemedine group, two from the placebo group), with intention-to-treat group sizes of 273 in the naldemedine group and 272 in the placebo group in COMPOSE-1, and 276 in the naldemedine group and 274 in the placebo group in COMPOSE-2. The proportion of responders in both trials was significantly higher with naldemedine than with placebo in COMPOSE-1 (130 responders [47·6%] of 273 in the naldemedine group vs 94 responders [34·6%] of 272 in the placebo group, difference 13·0% [95% CI 4·8-21·3]; p=0·002) and in COMPOSE-2 (145 [52·5%] of 276 vs 92 [33·6%] of 274, difference 18·9% [10·8-27·0]; p<0·0001). Incidence of adverse events with naldemedine was similar to placebo (COMPOSE-1: 132 [49%] of 271 in the naldemedine group vs 123 [45%] of 272 in the placebo group; COMPOSE-2: 136 [50%] of 271 vs 132 [48%] of 274). Treatment-related adverse events were noted in 59 (22%) of 271 patients in the naldemedine group and 45 (17%) of 272 in the placebo group in COMOPOSE-1, and in 54 (20%) of 271 patients in the naldemedine group and 31 (11%) of 274 in the placebo group of COMPOSE-2; the between-group differences were largely due to gastrointestinal disorders, which were more common with naldemedine than placebo (COMPOSE-1: 40 [15%] patients in the naldemedine group vs 18 [7%] in the placebo group; COMPOSE-2: 42 [16%] vs 20 [7%]). Naldemedine treatment led to a significantly higher responder rate than did placebo and was generally well tolerated. These results support that naldemedine could be a new option for the treatment of opioid-induced constipation in patients with chronic non-cancer pain. Shionogi & Co, Ltd. Copyright © 2017 Elsevier Ltd. All rights reserved.

Omega 3/6 fatty acids for reading in children: a randomized, double-blind, placebo-controlled trial in 9-year-old mainstream schoolchildren in Sweden.

PubMed

Johnson, Mats; Fransson, Gunnar; Östlund, Sven; Areskoug, Björn; Gillberg, Christopher

2017-01-01

Previous research has shown positive effects of Omega 3/6 fatty acids in children with inattention and reading difficulties. We aimed to investigate if Omega 3/6 improved reading ability in mainstream schoolchildren. We performed a 3-month parallel, randomized, double-blind, placebo-controlled trial followed by 3-month active treatment for all subjects. Mainstream schoolchildren aged 9-10 years were randomized 1:1 to receive three Omega 3/6 capsules twice daily or identical placebo. Assessments were made at baseline, 3 months, and 6 months. The primary outcome measure was the Logos test battery for evaluating reading abilities. The trial is registered with ClinicalTrials.gov, number NCT02557477. The study enrolled 154 children (active n = 78; placebo n = 76), of whom 122 completed the first 3 months (active n = 64; placebo n = 58) and 105 completed the whole study (active/active n = 55; placebo/active n = 50). Outcomes were assessed by per protocol (PP) and intention-to-treat (ITT) analyses. Active treatment was superior to placebo at 3 months for improvement in phonologic decoding time (PP active/placebo difference -0.16; 95% CI -0.03, -0.29; effect size (ES) .44; p = .005; and ITT ES .37; p = .036), in visual analysis time (PP active/placebo difference -0.19; 95% CI -0.05, -0.33; ES .49; p = .013; and ITT ES .40; p = .01), and for boys in phonologic decoding time (PP -0.22; 95% CI -0.03, -0.41; ES .62; p = .004). Children with ADHD-RS scores above the median showed treatment benefits in visual analysis time (PP ES .8, p = .009), reading speed per word (PP ES .61, p = .008), and phonologic decoding time per word (PP ES .85, p = .006). Adverse events were rare and mild, mainly stomach pain/diarrhea (active n = 9, placebo n = 2). Compared with placebo, 3 months of Omega 3/6 treatment improved reading ability - specifically the clinically relevant 'phonologic decoding time' and 'visual analysis time' - in mainstream schoolchildren. In particular, children with attention problems showed treatment benefits. © 2016 Association for Child and Adolescent Mental Health.

Efficacy and safety of biologic therapies for systemic lupus erythematosus treatment: systematic review and meta-analysis.

PubMed

Borba, Helena Hiemisch Lobo; Wiens, Astrid; de Souza, Thais Teles; Correr, Cassyano Januário; Pontarolo, Roberto

2014-04-01

The objectives of this study were to evaluate the efficacy, safety, and tolerability of biologic drugs compared with placebo for systemic lupus erythematosus (SLE) treatment. A systematic review evaluating the efficacy and safety of biologic therapies compared with placebo in adult SLE patients treatment was performed. Data from studies performed before September 2013 were collected from several databases (MEDLINE, Cochrane Library, SCIELO, Scopus, and International Pharmaceutical Abstracts). Study eligibility criteria included randomized, double-blind, placebo-controlled trials; regarding treatment with biologic agents in SLE adult patients; and published in English, German, Portuguese, and Spanish. Extracted data were statistically analyzed in a meta-analysis using the Review Manager (RevMan) 5.1 software. Efficacy outcomes included the SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index) score, the SRI (Systemic Lupus Erythematosus Responder Index), normalization of low C3 (<90 mg/dL), anti-double-stranded DNA positive to negative, and no new BILAG (British Isles Lupus Assessment Group index) 1A or 2B flares. Data on safety profile included adverse events, serious and severe adverse events, death, malignancy, infections, and infusion reactions. We also evaluated withdrawals from treatment due to lack of efficacy or adverse events. Thirteen randomized placebo-controlled trials met the criteria for data extraction for systematic review. A meta-analysis regarding the efficacy and safety of belimumab compared with placebo involving four of these trials was undertaken and the remainder contributed to a meta-analysis of the safety of biologic agents. In addition, two trials allowed the performance of a meta-analysis regarding the efficacy and safety of rituximab compared with placebo. Belimumab was more effective than placebo in most evaluated outcomes. No significant differences in the safety and tolerability data were observed between the belimumab and placebo groups. No differences were observed between the rituximab and placebo groups for the efficacy outcomes or safety parameters. Extracted data from the 13 studies were pooled, allowing assessment of the safety of biologic drugs. The meta-analysis revealed a satisfactory safety profile of these agents when used for SLE treatment, as there were no significant differences between the two evaluated groups (biologic agents and placebo) for all outcomes analyzed. Belimumab exhibited a satisfactory profile regarding efficacy, safety, and tolerability. Rituximab showed no superiority over placebo in terms of efficacy, despite its suitable safety profile. Biologic agents exhibited a good safety profile for SLE treatment, indicating that these agents are promising therapies and should be further investigated.

Sumatriptan (intranasal route of administration) for acute migraine attacks in adults

PubMed Central

Derry, Christopher J; Derry, Sheena; Moore, R Andrew

2014-01-01

Background Migraine is a highly disabling condition for the individual and also has wide-reaching implications for society, healthcare services, and the economy. Sumatriptan is an abortive medication for migraine attacks, belonging to the triptan family. Intranasal administration may be preferable to oral for individuals experiencing nausea and/or vomiting, although it is primarily absorbed in the gut, not the nasal mucosa. Objectives To determine the efficacy and tolerability of intranasal sumatriptan compared to placebo and other active interventions in the treatment of acute migraine attacks in adults. Search methods We searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, online databases, and reference lists for studies through 13 October 2011. Selection criteria We included randomised, double-blind, placebo- and/or active-controlled studies using intranasal sumatriptan to treat a migraine headache episode, with at least 10 participants per treatment arm. Data collection and analysis Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate relative risk (or ‘risk ratio’) and numbers needed to treat to benefit (NNT) or harm (NNH) compared to placebo or a different active treatment. Main results Twelve studies (4755 participants) compared intranasal sumatriptan with placebo or an active comparator. Most of the data were for the 10 mg and 20 mg doses. Sumatriptan surpassed placebo for all efficacy outcomes. For sumatriptan 10 mg versus placebo the NNTs were 7.3, 7.4, and 5.5 for pain-free at two hours, and headache relief at one and two hours, respectively. For sumatriptan 20 mg versus placebo the NNTs were 4.7, 4.9, and 3.5, respectively, for the same outcomes. The 20 mg dose was significantly better than the 10 mg dose for each of these three primary efficacy outcomes. Relief of headache-associated symptoms, including nausea, photophobia, and phonophobia, was greater with sumatriptan than with placebo, and use of rescue medication was lower with sumatriptan than placebo. For the most part, adverse events were transient and mild and were more common with sumatriptan than placebo. Direct comparison of sumatriptan with active treatments was limited to two studies, one comparing sumatriptan 20 mg and dihydroergotamine (DHE) 1 mg, and one comparing sumatriptan 20 mg with rizatriptan 10 mg. Authors’ conclusions Intranasal sumatriptan is effective as an abortive treatment for acute migraine attacks, relieving pain, nausea, photophobia, phonophobia, and functional disability, but is associated with increased adverse events compared with placebo. PMID:22336867

[Controlled clinical assay in Clonidine, arginine aspartate, alpha-ketoglutarate of Ornithine and Ciproheptadine as growth stimulants in children with short stature].

PubMed

Herranz Jordán, B; Moreno Romero, F; Cardesa García, J J; Santos Hurtado, I; Aparicio Palomino, A; Requena Guerrero, F

1993-06-01

Eighty-one healthy prepubertal children of short stature, between two and twelve years of age, were divided into four homogeneous groups. Each group was treated with a placebo for one year and for a second year with one of the following drugs (double blind): clonidine (CI), arginine asprate (AA), ornithine alphaketoglutare (OKG), or cyproheptadine (Cp). CI and OKG did not better the standard deviation of height. AA and Cp did, but to no greater extent than the placebo. The growth rate did not change in any group. The ratio of bone age/chronological age was significantly higher at the end of the OKG year than at the end of the year with placebo, a difference that was not found in any other group. The prognosis of adult height (TW2) did not change in any group. The standard deviation of weight increased in all groups, both with the placebo and the various drugs, without significant differences between the groups. The CI caused frequent clinical side effects, including a reversible increase in transaminases in one child. The Cp stimulated hunger. The AA and OKG did not produce side-effects and the placebo increased appetite in 11% of the children. Somatomedin C was significantly higher after one year with Cp than after one year with the placebo, significantly higher after the placebo than after CI and AA and there was no difference between the treatment with the placebo and OKG. Growth hormone values in a 24 hour urine sample were so scattered that we do not consider them helpful.(ABSTRACT TRUNCATED AT 250 WORDS)

Randomized study of adjunctive belimumab in participants with generalized myasthenia gravis

PubMed Central

Hewett, Karen; Sanders, Donald B.; Grove, Richard A.; Broderick, Christine L.; Rudo, Todd J.; Bassiri, Ashlyn; Zvartau-Hind, Marina

2018-01-01

Objective To investigate the efficacy and safety of belimumab, a fully human immunoglobulin G1λ monoclonal antibody against B-lymphocyte stimulator, in participants with generalized myasthenia gravis (MG) who remained symptomatic despite standard of care (SoC) therapy. Methods Eligible participants with MG were randomized 1:1 to receive IV belimumab 10 mg/kg or placebo in this phase II, placebo-controlled, multicenter, double-blind study (NCT01480596; BEL115123). Participants received SoC therapies throughout the 24-week treatment phase and 12-week follow-up period. The primary efficacy endpoint was mean change from baseline in the Quantitative Myasthenia Gravis (QMG) scale at week 24; safety assessments included the frequency and severity of adverse events (AEs) and serious AEs. Results Forty participants were randomized (placebo n = 22; belimumab n = 18). The mean change in QMG score from baseline at week 24 was not significantly different for belimumab vs placebo (p = 0.256). There were no statistically significant differences between treatment groups for secondary endpoints, including the MG Composite and MG–Activity of Daily Living scores. Acetylcholine receptor antibody levels decreased over time in both treatment groups. No unexpected AEs were identified and occurrence was similar in the belimumab (78%) and placebo (91%) groups. One participant receiving placebo died (severe sepsis) during the treatment phase. Conclusions The primary endpoint was not met for belimumab in participants with generalized MG receiving SoC. There was no significant difference in mean change in the QMG score at week 24 for belimumab vs placebo. The safety profile of belimumab was consistent with previous systemic lupus erythematosus studies. Classification of evidence This study provides Class I evidence that for participants with generalized MG, belimumab did not significantly improve QMG score compared with placebo. PMID:29661905

The RAndomized Placebo Phase Study Of Rilonacept in the Treatment of Systemic Juvenile Idiopathic Arthritis (RAPPORT)

PubMed Central

Ilowite, Norman T.; Prather, Kristi; Lokhnygina, Yuliya; Schanberg, Laura E.; Elder, Melissa; Milojevic, Diana; Verbsky, James W.; Spalding, Steven J.; Kimura, Yukiko; Imundo, Lisa F.; Punaro, Marilynn G.; Sherry, David D.; Tarvin, Stacey E.; Zemel, Lawrence S.; Birmingham, James D.; Gottlieb, Beth S.; Miller, Michael L.; O'Neil, Kathleen; Ruth, Natasha M.; Wallace, Carol A.; Singer, Nora G.; Sandborg, Christy I.

2015-01-01

Background Interleukin-1 plays a pivotal role in in the pathogenesis of systemic juvenile idiopathic arthritis (sJIA). We assessed the efficacy and safety of rilonacept (IL-1 trap), an IL-1 inhibitor, in a randomized, double-blind, placebo-controlled trial. Methods An initial 4-week double-blind placebo phase was incorporated into a 24-week randomized multi-center design, followed by an open label phase. We randomized 71 children with at least 2 active joints 1:1 to 2 arms of the study. Patients in the rilonacept arm received rilonacept (4.4mg/kg loading dose followed by 2.2mg/kg weekly, subcutaneously) from day 0; patients in the placebo arm received placebo for 4 weeks followed by a loading dose of rilonacept at week 4 followed by weekly maintenance doses. The primary endpoint was time to response, using adapted JIA ACR30 response criteria coupled with absence of fever and taper of systemic corticosteroids using pre-specified criteria. Results Time to response was shorter in the rilonacept arm than in the placebo arm (Chi-square 7.235, P=.007). Secondary analysis showed 20/35 (57%) of patients in the rilonacept arm responded at week 4 compared to 9/33 (27%) in the placebo arm (P=.016) using the same response criteria. Exacerbation of sJIA (4) was the most common SAE. More patients in the rilonacept arm had elevated liver transaminases, including more than three times the upper limits of normal, as compared to those in the placebo arm. Adverse events were similar in the two arms of the study. Conclusions Rilonacept was generally well tolerated and demonstrated efficacy in active sJIA. PMID:24839206

The effect of perioperative ketorolac on pain control in pregnancy termination.

PubMed

Roche, Natalie E; Li, Dongchen; James, Denise; Fechner, Adam; Tilak, Vasanti

2012-03-01

The study was conducted to evaluate the effect of perioperative ketorolac on pain associated with first-trimester aspiration abortion. A double-blind, randomized, placebo-controlled trial was performed involving pregnant women up to 14 weeks' gestation who desired pregnancy termination. Subjects were randomized to receive ketorolac 30 mg intravenously (n=31) or placebo (n=45) at the time of induction of anesthesia. Postoperative pain was assessed using a visual analog scale (VAS). The primary outcome was pain control as determined by VAS score. Secondary measures of patient use of supplemental postoperative pain medications and patient satisfaction were assessed. Subjects in the ketorolac group had lower postoperative pain scores on the VAS at all time points compared to the placebo group, but the difference was not statistically significant. The ketorolac group used less postoperative acetaminophen compared to the placebo group (6.5% versus 35.6%), respectively. Subjects in the placebo group and the ketorolac group had similar requirements for postoperative narcotics in the recovery room (22.2% versus 19.4%). Patient satisfaction with pain level was equivalent between the groups at all postoperative end points. There was no observed difference in perioperative blood loss observed between the two groups. Perioperative ketorolac has the same effect on postoperative pain as determined by VAS as placebo. The use of ketorolac at the 30-mg dose cannot be recommended for better pain control for patients undergoing first-trimester pregnancy termination by suction curettage. The only positive effect of the use of ketorolac compared to placebo was a reduction in the use of acetaminophen. Ketorolac use does not appear to change blood loss in the operating room or through postoperative day 1 compared to placebo. Copyright © 2012 Elsevier Inc. All rights reserved.

High-altitude headache: the effects of real vs sham oxygen administration.

PubMed

Benedetti, Fabrizio; Durando, Jennifer; Giudetti, Lucia; Pampallona, Alan; Vighetti, Sergio

2015-11-01

High-altitude, or hypobaric hypoxia, headache has recently emerged as an interesting model to study placebo and nocebo responses, and particularly their peripheral mechanisms. In this study, we analyze the response of this type of headache to either real or sham (placebo) oxygen (O(2)) administration at an altitude of 3500 m, where blood oxygen saturation (SO(2)) drops from the normal value of about 98% to about 85%. In a trial in which a double-blind administration of either 100% O(2) or sham O(2) was administered, we tested pre- and post-exercise headache, along with fatigue, heart rate (HR) responses, and prostaglandin E(2) (PGE(2)) salivary concentration. Although real O(2) breathing increased SO(2) along with a decrease in pre- and post-exercise headache, fatigue, HR, and PGE(2), placebo O(2) changed neither pre-/post-exercise headache nor SO(2)/HR/PGE(2), but it decreased fatigue. However, in another group of subjects, when sham O(2) was delivered after 2 previous exposures to O(2) (O(2) preconditioning), it decreased fatigue, post-exercise headache, HR, and PGE(2), yet without any increase in SO(2). Three main findings emerge from these data. First, placebo O(2) is effective in reducing post-exercise headache, along with HR and PGE(2) decrease, only after O(2) preconditioning. Second, pre-exercise (at rest) headache is not affected by placebo O(2), which emphasizes the limits of a placebo treatment at high altitude. Third, fatigue is affected by placebo O(2) even without prior O(2) conditioning, which suggests the higher placebo sensitivity of fatigue compared with headache pain at high altitude.

Small Amounts of Gluten in Subjects With Suspected Nonceliac Gluten Sensitivity: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial.

PubMed

Di Sabatino, Antonio; Volta, Umberto; Salvatore, Chiara; Biancheri, Paolo; Caio, Giacomo; De Giorgio, Roberto; Di Stefano, Michele; Corazza, Gino R

2015-09-01

There is debate over the existence of nonceliac gluten sensitivity (NCGS) intestinal and extraintestinal symptoms in response to ingestion of gluten-containing foods by people without celiac disease or wheat allergy. We performed a randomized, double-blind, placebo-controlled, cross-over trial to determine the effects of administration of low doses of gluten to subjects with suspected NCGS. We enrolled 61 adults without celiac disease or a wheat allergy who believed ingestion of gluten-containing food to be the cause of their intestinal and extraintestinal symptoms. Participants were assigned randomly to groups given either 4.375 g/day gluten or rice starch (placebo) for 1 week, each via gastrosoluble capsules. After a 1-week gluten-free diet, participants crossed over to the other group. The primary outcome was the change in overall (intestinal and extraintestinal) symptoms, determined by established scoring systems, between gluten and placebo intake. A secondary outcome was the change in individual symptom scores between gluten vs placebo. According to the per-protocol analysis of data from the 59 patients who completed the trial, intake of gluten significantly increased overall symptoms compared with placebo (P = .034). Abdominal bloating (P = .040) and pain (P = .047), among the intestinal symptoms, and foggy mind (P = .019), depression (P = .020), and aphthous stomatitis (P = .025), among the extraintestinal symptoms, were significantly more severe when subjects received gluten than placebo. In a cross-over trial of subjects with suspected NCGS, the severity of overall symptoms increased significantly during 1 week of intake of small amounts of gluten, compared with placebo. Clinical trial no: ISRCTN72857280. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Tofacitinib induction and maintenance therapy in East Asian patients with active ulcerative colitis: subgroup analyses from three phase 3 multinational studies.

PubMed

Motoya, Satoshi; Watanabe, Mamoru; Kim, Hyo Jong; Kim, Young Ho; Han, Dong Soo; Yuasa, Hirotoshi; Tabira, Junichi; Isogawa, Naoki; Arai, Shoko; Kawaguchi, Isao; Hibi, Toshifumi

2018-04-01

Tofacitinib is an oral, small-molecule Janus kinase inhibitor being investigated for ulcerative colitis (UC). In OCTAVE Induction 1 and 2, patients with moderately to severely active UC received placebo or tofacitinib 10 mg twice daily (BID) for 8 weeks. Clinical responders in OCTAVE Induction were re-randomized to 52 weeks' therapy with placebo, tofacitinib 5 mg BID, or tofacitinib 10 mg BID. We conducted post-hoc efficacy and safety analyses of East Asian patients in OCTAVE Induction 1 and 2 and OCTAVE Sustain. A total of 121 East Asian (Japan, Korea, and Taiwan) patients were randomized in OCTAVE Induction 1 and 2 (placebo, n=26; tofacitinib 10 mg BID, n=95), and 63 in OCTAVE Sustain (placebo, n=20; tofacitinib 5 mg BID, n=22; tofacitinib 10 mg BID, n=21). At week 8 of OCTAVE Induction 1 and 2, 18.9% of patients (18/95) achieved remission with tofacitinib 10 mg BID versus 3.8% (1/26) with placebo. In OCTAVE Sustain, the week 52 remission rates were 45.5% (10/22), 47.6% (10/21), and 15.0% (3/20) with 5 mg BID, 10 mg BID, and placebo, respectively. Adverse event rates were similar between groups in OCTAVE Induction and numerically higher with tofacitinib in OCTAVE Sustain. Serious adverse event rates were similar across groups in all studies. Infections were numerically more frequent with tofacitinib than placebo. Increases in serum lipid levels were observed with tofacitinib. In East Asian patients with UC, tofacitinib demonstrated numerically greater efficacy versus placebo as induction and maintenance therapy, with a safety profile consistent with the global study population. ClinicalTrials.gov: NCT01465763; NCT01458951; NCT01458574.

Efficacy and Safety of Paliperidone Extended Release 1.5 mg/day—A Double-blind, Placebo- and Active-Controlled, Study in the Treatment of Patients with Schizophrenia

PubMed Central

Coppola, Danielle; Melkote, Rama; Lannie, Caroline; Singh, Jaskaran; Nuamah, Isaac; Gopal, Srihari; Hough, David; Palumbo, Joseph

2011-01-01

Background Paliperidone extended-release (paliperidone ER) is an approved oral antipsychotic medication (dosing range 3–12 mg/day) for treatment of schizophrenia and schizoaffective disorder in adults. Methods In this 3-arm, double-blind, placebo- and active-controlled, parallel-group study, paliperidone ER 1.5 mg was assessed to determine the lowest efficacious dose in patients (N = 201) with acute schizophrenia. Paliperidone ER 6 mg was included for assay sensitivity. Results Patients (intent-to-treat analysis set) had a mean age of 39.4 years; 74% were men, 43% Asian, and 40% black. The baseline mean (SD) Positive and Negative Syndrome Scale (PANSS) total score was 92.6 (13.02) and the mean (SD) change from baseline to endpoint was: placebo group, –11.4 (20.81); paliperidone ER 1.5 mg group, –8.9 (23.31); and paliperidone ER 6 mg group, –15.7 (26.25). Differences between paliperidone groups versus placebo were not significant (paliperidone ER 1.5 mg [p = 0.582], paliperidone ER 6 mg, [p = 0.308]). Safety results of paliperidone ER 1.5 mg and placebo were comparable. The most frequently reported treatment emergent adverse events (≥10%) were: placebo group—headache (15.6%) and psychotic disorder (14.1%); paliperidone ER 1.5 mg group—insomnia (13.6%); and paliperidone ER 6 mg group—headache (11.4%), insomnia (10%), and tremor (10%). Conclusions In this study, paliperidone ER 1.5 mg did not demonstrate efficacy in patients with acute schizophrenia. A markedly high placebo response was noted. Assay sensitivity with the 6 mg dose was not established. Paliperidone ER 1.5 mg was generally tolerable with a safety profile comparable to placebo. PMID:27738355

Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study.

PubMed

Giovannoni, Gavin; Soelberg Sorensen, Per; Cook, Stuart; Rammohan, Kottil; Rieckmann, Peter; Comi, Giancarlo; Dangond, Fernando; Adeniji, Abidemi K; Vermersch, Patrick

2017-08-01

In the 2-year CLARITY study, cladribine tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis (MS). To assess the safety and efficacy of cladribine treatment in a 2-year Extension study. In this 2-year Extension study, placebo recipients from CLARITY received cladribine 3.5 mg/kg; cladribine recipients were re-randomized 2:1 to cladribine 3.5 mg/kg or placebo, with blind maintained. A total of 806 patients were assigned to treatment. Adverse event rates were generally similar between groups, but lymphopenia Grade ⩾ 3 rates were higher with cladribine than placebo (Grade 4 lymphopenia occurred infrequently). In patients receiving cladribine 3.5 mg/kg in CLARITY and experiencing lymphopenia Grade ⩾ 3 in the Extension, >90% of those treated with cladribine 3.5 mg/kg and all treated with placebo in the Extension, recovered to Grade 0-1 by study end. Cladribine treatment in CLARITY produced efficacy improvements that were maintained in patients treated with placebo in the Extension; in patients treated with cladribine 3.5 mg/kg in CLARITY, approximately 75% remained relapse-free when given placebo during the Extension. Cladribine tablets treatment for 2 years followed by 2 years' placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening. No clinical improvement in efficacy was apparent following further treatment with cladribine tablets after the initial 2-year treatment period in this trial setting.

Topical nitroglycerin and lidocaine locally vasodilate the radial artery without affecting systemic blood pressure: a dose-finding phase I study.

PubMed

Majure, David T; Hallaux, Melanie; Yeghiazarians, Yerem; Boyle, Andrew J

2012-10-01

Small radial artery diameter (RAD) and vasospasm are barriers to radial artery cannulation. We performed this study to determine if topical nitroglycerin and/or nitroglycerin plus topical lidocaine increases RAD without affecting systemic blood pressure. This was a randomized, double-blind, placebo-controlled study. In the first visit, to determine the optimal dose of nitroglycerin, subjects were randomized to either 15 or 30 mg nitroglycerin on one wrist and placebo on the other. In visit 2, to assess for any effect of lidocaine on the vasodilator function of nitroglycerin, the same subjects were randomized to 20 mg lidocaine + 30 mg nitroglycerin vs 20 mg lidocaine + placebo, or 40 mg lidocaine + 30 mg nitroglycerin vs 40 mg lidocaine + placebo. In both visits, blood pressure and RAD using ultrasonography were measured for 2 hours. In visit 1, both nitroglycerin groups significantly increased RAD, with greater increases with 30 mg nitroglycerin (P < .01) and no significant increase in RAD in placebo wrists. In visit 2, increase in RAD was significantly greater with 20 mg lidocaine + 30 mg nitroglycerin vs 20 mg lidocaine + placebo (P < .001), and 40 mg lidocaine + 30 mg nitroglycerin vs 40 mg lidocaine + placebo (P < .001), indicating that lidocaine does not alter the effect of nitroglycerin. There were significant increases in RAD seen as early as 30 minutes. There were no significant change in RAD in lidocaine + placebo-treated wrists and no change in blood pressure in any group. Topical nitroglycerin and lidocaine significantly increase RAD within 30 to 60 minutes with no effect on contralateral radial artery or blood pressure, indicating a direct, local effect on the radial artery. (Clinicaltrials.gov number NCT00686231). Copyright © 2012 Elsevier Inc. All rights reserved.

Highlights from the 2013 Science of Placebo thematic workshop

PubMed Central

Annoni, Marco

2013-01-01

In the last 30 years, a converging series of laboratory experiments, clinical trials, and neurocognitive studies have identified several key mechanisms of placebo effects. These studies suggest not only that placebo responses may be ubiquitous across research and clinical settings, but also that they can significantly modulate symptoms across a wide spectrum of highly prevalent conditions such as acute pain, chronic pain, anxiety, depression, Parkinson’s disease, and nausea, just to name a few. In order to inform the medical community about the most recent advances in the field of placebo studies, a thematic workshop entitled “The Science of Placebo” was held at the Beth Israel Deaconesses Medical Center (BIDMC), Harvard Medical School, in Boston (MA), on the 19–20 of June 2013. The workshop, sponsored by The Robert Wood Johnson Foundation, was organised by the Program in Placebo Studies and the Therapeutic Encounter, a Harvard-wide network of researchers dedicated to the study of the placebo phenomenon hosted by the BIDMC. The event was structured as a series of four public lectures, each delivered by a leading investigator in the field of placebo studies. The four keynote speakers were Fabrizio Benedetti, professor of neurophysiology and human physiology at the University of Turin Medical School and at the National Institute of Neuroscience in Italy; Tor Wager, director of the Cognitive and Affective Control Laboratory and associate professor of psychology and neuroscience at the University of Colorado; Predrag Petrovic, psychiatrist and researcher in the Department of Clinical Neuroscience at the Karolinska Institute in Stockholm; and Ted Kaptchuk, director of the Program in Placebo Studies and associate professor of medicine at Harvard Medical School. PMID:24019848

Performance effects of acute β-alanine induced paresthesia in competitive cyclists.

PubMed

Bellinger, Phillip M; Minahan, Clare L

2016-01-01

β-alanine is a common ingredient in supplements consumed by athletes. Indeed, athletes may believe that the β-alanine induced paresthesia, experienced shortly after ingestion, is associated with its ergogenic effect despite no scientific mechanism supporting this notion. The present study examined changes in cycling performance under conditions of β-alanine induced paresthesia. Eight competitive cyclists (VO2max = 61.8 ± 4.2 mL·kg·min(-1)) performed three practices, one baseline and four experimental trials. The experimental trials comprised a 1-km cycling time trial under four conditions with varying information (i.e., athlete informed β-alanine or placebo) and supplement content (athlete received β-alanine or placebo) delivered to the cyclist: informed β-alanine/received β-alanine, informed placebo/received β-alanine, informed β-alanine/received placebo and informed placebo/received placebo. Questionnaires were undertaken exploring the cyclists' experience of the effects of the experimental conditions. A possibly likely increase in mean power was associated with conditions in which β-alanine was administered (±95% CL: 2.2% ± 4.0%), but these results were inconclusive for performance enhancement (p = 0.32, effect size = 0.18, smallest worthwhile change = 56% beneficial). A possibly harmful effect was observed when cyclists were correctly informed that they had ingested a placebo (-1.0% ± 1.9%). Questionnaire data suggested that β-alanine ingestion resulted in evident sensory side effects and six cyclists reported placebo effects. Acute ingestion of β-alanine is not associated with improved 1-km TT performance in competitive cyclists. These findings are in contrast to the athlete's "belief" as cyclists reported improved energy and the ability to sustain a higher power output under conditions of β-alanine induced paresthesia.

Randomised placebo-controlled trials of surgery: ethical analysis and guidelines.

PubMed

Savulescu, Julian; Wartolowska, Karolina; Carr, Andy

2016-12-01

Use of a placebo control in surgical trials is a divisive issue. We argue that, in principle, placebo controls for surgery are necessary in the same way as for medicine. However, there are important differences between these types of trial, which both increase justification and limit application of surgical studies. We propose that surgical randomised placebo-controlled trials are ethical if certain conditions are fulfilled: (1) the presence of equipoise, defined as a lack of unbiased evidence for efficacy of an intervention; (2) clinically important research question; (3) the risk to patients is minimised and reasonable; (4) there is uncertainty about treatment allocation rather than deception; (5) there is preliminary evidence for efficacy, which justifies a placebo-controlled design; and (6) ideally, the placebo procedure should have some direct benefit to the patient, for example, as a diagnostic tool. Placebo-controlled trials in surgery will most often be justified when surgery is performed to improve function or relieve symptoms and when objective outcomes are not available, while the risk of mortality or significant morbidity is low. In line with medical placebo-controlled trials, the surgical trial (1) should be sufficiently powered and (2) standardised so that its results are valid, (3) consent should be valid, (4) the standard treatment or rescue medication should be provided if possible, and (5) after the trial, the patients should be told which treatment they received and there should be provision for post-trial care if the study may result in long-term negative effects. We comment and contrast our guidelines with those of the American Medical Association. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Myofascial trigger point-focused head and neck massage for recurrent tension-type headache: A randomized, placebo-controlled clinical trial

PubMed Central

Moraska, Albert F.; Stenerson, Lea; Butryn, Nathan; Krutsch, Jason P.; Schmiege, Sarah J.; Mann, J. Douglas

2014-01-01

Objective Myofascial trigger points (MTrPs) are focal disruptions in skeletal muscle that can refer pain to the head and reproduce the pain patterns of tension-type headache (TTH). The present study applied massage focused on MTrPs of subjects with TTH in a placebo-controlled, clinical trial to assess efficacy on reducing headache pain. Methods Fifty-six subjects with TTH were randomized to receive 12 massage or placebo (detuned ultrasound) sessions over six weeks, or to wait-list. Trigger point release (TPR) massage focused on MTrPs in cervical musculature. Headache pain (frequency, intensity and duration) was recorded in a daily headache diary. Additional outcome measures included self-report of perceived clinical change in headache pain and pressure-pain threshold (PPT) at MTrPs in the upper trapezius and sub-occipital muscles. Results From diary recordings, group differences across time were detected in headache frequency (p=0.026), but not for intensity or duration. Post hoc analysis indicated headache frequency decreased from baseline for both massage (p<0.0003) and placebo (p=0.013), but no difference was detected between massage and placebo. Subject report of perceived clinical change was a greater reduction in headache pain for massage than placebo or wait-list groups (p=0.002). PPT improved in all muscles tested for massage only (all p's<0.002). Discussion Two findings from this study are apparent: 1) MTrPs are important components in the treatment of TTH, and 2) TTH, like other chronic conditions, is responsive to placebo. Clinical trials on headache that do not include a placebo group are at risk for overestimating the specific contribution from the active intervention. PMID:25329141

Nonsteroidal Anti-inflammatory Drugs for Sciatica: An Updated Cochrane Review.

PubMed

Rasmussen-Barr, Eva; Held, Ulrike; Grooten, Wilhelmus J A; Roelofs, Pepijn D D M; Koes, Bart W; van Tulder, Maurits W; Wertli, Maria M

2017-04-15

Systematic review and meta-analysis. To determine the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) on pain reduction, overall improvement, and reported adverse effects in people with sciatica. NSAIDs are one of the most frequently prescribed drugs for sciatica. We updated a 2008 Cochrane Review through June 2015. Randomized controlled trials that compared NSAIDs with placebo, with other NSAIDs, or with other medication were included. Outcomes included pain using mean difference (MD, 95% confidence intervals [95% CI]). For global improvement and adverse effects risk ratios (RR, 95% CI) were used. We assessed level of evidence using the Grades of Recommendation, Assessment, Development and Evaluation approach. Ten trials were included (N = 1651). Nine out of 10 trials were assessed at high risk of bias. For pain reduction (visual analog scale, 0 to 100) NSAIDs were no more effective than placebo (MD -4.56, 95% CI -11.11 to 1.99, quality of evidence: very low). For global improvement NSAIDs were more effective than placebo (RR 1.14 [95% CI 1.03 to 1.27], low quality of evidence). One trial reported the effect of NSAIDs on disability with very low-quality evidence that NSAIDs are no more effective than placebo. There was low-quality evidence that the risk for adverse effects is higher for NSAID than placebo (RR 1.40, 95% CI 1.02 to 1.93). Our findings show very low-quality evidence that the efficacy of NSAIDs for pain reduction is comparable with that of placebo, low-quality evidence that NSAIDs is better than placebo for global improvement and low-quality evidence for higher risk of adverse effects using NSAIDs compared with placebo. The findings must be interpreted with caution, due to small study samples, inconsistent results, and a high risk of bias in the included trials. 1.

Buprenorphine Implants for Treatment of Opioid Dependence: Randomized Comparison to Placebo and Sublingual Buprenorphine/Naloxone

PubMed Central

Rosenthal, Richard N.; Ling, Walter; Casadonte, Paul; Vocci, Frank; Bailey, Genie L.; Kampman, Kyle; Patkar, Ashwin; Chavoustie, Steven; Blasey, Christine; Sigmon, Stacey; Beebe, Katherine L.

2015-01-01

Aims To evaluate safety and efficacy of buprenorphine implants (BI) versus placebo implants (PI) for the treatment of opioid dependence. A secondary aim compared BI to open-label sublingual buprenorphine/naloxone tablets (BNX). Design Randomized, double-blind, placebo-controlled trial. Subjects received either 4 buprenorphine implants (80 mg/implant) (n=114), 4 placebo implants (n=54), or open-label BNX (12–16 mg/d) (n=119). Setting 20 addiction treatment centers. Participants Adult outpatients (ages 18 to 65) with DSM-IV-TR opioid dependence. Measurements The primary efficacy endpoint was the percent of urine samples negative for opioids collected from weeks 1 to 24, examined as a cumulative distribution function (CDF). Findings The BI CDF was significantly different from placebo (P<.0001). Mean (95% CI) proportions of urines negative for opioids were: BI: 31.2% (25.3, 37.1) and PI: 13.4% (8.3, 18.6). BI subjects had a higher study completion rate relative to placebo (64% vs. 26%, P<.0001), lower clinician-rated (P<.0001) and patient-rated (P<.0001) withdrawal, lower patient-ratings of craving (P<.0001), and better subjects’ (P=.031) and clinicians’ (P=.022) global ratings of improvement. BI also resulted in significantly lower cocaine use (P=.0016). Minor implant-site reactions were comparable in the buprenorphine (27.2% [31/114]) and placebo groups (25.9% [14/54]). BI were non-inferior to BNX on percent urines negative for opioids [mean (95% CI): 33.5 (27.3, 39.6); CI for the difference of proportions, (−10.7, 6.2)]. Conclusions Compared with placebo, buprenorphine implants result in significantly less frequent opioid use, and are non-inferior to sublingual buprenorphine/naloxone tablets. PMID:23919595

I.31, a new combination of probiotics, improves irritable bowel syndrome-related quality of life

PubMed Central

Lorenzo-Zúñiga, Vicente; Llop, Elba; Suárez, Cristina; Álvarez, Beatriz; Abreu, Luis; Espadaler, Jordi; Serra, Jordi

2014-01-01

AIM: To determine the dose-related effects of a novel probiotic combination, I.31, on irritable bowel syndrome (IBS)-related quality of life (IBS-QoL). METHODS: A multicenter, randomized, double-blind, placebo-controlled intervention clinical trial with three parallel arms was designed. A total of 84 patients (53 female, 31 male; age range 20-70 years) with IBS and diarrhea according to Rome-III criteria were randomly allocated to receive one capsule a day for 6 wk containing: (1) I.31 high dose (n = 28); (2) I.31 low dose (n = 27); and (3) placebo (n = 29). At baseline, and 3 and 6 wk of treatment, patients filled the IBSQoL, Visceral Sensitivity Index (VSI), and global symptom relief questionnaires. RESULTS: During treatment, IBS-QoL increased in all groups, but this increment was significantly larger in patients treated with I.31 than in those receiving placebo (P = 0.008). After 6 wk of treatment, IBS-QoL increased by 18 ± 3 and 22 ± 4 points in the high and the low dose groups, respectively (P = 0.041 and P = 0.023 vs placebo), but only 9 ± 3 in the placebo group. Gut-specific anxiety, as measured with VSI, also showed a significantly greater improvement after 6 wk of treatment in patients treated with probiotics (by 10 ± 2 and 14 ± 2 points, high and low dose respectively, P < 0.05 for both vs 7 ± 1 score increment in placebo). Symptom relief showed no significant changes between groups. No adverse drug reactions were reported following the consumption of probiotic or placebo capsules. CONCLUSION: A new combination of three different probiotic bacteria was superior to placebo in improving IBS-related quality of life in patients with IBS and diarrhea. PMID:25024629

I.31, a new combination of probiotics, improves irritable bowel syndrome-related quality of life.

PubMed

Lorenzo-Zúñiga, Vicente; Llop, Elba; Suárez, Cristina; Alvarez, Beatriz; Abreu, Luis; Espadaler, Jordi; Serra, Jordi

2014-07-14

To determine the dose-related effects of a novel probiotic combination, I.31, on irritable bowel syndrome (IBS)-related quality of life (IBS-QoL). A multicenter, randomized, double-blind, placebo-controlled intervention clinical trial with three parallel arms was designed. A total of 84 patients (53 female, 31 male; age range 20-70 years) with IBS and diarrhea according to Rome-III criteria were randomly allocated to receive one capsule a day for 6 wk containing: (1) I.31 high dose (n = 28); (2) I.31 low dose (n = 27); and (3) placebo (n = 29). At baseline, and 3 and 6 wk of treatment, patients filled the IBSQoL, Visceral Sensitivity Index (VSI), and global symptom relief questionnaires. During treatment, IBS-QoL increased in all groups, but this increment was significantly larger in patients treated with I.31 than in those receiving placebo (P = 0.008). After 6 wk of treatment, IBS-QoL increased by 18 ± 3 and 22 ± 4 points in the high and the low dose groups, respectively (P = 0.041 and P = 0.023 vs placebo), but only 9 ± 3 in the placebo group. Gut-specific anxiety, as measured with VSI, also showed a significantly greater improvement after 6 wk of treatment in patients treated with probiotics (by 10 ± 2 and 14 ± 2 points, high and low dose respectively, P < 0.05 for both vs 7 ± 1 score increment in placebo). Symptom relief showed no significant changes between groups. No adverse drug reactions were reported following the consumption of probiotic or placebo capsules. A new combination of three different probiotic bacteria was superior to placebo in improving IBS-related quality of life in patients with IBS and diarrhea.

Prolonged remission from hepatic encephalopathy with rifaximin: results of a placebo crossover analysis.

PubMed

Bajaj, J S; Barrett, A C; Bortey, E; Paterson, C; Forbes, W P

2015-01-01

Rifaximin therapy reduced risk of hepatic encephalopathy (HE) recurrence and HE-related hospitalisations during a 6-month, randomised, placebo-controlled trial (RCT) and a 24-month open-label maintenance (OLM) study. However, the impact of crossover from placebo to rifaximin therapy is unclear. To study the impact of crossing over from placebo to rifaximin treatment on breakthrough HE and hospitalisation rates using a within-subjects design. Adults with cirrhosis and history of overt HE episodes, currently in HE remission, received placebo during the RCT and crossed over to rifaximin 550 mg twice daily during the OLM study. Rate of breakthrough overt HE episodes, hospitalisations and incidence and rate of adverse events (AEs) were analysed during RCT and first 6 months of OLM. Of 82 patients randomised to placebo in the RCT who crossed over to the OLM study, 39 experienced an HE episode during the RCT compared with 14 during the OLM study (P < 0.0001). Significantly lower rates of HE events were observed with rifaximin treatment compared with placebo treatment (P < 0.0001). Rates of HE-related hospitalisation were numerically lower during rifaximin treatment compared with placebo treatment, although not significant. Rates of most common AEs, serious AEs and infection-related AEs were similar between the two treatments. This analysis confirms the repeatability of results from the RCT on safety and efficacy of rifaximin 550 mg twice daily in reducing the risk of hepatic encephalopathy recurrence, and suggests these findings are translatable outside of a rigorous, controlled trial setting. © 2014 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Efficacy and Safety of Paliperidone Extended Release 1.5 mg/day-A Double-blind, Placebo- and Active-Controlled, Study in the Treatment of Patients with Schizophrenia.

PubMed

Coppola, Danielle; Melkote, Rama; Lannie, Caroline; Singh, Jaskaran; Nuamah, Isaac; Gopal, Srihari; Hough, David; Palumbo, Joseph

2011-05-15

Paliperidone extended-release (paliperidone ER) is an approved oral antipsychotic medication (dosing range 3-12 mg/day) for treatment of schizophrenia and schizoaffective disorder in adults. In this 3-arm, double-blind, placebo- and active-controlled, parallel-group study, paliperidone ER 1.5 mg was assessed to determine the lowest efficacious dose in patients (N = 201) with acute schizophrenia. Paliperidone ER 6 mg was included for assay sensitivity. Patients (intent-to-treat analysis set) had a mean age of 39.4 years; 74% were men, 43% Asian, and 40% black. The baseline mean (SD) Positive and Negative Syndrome Scale (PANSS) total score was 92.6 (13.02) and the mean (SD) change from baseline to endpoint was: placebo group, -11.4 (20.81); paliperidone ER 1.5 mg group, -8.9 (23.31); and paliperidone ER 6 mg group, -15.7 (26.25). Differences between paliperidone groups versus placebo were not significant (paliperidone ER 1.5 mg [p = 0.582], paliperidone ER 6 mg, [p = 0.308]). Safety results of paliperidone ER 1.5 mg and placebo were comparable. The most frequently reported treatment emergent adverse events (≥10%) were: placebo group-headache (15.6%) and psychotic disorder (14.1%); paliperidone ER 1.5 mg group-insomnia (13.6%); and paliperidone ER 6 mg group-headache (11.4%), insomnia (10%), and tremor (10%). In this study, paliperidone ER 1.5 mg did not demonstrate efficacy in patients with acute schizophrenia. A markedly high placebo response was noted. Assay sensitivity with the 6 mg dose was not established. Paliperidone ER 1.5 mg was generally tolerable with a safety profile comparable to placebo.

Buprenorphine implants for treatment of opioid dependence: randomized comparison to placebo and sublingual buprenorphine/naloxone.

PubMed

Rosenthal, Richard N; Ling, Walter; Casadonte, Paul; Vocci, Frank; Bailey, Genie L; Kampman, Kyle; Patkar, Ashwin; Chavoustie, Steven; Blasey, Christine; Sigmon, Stacey; Beebe, Katherine L

2013-12-01

To evaluate the safety and efficacy of buprenorphine implants (BI) versus placebo implants (PI) for the treatment of opioid dependence. A secondary aim compared BI to open-label sublingual buprenorphine/naloxone tablets (BNX). Randomized, double-blind, placebo-controlled trial. Subjects received either four buprenorphine implants (80 mg/implant) (n = 114), four placebo implants (n = 54) or open-label BNX (12-16 mg/day) (n = 119). Twenty addiction treatment centers. Adult out-patients (ages 18-65) with DSM-IV-TR opioid dependence. The primary efficacy end-point was the percentage of urine samples negative for opioids collected from weeks 1 to 24, examined as a cumulative distribution function (CDF). The BI CDF was significantly different from placebo (P < 0.0001). Mean [95% confidence interval (CI)] proportions of urines negative for opioids were: BI = 31.2% (25.3, 37.1) and PI = 13.4% (8.3, 18.6). BI subjects had a higher study completion rate relative to placebo (64 versus 26%, P < 0.0001), lower clinician-rated (P < 0.0001) and patient-rated (P < 0.0001) withdrawal, lower patient-ratings of craving (P < 0.0001) and better subjects' (P = 0.031) and clinicians' (P = 0.022) global ratings of improvement. BI also resulted in significantly lower cocaine use (P = 0.0016). Minor implant-site reactions were comparable in the buprenorphine [27.2% (31 of 114)] and placebo groups [25.9% (14 of 54)]. BI were non-inferior to BNX on percentage of urines negative for opioids [mean (95% CI) = 33.5 (27.3, 39.6); 95% CI for the difference of proportions = (-10.7, 6.2)]. Compared with placebo, buprenorphine implants result in significantly less frequent opioid use and are non-inferior to sublingual buprenorphine/naloxone tablets. © 2013 Society for the Study of Addiction.

Efficacy and Safety of Drotaverine Hydrochloride in Children with Recurrent Abdominal Pain: A Randomized Placebo Controlled Trial.

PubMed

Narang, Manish; Shah, Dheeraj; Akhtar, Hina

2015-10-01

To evaluate the efficacy and safety of Drotaverine hydrochroride in children with recurrent abdominal pain. Double blind, randomized placebo-controlled trial. Pediatric Gastroenterology clinic of a teaching hospital. 132 children (age 4-12 y) with recurrent abdominal pain (Apley Criteria) randomized to receivedrotaverine (n=66) or placebo (n=66) orally. Children between 4-6 years of age received 10 mL syrup orally (20 mg drotaverine hydrochloride or placebo) thrice daily for 4 weeks while children >6 years of age received one tablet orally (40 mg drotaverine hydrochloride or placebo) thrice daily for 4 weeks. Primary: Number of episodes of pain during 4 weeks of use of drug/placebo and number of pain-free days. Secondary: Number of school days missed during the study period, parental satisfaction (on a Likert scale), and occurrence of solicited adverse effects. Reduction in number of episodes of abdominal pain [mean (SD) number of episodes 10.3 (14) vs 21.6 (32.4); P=0.01] and lesser school absence [mean (SD) number of school days missed 0.25 (0.85) vs 0.71 (1.59); P=0.05] was noticed in children receiving drotaverine in comparison to those who received placebo. The number of pain-free days, were comparable in two groups [17.4 (8.2) vs 15.6 (8.7); P=0.23]. Significant improvement in parental satisfaction score was noticed on Likert scale by estimation of mood, activity, alertness, comfort and fluid intake. Frequency of adverse events during follow-up period was comparable between children receiving drotaverine or placebo (46.9% vs 46.7%; P=0.98). Drotaverine hydrochloride is an effective and safe pharmaceutical agent in the management of recurrent abdominal pain in children.

Myofascial trigger point-focused head and neck massage for recurrent tension-type headache: a randomized, placebo-controlled clinical trial.

PubMed

Moraska, Albert F; Stenerson, Lea; Butryn, Nathan; Krutsch, Jason P; Schmiege, Sarah J; Mann, John D

2015-02-01

Myofascial trigger points (MTrPs) are focal disruptions in the skeletal muscle that can refer pain to the head and reproduce the pain patterns of tension-type HA (TTH). The present study applied massage focused on MTrPs of patients with TTH in a placebo-controlled, clinical trial to assess efficacy on reducing headache (HA) pain. Fifty-six patients with TTH were randomized to receive 12 massage or placebo (detuned ultrasound) sessions over 6 weeks, or to wait-list. Trigger point release massage focused on MTrPs in cervical musculature. HA pain (frequency, intensity, and duration) was recorded in a daily HA diary. Additional outcome measures included self-report of perceived clinical change in HA pain and pressure-pain threshold at MTrPs in the upper trapezius and suboccipital muscles. From diary recordings, group differences across time were detected in HA frequency (P=0.026), but not for intensity or duration. Post hoc analysis indicated that HA frequency decreased from baseline for both massage (P<0.0003) and placebo (P=0.013), but no difference was detected between massage and placebo. Patient report of perceived clinical change was greater reduction in HA pain for massage than placebo or wait-list groups (P=0.002). Pressure-pain threshold improved in all muscles tested for massage only (all P's<0.002). Two findings from this study are apparent: (1) MTrPs are important components in the treatment of TTH, and (2) TTH, like other chronic conditions, is responsive to placebo. Clinical trials on HA that do not include a placebo group are at risk for overestimating the specific contribution from the active intervention.

Parecoxib relieves pain and has an opioid-sparing effect following major gastrointestinal surgery.

PubMed

Essex, Margaret Noyes; Xu, Hao; Parsons, Bruce; Xie, Li; Li, Chunming

2017-01-01

Parecoxib provides analgesia following a variety of surgeries, including minor gastrointestinal procedures. To our knowledge, there is no data on parecoxib following major gastrointestinal surgery. This study assessed the efficacy and opioid-sparing effects of parecoxib following major gastrointestinal surgeries. Patients in this analysis were a subset from a large, randomized, double-blind, placebo-controlled trial of parecoxib following noncardiac surgeries and consisted of those undergoing a variety of major gastrointestinal surgeries via laparotomy. Pain, pain interference with function, supplemental opioid utilization, opioid-related symptoms, and Patient/Physician Global Evaluation of Study Medication were compared between placebo and parecoxib groups in the 2-3 days following surgery. Significantly ( p <0.001) lower pain scores were observed in the parecoxib group (n=111), relative to placebo (n=126), on Day 2 (-33%) and Day 3 (-35%). Pain interference with function scores was also significantly ( p <0.001) lower among patients receiving parecoxib compared with placebo on Day 2 (-29%) and Day 3 (-36%). At 24, 48, and 72 hours, the cumulative amount of supplemental morphine consumed was 45%, 41%, and 40% less in patients receiving parecoxib compared with placebo (all p <0.001). The risk of experiencing ≥1 opioid-related symptoms was also significantly lower with parecoxib than with placebo on Day 2 (relative risk=0.75; p <0.001). Specifically, the risks of fatigue and drowsiness were significantly (both p <0.05) lower in patients receiving parecoxib compared to those receiving placebo. Patient and Physician Global Evaluation of Study Medication scores were significantly better in the parecoxib group than in the placebo group ( p <0.001). This study is the first to demonstrate that multiple-dose parecoxib, initiated upon recovery from anesthesia, provides analgesia and opioid-sparing effects following a variety of major gastrointestinal surgeries employing laparotomy.

Itopride in functional dyspepsia: results of two phase III multicentre, randomised, double-blind, placebo-controlled trials.

PubMed

Talley, N J; Tack, J; Ptak, T; Gupta, R; Giguère, M

2008-06-01

Functional dyspepsia (FD) is a common disorder but there is currently little efficacious drug therapy. Itopride, a prokinetic approved in several countries, showed promising efficacy in FD in a phase IIb trial. The aim of this study was to test the efficacy and safety of this drug in FD. Two similar placebo-controlled clinical trials were conducted (International and North America). Males and females, 18-65 years old, with a diagnosis of FD (Rome II) and the absence (by upper endoscopy) of any relevant structural disease were recruited. All were negative for Helicobacter pylori and, if present, heartburn could not exceed one episode per week. Following screening, patients were randomised to itopride 100 mg three times daily or identical placebo. The co-primary end points were: (1) global patient assessment (GPA) of efficacy; and (2) Leeds Dyspepsia Questionnaire (LDQ). Symptoms were evaluated at weeks 2, 4 and 8. Secondary measures of efficacy included Nepean Dyspepsia Index (NDI) quality of life. The GPA responder rates at week 8 on itopride versus placebo were similar in both trials (45.2% vs 45.6% and 37.8 vs 35.4%, respectively; p = NS). A significant benefit of itopride over placebo was observed for the LDQ responders in the International (62% vs 52.7%, p = 0.04) but not the North American trial (46.9% vs 44.8%). The safety and tolerability profile were comparable with placebo, with the exception of prolactin elevations, which occurred more frequently on itopride (18/579) than placebo (1/591). In this population with FD, itopride did not show a difference in symptom response from placebo.

Early interventional treatment with intranasal corticosteroids compared with postonset treatment in pollinosis.

PubMed

Higaki, Takaya; Okano, Mitsuhiro; Makihara, Seiichiro; Fujiwara, Tazuko; Haruna, Takenori; Noda, Yohei; Kariya, Shin; Nishizaki, Kazunori

2012-12-01

The usefulness of early interventional treatment (EIT) with intranasal corticosteroids (INSs) compared with postonset treatment (POT) has not been clarified. To study the efficacy and safety of EIT with INSs compared with POT and placebo in Japanese cedar/cypress pollinosis. We designed a 3-armed, double-blinded, randomized, placebo-controlled trial. Patients received mometasone furoate nasal spray (EIT group: n = 25), placebo (n = 25), or 4 weeks of placebo followed by 8 weeks of mometasone (POT group: n = 25) for a 12-week period starting on February 1, 2011. The primary end point was the comparison of the total nasal symptom score (TNSS) among the 3 groups. Total ocular symptom score (TOSS), total naso-ocular symptom score (TSS), Allergic Rhinitis and Its Impact (ARIA) on Asthma classification, and safety were the main secondary end points. The placebo and POT groups, but not the EIT group, had a significant exacerbation of TNSS and TOSS soon after the start of pollen counts being high on consecutive days. The 12-week mean TSS in the EIT group (score, 2.3) was significantly lower than in the placebo (5.0; P < .01) and POT (3.9; P = .03) groups. All patients in the placebo and POT groups were classified as having persistent rhinitis, whereas 80% of the EIT group met the ARIA classification criteria (P = .03). The quality-of-life score and nasal eosinophil cationic protein levels were lower in the EIT and POT groups compared with the placebo group. Daytime sleepiness, smell disturbance, and the mean dose of loratadine taken as the rescue medication were similar. Treatment with mometasone was well tolerated. EIT with INSs is superior to POT in controlling pollinosis. Copyright © 2012 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Effects of nandrolone decanoate compared with placebo or testosterone on HIV-associated wasting.

PubMed

Gold, J; Batterham, M J; Rekers, H; Harms, M K; Geurts, T B P; Helmyr, P M E; Silva de Mendonça, J; Falleiros Carvalho, L H; Panos, G; Pinchera, A; Aiuti, F; Lee, C; Horban, A; Gatell, J; Phanuphak, P; Prasithsirikul, W; Gazzard, B; Bloch, M; Danner, S A

2006-04-01

Objectives Current research is unclear about the most effective pharmacological agents for managing the loss of weight and fat-free mass common in HIV/AIDS. The aim of this study was to compare nandrolone decanoate with placebo and testosterone. Methods The study was a multicentre randomized double-blind placebo-controlled trial. Three hundred and three adult HIV-positive male patients with a weight loss of 5-15% in the last 12 months, or a body mass index of 17-19 kg/m(2), or a body cell mass/height ratio lower than 13.5 kg/m, were randomly assigned to receive nandrolone decanoate (150 mg), testosterone (250 mg) or placebo intramuscularly every 2 weeks for 12 weeks. Fat-free mass, weight, immune markers and perception of treatment were the main outcome measures. Results Treatment with nandrolone resulted in significantly greater increases in fat-free mass [mean increase 1.34 kg; 95% confidence interval (CI) 0.60; 2.08 kg] and in weight (mean increase 1.48 kg; 95% CI 0.82; 2.14 kg) compared with placebo. The mean increase in weight with nandrolone of 1.00 kg (95% CI 0.27; 1.74 kg) when compared with testosterone was significant, although the difference in fat free mass did not reach significance (mean increase 0.69 kg; 95% CI-0.13; 1.51 kg). Patient perception of benefit was significantly greater in the nandrolone group when compared with both the placebo and the testosterone groups. Conclusions Treatment with nandrolone decanoate increased body weight when compared with placebo and testosterone. Nandrolone decanoate treatment resulted in greater increases in fat-free mass than placebo and demonstrated a trend for a significant increase when compared with testosterone.

Fixed-dose combination PRO 160/120 of sabal and urtica extracts improves nocturia in men with LUTS suggestive of BPH: re-evaluation of four controlled clinical studies.

PubMed

Oelke, Matthias; Berges, Richard; Schläfke, Sandra; Burkart, Martin

2014-10-01

To determine the effects of the herbal fixed-dose combination PRO 160/120 (extracts from saw palmetto fruits and stinging nettle roots) on nocturnal voiding frequency, as measured by question 7 of the IPSS questionnaire, in patients with moderate-to-severe LUTS/BPH after 24 weeks of treatment compared to placebo, to the α-blocker tamsulosin, or to the 5α-reductase inhibitor finasteride. The study is about post hoc evaluation of four published randomized, double-blind clinical trials on PRO 160/120, two compared with placebo, one with finasteride and one with tamsulosin. In addition, a pooled data analysis of the two placebo-controlled trials was conducted. We analyzed data from a total of 922 patients with a mean age of 66 years and a mean baseline nocturnal voiding frequency of 2.1. In the pooled analysis of placebo-controlled trials, nocturnal voids improved by 0.8 (29 %) with PRO 160/120 compared to 0.6 (18 %) with placebo (p = 0.015, Wilcoxon test, one-tailed). The 69 % responder rate to PRO 160/120 was significantly superior to the placebo response (52 %; p = 0.003, χ (2)-test, two-tailed). The majority of responders improved by 1 void/night. Absolute improvements and response rates were consistently higher with PRO 160/120 than with placebo over a range of baseline nocturnal voiding frequencies. There were no differences between PRO 160/120 and finasteride or tamsulosin regarding absolute improvement of nocturnal voids or responds rates. PRO 160/120 significantly improved nocturnal voiding frequency compared to placebo and similar to tamsulosin or finasteride.

Effects of a gel forming dietary fiber, guar gum, on the absorption of glibenclamide and metabolic control and serum lipids in patients with non-insulin-dependent (type 2) diabetes.

PubMed

Uusitupa, M; Södervik, H; Silvasti, M; Karttunen, P

1990-04-01

Nine patients with non-insulin-dependent diabetes (NIDDM) treated with glibenclamide (3.5 mg b.i.d.) participated in this randomized double-blind placebo controlled crossover study to evaluate the effects of granulated guar gum (5 g t.i.d. with meals) on the absorption of glibenclamide and metabolic control and serum lipids. Each treatment period lasted for 4 weeks, and there was a wash-out period of one week between the treatments. The fasting blood glucose (10.5 +/- 3.4 mmol/l on guar gum vs 11.3 +/- 3.7 mmol/l on placebo, p less than 0.05) and serum total cholesterol (5.9 +/- 1.4 mmol/l on guar gum vs 6.6 +/- 1.6 mmol/l on placebo; p less than 0.05) levels were lower after the treatment with guar gum than placebo. No significant differences were observed in serum triglycerides or HDL cholesterol between guar gum and placebo treatments. The administration of guar gum together with glibenclamide did not change significantly the maximum concentration (223 +/- 196 ng/ml on guar gum vs 184 +/- 138 ng/ml on placebo; n = 7, NS) or area under the curve (AUC0-6) [729 +/- 813 (ng/ml) X h on guar gum vs 560 +/- 513 (ng/ml) X h on placebo; NS] of glibenclamide. The fasting serum glibenclamide concentrations were similar at the end of the 4-week treatment period with guar gum and placebo. In conclusion, guar gum improved the metabolic control and decreased serum lipids of patients with NIDDM. In addition, guar gum ingested with glibenclamide did not interfere with the absorption of glibenclamide.

Efficacy and Safety of Methylnaltrexone for Opioid-Induced Constipation in Patients With Chronic Noncancer Pain

PubMed Central

Viscusi, Eugene R.; Barrett, Andrew C.; Paterson, Craig; Forbes, William P.

2016-01-01

Background and Objectives In patients with chronic noncancer pain, subcutaneous methylnaltrexone for opioid-induced constipation (OIC) was examined in a randomized controlled trial (RCT) followed by an open-label extension (OLE). This study examined the reproducibility of RCT findings by analyzing data from placebo-treated patients who crossed over to methylnaltrexone. Methods Adults with less than 3 weekly rescue-free bowel movements (RFBMs), taking 50 mg or more of an oral morphine equivalent per day, were randomized to receive methylnaltrexone 12 mg or placebo for 4 weeks, followed by open-label methylnaltrexone 12 mg as needed for 8 weeks. Results A total of 134 placebo-treated patients (median morphine equivalent dose, 150 mg/d; mean of 1.1 RFBM per week) crossed over to methylnaltrexone in OLE. During the RCT, 9.7% of placebo-treated patients experienced an RFBM within 4 hours of first dose and 9.0% of all placebo injections resulted in an RFBM within 4 hours compared with 45.9% and 34.5%, respectively, with methylnaltrexone treatment in the OLE. When expressed as percentage of patients experiencing 3 or more RFBMs per week and a 1-RFBM increase over baseline, weekly values ranged from 35% to 40% during placebo treatment; at week 5 of OLE methylnaltrexone, this percentage increased to more than 70% and remained relatively stable throughout the OLE. The most common adverse events during methylnaltrexone treatment were abdominal pain (9.7% vs 1.5% for placebo) and nausea (5.2% vs 6.7%). Conclusions Findings during placebo treatment further establish the profile of OIC and support that little or no gastrointestinal tolerance develops across time. Findings under open-label conditions established the reproducibility and durability of methylnaltrexone for OIC. PMID:26650429

Double-Blind, Placebo-Controlled, Randomized Trial of Selenium in Graves Hyperthyroidism.

PubMed

Kahaly, George J; Riedl, Michaela; König, Jochem; Diana, Tanja; Schomburg, Lutz

2017-11-01

Supplemental selenium (Se) may affect the clinical course of Graves disease (GD). Evaluate efficacy of add-on Se on medical treatment in GD. Double-blind, placebo-controlled, randomized supplementation trial. Academic endocrine outpatient clinic. Seventy untreated hyperthyroid patients with GD. Additionally to methimazole (MMI), patients received for 24 weeks either sodium selenite 300 µg/d po or placebo. MMI was discontinued at 24 weeks in euthyroid patients. Response rate (week 24), recurrence rate (week 36), and safety. A response was registered in 25 of 31 patients (80%) and in 27 of 33 (82%) at week 24 [odds ratio (OR) 0.93; 95% confidence interval (CI), 0.26 to 3.25; P = 0.904] in the Se (+MMI) and placebo (+MMI) groups, respectively. During a 12-week follow-up, 11 of 23 (48%) and 12 of 27 (44%) relapsed (OR 1.13; 95% CI, 0.29 to 2.66; P = 0.81) in the Se and placebo groups, respectively. Serum concentrations of Se and selenoprotein P were unrelated to response or recurrence rates. At week 36, 12 of 29 (41%) and 15 of 33 (45%) were responders and still in remission in the Se and placebo groups, respectively (OR 0.85; 95% CI, 0.31 to 2.32; P = 0.80). Serum levels of free triiodothyronine/free tetraiodothyronine, thyroid-stimulating hormone receptor antibody, prevalence of moderate to severe Graves orbitopathy, thyroid volume, and MMI starting dose were significantly lower in responders than in nonresponders. A total of 56 and 63 adverse events occurred in the Se and placebo groups, respectively (P = 0.164), whereas only one drug-related side effect (2.9%) was noted in 35 patients on placebo + MMI. Supplemental Se did not affect response or recurrence rates in GD. Copyright © 2017 Endocrine Society

Speed of Improvement in Symptoms of Depression With Desvenlafaxine 50 mg and 100 mg Compared With Placebo in Patients With Major Depressive Disorder.

PubMed

Katzman, Martin A; Nierenberg, Andrew A; Wajsbrot, Dalia B; Meier, Ellen; Prieto, Rita; Pappadopulos, Elizabeth; Mackell, Joan; Boucher, Matthieu

2017-10-01

This post hoc analysis examined the time point at which clinically significant improvement in major depressive disorder (MDD) symptoms occurs with desvenlafaxine versus placebo. Data were pooled from 9 short-term, double-blind, placebo-controlled studies in adults with MDD randomly assigned to desvenlafaxine 50 mg/d, 100 mg/d, or placebo. A mixed-effects model for repeated-measures analysis of change from baseline score was used to determine the time point at which desvenlafaxine treatment groups separated from placebo on the 17-item Hamilton Rating Scale for Depression and psychosocial outcomes. The association between early improvement and week 8 outcomes was examined using logistic regression analyses. Time to remission for patients with early improvement versus without early improvement was assessed using Kaplan-Meier techniques. Comparisons between groups were performed with log-rank tests. In the intent-to-treat population (N = 4279 patients: desvenlafaxine 50 mg/d, n = 1714; desvenlafaxine 100 mg/d, n = 870; placebo, n = 1695), a statistically significant improvement on the 17-item Hamilton Rating Scale for Depression was observed with desvenlafaxine 50 mg/d at week 1 (P = 0.0129) and with desvenlafaxine 100 mg/d at week 2 (P = 0.0002) versus placebo. Early improvement was a significant predictor of later remission. Treatment assignment, baseline depression scale scores, and race were significantly associated with probability of early improvement. On several measures of depressive symptoms and function, desvenlafaxine 50 mg/d and 100 mg/d separated from placebo as early as week 1 and no later than week 4 in patients with MDD. These findings suggest that clinicians may be able to use depression rating scale scores early in treatment as a guide to inform treatment optimization.

Evaluation of the efficacy of cysteamine 5% cream in the treatment of epidermal melasma: a randomized double-blind placebo-controlled trial.

PubMed

Mansouri, P; Farshi, S; Hashemi, Z; Kasraee, B

2015-07-01

Melasma is a difficult-to-treat hyperpigmentary disorder. While cysteamine is a known potent depigmenting agent, its efficacy in treating melasma has not been tested. To study the efficacy of cysteamine 5% cream in the treatment of patients with epidermal melasma. In this double-blind randomized study, participating patients (n = 50) received either placebo (n = 25) or cysteamine cream (n = 25). Cysteamine cream or placebo were applied on the lesions once a day at bedtime over 4 months. The efficacy of treatments was determined through Mexameter skin colorimetry, Melasma Area Severity Index (MASI) score, Investigator's Global Assessment (IGA) and patients' questionnaires, all performed at baseline and after 2 and 4 months of treatment. At baseline, the mean differences between pigmented and normal skin (calculated by Mexameter) were 75.2 ± 37 and 68.9 ± 31 in the cysteamine and placebo groups, respectively. After 2 and 4 months of application of cysteamine and placebo cream, the mean differences were 39.7 ± 16.6 and 26.2 ± 16 in the cysteamine group, and 63.8 ± 28.6 and 60.7 ± 27.3 in the placebo group, respectively. Statistically significant differences were found between the group outcomes at both points (P = 0.001 and P < 0.001). At the end of the treatment, the MASI scores were significantly lower in the cysteamine group vs. placebo (7.2 ± 5.5 vs. 11.6 ± 7.9, P = 0.02). The IGA and patients' viewpoints indicated significant efficacy of cysteamine cream vs. placebo. Cysteamine cream showed significant efficacy in the treatment of melasma. © 2014 British Association of Dermatologists.

A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis.

PubMed

Abzug, Mark J; Michaels, Marian G; Wald, Ellen; Jacobs, Richard F; Romero, José R; Sánchez, Pablo J; Wilson, Gregory; Krogstad, Paul; Storch, Gregory A; Lawrence, Robert; Shelton, Mark; Palmer, April; Robinson, Joan; Dennehy, Penelope; Sood, Sunil K; Cloud, Gretchen; Jester, Penelope; Acosta, Edward P; Whitley, Richard; Kimberlin, David

2016-03-01

Neonatal enterovirus sepsis has high mortality. Antiviral therapy is not available. Neonates with suspected enterovirus sepsis (hepatitis, coagulopathy, and/or myocarditis) with onset at ≤15 days of life were randomized 2:1 to receive oral pleconaril or placebo for 7 days. Serial virologic (oropharynx, rectum, urine, serum), clinical, pharmacokinetic, and safety evaluations were performed. Sixty-one subjects were enrolled (43 treatment, 18 placebo), of whom 43 were confirmed enterovirus infected (31 treatment, 12 placebo). There was no difference in day 5 oropharyngeal culture positivity (primary endpoint; 0% in both groups). However, enterovirus-infected subjects in the treatment group became culture negative from all anatomic sites combined faster than placebo group subjects (median 4.0 versus 7.0 days, P = .08), and fewer subjects in the treatment group remained polymerase chain reaction (PCR)-positive from the oropharynx when last sampled (23% versus 58%, P = .02; median, 14.0 days). By intent to treat, 10/43 (23%) subjects in the treatment group and 8/18 (44%) in the placebo group died (P = .02 for 2-month survival difference); among enterovirus-confirmed subjects, 7/31 (23%) in the treatment group died versus 5/12 (42%) in the placebo group (P = .26). All pleconaril recipients attained concentrations greater than the IC90 after the first study day, but 38% were less than the IC90 during the first day of treatment. One subject in the treatment group and three in the placebo group had treatment-related adverse events. Shorter times to culture and PCR negativity and greater survival among pleconaril recipients support potential efficacy and warrant further evaluation. © The Author 2015. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Lixisenatide Therapy in Older Patients With Type 2 Diabetes Inadequately Controlled on Their Current Antidiabetic Treatment: The GetGoal-O Randomized Trial.

PubMed

Meneilly, Graydon S; Roy-Duval, Christine; Alawi, Hasan; Dailey, George; Bellido, Diego; Trescoli, Carlos; Manrique Hurtado, Helard; Guo, Hailing; Pilorget, Valerie; Perfetti, Riccardo; Simpson, Hamish

2017-04-01

To evaluate the efficacy and safety of lixisenatide versus placebo on glycemic control in older patients with type 2 diabetes uncontrolled on their current antidiabetic treatment. In this phase III, double-blind, randomized, placebo-controlled, two-arm, parallel-group, multicenter trial, patients aged ≥70 years were randomized to receive once-daily lixisenatide 20 μg or placebo before breakfast concomitantly with their existing antidiabetic therapy (including insulin) for 24 weeks. Patients at risk for malnutrition or with moderate to severe cognitive impairment were excluded. The primary end point was absolute change in HbA 1c from baseline to week 24. Secondary end points included change from baseline to week 24 in 2-h postprandial plasma glucose (PPG) and body weight. A total of 350 patients were randomized. HbA 1c decreased substantially with lixisenatide (-0.57% [6.2 mmol/mol]) compared with placebo (+0.06% [0.7 mmol/mol]) from baseline to week 24 ( P < 0.0001). Mean reduction in 2-h PPG was significantly greater with lixisenatide (-5.12 mmol/L) than with placebo (-0.07 mmol/L; P < 0.0001). A greater decrease in body weight was observed with lixisenatide (-1.47 kg) versus placebo (-0.16 kg; P < 0.0001). The safety profile of lixisenatide in this older population, including rates of nausea and vomiting, was consistent with that observed in other lixisenatide studies. Hypoglycemia was reported in 17.6% of patients with lixisenatide versus 10.3% with placebo. In nonfrail older patients uncontrolled on their current antidiabetic treatment, lixisenatide was superior to placebo in HbA 1c reduction and in targeting postprandial hyperglycemia, with no unexpected safety findings. © 2017 by the American Diabetes Association.

Randomized controlled trial of zonisamide for the treatment of refractory partial-onset seizures.

PubMed

Faught, E; Ayala, R; Montouris, G G; Leppik, I E

2001-11-27

Zonisamide is a sulfonamide antiepilepsy drug with sodium and calcium channel-blocking actions. Experience in Japan and a previous European double-blind study have demonstrated its efficacy against partial-onset seizures. A randomized, double-blind, placebo-controlled trial enrolling 203 patients was conducted at 20 United States sites to assess zonisamide efficacy and dose response as adjunctive therapy for refractory partial-onset seizures. Zonisamide dosages were elevated by 100 mg/d each week. The study design allowed parallel comparisons with placebo for three dosages and a final crossover to 400 mg/d of zonisamide for all patients. The primary efficacy comparison was change in seizure frequency from a 4-week placebo baseline to weeks 8 through 12 on blinded therapy. At 400 mg/d, zonisamide reduced the median frequency of all seizures by 40.5% from baseline, compared with a 9% reduction (p = 0.0009) with placebo treatment, and produced a > or =50% seizure reduction (responder rate) in 42% of patients. A dosage of 100 mg/d produced a 20.5% reduction in median seizure frequency (p = 0.038 compared with placebo) and a dosage of 200 mg/d produced a 24.7% reduction in median seizure frequency (p = 0.004 compared with placebo). Dropouts from adverse events (10%) did not differ from placebo (8.2%, NS). The only adverse event differing significantly from placebo was weight loss, though somnolence, anorexia, and ataxia were slightly more common with zonisamide treatment. Serum zonisamide concentrations rose with increasing dose. Zonisamide is effective and well tolerated as an adjunctive agent for refractory partial-onset seizures. The minimal effective dosage was 100 mg/d, but 400 mg/d was the most effective dosage.

Beneficial Effects of GH in Young Adults With Prader-Willi Syndrome: A 2-Year Crossover Trial.

PubMed

Kuppens, Renske J; Bakker, Nienke E; Siemensma, Elbrich P C; Tummers-de Lind van Wijngaarden, Roderick F A; Donze, Stephany H; Festen, Dederieke A M; van Alfen-van der Velden, Janielle A E M; Stijnen, Theo; Hokken-Koelega, Anita C S

2016-11-01

Patients with Prader-Willi syndrome (PWS) are severely at risk to develop morbid obesity, diabetes mellitus type 2, and cardiovascular disease, leading to high mortality. They have an increased fat mass (FM) and decreased lean body mass (LBM). During childhood, GH treatment counteracts the natural course of increasing obesity. Discontinuation of GH treatment at attainment of adult height (AH) might deteriorate their improved clinical condition, whereas continuation might benefit them. To investigate the effects of GH versus placebo on body composition in young adults with PWS who were GH treated for many years during childhood and had attained AH. Two-year, randomized, double-blind, placebo-controlled crossover study with stratification for gender and body mass index in 27 young adults with PWS. PWS Reference Center in The Netherlands. Crossover intervention with GH (0.67 mg/m 2 · d) and placebo, both during 1 year. Body composition, measured by dual-energy x-ray absorptiometry. During placebo, FM increased (relative change +21.5%; P < .001). Compared with placebo, GH treatment resulted in lower FM (-2.9 kg; P = .004) and higher LBM (+1.5 kg; P = .005), representing relative changes of -17.3% FM and +3.5% LBM. Both limb and trunk FM percentage were lower during GH versus placebo (relative change +17.3% and +15.6%; P < .001 and P = .007, respectively). No GH-related adverse events occurred. GH-treated young adults with PWS who have attained AH benefit from continuation of GH treatment. FM increases during placebo, whereas GH versus placebo results in lower FM and higher LBM. Thus, GH treatment maintains the improved body composition without safety concerns.

Effects of Lignocaine Administered Intravenously or Intratracheally on Airway and Hemodynamic Responses during Emergence and Extubation in Patients Undergoing Elective Craniotomies in Supine Position.

PubMed

Shabnum, Tabasum; Ali, Zulfiqar; Naqash, Imtiaz Ahmad; Mir, Aabid Hussain; Azhar, Khan; Zahoor, Syed Amer; Mir, Abdul Waheed

2017-01-01

Sympathoadrenergic responses during emergence and extubation can lead to an increase in heart rate (HR) and blood pressure whereas increased airway responses may lead to coughing and laryngospasm. The aim of our study was to compare the effects of lignocaine administered intravenously (IV) or intratracheally on airway and hemodynamic responses during emergence and extubation in patients undergoing elective craniotomies. Sixty patients with physical status American Society of Anaesthesiologists Classes I and II aged 18-70 years, scheduled to undergo elective craniotomies were included. The patients were randomly divided into three groups of twenty patients; Group 1 receiving IV lignocaine and intratracheal placebo (IV group), Group 2 receiving intratracheal lignocaine and IV placebo (I/T group), and Group 3 receiving IV and intratracheal placebo (placebo group). The tolerance to the endotracheal tube was monitored, and number of episodes of cough was recorded during emergence and at the time of extubation. Hemodynamic parameters such as HR and blood pressure (systolic, diastolic, mean arterial pressure) were also recorded. There was a decrease of HR in both IV and intratracheal groups in comparison with placebo group ( P < 0.005). Rise in blood pressure (systolic blood pressure, diastolic blood pressure and mean arterial pressure) was comparable in both Groups 1 and 2 but was lower in comparison with placebo group ( P < 0.005). Cough suppression was comparable in all the three groups. Grade III cough (15%) was documented only in placebo group. Both IV and intratracheal lignocaine are effective in attenuation of hemodynamic response if given within 20 min from skull pin removal to extubation. There was comparable cough suppression through intratracheal route and IV routes than the placebo group.

Randomised controlled trial of homoeopathy versus placebo in perennial allergic rhinitis with overview of four trial series

PubMed Central

Taylor, Morag A; Reilly, David; Llewellyn-Jones, Robert H; McSharry, Charles; Aitchison, Tom C

2000-01-01

Objective To test the hypothesis that homoeopathy is a placebo by examining its effect in patients with allergic rhinitis and so contest the evidence from three previous trials in this series. Design Randomised, double blind, placebo controlled, parallel group, multicentre study. Setting Four general practices and a hospital ear, nose, and throat outpatient department. Participants 51 patients with perennial allergic rhinitis. Intervention Random assignment to an oral 30c homoeopathic preparation of principal inhalant allergen or to placebo. Main outcome measures Changes from baseline in nasal inspiratory peak flow and symptom visual analogue scale score over third and fourth weeks after randomisation. Results Fifty patients completed the study. The homoeopathy group had a significant objective improvement in nasal airflow compared with the placebo group (mean difference 19.8 l/min, 95% confidence interval 10.4 to 29.1, P=0.0001). Both groups reported improvement in symptoms, with patients taking homoeopathy reporting more improvement in all but one of the centres, which had more patients with aggravations. On average no significant difference between the groups was seen on visual analogue scale scores. Initial aggravations of rhinitis symptoms were more common with homoeopathy than placebo (7 (30%) v 2 (7%), P=0.04). Addition of these results to those of three previous trials (n=253) showed a mean symptom reduction on visual analogue scores of 28% (10.9 mm) for homoeopathy compared with 3% (1.1 mm) for placebo (95% confidence interval 4.2 to 15.4, P=0.0007). Conclusion The objective results reinforce earlier evidence that homoeopathic dilutions differ from placebo. PMID:10948025

The placebo effect in sports performance: a brief review.

PubMed

Beedie, Christopher J; Foad, Abigail J

2009-01-01

The placebo effect, with its central role in clinical trials, is acknowledged as a factor in sports medicine, although until recently little has been known about the likely magnitude and extent of the effect in any specific research setting. Even less is known about the prevalence of the effect in competitive sport. The present paper reviews 12 intervention studies in sports performance. All examine placebo effects associated with the administration of an inert substance believed by subjects to be an ergogenic aid. Placebo effects of varying magnitudes are reported in studies addressing sports from weightlifting to endurance cycling. Findings suggest that psychological variables such as motivation, expectancy and conditioning, and the interaction of these variables with physiological variables, might be significant factors in driving both positive and negative outcomes. Programmatic research involving the triangulation of data, and investigation of contextual and personality factors in the mediation of placebo responses may help to advance knowledge in this area.

Minoxidil 2% lotion for eyebrow enhancement: a randomized, double-blind, placebo-controlled, spilt-face comparative study.

PubMed

Lee, Saridpong; Tanglertsampan, Chuchai; Tanchotikul, Mingkwan; Worapunpong, Nigun

2014-02-01

Topical minoxidil has been successfully used to treat androgenetic alopecia. It can also be applied to enhance eyebrows. However, there is no study comparing minoxidil lotion with placebo for eyebrow enhancement. In this trial, we determined the efficacy and safety of minoxidil 2% lotion for eyebrow enhancement compared with placebo. Forty patients were randomized for minoxidil on the eyebrow on one side of the face and placebo on the other. Efficacy was evaluated by global photographic assessment, eyebrow diameter, eyebrow count and subject's satisfaction. Side-effects were also evaluated. Thirty-nine patients (97.5%) completed the study. After 16 weeks, the minoxidil group achieved significantly better results in all measured outcomes compared to the placebo group. Side-effects were minor and did not preclude patients from continuing the study. Our study suggests that minoxidil 2% lotion is a safe and effective treatment for eyebrow hypotrichosis. © 2014 Japanese Dermatological Association.

Accounting for perception, placebo and unmasking effects in estimating treatment effects in randomised clinical trials.

PubMed

Jamshidian, Farid; Hubbard, Alan E; Jewell, Nicholas P

2014-06-01

There is a rich literature on the role of placebos in experimental design and evaluation of therapeutic agents or interventions. The importance of masking participants, investigators and evaluators to treatment assignment (treatment or placebo) has long been stressed as a key feature of a successful trial design. Nevertheless, there is considerable variability in the technical definition of the placebo effect and the impact of treatment assignments being unmasked. We suggest a formal concept of a 'perception effect' and define unmasking and placebo effects in the context of randomised trials. We employ modern tools from causal inference to derive semi-parametric estimators of such effects. The methods are illustrated on a motivating example from a recent pain trial where the occurrence of treatment-related side effects acts as a proxy for unmasking. © The Author(s) 2011 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

[Critical of the additive model of the randomized controlled trial].

PubMed

Boussageon, Rémy; Gueyffier, François; Bejan-Angoulvant, Theodora; Felden-Dominiak, Géraldine

2008-01-01

Randomized, double-blind, placebo-controlled clinical trials are currently the best way to demonstrate the clinical effectiveness of drugs. Its methodology relies on the method of difference (John Stuart Mill), through which the observed difference between two groups (drug vs placebo) can be attributed to the pharmacological effect of the drug being tested. However, this additive model can be questioned in the event of statistical interactions between the pharmacological and the placebo effects. Evidence in different domains has shown that the placebo effect can influence the effect of the active principle. This article evaluates the methodological, clinical and epistemological consequences of this phenomenon. Topics treated include extrapolating results, accounting for heterogeneous results, demonstrating the existence of several factors in the placebo effect, the necessity to take these factors into account for given symptoms or pathologies, as well as the problem of the "specific" effect.

The use of Lactobacillus GG in irritable bowel syndrome in children: a double-blind randomized control trial.

PubMed

Bauserman, Melissa; Bausserman, Melissa; Michail, Sonia

2005-08-01

To determine whether oral administration of the probiotic Lactobacillus GG under randomized, double-blinded, placebo-controlled conditions would improve symptoms of irritable bowel syndrome (IBS) in children. Fifty children fulfilling the Rome II criteria for IBS were given Lactobacillus GG or placebo for 6 weeks. Response to therapy was recorded and collected on a weekly basis using the Gastrointestinal Symptom Rating Scale (GSRS). Lactobacillus GG was not superior to placebo in relieving abdominal pain (40.0% response rate in the placebo group vs 44.0% in the Lactobacillus GG group; P=.774). There was no difference in the other gastrointestinal symptoms, except for a lower incidence of perceived abdominal distention (P=.02 favoring Lactobacillus GG). Lactobacillus GG was not superior to placebo in the treatment of abdominal pain in children with IBS but may help relieve such symptoms as perceived abdominal distention.

Placebo neural systems: nitric oxide, morphine and the dopamine brain reward and motivation circuitries.

PubMed

Fricchione, Gregory; Stefano, George B

2005-05-01

Evidence suggests that the placebo response is related to the tonic effects of constitutive nitric oxide in neural, vascular and immune tissues. Constitutive nitric oxide levels play a role in the modulation of dopamine outflow in the nigrostriatal movement and the mesolimbic and mesocortical reward and motivation circuitries. Endogenous morphine, which stimulates constitutive nitric oxide, may be an important signal molecule working at mu receptors on gamma aminobutyric acid B interneurons to disinhibit nigral and tegmental dopamine output. We surmise that placebo induced belief will activate the prefrontal cortex with downstream stimulatory effects on these dopamine systems as well as on periaqueductal grey opioid output neurons. Placebo responses in Parkinson's disease, depression and pain disorder may result. In addition, mesolimbic/mesocortical control of the stress response systems may provide a way for the placebo response to benefit other medical conditions.

Comparative gastrointestinal blood loss associated with placebo, aspirin, and nabumetone as assessed by radiochromium (/sup 51/Cr)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lussier, A.; Davis, A.; Lussier, Y.

Nabumetone differs from most other nonsteroidal anti-inflammatory drugs. It is presented to the gut as a nonacidic prodrug, and is metabolized to its active form after absorption. Studies in animals and humans suggest it is less irritating to the gastrointestinal mucosa. This study compared the gastrointestinal microbleeding induced by nabumetone to aspirin (acetylsalicylic acid, ASA), and placebo in a double blind parallel study using chromium /sup 51/Cr labelled red cells to quantitate fecal blood loss (FBL) in healthy volunteers. Thirty subjects were randomized to treatment with nabumetone (2000 mg), ASA (3.6 g) or placebo for 21 days following a 7more » day placebo period. Six subjects served as untreated controls. FBL in nabumetone treated subjects was not significantly different to placebo or untreated subjects. In contrast, ASA-treated subjects exhibited significantly increased FBL than the other 3 groups (P less than .0001).« less

SA17. Response to Treatment With Valbenazine (NBI-98854) in Subjects With Tardive Dyskinesia

PubMed Central

Kane, John; Josiassen, Richard; Burke, Joshua; Jimenez, Roland; Siegert, Scott; Liang, Grace

2017-01-01

Abstract Background: Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder resulting from exposure to dopamine receptor-blocking agents (DRBAs), such as antipsychotics. Valbenazine is a novel and highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor that is being evaluated for the treatment of TD and other movement disorders. Clinical studies include a Phase 3 trial of valbenazine in adults who had TD and underlying schizophrenia/schizoaffective disorder or mood disorder (KINECT 3; NCT02274558). The primary end point of this trial was met as demonstrated by a significant difference between valbenazine 80 mg/day and placebo for the Abnormal Involuntary Movement Scale (AIMS) dyskinesia total score (Items 1–7) change from baseline. Additional analyses of AIMS data from this trial were conducted to assess treatment response in subjects with TD. Methods: In this 6-week, double-blind, placebo-controlled trial, subjects were randomized 1:1:1 to once-daily treatment with valbenazine 80 mg, valbenazine 40 mg, or placebo. Treatment response was defined as ≥50% reduction in the AIMS total score. AIMS responders were analyzed by study visit (Weeks 2, 4, and 6) in the intent-to-treat (ITT) population and in subgroups categorized by underlying psychiatric diagnosis (schizophrenia/schizoaffective disorder or mood disorder). Numbers needed to treat (NNTs) were calculated for AIMS responders (valbenazine vs placebo) at Week 6. Significance testing was not conducted in the subgroups. Results: At Week 6 in the ITT population (N = 225), AIMS responder rates were significantly higher with valbenazine than with placebo: 80 mg, 40.0% (P < .0001; NNT = 4); 40 mg, 23.8% (P = .0200; NNT=7); placebo, 8.7%. Treatment with valbenazine 80 mg versus placebo also resulted in significantly higher responder rates at Week 2 (23.4% vs 5.3%, P = .0016) and Week 4 (28.8% vs 9.7%, P = 0.0039). Subjects treated with valbenazine 40 mg also had higher response rates at Week 2 (14.3% vs 5.3%) and Week 4 (15.6% vs 9.7%) relative to placebo-treated subjects, but the differences were not statistically significant. In subjects with schizophrenia/schizoaffective disorder (n = 148) or mood disorder (n = 77), AIMS responder rates were higher with valbenazine than placebo at all study visits. The highest responder rates were found at Week 6 and similar in the schizophrenia subgroup (80 mg, 40.9%, NNT = 4; 40 mg, 26.2%, NNT = 6; placebo, 9.3%) and mood subgroup (80 mg, 38.5%, NNT = 4; 40 mg, 19.0%, NNT=9; placebo, 7.7%). Conclusion: These study results, based on a rigorous definition of treatment response, indicate that substantial TD improvements occurred more frequently with valbenazine than placebo in adults diagnosed with schizophrenia/schizoaffective disorder or mood disorder. A significant difference between the 80-mg dose and placebo for the AIMS response was observed as early as 2 weeks of treatment.

Risperidone Improves Behavioral Symptoms in Children with Autism in a Randomized, Double-Blind, Placebo-Controlled Trial

ERIC Educational Resources Information Center

Pandina, Gahan J.; Bossie, Cynthia A.; Youssef, Eriene; Zhu, Young; Dunbar, Fiona

2007-01-01

Subgroup analysis of children (5-12 years) with autism enrolled in an 8-week, double-blind, placebo-controlled trial of risperidone for pervasive developmental disorders. The primary efficacy measure was the Aberrant Behavior Checklist-Irritability (ABC-I) subscale. Data were available for 55 children given risperidone (n = 27) or placebo (n =…

Does EEG-Neurofeedback Improve Neurocognitive Functioning in Children with Attention-Deficit/Hyperactivity Disorder? A Systematic Review and a Double-Blind Placebo-Controlled Study

ERIC Educational Resources Information Center

Vollebregt, Madelon A.; van Dongen-Boomsma, Martine; Buitelaar, Jan K.; Slaats-Willemse, Dorine

2014-01-01

Background: The number of placebo-controlled randomized studies relating to EEG-neurofeedback and its effect on neurocognition in attention-deficient/hyperactivity disorder (ADHD) is limited. For this reason, a double blind, randomized, placebo-controlled study was designed to assess the effects of EEG-neurofeedback on neurocognitive functioning…

Safety and Efficacy of ABT-089 in Pediatric Attention-Deficit/Hyperactivity Disorder: Results from Two Randomized Placebo-Controlled Clinical Trials

ERIC Educational Resources Information Center

Wilens, Timothy E.; Gault, Laura M.; Childress, Ann; Kratochvil, Christopher J.; Bensman, Lindsey; Hall, Coleen M.; Olson, Evelyn; Robieson, Weining Z.; Garimella, Tushar S.; Abi-Saab, Walid M.; Apostol, George; Saltarelli, Mario D.

2011-01-01

Objective: To assess the safety and efficacy of ABT-089, a novel alpha[subscript 4]beta[subscript 2] neuronal nicotinic receptor partial agonist, vs. placebo in children with attention-deficit/hyperactivity disorder (ADHD). Method: Two multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of children 6 through 12 years…

Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance

DTIC Science & Technology

2010-09-30

a novel hypocretiniorexin antagonist, almorexant (ALM), to a standard hypnotic , zolpidem (ZOL), and placebo (PBO) on neurocognitive performance at...Placebo-Controlled, Randomized, Parallel- Group Study Comparing the Effect of a Novel HypocretiniOrexin Antagonist (Almorexant) Versus a Standard Hypnotic ...Group Study Comparing the Effect of a Novel HypocretiniOrexin Antagonist (Almorexant) Versus a Standard Hypnotic (Zolpidem) and Placebo on

Experimental motion sickness - Efficacy of transdermal scopolamine plus ephedrine

NASA Technical Reports Server (NTRS)

Graybiel, A.; Cramer, D. B.; Wood, C. D.

1981-01-01

A double-blind, placebo-controlled study compared the efficacy of transdermal therapeutic system-scopolamine administered alone and combined with ephedrine sulfate given orally in doses of 12.5, 25, and 50 mg. Eight normal male students were exposed to stressful accelerations in a slow-rotation room after receiving 10 apparently identical treatments comprising the four drugs and six placebos. Efficacy of the drug was defined in terms of the placebo range and categorized as beneficial, inconsequential, or detrimental. None of the effects was detrimental. Overall beneficial effects were 60% for transdermal therapeutic system-scopolamine (plus placebo) and 57% for the three transdermal therapeutic system-scopolamine plus ephedrine combinations.

Placebo Mechanisms of Manual Therapy: A Sheep in Wolf's Clothing?

PubMed

Bialosky, Joel E; Bishop, Mark D; Penza, Charles W

2017-05-01

When a physical therapist provides a manual therapy (MT) intervention for a patient presenting with pain and the patient experiences a positive clinical outcome, we cannot answer as to why this occurs. Would we continue to devote valuable time and financial resources to learning and improving our skills in providing MT interventions if the related clinical outcomes were placebo responses? In this Viewpoint, the authors conceptualize placebo as an active and important mechanism of MT and argue that placebo mechanisms deserve consideration as an important component of the treatment effect. J Orthop Sports Phys Ther 2017;47(5):301-304. doi:10.2519/jospt.2017.0604.

Eradication of early P. aeruginosa infection in children <7 years of age with cystic fibrosis: The early study.

PubMed

Ratjen, Felix; Moeller, Alexander; McKinney, Martha L; Asherova, Irina; Alon, Nipa; Maykut, Robert; Angyalosi, Gerhild

2018-04-20

Antibiotic eradication treatment is the standard-of-care for cystic fibrosis (CF) patients with early Pseudomonas aeruginosa (Pa)-infection; however, evidence from placebo-controlled trials is limited. This double-blind, placebo-controlled trial randomised CF patients <7 years (N = 51) with early Pa-infection to tobramycin inhalation solution (TOBI 300 mg) or placebo (twice daily) for 28 days with an optional cross-over on Day 35. Primary endpoint was proportion of patients having throat swabs/sputum free of Pa on Day 29. On Day 29, 84.6% patients in the TOBI versus 24.0% in the placebo group were Pa-free (p < 0.001). At the end of the cross-over period, 76.0% patients receiving TOBI in the initial 28 days were Pa-free compared to 47.8% receiving placebo initially. Adverse events were consistent with the TOBI safety profile with no differences between TOBI and placebo. TOBI was effective in eradicating early Pa-infection with a favourable safety profile in young CF patients. NCT01082367. Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Improving depression and enhancing resilience in family dementia caregivers: a pilot randomized placebo-controlled trial of escitalopram.

PubMed

Lavretsky, Helen; Siddarth, Prabha; Irwin, Michael R

2010-02-01

This study examined the potential of an antidepressant drug, escitalopram, to improve depression, resilience to stress, and quality of life in family dementia caregivers in a randomized placebo-controlled double-blinded trial. Forty family caregivers (43-91 years of age, 25 children and 15 spouses; 26 women) who were taking care of their relatives with Alzheimer disease were randomized to receive either escitalopram 10 mg/day or placebo for 12 weeks. Severity of depression, resilience, burden, distress, quality of life, and severity of care-recipient's cognitive and behavioral disturbances were assessed at baseline and over the course of the study. The Hamilton Depression Rating Scale scores at baseline ranged between 10 and 28. The groups were stratified by the diagnosis of major and minor depression. Most outcomes favored escitalopram over placebo. The severity of depression improved, and the remission rate was greater with the drug compared with placebo. Measures of anxiety, resilience, burden, and distress improved on escitalopram compared with placebo. Among caregivers, this small randomized controlled trial found that escitalopram use resulted in improvement in depression, resilience, burden and distress, and quality of life. Our results need to be confirmed in a larger sample.

[Long-term effect of policosanol on the functional recovery of non-cardioembolic ischemic stroke patients: a one year study].

PubMed

Sanchez, J; Illnait, J; Mas, R; Mendoza, S; Fernandez, L; Mesa, M; Vega, H; Fernandez, J; Reyes, P; Ruiz, D

2017-02-16

Stroke is a leading cause of mortality and disability. Policosanol has been effective in brain ischemia models. The aim of this study is to investigate whether policosanol, added to aspirin therapy within 30 days of stroke onset, is better than placebo + aspirine for the long-term recovery of non-cardioembolic ischemic stroke subjects. Randomized, double-blind, placebo-controlled study. Eighty patients (mean age: 69 years) within 30 days of onset, with a modified Rankin Scale score (mRS) 2 to 4, were included. They were randomized in two groups (policosanol + aspirine or placebo + aspirine) for 12 months. Policosanol + aspirine decreased significantly mean mRS from the first interim check-up (1.5 months). The treatment even improved after long-term therapy. More policosanol + aspirin (87.5%) than placebo + aspirine (0%) patients achieved mRSs <= 1. Policosanol + aspirine increased significantly Barthel Index, lowered LDL-cholesterol and increased HDL-cholesterol versus placebo + aspirin. Long-term (12 months) administration of policosanol + aspirin given after suffering non-cardioembolic ischemic stroke was shown to be better than placebo + aspirin in improving functional outcomes when used among patients with non-cardioembolic ischemic stroke of moderate severity.

Effects of the NMDA antagonist memantine on human methamphetamine discrimination.

PubMed

Hart, Carl L; Haney, Margaret; Foltin, Richard W; Fischman, Marian W

2002-12-01

The discriminative stimulus effects of N-methyl- D-aspartate (NMDA) antagonists have been assessed in laboratory animals. To date, no published study has assessed their ability to alter methamphetamine-related discriminative stimulus effects in humans. This study investigated the discriminative stimulus, subjective (e.g. "Good Drug Effect"), psychomotor performance, and cardiovascular effects (e.g. blood pressure) of oral methamphetamine following acute oral memantine (a non-competitive NMDA antagonist) in humans. Initially, participants were trained to discriminate 10 mg methamphetamine from placebo using a standard two-response procedure (drug versus placebo). Then, the effects of memantine (0, 40 mg) on methamphetamine discrimination were examined across several methamphetamine doses (0, 5, 10, 20 mg) using a novel-response procedure (drug versus placebo versus novel). Following placebo pretreatment, 10 mg methamphetamine produced 99% methamphetamine-appropriate responding and placebo produced 75% placebo-appropriate responding. Following memantine pretreatment, participants responded as if they had been given a novel compound, although memantine did not significantly alter most subjective-effects ratings following methamphetamine. Memantine alone produced "positive" subjective effects and novel drug-appropriate responding. These data indicate that the memantine-methamphetamine combination produced novel discriminative stimulus effects and that memantine produced some stimulant-like subjective effects.

Placebo studies and ritual theory: a comparative analysis of Navajo, acupuncture and biomedical healing

PubMed Central

Kaptchuk, Ted J.

2011-01-01

Using a comparative analysis of Navajo healing ceremonials, acupuncture and biomedical treatment, this essay examines placebo studies and ritual theory as mutually interpenetrating disciplines. Healing rituals create a receptive person susceptible to the influences of authoritative culturally sanctioned ‘powers’. The healer provides the sufferer with imaginative, emotional, sensory, moral and aesthetic input derived from the palpable symbols and procedures of the ritual process—in the process fusing the sufferer's idiosyncratic narrative unto a universal cultural mythos. Healing rituals involve a drama of evocation, enactment, embodiment and evaluation in a charged atmosphere of hope and uncertainty. Experimental research into placebo effects demonstrates that routine biomedical pharmacological and procedural interventions contain significant ritual dimensions. This research also suggests that ritual healing not only represents changes in affect, self-awareness and self-appraisal of behavioural capacities, but involves modulations of symptoms through neurobiological mechanisms. Recent scientific investigations into placebo acupuncture suggest several ways that observations from ritual studies can be verified experimentally. Placebo effects are often described as ‘non-specific’; the analysis presented here suggests that placebo effects are the ‘specific’ effects of healing rituals. PMID:21576142

An exploration of the relationship between placebo and homeopathy and the implications for clinical trial design

PubMed Central

Haresnape, Claire

2013-01-01

Placebo appears to be a real neurobiological phenomenon that has evolved through the selection pressure to be able to heal ourselves. The complex language and social structures of humans means that we can attribute meaning to therapeutic encounters with culturally sanctioned authority figures and we can use our attachment to such figures to generate hope for recovery. Different mechanisms may be involved in the neurobiological aspect of placebo including anxiety, learning, conditioning as well as individual genetic variation. Examination of the published work shows that while some trials do seem to indicate a specific mode of action for homeopathic remedies other trials do not and this is an issue that needs to be addressed at the trial design stage. A clinical trial that includes both a placebo group and a non-participating control arm is the most powerful design for separating the non-specific and polymorphic placebo effect from the specific effects of trial medication. The control variables in a trial of homeopathic medication should also include the process of consultation as this may assume a meaning for the individual that can also be associated with a placebo effect. PMID:24040505

Green Tea, Intermittent Sprinting Exercise, and Fat Oxidation

PubMed Central

Gahreman, Daniel; Wang, Rose; Boutcher, Yati; Boutcher, Stephen

2015-01-01

Fat oxidation has been shown to increase after short term green tea extract (GTE) ingestion and after one bout of intermittent sprinting exercise (ISE). Whether combining the two will result in greater fat oxidation after ISE is undetermined. The aim of the current study was to investigate the combined effect of short term GTE and a single session of ISE upon post-exercise fat oxidation. Fourteen women consumed three GTE or placebo capsules the day before and one capsule 90 min before a 20-min ISE cycling protocol followed by 1 h of resting recovery. Fat oxidation was calculated using indirect calorimetry. There was a significant increase in fat oxidation post-exercise compared to at rest in the placebo condition (p < 0.01). After GTE ingestion, however, at rest and post-exercise, fat oxidation was significantly greater (p < 0.05) than that after placebo. Plasma glycerol levels at rest and 15 min during post-exercise were significantly higher (p < 0.05) after GTE consumption compared to placebo. Compared to placebo, plasma catecholamines increased significantly after GTE consumption and 20 min after ISE (p < 0.05). Acute GTE ingestion significantly increased fat oxidation under resting and post-exercise conditions when compared to placebo. PMID:26184298

Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial.

PubMed

Koren, Gideon; Clark, Shannon; Hankins, Gary D V; Caritis, Steve N; Miodovnik, Menachem; Umans, Jason G; Mattison, Donald R

2010-12-01

To evaluate the effectiveness of Diclectin (doxylamine succinate 10 mg-pyridoxine hydrochloride 10 mg, delayed-release preparation) as compared with placebo for nausea and vomiting of pregnancy. A randomized, double-blind, multicenter placebo controlled trial studying pregnant women suffering from nausea and vomiting of pregnancy, analyzed by intention to treat. Women received Diclectin (n = 131) or placebo (n = 125) for 14 days. Nausea and vomiting of pregnancy symptoms were evaluated daily using the pregnancy unique quantification of emesis scale. Diclectin use resulted in a significantly larger improvement in symptoms of nausea and vomiting of pregnancy compared with placebo based on both the pregnancy unique quantification of emesis score (-4.8 ± 2.7 vs -3.9 ± 2.6; P = .006) and quality of life. After the trial, 64 (48.9%) women receiving Diclectin asked to continue compassionate use of their medication, as compared with 41 (32.8%) of placebo-treated women (P = .009). Diclectin delayed release formulation of doxylamine succinate and pyridoxine hydrochloride is effective and well tolerated in treating nausea and vomiting of pregnancy. Copyright © 2010 Mosby, Inc. All rights reserved.

A comparison of placebo response with major depressive disorder in patients recruited through newspaper advertising versus consultation referrals.

PubMed

Miller, C A; Hooper, C L; Bakish, D

1997-01-01

Recent evidence indicates few differences between patients recruited through advertising and by consultation referral, and there is some suggestion that those recruited through advertising are more representative of the target community population. However little has been reported on differences in placebo response and compliance in these two patient groups. We conducted a retrospective chart review of 49 patients with major depressive disorder (MDD), recruited through advertising or consultation, randomized to placebo in five clinical trials. Variables included demographics, clinical history, efficacy, compliance, and completion data. Homogeneity was demonstrated for most variables. Differences in placebo groups included significantly lower Hamilton Rating Scale for Depression (HAM-D) scores for the advertisement group throughout the trials. Advertisement patients were also more likely to be early placebo responders and in remission at Days 14 and 28. No differences were found in completion rates or reasons for early termination. Compliance was excellent for both groups. Early placebo response of the advertisement group reinforces the need for trials of at least 8 weeks. In addition, consultation patients may have a more severe illness and be treatment resistant, suggesting they are less generalizable to community practice populations.

Fingolimod (FTY-720) is Capable of Reversing Tumor Necrosis Factor Induced Decreases in Cochlear Blood Flow.

PubMed

Bertlich, Mattis; Ihler, Friedrich; Weiss, Bernhard G; Freytag, Saskia; Jakob, Mark; Strupp, Michael; Pellkofer, Hannah; Canis, Martin

2017-09-01

The potential of Fingolimod (FTY-720), a sphingosine-1-phosphate analogue, to revoke the changes in cochlear blood flow induced by tumor necrosis factor (TNF) was investigated. Impairment of cochlear blood flow has often been considered as the common final pathway of various inner ear pathologies. TNF, an ubiquitous cytokine, plays a major role in these pathologies, reducing cochlear blood flow via sphingosine-1-phosphate-signaling. Fifteen Dunkin-Hartley guinea pigs were randomly assigned to one of three groups (placebo/placebo, TNF/placebo, TNF/FTY-720). Cochlear microcirculation was quantified over 60 minutes by in vivo fluorescence microscopy before and after topical application of placebo or TNF (5 ng/ml) and after subsequent application of placebo or FTY-720 (200 μg/ml). Treatment with TNF led to a significant decrease of cochlear blood flow.Following this, application of placebo caused no significant changes while application of FTY-720 caused a significant rise in cochlear blood flow. FTY-720 is capable of reversing changes in cochlear blood flow induced by application of TNF. This makes FTY-720 a valid candidate for potential treatment of numerous inner ear pathologies.

Efficacy of Trimetazidine Dihydrochloride for Relieving Chronic Tinnitus: A Randomized Double-Blind Study

PubMed Central

Kumral, Tolgar Lütfi; Yıldırım, Güven; Berkiten, Güler; Saltürk, Ziya; Ataç, Enes; Atar, Yavuz; Uyar, Yavuz

2016-01-01

Objectives. To evaluate the efficacy of trimetazidine dihydrochloride as a treatment for chronic tinnitus. Methods. A total of 97 chronic tinnitus patients were evaluated in this randomized, prospective, double-blind, placebo-controlled trial. After assessing for eligibility, 82 patients were randomly assigned into placebo or trimetazidine groups according to the medication. The trimetazidine group received 20×3 mg/day per oral trimetazidine dihydrochloride and the placebo group received 20×3 mg/day per oral placebo for 3 months. Tinnitus handicap inventory (THI), visual analogue scale (VAS) questionnaires and audiometric results were used to determine the effectiveness of trimetazidine treatment. Results. The study group comprised 82 tinnitus subjects, 42 (51%) of whom received trimetazidine dihydrochloride and 40 (49%) who received placebo. There was no significant difference between placebo and trimetazidine groups in THI grade and VAS (both pre- and posttreatment scores) (P>0.05) and no significant improvement was observed in subjective loudness score in either group (P>0.05). Additionally there was no significant difference between groups in pre- and posttreatment pure tone hearing thresholds at all measured frequencies (P>0.05). Conclusion. Trimetazidine dihydrochloride therapy was ineffective for relieving chronic tinnitus. PMID:27230273

Long-term safety and tolerability of saxagliptin add-on therapy in older patients (aged ≥65 years) with type 2 diabetes

PubMed Central

Iqbal, Nayyar; Allen, Elsie; Öhman, Peter

2014-01-01

Background Treatment decisions for older patients with type 2 diabetes mellitus must balance glycemic control and adverse event risk. The objective of this study was to evaluate the long-term safety and tolerability of saxagliptin 5 mg as add-on therapy to common antihyperglycemic drugs in patients aged ≥65 years and <65 years. Methods Pooled adverse event data from three placebo-controlled trials of 76–206 weeks’ duration in older (≥65 years) and younger (<65 years) patients receiving saxagliptin 5 mg or matching placebo added to metformin, glyburide, or a thiazolidinedione were analyzed. Measurements were calculated from day of first dose to specified event or last dose and included time at risk for adverse events, treatment-related adverse events, serious adverse events, adverse events leading to discontinuation, and events of special interest. Weighted incidence rates (number of events/total time) and incidence rate ratios (saxagliptin/placebo) with 95% confidence intervals were calculated (Mantel-Haenszel test). Results A total of 205 older (mean age 69 years; saxagliptin, n=99; placebo, n=106) and 1,055 younger (mean age 52 years; saxagliptin, n=531; placebo, n=524) patients were assessed. Regardless of age category, the adverse event incidence rates were generally similar between treatments, with confidence intervals for incidence rate ratios bridging 1. Treatment-related adverse events occurred in 36 older patients receiving saxagliptin versus 32 receiving placebo (incidence rate 34.1 versus 27.1 per 100 person-years) and in 150 younger patients in both treatment groups (incidence rate 24.0 versus 27.8 per 100 person-years). With saxagliptin versus placebo, serious adverse events occurred in eight versus 14 older (incidence rate 5.7 versus 9.9 per 100 person-years) and 49 versus 44 younger patients (incidence rate 6.5 versus 6.6 per 100 person-years). There were two deaths (one patient ≥65 years) with saxagliptin and six (none aged ≥65 years) with placebo. Older patients rarely experienced symptomatic confirmed hypoglycemia (fingerstick glucose ≤50 mg/dL; saxagliptin, n=1; placebo, n=2). Conclusion Saxagliptin add-on therapy was generally well tolerated in older patients aged ≥65 years with type 2 diabetes mellitus, with a long-term safety profile similar to that of placebo. PMID:25214775

Long-term safety and tolerability of saxagliptin add-on therapy in older patients (aged ≥ 65 years) with type 2 diabetes.

PubMed

Iqbal, Nayyar; Allen, Elsie; Öhman, Peter

2014-01-01

Treatment decisions for older patients with type 2 diabetes mellitus must balance glycemic control and adverse event risk. The objective of this study was to evaluate the long-term safety and tolerability of saxagliptin 5 mg as add-on therapy to common antihyperglycemic drugs in patients aged ≥ 65 years and <65 years. Pooled adverse event data from three placebo-controlled trials of 76-206 weeks' duration in older (≥ 65 years) and younger (<65 years) patients receiving saxagliptin 5 mg or matching placebo added to metformin, glyburide, or a thiazolidinedione were analyzed. Measurements were calculated from day of first dose to specified event or last dose and included time at risk for adverse events, treatment-related adverse events, serious adverse events, adverse events leading to discontinuation, and events of special interest. Weighted incidence rates (number of events/total time) and incidence rate ratios (saxagliptin/placebo) with 95% confidence intervals were calculated (Mantel-Haenszel test). A total of 205 older (mean age 69 years; saxagliptin, n=99; placebo, n=106) and 1,055 younger (mean age 52 years; saxagliptin, n=531; placebo, n=524) patients were assessed. Regardless of age category, the adverse event incidence rates were generally similar between treatments, with confidence intervals for incidence rate ratios bridging 1. Treatment-related adverse events occurred in 36 older patients receiving saxagliptin versus 32 receiving placebo (incidence rate 34.1 versus 27.1 per 100 person-years) and in 150 younger patients in both treatment groups (incidence rate 24.0 versus 27.8 per 100 person-years). With saxagliptin versus placebo, serious adverse events occurred in eight versus 14 older (incidence rate 5.7 versus 9.9 per 100 person-years) and 49 versus 44 younger patients (incidence rate 6.5 versus 6.6 per 100 person-years). There were two deaths (one patient ≥ 65 years) with saxagliptin and six (none aged ≥ 65 years) with placebo. Older patients rarely experienced symptomatic confirmed hypoglycemia (fingerstick glucose ≤ 50 mg/dL; saxagliptin, n=1; placebo, n=2). Saxagliptin add-on therapy was generally well tolerated in older patients aged ≥ 65 years with type 2 diabetes mellitus, with a long-term safety profile similar to that of placebo.

Efficacy and Safety of SSRIs, SNRIs, and Placebo in Common Psychiatric Disorders: A Comprehensive Meta-Analysis in Children and Adolescents

PubMed Central

Locher, Cosima; Koechlin, Helen; Zion, Sean R; Werner, Christoph; Pine, Daniel S.; Kirsch, Irving; Kessler, Ronald C.; Kossowsky, Joe

2017-01-01

Importance Depressive disorders (DD), anxiety disorders (AD), obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD) are common mental disorders in children and adolescents. Objective To examine the relative efficacy and safety of SSRIs, SNRIs and placebo for the treatment of DD, AD, OCD, and PTSD in children and adolescents. Data Sources PubMed, Embase, PsycINFO, Web of Science, and Cochrane through August 2016. Study Selection Published and unpublished randomized, double-blind, placebo-controlled studies of SSRIs or SNRIs in youths diagnosed with DD, AD, OCD, or PTSD were included. Trials using other antidepressants (e.g. tricyclic antidepressants, MAOIs) were excluded. Data Extraction and Synthesis Effect sizes, (ES) calculated as standardized mean differences (Hedges’g) and Risk Ratios (RR) for adverse events, were assessed in a random-effects model. Main Outcome(s) and Measure(s) Primary outcomes, as defined by authors on pre- and post-intervention data, mean change data, and side effect data, were extracted independently by multiple observers following PRISMA guidelines. Results We deemed 36 studies eligible, including 6778 participants; 17 studies for DD, 10 for AD, 8 for OCD and one for PTSD., SSRIs and SNRIs were significantly more effective compared to placebo, yielding a small effect size (g=0.32, p<.001). AD (g=0.56, p<.001) showed significantly larger between-group ES than DD (g=0.20, p<.001). This difference was driven primarily by the placebo response: patients with DD exhibited significantly larger placebo responses (g=1.57, p<.001) compared to those with AD (g=1.03, p<.001). Of note is the relatively large effect size for SSRIs for anxiety disorders g=0.71, p<.001. Compared to placebo, patients taking an antidepressant reported significantly more treatment emergent adverse events (RR=1.07, p=.001 or RR=1.49, p<.001, depending on the reporting method), serious adverse events (RR=1.76, p<.001) and study discontinuation due to side effects (RR=1.79, p<.001). Conclusion and Relevance SSRIs and SNRIs are more effective than placebo, however, the effect is small and disorder-specific, yielding a larger effect for AD than for other conditions. Response to placebo is large, especially in DD. Serious adverse events are significantly more common in SSRIs and SNRIs than placebo. PMID:28854296

Trial of Amitriptyline, Topiramate, and Placebo for Pediatric Migraine

PubMed Central

Powers, Scott W.; Coffey, Christopher S.; Chamberlin, Leigh A.; Ecklund, Dixie J.; Klingner, Elizabeth A.; Yankey, Jon W.; Korbee, Leslie L.; Porter, Linda L.; Hershey, Andrew D.

2016-01-01

BACKGROUND Which, medication, if any, to use to prevent the headache of pediatric migraine has not been established. METHODS We conducted a randomized, double-blind, placebo-controlled trial of amitriptyline (1 mg per kilogram of body weight per day), topiramate (2 mg per kilogram per day), and placebo in children and adolescents 8 to 17 years of age with migraine. Patients were randomly assigned in a 2:2:1 ratio to receive one of the medications or placebo. The primary outcome was a relative reduction of 50% or more in the number of headache days in the comparison of the 28-day baseline period with the last 28 days of a 24-week trial. Secondary outcomes were headache-related disability, headache days, number of trial completers, and serious adverse events that emerged during treatment. RESULTS A total of 361 patients underwent randomization, and 328 were included in the primary efficacy analysis (132 in the amitriptyline group, 130 in the topiramate group, and 66 in the placebo group). The trial was concluded early for futility after a planned interim analysis. There were no significant between-group differences in the primary outcome, which occurred in 52% of the patients in the amitriptyline group, 55% of those in the topiramate group, and 61% of those in the placebo group (amitriptyline vs. placebo, P = 0.26; topiramate vs. placebo, P = 0.48; amitriptyline vs. topiramate, P = 0.49). There were also no significant between-group differences in headache-related disability, headache days, or the percentage of patients who completed the 24-week treatment period. Patients who received amitriptyline or topiramate had higher rates of several adverse events than those receiving placebo, including fatigue (30% vs. 14%) and dry mouth (25% vs. 12%) in the amitriptyline group and paresthesia (31% vs. 8%) and weight loss (8% vs. 0%) in the topiramate group. Three patients in the amitriptyline group had serious adverse events of altered mood, and one patient in the topiramate group had a suicide attempt. CONCLUSIONS There were no significant differences in reduction in headache frequency or headache-related disability in childhood and adolescent migraine with amitriptyline, topiramate, or placebo over a period of 24 weeks. The active drugs were associated with higher rates of adverse events. (Funded by the National Institutes of Health; CHAMP ClinicalTrials.gov number, NCT01581281). PMID:27788026

Effects of early thyroxine treatment on development and growth at age 10.7 years: follow-up of a randomized placebo-controlled trial in children with Down's syndrome.

PubMed

Marchal, Jan Pieter; Maurice-Stam, Heleen; Ikelaar, Nadine A; Klouwer, Femke C C; Verhorstert, Kim W J; Witteveen, M Emma; Houtzager, Bregje A; Grootenhuis, Martha A; van Trotsenburg, A S Paul

2014-12-01

In 2-year-old children with Down's syndrome (DS), early T4 treatment was found to result in slightly better motor development and growth. This study sought to determine long-term effects of early T4 treatment on development and growth in children with DS with either an elevated or normal neonatal TSH concentration. Patients received a single follow-up visit 8.7 years after a randomized placebo-controlled trial (RCT) comparing T4 and placebo treatment during the first 2 years of life. Dutch Academic Hospital. All children who completed the RCT (N = 181, of 196 randomly assigned children) were invited for the follow-up study. A total of 123 participants enrolled, at a mean age of 10.7 years. T4 or placebo treatment from the neonatal period until 2 years. Primary: mental and motor development. Secondary: communication skills, fine-motor coordination, height, weight, and head circumference (HC). Outcomes were compared between T4- and placebo-treated children, and between treatment groups with either a normal (<5 mIU/L), or elevated (≥ 5 mIU/L) TSH concentration at original trial entry. Mental or motor development, communication skills, or fine-motor coordination did not differ between T4- (N = 64) and placebo-treated children (N = 59). T4-treated children had a larger HC (50.4 vs 49.8 cm, P = .04) and tended to be taller (133.2 vs 131.1 cm, P = .06). These differences were somewhat greater in children with TSH ≥ 5 mIU/L (HC: T4, 50.5 vs placebo, 49.7 cm; P = .01; height: T4, 133.8 vs placebo, 130.8 cm; P = .02), but were not found in children with TSH <5 mIU/L (HC: T4, 50.1 vs placebo, 50.0 cm; P = .75; height: T4, 132.1 vs placebo, 131.6 cm; P = .22). Early T4 treatment of children with DS does not seem to benefit mental or motor development later in life. However, the positive effect on growth is still measurable, especially in children with an elevated plasma TSH concentration in the neonatal period.

Does Long-Term Itraconazole Prophylaxis Result in In Vitro Azole Resistance in Mucosal Candida albicans Isolates from Persons with Advanced Human Immunodeficiency Virus Infection?

PubMed Central

Goldman, Mitchell; Cloud, Gretchen A.; Smedema, Melinda; LeMonte, Ann; Connolly, Patricia; McKinsey, David S.; Kauffman, Carol A.; Moskovitz, Bruce; Wheat, L. Joseph

2000-01-01

The effects of prolonged itraconazole exposure on the susceptibility of Candida albicans isolates to itraconazole and fluconazole have not been well characterized. A recent placebo-controlled study of long-term itraconazole antifungal prophylaxis in persons with advanced human immunodeficiency virus infection afforded the opportunity to address this question. Mucosal Candida sp. isolates were obtained from subjects who developed oropharyngeal or esophageal candidiasis, and in vitro susceptibilities of the last isolate obtained at removal from the study as a prophylaxis failure were compared in itraconazole and placebo recipients. More subjects in the placebo group (74 of 146 [51%]) than in the itraconazole group (51 of 149 [34%]) developed mucosal candidiasis (P = 0.004). A total of 112 isolates were recovered from 56 of the 74 (76%) subjects with mucosal candidiasis assigned to the placebo group, compared to 97 isolates from 45 of the 51 (88%) subjects in the itraconazole group. C. albicans accounted for 98% of isolates in the placebo group and 89% of isolates in the itraconazole group. The itraconazole MIC at which 50% of the isolates tested were inhibited (MIC50) for last-episode isolates from the itraconazole group was 0.125 μg/ml compared to 0.015 μg/ml for the placebo group subjects, P = 0.0001. The MIC50 of fluconazole for the last isolates from the itraconazole group was 1.5 μg/ml compared to 0.5 μg/ml for the placebo subjects (P = 0.005). A lower proportion of isolates recovered from subjects on itraconazole therapy were classified as susceptible to itraconazole (63%) compared to isolates from the placebo group (96%) (P = 0.001). Similarly, a lower proportion of C. albicans isolates from subjects on itraconazole therapy were susceptible to fluconazole (78%) compared to isolates from the placebo group (96%) (P = 0.01). Also, the proportion of isolates that were not fully susceptible to itraconazole or fluconazole was greater in patients assigned to the itraconazole group than the placebo group (itraconazole susceptibility, 37 and 4%, respectively (P = 0.001); fluconazole susceptibility, 23 and 4%, respectively (P = 0.01). In conclusion, long-term itraconazole prophylaxis in patients with AIDS is associated with reduction in susceptibility to itraconazole and cross-resistance to fluconazole. PMID:10817713

Multicenter, placebo-controlled trial of lorcaserin for weight management.

PubMed

Smith, Steven R; Weissman, Neil J; Anderson, Christen M; Sanchez, Matilde; Chuang, Emil; Stubbe, Scott; Bays, Harold; Shanahan, William R

2010-07-15

Lorcaserin is a selective serotonin 2C receptor agonist that could be useful in reducing body weight. In this double-blind clinical trial, we randomly assigned 3182 obese or overweight adults (mean body-mass index [the weight in kilograms divided by the square of the height in meters] of 36.2) to receive lorcaserin at a dose of 10 mg, or placebo, twice daily for 52 weeks. All patients also underwent diet and exercise counseling. At week 52, patients in the placebo group continued to receive placebo but patients in the lorcaserin group were randomly reassigned to receive either placebo or lorcaserin. Primary outcomes were weight loss at 1 year and maintenance of weight loss at 2 years. Serial echocardiography was used to identify patients in whom valvulopathy (as defined by the Food and Drug Administration) developed. At 1 year, 55.4% of patients (883 of 1595) receiving lorcaserin and 45.1% of patients (716 of 1587) receiving placebo remained in the trial; 1553 patients continued into year 2. At 1 year, 47.5% of patients in the lorcaserin group and 20.3% in the placebo group had lost 5% or more of their body weight (P<0.001), corresponding to an average loss of 5.8+/-0.2 kg with lorcaserin and 2.2+/-0.1 kg with placebo during year 1 (P<0.001). Among the patients who received lorcaserin during year 1 and who had lost 5% or more of their baseline weight at 1 year, the loss was maintained in more patients who continued to receive lorcaserin during year 2 (67.9%) than in patients who received placebo during year 2 (50.3%, P<0.001). Among 2472 patients evaluated at 1 year and 1127 evaluated at 2 years, the rate of cardiac valvulopathy was not increased with the use of lorcaserin. Among the most frequent adverse events reported with lorcaserin were headache, dizziness, and nausea. The rates of serious adverse events in the two groups were similar. In conjunction with behavioral modification, lorcaserin was associated with significant weight loss and improved maintenance of weight loss, as compared with placebo. (Funded by Arena Pharmaceuticals; ClinicalTrials.gov number, NCT00395135.) 2010 Massachusetts Medical Society

Arnica Ointment 10% Does Not Improve Upper Blepharoplasty Outcome: A Randomized, Placebo-Controlled Trial.

PubMed

van Exsel, Denise C E; Pool, Shariselle M W; van Uchelen, Jeroen H; Edens, Mireille A; van der Lei, Berend; Melenhorst, Wynand B W H

2016-07-01

It has been suggested that arnica can reduce postoperative edema and ecchymosis associated with cosmetic surgical procedures and improve outcome. Despite a high incidence of arnica use among upper blepharoplasty patients, evidence to support its treatment effect is lacking. The authors performed a randomized, double-blind, placebo-controlled trial to investigate the efficacy of arnica ointment after upper blepharoplasty. One hundred thirty-six bilateral upper blepharoplasty patients were randomized between arnica ointment 10% and placebo ointment. In both study arms, one periorbital area was designated as the treatment side (either arnica or placebo ointment), and the contralateral side served as an untreated (no ointment) internal control. As the primary endpoint, the overall periorbital appearance as based on light photography and judged by a medical and nonmedical panel, was assessed after 3 days, 7 days, and 6 weeks. Secondary endpoints were swelling, ecchymosis, erythema, pain, and patient satisfaction with recovery and outcome. There was no significant difference between arnica and placebo in overall judgment of periorbital appearance 3 days, 7 days, and 6 weeks after surgery. Furthermore, swelling, ecchymosis, erythema, pain, and patient satisfaction with recovery and outcome did not differ between arnica and placebo. Postoperative outcome in untreated eyelids was not different from eyelids treated with either arnica or placebo on any of the studied outcome measures. The authors' study demonstrates that topical arnica ointment after upper blepharoplasty does not improve postoperative outcome. Therapeutic, II.

Oral scopolamine augmentation in moderate to severe major depressive disorder: a randomized, double-blind, placebo-controlled study.

PubMed

Khajavi, Danial; Farokhnia, Mehdi; Modabbernia, Amirhossein; Ashrafi, Mandana; Abbasi, Seyed-Hesammedin; Tabrizi, Mina; Akhondzadeh, Shahin

2012-11-01

To evaluate the antidepressant effect of oral scopolamine as an adjunct to citalopram. In this randomized double-blind placebo-controlled study, patients were assessed in the outpatient clinics of 2 large hospitals from November 2011 to January 2012. Forty patients (18-55 years) with major depressive disorder (DSM-IV-TR criteria) and 17-Item Hamilton Depression Rating Scale (HDRS) score ≥ 22 were randomly assigned to scopolamine hydrobromide (1 mg/d) (n = 20) or placebo (n = 20) in addition to citalopram for 6 weeks. HDRS score was measured at baseline and days 4, 7, 14, 28, and 42. The primary outcome measure was HDRS score change from baseline to week 6 in the scopolamine group versus the placebo group. Response was defined as ≥ 50% decrease in HDRS score; remission, as HDRS score ≤ 7. Augmentation with scopolamine was significantly more effective than placebo (F(1,38) = 5.831, P = .021). Patients receiving scopolamine showed higher rates of response (65%, 13/20 at week 4) and remission (65%, 13/20 at week 6) than the placebo group (30%, 6/20 and 20%, 4/20, respectively; P = .027, P = .004, respectively). Patients in the scopolamine group showed higher rates of dry mouth, blurred vision, and dizziness than the placebo group. Oral scopolamine is a safe and effective adjunct for treatment of patients with moderate to severe major depressive disorder. Iranian Registry of Clinical Trials identifier: IRCT201201181556N31. © Copyright 2012 Physicians Postgraduate Press, Inc.

Baricitinib in adult patients with moderate-to-severe atopic dermatitis: a phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study.

PubMed

Guttman-Yassky, Emma; Silverberg, Jonathan I; Nemoto, Osamu; Forman, Seth B; Wilke, August; Prescilla, Randy; de la Peña, Amparo; Nunes, Fabio P; Janes, Jonathan; Gamalo, Margaret; Donley, David; Paik, Jim; DeLozier, Amy M; Nickoloff, Brian J; Simpson, Eric L

2018-02-01

Baricitinib, an oral selective inhibitor of Janus kinase (JAK)1 and JAK2, modulates pro-inflammatory cytokine signaling. The efficacy and safety of baricitinib were evaluated in patients with moderate-to-severe atopic dermatitis (AD). In this phase 2, randomized, double-blind, placebo-controlled study, 124 patients with moderate-to-severe AD applied topical corticosteroids (TCS) for 4 weeks before randomization to once daily placebo, baricitinib 2 mg, or baricitinib 4 mg for 16 weeks. Use of TCS was permitted during the study. Primary outcome was the proportion of patients achieving ≥50% reduction in the Eczema Area and Severity Index (EASI-50) compared to placebo. Significantly more baricitinib 4-mg patients achieved EASI-50 compared to placebo (61% vs 37%; P=0.027) at 16 weeks. The proportion of baricitinib 2- and 4-mg patients achieving EASI-50 compared to placebo was significant as early as week 4. Baricitinib also improved pruritus and sleep loss. Treatment-emergent adverse events were reported in 24 (49%) placebo, 17 (46%) baricitinib 2-mg, and 27 (71%) baricitinib 4-mg patients. A TCS standardization period prior to randomization reduced disease severity, limiting the ability to compare results to baricitinib monotherapy. Longer studies are required to confirm baricitinib efficacy and safety in AD patients. Baricitinib used with TCS reduced inflammation and pruritus in patients with moderate-to-severe atopic dermatitis (AD). Copyright © 2018. Published by Elsevier Inc.

Soy germ extract alleviates menopausal hot flushes: placebo-controlled double-blind trial.

PubMed

Imhof, Martin; Gocan, Anca; Imhof, Marianne; Schmidt, Mathias

2018-05-30

A double-blind, placebo-controlled study was performed to assess the potency of a soy germ preparation for the alleviation of menopausal hot flushes. Caucasian women with at least seven hot flushes daily were treated with soy germ extract (100 mg isoflavone glycosides) daily or with placebo for 12 weeks, followed by 12 weeks of open treatment with soy. Outcome parameters were the number of hot flushes and the evaluation of the Greene Climacteric Scale. A total of 192 women were included. As the hot flush diaries from one study centre were lost, the assessment of hot flushes was based on 136 participants (soy: 54 women; placebo: 82 women). After 12 weeks, 180 women were available for the analysis of Greene Scale and safety (soy and placebo: each 90 women). Hot flushes were reduced by 43.3% (-3.5 hot flushes) with soy and by 30.8% with placebo (-2.6; p < 0.001). After the open treatment phase with soy, both original groups showed a reduction of 68% of hot flushes. A subgroup analysis showed better effects for soy when symptoms were classified as "severe" at baseline. After 12 weeks of double-blind treatment, there was an improvement from baseline values of 71 and 78% with soy with the items "hot flushes" and "sweating", compared with 24% for both items with placebo. Hormonal safety parameters remained uninfluenced. Soy germ extract with 100 mg of isoflavone glycosides was shown to modestly, but significantly reduce menopausal hot flushes.

Moderation of nicotine effects on covert orienting of attention tasks by poor placebo performance and cue validity.

PubMed

Hammersley, Jonathan J; Gilbert, David G; Rzetelny, Adam; Rabinovich, Norka E

2016-10-01

Given baseline-dependent effects of nicotine on other forms of attention, there is reason to believe that inconsistent findings for the effects of nicotine on attentional orienting may be partly due to individual differences in baseline (abstinence state) functioning. Individuals with low baseline attention may benefit more from nicotine replacement. The effects of nicotine as a function of baseline performance (bottom, middle, and top third of mean reaction times during placebo) were assessed in 52 habitual abstinent smokers (26 females/26 males) utilizing an arrow-cued covert orienting of attention task. Compared to a placebo patch, a 14mg nicotine patch produced faster overall reaction times (RTs). In addition, individuals with slower RTs during the placebo condition benefitted more from nicotine on cued trials than did those who had shorter (faster) RTs during placebo. Nicotine also enhanced the validity effect (shorter RTs to validly vs. invalidly cued targets), but this nicotine benefit did not differ as a function of overall placebo-baseline performance. These findings support the view that nicotine enhances cued spatial attentional orienting in individuals who have slower RTs during placebo (nicotine-free) conditions; however, baseline-dependent effects may not generalize to all aspects of spatial attention. These findings are consistent with findings indicating that nicotine's effects vary as a function of task parameters rather than simple RT speeding or cognitive enhancement. Copyright © 2016 Elsevier Inc. All rights reserved.

Importance of beta 2-adrenoceptor stimulation in the suppression of intradermal antigen challenge by adrenaline.

PubMed Central

Warren, J B; Pixley, F J; Dollery, C T

1989-01-01

1. Seven atopic subjects received two injections of antigen and one of saline intradermally in the back on each of 4 separate days. They were pretreated with four different drug combinations: (a) adrenaline 0.3 mg subcutaneously over the deltoid muscle (b) subcutaneous adrenaline preceded by 5 mg of the specific beta 2-adrenoceptor antagonist ICI 118,551 orally (c) 8 mg of salbutamol orally (d) placebo. Tablets were given 2 h before and subcutaneous injections 15 min before the intradermal injections of saline and antigen. 2. The median flare response to intradermal low dose antigen and high dose antigen after pretreatment with adrenaline was 4% and 49% of the response seen following pretreatment with placebo (P less than 0.001). When adrenaline was preceded by ICI-118,551, the corresponding median flare responses were 2% and 44% (P less than 0.001) of the placebo response. The flare response after pretreatment with salbutamol was not significantly different from placebo. 3. Adrenaline suppressed the median weal response to the higher dose of antigen to 52% of the response after pretreatment with placebo (P less than 0.05). This suppression by adrenaline was blocked by pretreatment with ICI 118,551. The median weal response after the highest dose of antigen was suppressed by salbutamol to 66% of the response seen after placebo, although this was not significant even when a further three subjects were studied with either salbutamol or placebo.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2565729

Effects of calcium supplementation on body weight reduction in overweight calcium stone formers.

PubMed

Menon, Viviane Barcellos; Baxmann, Alessandra Calábria; Froeder, Leila; Martini, Lígia Araújo; Heilberg, Ita Pfeferman

2009-06-01

A randomized, placebo-controlled trial was conducted in overweight calcium stone-forming (CSF) patients, to evaluate the effect of calcium supplementation associated with a calorie-restricted diet on body weight (BW) and fat reduction and its potential changes upon serum and urinary parameters. Fifteen patients were placed on a hypocaloric diet for 3 months, supplemented with either calcium carbonate (CaCO(3), n = 8) or placebo (n = 7), 500 mg bid. Blood and 24-h urine samples were collected and body composition was assessed at baseline and after the intervention. At the end of the study, final BW was significantly lower vs baseline in both CaCO(3) (74 +/- 14 vs. 80 +/- 14 kg, P = 0.01) and placebo groups (80 +/- 10 vs. 87 +/- 9 kg, P = 0.02) but the mean percentage of loss of body weight and body fat did not differ between CaCO(3) and placebo (7.0 +/- 2.0 vs. 8.0 +/- 3.0%, P = 0.40 and 13.0 +/- 7.0 vs. 13.0 +/- 10.0%; P = 0.81, respectively). After CaCO(3) or placebo, no significant differences versus baseline were observed for urinary parameters in both CaCO(3) and placebo, except for a higher mean urinary citrate in placebo group. These data suggest that increasing calcium intake by calcium carbonate supplementation did not contribute to a further reduction of BW and fat in overweight CSF patients submitted to a hypocaloric diet nor altered urinary lithogenic parameters.

Effects of Saccharomyces boulardii in children with acute diarrhoea.

PubMed

Kurugöl, Z; Koturoğlu, G

2005-01-01

Certain probiotic agents, e.g. Lactobacillus GG, have shown efficacy in clinical trials for the treatment of acute childhood diarrhoea, but few studies have examined the effect of Saccharomyces boulardii. We evaluated the effect of S. boulardii in children with acute diarrhoea. Two hundred children were randomized to receive S. boulardii in a granulated form in a daily dose of 250 mg (S. boulardii group) or placebo (placebo group) for 5 d. Clinical and demographic characteristics on admission were similar between the study groups. The medians of the average stool frequency after the second day of the treatment were significantly lower in the S. boulardii group than in the placebo group (p = 0.003). The duration of diarrhoea significantly reduced in the S. boulardii group compared with the placebo group (4.7 vs 5.5 d, p = 0.03). The effect of S. boulardii on watery diarrhoea became apparent after the second day of the treatment. The duration of hospital stay was shorter in the S. boulardii group than in the placebo group (2.9 vs 3.9 d, p < 0.001). Four children from the placebo group versus only one child from the S. boulardii group had persisting diarrhoea. The placebo-controlled study suggested that S. boulardii significantly reduced the duration of acute diarrhoea and the duration of hospital stay. S. boulardii seems to be a promising agent for the amelioration of the course of acute diarrhoea in children when used therapeutically.

Metformin extended release treatment of adolescent obesity: a 48-week randomized, double-blind, placebo-controlled trial with 48-week follow-up.

PubMed

Wilson, Darrell M; Abrams, Stephanie H; Aye, Tandy; Lee, Phillip D K; Lenders, Carine; Lustig, Robert H; Osganian, Stavroula V; Feldman, Henry A

2010-02-01

Metformin has been proffered as a therapy for adolescent obesity, although long-term controlled studies have not been reported. To test the hypothesis that 48 weeks of daily metformin hydrochloride extended release (XR) therapy will reduce body mass index (BMI) in obese adolescents, as compared with placebo. Multicenter, randomized, double-blind, placebo-controlled clinical trial. The 6 centers of the Glaser Pediatric Research Network from October 2003 to August 2007. Obese (BMI > or = 95th percentile) adolescents (aged 13-18 years) were randomly assigned to the intervention (n = 39) or placebo groups. Intervention Following a 1-month run-in period, subjects following a lifestyle intervention program were randomized 1:1 to 48 weeks' treatment with metformin hydrochloride XR, 2000 mg once daily, or an identical placebo. Subjects were monitored for an additional 48 weeks. Main Outcome Measure Change in BMI, adjusted for site, sex, race, ethnicity, and age and metformin vs placebo. After 48 weeks, mean (SE) adjusted BMI increased 0.2 (0.5) in the placebo group and decreased 0.9 (0.5) in the metformin XR group (P = .03). This difference persisted for 12 to 24 weeks after cessation of treatment. No significant effects of metformin on body composition, abdominal fat, or insulin indices were observed. Metformin XR caused a small but statistically significant decrease in BMI when added to a lifestyle intervention program. clinicaltrials.gov Identifiers: NCT00209482 and NCT00120146.

Moderation of Nicotine Effects on Covert Orienting of Attention Tasks by Poor Placebo Performance and Cue Validity

PubMed Central

Gilbert, David G.; Rzetelny, Adam; Rabinovich, Norka E.

2016-01-01

Introduction and Rationale Given baseline-dependent effects of nicotine on other forms of attention, there is reason to believe that inconsistent findings for the effects of nicotine on attentional orienting may be partly due to individual differences in baseline (abstinence state) functioning. Individuals with low baseline attention may benefit more from nicotine replacement. Method The effects of nicotine as a function of baseline performance (bottom, middle, and top third of mean reaction times during placebo) were assessed in 52 habitual abstinent smokers (26 females/26 males) utilizing an arrow-cued covert orienting of attention task. Results Compared to a placebo patch, a 14 mg nicotine patch produced faster overall reaction times (RTs). In addition, individuals with slower RTs during the placebo condition benefitted more from nicotine on cued trials than did those who had shorter (faster) RTs during placebo. Nicotine also enhanced the validity effect (shorter RTs to validly vs. invalidly cued targets), but this nicotine benefit did not differ as a function of overall placebo-baseline performance. Conclusions These findings support the view that nicotine enhances cued spatial attentional orienting in individuals who have slower RTs during placebo (nicotine-free) conditions; however, baseline-dependent effects may not generalize to all aspects of spatial attention. These findings are consistent with findings indicating that nicotine’s effects vary as a function of task parameters rather than simple RT speeding or cognitive enhancement. PMID:27461547

A double-blind, placebo-controlled study of risperidone in adults with autistic disorder and other pervasive developmental disorders.

PubMed

McDougle, C J; Holmes, J P; Carlson, D C; Pelton, G H; Cohen, D J; Price, L H

1998-07-01

Neurobiological research has implicated the dopamine and serotonin systems in the pathogenesis of autism. Open-label reports suggest that the serotonin2A-dopamine D2 antagonist risperidone may be safe and effective in reducing the interfering symptoms of patients with autism. Thirty-one adults (age [mean+/-SD], 28.1+/-7.3 years) with autistic disorder (n=17) or pervasive developmental disorder not otherwise specified (n=14) participated in a 12-week double-blind, placebo-controlled trial of risperidone. Patients treated with placebo subsequently received a 12-week open-label trial of risperidone. For persons completing the study, 8 (57%) of 14 patients treated with risperidone were categorized as responders (daily dose [mean+/-SD], 2.9+/-1.4 mg) compared with none of 16 in the placebo group (P<.002). Risperidone was superior to placebo in reducing repetitive behavior (P<.001), aggression (P<.001), anxiety or nervousness (P<.02), depression (P<.03), irritability (P<.01), and the overall behavioral symptoms of autism (P<.02). Objective, measurable change in social behavior and language did not occur. Nine (60%) of 15 patients who received treatment with open-label risperidone following the double-blind placebo phase responded. Other than mild, transient sedation, risperidone was well tolerated, with no evidence of extrapyramidal effects, cardiac events, or seizures. Risperidone is more effective than placebo in the short-term treatment of symptoms of autism in adults.

Addition of atropine to submaximal exercise stress testing in patients evaluated for suspected ischaemia with SPECT imaging: a randomized, placebo-controlled trial.

PubMed

Manganelli, Fiore; Spadafora, Marco; Varrella, Paola; Peluso, Giuseppina; Sauro, Rosario; Di Lorenzo, Emilio; Rosato, Giuseppe; Daniele, Stefania; Cuocolo, Alberto

2011-02-01

To evaluate the effects of the addition of atropine to exercise testing in patients who failed to achieve their target heart rate (HR) during stress myocardial perfusion imaging with single-photon emission computed tomography (SPECT). The study was a prospective, randomized, placebo-controlled design. Patients with suspected or known coronary artery disease who failed to achieve a target HR (≥85% of maximal predicted HR) during exercise SPECT imaging were randomized to receive intravenous atropine (n=100) or placebo (n=101). The two groups of patients did not differ with respect to demographic or clinical characteristics. A higher proportion of patients in the atropine group achieved the target HR compared to the placebo group (60% versus 3%, p<0.0001). SPECT imaging was abnormal in a higher proportion of patients in the atropine group as compared to the placebo group (57% versus 42%, p<0.05). Stress-induced myocardial ischaemia was present in more patients in the atropine group as compared to placebo (47% versus 29%, p<0.01). In both groups of patients, no major side effects occurred. The addition of atropine at the end of exercise testing is more effective than placebo in raising HR to adequate levels, without additional risks of complications. The use of atropine in patients who initially failed to achieve their maximal predicted HR is associated with a higher probability of achieving a diagnostic myocardial perfusion study.

The effect of Neuragen PN® on Neuropathic pain: A randomized, double blind, placebo controlled clinical trial

PubMed Central

2010-01-01

Background A double blind, randomized, placebo controlled study to evaluate the safety and efficacy of the naturally derived topical oil, "Neuragen PN®" for the treatment of neuropathic pain. Methods Sixty participants with plantar cutaneous (foot sole) pain due to all cause peripheral neuropathy were recruited from the community. Each subject was randomly assigned to receive one of two treatments (Neuragen PN® or placebo) per week in a crossover design. The primary outcome measure was acute spontaneous pain level as reported on a visual analog scale. Results There was an overall pain reduction for both treatments from pre to post application. As compared to the placebo, Neuragen PN® led to significantly (p < .05) greater pain reduction. Fifty six of sixty subjects (93.3%) receiving Neuragen PN® reported pain reduction within 30 minutes. This reduction within 30 minutes occurred in only twenty one of sixty (35.0%) subjects receiving the placebo. In a break out analysis of the diabetic only subgroup, 94% of subjects in the Neuragen PN® group achieved pain reduction within 30 minutes vs 11.0% of the placebo group. No adverse events were observed. Conclusions This randomized, placebo controlled, clinical trial with crossover design revealed that the naturally derived oil, Neuragen PN®, provided significant relief from neuropathic pain in an all cause neuropathy group. Participants with diabetes within this group experienced similar pain relief. Trial registration ISRCTN registered: ISRCTN13226601 PMID:20487567

Impact of empagliflozin on blood pressure in dipper and non-dipper patients with type 2 diabetes mellitus and hypertension.

PubMed

Chilton, Robert; Tikkanen, Ilkka; Hehnke, Uwe; Woerle, Hans J; Johansen, Odd Erik

2017-11-01

In the EMPA-REG BP trial, empagliflozin significantly reduced systolic and diastolic blood pressure (SBP and DBP) compared with placebo at week 12 in patients with type 2 diabetes mellitus (T2DM) and hypertension. In a post-hoc analysis, we assessed the effect of empagliflozin on SBP and DBP using 24-hour ambulatory BP monitoring in patients categorized as dippers (sleep-time mean SBP ≤ 90% of awake-time mean; n = 417) or non-dippers (sleep-time mean SBP > 90% of awake-time mean; n = 350). In dippers, adjusted mean (SE) changes from baseline in mean 24-hour SBP (mm Hg) at week 12 were -0.2 (0.7) with placebo vs -3.8 (0.6) and -3.9 (0.7) with empagliflozin 10 and 25 mg, respectively (both P  < .001 vs placebo). In non-dippers, these changes were 1.0 (0.7) with placebo vs -1.6 (0.7) with empagliflozin 10 mg ( P  = .013 vs placebo) and -3.8 (0.7) with empagliflozin 25 mg ( P  < .001 vs placebo). In both dippers and non-dippers, SBP and DBP patterns over 24 hours were maintained. There were no clinically relevant changes in heart rate with empagliflozin. In conclusion, empagliflozin significantly reduced mean 24-hour SBP compared with placebo in dippers and non-dippers. © 2017 John Wiley & Sons Ltd.

Experimental cardiac arrest treatment with adrenaline, vasopressin, or placebo.

PubMed

Palácio, Manoel Ângelo Gomes; Paiva, Edison Ferreira de; Azevedo, Luciano Cesar Pontes de; Timerman, Ari

2013-12-01

The effect of vasoconstrictors in prolonged cardiopulmonary resuscitation (CPR) has not been fully clarified. To evaluate adrenaline and vasopressin pressure effect, and observe the return of spontaneous circulation (ROSC). A prospective, randomized, blinded, and placebo-controlled study. After seven minutes of untreated ventricular fibrillation, pigs received two minutes cycles of CPR. Defibrillation was attempted (4 J/kg) once at 9 minutes, and after every cycle if a shockable rhythm was present, after what CPR was immediately resumed. At 9 minutes and every five minutes intervals, 0.02 mg/kg (n = 12 pigs) adrenaline, or 0.4 U/kg (n = 12) vasopressin, or 0.2 mL/kg (n = 8) 0.9% saline solution was administered. CPR continued for 30 minutes or until the ROSC. Coronary perfusion pressure increased to about 20 mmHg in the three groups. Following vasoconstrictors doses, pressure level reached 35 mmHg versus 15 mmHg with placebo (p < 0.001). Vasopressin effect remained at 15-20 mmHg after three doses versus zero with adrenaline or placebo. ROSC rate differed (p = 0.031) among adrenaline (10/12), vasopressin (6/12), and placebo (2/8). Time-to-ROSC did not differ (16 minutes), nor the number of doses previously received (one or two). There was no difference between vasoconstrictors, but against placebo, only adrenaline significantly increased the ROSC rate (p = 0.019). The vasoconstrictors initial pressure effect was equivalent and vasopressin maintained a late effect at prolonged resuscitation. Nevertheless, when compared with placebo, only adrenaline significantly increased the ROSC rate.

Efficacy of maropitant in the prevention of delayed vomiting associated with administration of doxorubicin to dogs.

PubMed

Rau, S E; Barber, L G; Burgess, K E

2010-01-01

Vomiting, nausea, inappetence, and diarrhea are common delayed adverse effects of doxorubicin. Maropitant, a neurokinin-1 receptor antagonist, is known to prevent acute vomiting in dogs receiving cisplatin. To evaluate the efficacy of maropitant in preventing delayed vomiting after administration of doxorubicin to dogs. Fifty-nine dogs with cancer. This randomized, double-blind, placebo-controlled study used a cross-over design. Dogs were randomized into 1 of 2 treatment groups. Group A received maropitant after the 1st doxorubicin, and placebo after the 2nd. Group B received placebo first, and maropitant second. Maropitant (2 mg/kg) or placebo tablets were administered PO for 5 days after doxorubicin treatment. Owners completed visual analog scales based on Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events to grade their pet's clinical signs during the week after administration of doxorubicin. Statistical differences in gastrointestinal toxicosis and myelosuppression between maropitant and placebo treatments were evaluated. Significantly fewer dogs had vomiting (P=.001) or diarrhea (P=.041), and the severity of vomiting (P<.001) and diarrhea (P=.024) was less the week after doxorubicin when receiving maropitant compared with placebo. No differences were found between maropitant and placebo for other gastrointestinal and bone marrow toxicoses. Maropitant is effective in preventing delayed vomiting induced by doxorubicin. Its prophylactic use might improve quality of life and decrease the need for dose reductions in certain dogs. Copyright © 2010 by the American College of Veterinary Internal Medicine.

Treatment of Non-neurogenic Overactive Bladder with OnabotulinumtoxinA: Systematic Review and Meta-analysis of Prospective, Randomized, Placebo-controlled Clinical Trials.

PubMed

Arruda, Raquel Martins; Takano, Claudia Cristina; Girão, Manoel João Batista Castelo; Haddad, Jorge Milhem; Aleixo, Gabriel Francisco; Castro, Rodrigo Aquino

2018-04-01

We performed a systematic review and meta-analysis of randomized placebo-controlled trials that studied non-neurogenic overactive bladder patients who were treated with 100 units of onabotulinumtoxinA or placebo. The primary purpose of our study was to evaluate the clinical effectiveness with regard to urinary urgency, urinary frequency, nocturia, and incontinence episodes. Our secondary purpose consisted of evaluating the adverse effects. Our initial search yielded 532 entries. Of these, seven studies met all the inclusion criteria (prospective, randomized, placebo-controlled studies, ≥ 3 points on the Jadad scale) and were selected for analysis. For all primary endpoints, the toxin was more effective than placebo ( p  < 0.0001; 95% confidence interval [95CI]), namely: urgency (mean difference = -2.07; 95CI = [-2.55-1.58]), voiding frequency (mean difference = -1.64; 95CI = [-2.10-1.18]), nocturia (mean difference = -0.25; 95CI = [-0.39-0.11]) and incontinence episodes (mean difference = -2.06; 95CI= [-2.60-1.52]). The need for intermittent catheterization and the occurrence of urinary tract infection (UTI) were more frequent in patients treated with onabotulinumtoxinA than in patients treated with placebo ( p  < 0.0001). Compared with placebo, onabotulinumtoxinA had significantly and clinically relevant reductions in overactive bladder symptoms and is associated with higher incidence of intermittent catheterization and UTI. Thieme Revinter Publicações Ltda Rio de Janeiro, Brazil.

Physical dependence increases the relative reinforcing effects of caffeine versus placebo.

PubMed

Garrett, B E; Griffiths, R R

1998-10-01

Using a within-subject cross-over design, this study examined the role of physical dependence in caffeine reinforcement by experimentally manipulating physical dependence. Each subject was exposed to two chronic drug phases (300 mg/70 kg/day caffeine and placebo) for 9-12 days, with order of phases counterbalanced across subjects. On 2 separate days immediately following each of the chronic drug exposures, subjects received acute doses of either caffeine (300 mg/70 kg) or placebo in counterbalanced order. The reinforcing effects of these drugs were then determined by using a multiple-choice procedure in which subjects made a series of discrete choices between receiving varying amounts of money or receiving the drug again, and a choice between the two drugs. To ensure that subjects completed the form carefully, following exposure to both of the acute drug administrations, one of the subject's previous choices from the multiple-choice form was randomly selected and the consequence of that choice was implemented. When subjects were maintained on chronic caffeine, they were willing to forfeit significantly more money and showed significant increases in typical withdrawal symptoms (e.g. fatigue, mood disturbance) after receiving placebo as compared to the other three conditions. When subjects were maintained on chronic caffeine, they also chose to receive caffeine over placebo twice as often than when they were maintained on chronic placebo. These findings provide the strongest evidence to date indicating that caffeine physical dependence increases the relative reinforcing effects of caffeine versus placebo.

Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso-occlusive crises in patients with sickle cell disease: a phase III randomized, placebo-controlled, double-blind study of the Gardos channel blocker senicapoc (ICA-17043).

PubMed

Ataga, Kenneth I; Reid, Marvin; Ballas, Samir K; Yasin, Zahida; Bigelow, Carolyn; James, Luther St; Smith, Wally R; Galacteros, Frederic; Kutlar, Abdullah; Hull, James H; Stocker, Jonathan W

2011-04-01

Red blood cell (RBC) hydration is regulated in part by the Ca(2+) -activated K(+) efflux (Gardos) channel. Senicapoc selectively blocks potassium efflux through the Gardos channel, reducing RBC dehydration and haemolysis, and increasing haemoglobin levels in sickle cell disease (SCD). This randomized, placebo-controlled trial was designed to determine the safety and clinical efficacy of senicapoc in SCD patients. One hundred and forty-five patients were randomized to receive senicapoc and 144 patients to receive placebo for 52 weeks. Consistent with a previous study, patients in the senicapoc group had significantly increased haematocrit, haemoglobin, and decreased numbers of both dense erythrocytes and reticulocytes when compared to the placebo group. The unblinded Data Monitoring Committee terminated this study early due to a lack of efficacy when it determined that, despite improvements in anaemia and haemolysis, no significant improvement in the rate of sickle cell painful crises was observed in patients treated with senicapoc compared to those on placebo (0·38 vs. 0·31, respectively). Comparisons of the times to first, second and third crises between the senicapoc and placebo groups were not statistically significant. Nausea and urinary tract infections occurred more frequently in the senicapoc group than placebo. Serious adverse events were similar in the two groups. © 2011 Blackwell Publishing Ltd.

Mifepristone versus placebo to treat uterine myoma: a double-blind, randomized clinical trial

PubMed Central

Esteve, Josep Lluis Carbonell; Acosta, Rita; Pérez, Yasmirian; Rodriguez, Barbara; Seigler, Isabel; Sanchez, Carlos; Tomasi, Giuseppe

2013-01-01

Objective To evaluate the efficacy, safety, and quality of life of 5 mg mifepristone per day compared with a placebo in treating uterine fibroids. Design Randomized, double-blind clinical study. Location Eusebio Hernández Gynecology and Obstetrics Teaching Hospital, Havana, Cuba. Subjects One hundred twenty-four subjects with symptomatic uterine fibroids. Treatment One daily capsule of 5 mg mifepristone or a mifepristone placebo over 3 months. Variables in evaluating safety Changes in fibroid and uterine volumes, changes in symptom prevalence and intensity, and changes in quality of life. Results Three months into treatment, fibroid volume was reduced by 28.5% in the mifepristone group with an increase of 1.8% in the placebo group (P = 0.031). There were significant differences between the groups with respect to pelvic pain prevalence (P = 0.006), pelvic pressure (P = 0.027), rectal pain (P = 0.013), hypermenorrhea (P < 0.001), and metrorrhagia (P = 0.002) at the end of treatment. Amenorrhea was 93.1% and 4.3% in the mifepristone and placebo groups, respectively (P < 0.001). Treatment side effects were significantly greater in the mifepristone group. Estradiol levels did not differ significantly between the placebo and mifepristone groups at the end of treatment. Improvement in quality of life was significantly greater in the categories of “symptoms” (P = 0.004) and “activity” (P = 0.045) in the mifepristone group. Conclusion The 5 mg dosage of mifepristone presented significantly superior efficacy compared to the placebo. PMID:23843709

Efficacy and safety of intravenous belimumab in Japanese patients with systemic lupus erythematosus: a subgroup analysis of a Phase 3 randomized placebo-controlled trial.

PubMed

Tanaka, Yoshiya; Bass, Damon; Chu, Myron; Egginton, Sally; Ji, Beulah; Struemper, Herbert; Roth, David

2018-05-24

To assess the efficacy and safety of intravenous belimumab plus standard systemic lupus erythematosus (SLE) therapy (SoC) in Japanese patients with SLE. A Phase 3, multicenter, double-blind, placebo-controlled, 52-week study (BEL 113750; NCT01345253) in patients with SLE, randomized 2:1 to belimumab 10 mg/kg plus SoC or placebo plus SoC to Week 48. Sixty of 707 randomized patients were enrolled from study centers in Japan (belimumab, n = 39; placebo, n = 21). In this cohort, more patients achieved SLE Responder Index 4 response at Week 52 in the belimumab group compared with placebo (46.2% [18/39] vs 25.0% [5/20]; odds ratio, 2.57 [95% confidence interval: 0.78, 8.47]; p = 0.1204). Fewer patients receiving belimumab experienced a severe flare through Week 52, with longer median time to flare compared with placebo. More patients with baseline prednisone dose >7.5 mg/day receiving belimumab had a dose reduction of ≥25% from baseline to ≤7.5 mg/day during Weeks 40 to 52, compared with placebo. No new safety issues were identified within the Japanese cohort. In Japanese patients with SLE, belimumab improved disease activity, with efficacy and safety results similar and consistent to the pivotal Phase 3 trials, suggesting that belimumab is a potential treatment option in this population.

Alfentanil and placebo analgesia: no sex differences detected in models of experimental pain.

PubMed

Olofsen, Erik; Romberg, Raymonda; Bijl, Hans; Mooren, René; Engbers, Frank; Kest, Benjamin; Dahan, Albert

2005-07-01

To assess whether patient sex contributes to the interindividual variability in alfentanil analgesic sensitivity, the authors compared male and female subjects for pain sensitivity after alfentanil using a pharmacokinetic-pharmacodynamic modeling approach. Healthy volunteers received a 30-min alfentanil or placebo infusion on two occasions. Analgesia was measured during the subsequent 6 h by assaying tolerance to transcutaneous electrical stimulation (eight men and eight women) of increasing intensity or using visual analog scale scores during treatment with noxious thermal heat (five men and five women). Sedation was concomitantly measured. Population pharmacokinetic-pharmacodynamic models were applied to the analgesia and sedation data using NONMEM. For electrical pain, the placebo and alfentanil models were combined post hoc. Alfentanil and placebo analgesic responses did not differ between sexes. The placebo effect was successfully incorporated into the alfentanil pharmacokinetic-pharmacodynamic model and was responsible for 20% of the potency of alfentanil. However, the placebo effect did not contribute to the analgesic response variability. The pharmacokinetic-pharmacodynamic analysis of the electrical and heat pain data yielded similar values for the potency parameter, but the blood-effect site equilibration half-life was significantly longer for electrical pain (7-9 min) than for heat pain (0.2 min) or sedation (2 min). In contrast to the ample literature demonstrating sex differences in morphine analgesia, neither sex nor subject expectation (i.e., placebo) contributes to the large between-subject response variability with alfentanil analgesia. The difference in alfentanil analgesia onset and offset between pain tests is discussed.

'Oxytocin' for the outwardly oriented: Evidence for interactive effects in placebo responding.

PubMed

Darragh, Margot; Booth, Roger J; Consedine, Nathan S

2016-04-01

In order to harness the placebo effect for clinical benefit, more research is needed to determine who might be responsive to a placebo treatment. Recently, a two-faceted Transactional Model of Placebo Responding (TMPR) was offered, which suggests different personality types might respond to different contextual cues. The current study directly tested this model by manipulating treatment descriptors to match the two purported facets of responsiveness. Physically healthy volunteers (N=77) experiencing life stress were randomised to either the: (1) wait-list control, (2) 'serotonin treatment' group; or (3) 'oxytocin treatment' group. Both treatment groups received an 'antistress' intranasal spray (placebo). The 'serotonin' and 'oxytocin' treatments were described to appeal to the two purported facets responsiveness set out in the TMPR, inward and outward orientation. The BIS/BAS scale was used as proxies for inward (BIS) and outward (BAS) orientation. It was hypothesised that high BAS types would be more responsive to the 'oxytocin' and high BIS types would be more responsive to the 'serotonin'. Findings provide partial support for hypotheses, with high but not low BAS types having a greater response to the 'oxytocin' placebo; but the pattern of responses from high BIS types were contrary to predictions. Findings indicate interactions between personality type and environmental cues may contribute to placebo responding, but more research is needed to investigate possible operationalisations of responsiveness and the contextual cues to which different types may respond. Copyright © 2016 Elsevier Inc. All rights reserved.

Ombrabulin plus cisplatin versus placebo plus cisplatin in patients with advanced soft-tissue sarcomas after failure of anthracycline and ifosfamide chemotherapy: a randomised, double-blind, placebo-controlled, phase 3 trial.

PubMed

Blay, Jean-Yves; Pápai, Zsuzsanna; Tolcher, Anthony W; Italiano, Antoine; Cupissol, Didier; López-Pousa, Antonio; Chawla, Sant P; Bompas, Emmanuelle; Babovic, Nada; Penel, Nicolas; Isambert, Nicolas; Staddon, Arthur P; Saâda-Bouzid, Esma; Santoro, Armando; Franke, Fabio A; Cohen, Patrick; Le-Guennec, Solenn; Demetri, George D

2015-05-01

Ombrabulin (AVE8062) disrupts the vasculature of established tumours and has shown preclinical synergistic anti-tumour activity when combined with cisplatin. In this phase 3 trial, we aimed to assess the efficacy and safety of ombrabulin plus cisplatin compared with placebo plus cisplatin in patients with advanced soft-tissue sarcomas. We did this multinational, randomised, double-blind, placebo-controlled phase 3 study at 44 centres in ten countries. Patients aged 18 years and older with metastatic soft-tissue sarcomas, an Eastern Cooperative Oncology Group performance status of 0-2, and who had previously received treatment with anthracycline and ifosfamide were randomly assigned (1:1) to intravenous infusion of ombrabulin 25 mg/m(2) plus cisplatin 75 mg/m(2) or intravenous infusion of placebo plus cisplatin 75 mg/m(2) every 3 weeks. Patients were allocated to treatment using a permuted blocks randomisation scheme (block size of four) via an interactive voice-response system, and stratified by histological subtype. Patients, medical staff, study investigators, and individuals who handled and analysed the data were masked to treatment assignment. Our primary endpoint was median progression-free survival in the intention-to-treat population. Safety analyses were done on all randomised patients who received at least one dose of study drug. This trial is now closed, and is registered with ClinicalTrials.gov, number NCT00699517. Between June 13, 2008, and April 26, 2012, we randomly assigned 355 patients to ombrabulin plus cisplatin (n=176) or placebo plus cisplatin (n=179). Median duration of follow-up was 27·9 (IQR 20·9-33·2) in the placebo group and 30·5 months (20·7-37·6) in the ombrabulin group. Progression-free survival was slightly, but significantly, improved in the ombrabulin group compared with the placebo group (median 1·54 months [95% CI 1·45-2·69] vs 1·41 [1·38-1·58] months; hazard ratio 0·76 [95% CI 0·59-0·98]; p=0·0302). Grade 3 or 4 adverse events occurred more frequently in individuals in the ombrabulin group than in those in the placebo group and included neutropenia (34 [19%] in the ombrabulin group vs 14 [8%] in the placebo group) and thrombocytopenia (15 [8%] vs six [3%] for placebo). Adverse events leading to death occurred in 18 patients in the ombrabulin group and 10 patients in the placebo group. The combination of ombrabulin and cisplatin significantly improved progression-free survival; however, it did not show a sufficient clinical benefit in patients with advanced soft-tissue sarcomas to support its use as a therapeutic option. Predictive biomarkers are needed for the rational clinical development of tumour vascular-disrupting drugs for soft-tissue sarcomas. Sanofi. Copyright © 2015 Elsevier Ltd. All rights reserved.

Out-of-Hospital Administration of Intravenous Glucose-Insulin-Potassium in Patients With Suspected Acute Coronary Syndromes

PubMed Central

Selker, Harry P.; Beshansky, Joni R.; Sheehan, Patricia R.; Massaro, Joseph M.; Griffith, John L.; D’Agostino, Ralph B.; Ruthazer, Robin; Atkins, James M.; Sayah, Assaad J.; Levy, Michael K.; Richards, Michael E.; Aufderheide, Tom P.; Braude, Darren A.; Pirrallo, Ronald G.; Doyle, Delanor D.; Frascone, Ralph J.; Kosiak, Donald J.; Leaming, James M.; Van Gelder, Carin M.; Walter, Gert-Paul; Wayne, Marvin A.; Woolard, Robert H.; Opie, Lionel H.; Rackley, Charles E.; Udelson, James E.

2014-01-01

Context Laboratory studies suggest that in the setting of cardiac ischemia, immediate intravenous glucose-insulin-potassium (GIK) reduces ischemia-related arrhythmias and myocardial injury. Clinical trials have not consistently shown these benefits, possibly due to delayed administration. Objective To test out-of hospital emergency medical service (EMS) administration of GIK in the first hours of suspected acute coronary syndromes (ACS). Design, Setting, and Participants Randomized, placebo-controlled, double-blind effectiveness trial in 13 US cities (36 EMS agencies), from December 2006 through July 31, 2011, in which paramedics, aided by electrocardiograph (ECG)-based decision support, randomized 911 (871 enrolled) patients (mean age, 63.6 years; 71.0% men) with high probability of ACS. Intervention Intravenous GIK solution (n=411) or identical-appearing 5% glucose placebo (n=460) administered by paramedics in the out-of-hospital setting and continued for 12 hours. Main Outcome Measures The prespecified primary end point was progression of ACS to myocardial infarction (MI) within 24 hours, as assessed by biomarkers and ECG evidence. Prespecified secondary end points included survival at 30 days and a composite of prehospital or in-hospital cardiac arrest or in-hospital mortality, analyzed by intent-to-treat and by presentation with ST-segment elevation. Results There was no significant difference in the rate of progression to MI among patients who received GIK (n=200; 48.7%) vs those who received placebo (n=242; 52.6%) (odds ratio [OR], 0.88; 95% CI, 0.66–1.13; P=.28). Thirty-day mortality was 4.4% with GIK vs 6.1% with placebo (hazard ratio [HR], 0.72; 95% CI, 0.40–1.29; P=.27). The composite of cardiac arrest or in-hospital mortality occurred in 4.4% with GIK vs 8.7% with placebo (OR, 0.48; 95% CI, 0.27–0.85; P=.01). Among patients with ST-segment elevation (163 with GIK and 194 with placebo), progression to MI was 85.3% with GIK vs 88.7% with placebo (OR, 0.74; 95% CI, 0.40–1.38; P=.34); 30-day mortality was 4.9% with GIK vs 7.7% with placebo (HR, 0.63; 95% CI, 0.27–1.49; P=.29). The composite outcome of cardiac arrest or in-hospital mortality was 6.1% with GIK vs 14.4% with placebo (OR, 0.39; 95% CI, 0.18–0.82; P=.01). Serious adverse events occurred in 6.8% (n=28) with GIK vs 8.9% (n=41) with placebo (P=.26). Conclusions Among patients with suspected ACS, out-of-hospital administration of intravenous GIK, compared with glucose placebo, did not reduce progression to MI. Compared with placebo, GIK administration was not associated with improvement in 30-day survival but was associated with lower rates of the composite outcome of cardiac arrest or in-hospital mortality. Trial Registration clinicaltrials.gov Identifier: NCT00091507 PMID:22452807

Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials.

PubMed

Griffiths, Christopher E M; Reich, Kristian; Lebwohl, Mark; van de Kerkhof, Peter; Paul, Carle; Menter, Alan; Cameron, Gregory S; Erickson, Janelle; Zhang, Lu; Secrest, Roberta J; Ball, Susan; Braun, Daniel K; Osuntokun, Olawale O; Heffernan, Michael P; Nickoloff, Brian J; Papp, Kim

2015-08-08

Ixekizumab is a humanised monoclonal antibody against the proinflammatory cytokine interleukin 17A. We report two studies of ixekizumab compared with placebo or etanercept to assess the safety and efficacy of specifically targeting interleukin 17A in patients with widespread moderate-to-severe psoriasis. In two prospective, double-blind, multicentre, phase 3 studies (UNCOVER-2 and UNCOVER-3), eligible patients were aged 18 years or older, had a confirmed diagnosis of chronic plaque psoriasis at least 6 months before baseline (randomisation), 10% or greater body-surface area involvement at both screening and baseline visits, at least a moderate clinical severity as measured by a static physician global assessment (sPGA) score of 3 or more, and a psoriasis area and severity index (PASI) score of 12. Participants were randomly assigned (1:2:2:2) by computer-generated random sequence with an interactive voice response system to receive subcutaneous placebo, etanercept (50 mg twice weekly), or one injection of 80 mg ixekizumab every 2 weeks, or every 4 weeks after a 160 mg starting dose. Blinding was maintained with a double-dummy design. Coprimary efficacy endpoints were proportions of patients achieving sPGA score 0 or 1 and 75% or greater improvement in PASI at week 12. Analysis was by intention to treat. These trials are registered with ClinicalTrials.gov, numbers NCT01597245 and NCT01646177. Between May 30, 2012, and Dec 30, 2013, 1224 patients in UNCOVER-2 were randomly assigned to receive subcutaneous placebo (n=168), etanercept (n=358), or ixekizumab every 2 weeks (n=351) or every 4 weeks (n=347); between Aug 11, 2012, and Feb 27, 2014, 1346 patients in UNCOVER-3 were randomly assigned to receive placebo (n=193), etanercept (n=382), ixekizumab every 2 weeks (n=385), or ixekizumab every 4 weeks (n=386). At week 12, both primary endpoints were met in both studies. For UNCOVER-2 and UNCOVER-3 respectively, in the ixekizumab every 2 weeks group, PASI 75 was achieved by 315 (response rate 89·7%; [effect size 87·4% (97·5% CI 82·9-91·8) vs placebo; 48·1% (41·2-55·0) vs etanercept]) and 336 (87·3%; [80·0% (74·4-85·7) vs placebo; 33·9% (27·0-40·7) vs etanercept]) patients; in the ixekizumab every 4 weeks group, by 269 (77·5%; [75·1% (69·5-80·8) vs placebo; 35·9% (28·2-43·6) vs etanercept]) and 325 (84·2%; [76·9% (71·0-82·8) vs placebo; 30·8% (23·7-37·9) vs etanercept]) patients; in the placebo group, by four (2·4%) and 14 (7·3%) patients; and in the etanercept group by 149 (41·6%) and 204 (53·4%) patients (all p<0·0001 vs placebo or etanercept). In the ixekizumab every 2 weeks group, sPGA 0/1 was achieved by 292 (response rate 83·2%; [effect size 80·8% (97·5% CI 75·6-86·0) vs placebo; 47·2% (39·9-54·4) vs etanercept]) and 310 (80·5%; [73·8% (67·7-79·9) vs placebo; 38·9% (31·7-46·1) vs etanercept]) patients; in the ixekizumab every 4 weeks group by 253 (72·9%; [70·5% (64·6-76·5) vs placebo; 36·9% (29·1-44·7) vs etanercept]) and 291 (75·4%; [68·7% (62·3-75·0) vs placebo; 33·8% (26·3-41·3) vs etanercept]) patients; in the placebo group by four (2·4%) and 13 (6·7%) patients; and in the etanercept group by 129 (36·0%) and 159 (41·6%) patients (all p<0·0001 vs placebo or etanercept). In combined studies, serious adverse events were reported in 14 (1·9%) of 734 patients given ixekizumab every 2 weeks, 14 (1·9%) of 729 given ixekizumab every 4 weeks, seven (1·9%) of 360 given placebo, and 14 (1·9%) of 739 given etanercept; no deaths were noted. Both ixekizumab dose regimens had greater efficacy than placebo and etanercept over 12 weeks in two independent studies. These studies show that selectively neutralising interleukin 17A with a high affinity antibody potentially gives patients with psoriasis a new and effective biological therapy option. Eli Lilly and Co. Copyright © 2015 Elsevier Ltd. All rights reserved.

Vitamin D3 supplementation increases spine bone mineral density in adolescents and young adults with HIV infection being treated with tenofovir disoproxil fumarate: a randomized, placebo controlled trial

USDA-ARS?s Scientific Manuscript database

Background: Tenofovir disoproxil fumarate (TDF) decreases bone mineral density (BMD). We hypothesized vitamin D3 (VITD3) would increase BMD in adolescents/young adults receiving TDF. Methods: Randomized double-blind placebo-controlled trial of directly observed VITD3 50,000 IU vs. placebo every 4 ...

Treatment of canine atopic dermatitis with a commercial homeopathic remedy: A single-blinded, placebo-controlled study

PubMed Central

Scott, Danny W.; Miller, William H.; Senter, David A.; Cook, Christopher P.; Kirker, J. Edward; Cobb, Shaun M.

2002-01-01

A commercial homeopathic remedy and a placebo were administered orally as individual agents to 18 dogs with atopic dermatitis. The pruritus was reduced by less than 50% in only 2/18 dogs; 1 of these dogs was receiving the homeopathic remedy, the other was receiving the placebo. One dog vomited after administration of the homeopathic remedy. PMID:12170834

N-Acetylcysteine in the Treatment of Pediatric Trichotillomania: A Randomized, Double-Blind, Placebo-Controlled Add-On Trial

ERIC Educational Resources Information Center

Bloch, Michael H.; Panza, Kaitlyn E.; Grant, Jon E.; Pittenger, Christopher; Leckman, James F.

2013-01-01

Objective: To examine the efficacy of N-acetylcysteine (NAC) for the treatment of pediatric trichotillomania (TTM) in a double-blind, placebo-controlled, add-on study. Method: A total of 39 children and adolescents aged 8 to 17 years with pediatric trichotillomania were randomly assigned to receive NAC or matching placebo for 12 weeks. Our primary…

Prevalence and factors associated with use of placebo control groups in randomized controlled trials in psoriasis: a cross-sectional study.

PubMed

Katz, Kenneth A; Karlawish, Jason H; Chiang, David S; Bognet, Rachel A; Propert, Katherine J; Margolis, David J

2006-11-01

The ethics and science of using placebo control groups in clinical trials have been widely debated. Few studies, however, have examined factors associated with choice of control group. Our aim was to assess the prevalence of use of placebo controls in randomized controlled trials in psoriasis and to identify factors associated with use of placebo controls in these trials. This is a cross-sectional study of randomized controlled trials in psoriasis published from January 1, 2001 to December 20, 2005 and indexed in the Cochrane Central Register of Controlled Trials. We extracted data on types of control groups used, design issues (number of patients enrolled, primary end point), disease characteristics (psoriasis type and severity), and extrascientific issues (trial location, funding source, and year of publication). We used bivariable and multivariable logistic regression to determine factors associated with use of a placebo control group. Of 194 citations, 187 were available for review. One hundred thirty-five trials from 134 articles in 38 journals met inclusion criteria. Eighty-three trials (61.5%) enrolling 8171 subjects (41.7%) used active controls only, and 52 trials (38.5%) enrolling 11,406 subjects (58.3%) used placebo controls. Adjusted for trial location and funding source, trials significantly more likely to have used placebo controls included those conducted in the United States (odds ratio [OR], 5.79; 95% confidence interval [CI], 2.45-13.68; P < .001) and those funded by pharmaceutical companies (OR, 2.61; 95% CI, 1.19-5.73; P = .02). Predicted frequencies of placebo use ranged from 77.6% (industry-funded, conducted trials in the United States) to 18.6% (non-industry-funded trials not conducted in the United States). Our searches may not have identified all published trials, and we did not have access to data from unpublished trials. Use of placebo controls has been more common in psoriasis trials conducted in the United States and funded by pharmaceutical companies. The findings suggest that ethical and scientific issues related to choice of control group in psoriasis trials are interpreted markedly differently depending on trial location and funding source.

Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial.

PubMed

Armitage, Jane M; Bowman, Louise; Clarke, Robert J; Wallendszus, Karl; Bulbulia, Richard; Rahimi, Kazem; Haynes, Richard; Parish, Sarah; Sleight, Peter; Peto, Richard; Collins, Rory

2010-06-23

Blood homocysteine levels are positively associated with cardiovascular disease, but it is uncertain whether the association is causal. To assess the effects of reducing homocysteine levels with folic acid and vitamin B(12) on vascular and nonvascular outcomes. Double-blind randomized controlled trial of 12,064 survivors of myocardial infarction in secondary care hospitals in the United Kingdom between 1998 and 2008. 2 mg folic acid plus 1 mg vitamin B(12) daily vs matching placebo. First major vascular event, defined as major coronary event (coronary death, myocardial infarction, or coronary revascularization), fatal or nonfatal stroke, or noncoronary revascularization. Allocation to the study vitamins reduced homocysteine by a mean of 3.8 micromol/L (28%). During 6.7 years of follow-up, major vascular events occurred in 1537 of 6033 participants (25.5%) allocated folic acid plus vitamin B(12) vs 1493 of 6031 participants (24.8%) allocated placebo (risk ratio [RR], 1.04; 95% confidence interval [CI], 0.97-1.12; P = .28). There were no apparent effects on major coronary events (vitamins, 1229 [20.4%], vs placebo, 1185 [19.6%]; RR, 1.05; 95% CI, 0.97-1.13), stroke (vitamins, 269 [4.5%], vs placebo, 265 [4.4%]; RR, 1.02; 95% CI, 0.86-1.21), or noncoronary revascularizations (vitamins, 178 [3.0%], vs placebo, 152 [2.5%]; RR, 1.18; 95% CI, 0.95-1.46). Nor were there significant differences in the numbers of deaths attributed to vascular causes (vitamins, 578 [9.6%], vs placebo, 559 [9.3%]) or nonvascular causes (vitamins, 405 [6.7%], vs placebo, 392 [6.5%]) or in the incidence of any cancer (vitamins, 678 [11.2%], vs placebo, 639 [10.6%]). Substantial long-term reductions in blood homocysteine levels with folic acid and vitamin B(12) supplementation did not have beneficial effects on vascular outcomes but were also not associated with adverse effects on cancer incidence. isrctn.org Identifier: ISRCTN74348595.

The effect of vilazodone on sexual function during the treatment of major depressive disorder.

PubMed

Clayton, Anita H; Kennedy, Sidney H; Edwards, John B; Gallipoli, Susan; Reed, Carol R

2013-10-01

  Sexual dysfunction is common in major depressive disorder (MDD), and many serotonergic antidepressants adversely affect sexual function. Vilazodone, a novel serotonin (5-HT) reuptake inhibitor and 5-HT1A partial agonist approved for MDD, exerts its effects at the 5-HT transporter and at both presynaptic and postsynaptic 5-HT1A receptors. This mechanism may limit sexual dysfunction.   To summarize effects of vilazodone (40 mg/day, with food) on sexual function in adults with MDD.   Data sources were three Phase III studies: two 8-week, placebo-controlled studies (NCT00285376 and NCT00683592) and a 52-week open-label study (NCT00644358). Sexual function was assessed by analyzing changes from baseline to end of treatment (EOT) using validated measures.   Arizona Sexual Experience Scale or Changes in Sexual Functioning Questionnaire.   Population included 869 patients (vilazodone, 436; placebo, 433) from placebo-controlled studies and 599 patients from the open-label study. Sexual dysfunction prevalence was high (50%, men; 68%, women) before treatment and declined during treatment in vilazodone and placebo groups, indicating improvement on average. At EOT, stable/improved sexual function was observed in ≥91% of patients in placebo-controlled studies; treatment group differences in sexual dysfunction at EOT were not statistically significant for either sex. Differences vs. placebo in changes from baseline of sexual function scores were small and were generally not statistically significant; effect sizes (Cohen's D) were generally of low magnitude. In the placebo-controlled studies, 8.0% of vilazodone-treated patients and 0.9% of placebo-treated patients reported ≥1 sexual-function-related treatment-emergent adverse event (P<0.001).   Half of men and two thirds of women with MDD had sexual dysfunction at baseline; sexual function improved on average in both vilazodone and placebo groups. Results suggest that vilazodone may have a small adverse impact on sexual function in adults with MDD relative to the high prevalence of sexual dysfunction at baseline. © 2012 International Society for Sexual Medicine.

Desvenlafaxine Versus Placebo in a Fluoxetine-Referenced Study of Children and Adolescents with Major Depressive Disorder

PubMed Central

Murphy, William; Abbas, Richat; Chiles, Deborah; England, Richard D.; Ramaker, Sara; Wajsbrot, Dalia B.

2018-01-01

Abstract Objectives: To evaluate the short-term efficacy and safety of desvenlafaxine (25–50 mg/d) compared with placebo in children and adolescents with major depressive disorder (MDD). Methods: Outpatient children (7–11 years) and adolescents (12–17 years) who met DSM-IV-TR criteria for MDD and had screening and baseline Children's Depression Rating Scale–Revised (CDRS-R) total scores >40 were randomly assigned to 8-week treatment with placebo, desvenlafaxine (25, 35, or 50 mg/d based on baseline weight), or fluoxetine (20 mg/d). The primary efficacy endpoint was change from baseline in CDRS-R total score at week 8, analyzed using a mixed-effects model for repeated measures. Secondary efficacy endpoints included week 8 Clinical Global Impressions–Severity, Clinical Global Impressions–Improvement (CGI-I), and response (CGI-I ≤ 2). Safety assessments included adverse events, physical and vital sign measurements, laboratory evaluations, electrocardiogram, and the Columbia-Suicide Severity Rating Scale. Results: The safety population included 339 patients (children, n = 130; adolescents, n = 209). The primary endpoint, change from baseline in CDRS-R total score at week 8, did not statistically separate from placebo, for either desvenlafaxine (adjusted mean [standard error] change, −22.6 [1.17]) or fluoxetine (−24.8 [1.17]; placebo, −23.1 [1.18]). Week 8 CGI-I response rates were significantly greater for fluoxetine (78.2%; p = 0.017) than for placebo (62.6%); desvenlafaxine (68.7%) did not differ from placebo. Other secondary outcomes were consistent with those obtained with CDRS-R. Rates of treatment-emergent adverse events were comparable among treatment groups (desvenlafaxine, 60.0%; placebo, 70.5%; and fluoxetine, 64.3%). Conclusion: Desvenlafaxine did not demonstrate efficacy for treating MDD in children and adolescents in this trial. Because neither desvenlafaxine nor the reference medication, fluoxetine, demonstrated a statistically significant difference from placebo on the primary endpoint, this was considered a failed trial and no efficacy conclusions can be drawn. Desvenlafaxine 25–50 mg/d was generally safe and well tolerated in children and adolescents in this study. PMID:29189044

Evaluation of a multi-herb supplement for erectile dysfunction: a randomized double-blind, placebo-controlled study.

PubMed

Shah, Gaurang R; Chaudhari, Manojkumar V; Patankar, Suresh B; Pensalwar, Shrikant V; Sabale, Vilas P; Sonawane, Navneet A

2012-09-15

Evidence is lacking for multi-ingredient herbal supplements claiming therapeutic effect in sexual dysfunction in men. We examined the safety and efficacy of VigRX Plus (VXP) - a proprietary polyherbal preparation for improving male sexual function, in a double blind, randomized placebo-controlled, parallel groups, multi-centre study. 78 men aged 25-50 years of age; suffering from mild to moderate erectile dysfunction (ED), participated in this study. Subjects were randomized to receive VXP or placebo at a dose of two capsules twice daily for 12 weeks. The international index of erectile function (IIEF) was the primary outcome measure of efficacy. Other efficacy measures were: Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), Serum testosterone, Semen analysis, Investigator's Global assessment and Subjects' opinion. In subjects receiving VXP, the IIEF-Erectile Function (EF) scores improved significantly as compared to placebo. After 12 weeks of treatment, the mean (sd) IIEF-EF score at baseline increased from 16.08 (2.87) to 25.08 (4.56) in the VXP group versus 15.86 (3.24) to 16.47 (4.25) in the placebo group (P < 0.0001). Similar results were observed in each of the remaining four domains of the IIEF (orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction).There was a significant difference for VXP versus placebo comparison of mean (sd) EDITS scores of patients: 82.31(20.23) vs 36.78(22.53) and partners :(82.75(9.8) vs 18.50(9.44);P < 0.001. Thirty-five out of 39 (90%) subjects from the VXP group and one (3%) from the placebo group wished to continue with the treatment they received. Investigator's global assessment rated VXP therapy as very good to excellent in more than 50% patients and placebo therapy as fair to good in about 25% of patients. Incidence of side effects and subject's rating for tolerability of treatment was similar in both groups. VigRX Plus was well tolerated and more effective than placebo in improving sexual function in men. Clinical Trial Registry India, CTRI/2009/091/000099, 31-03-2009.

Efficacy and safety of fluocinolone acetonide, hydroquinone, and tretinoin cream in chinese patients with melasma: a randomized, double-blind, placebo-controlled, multicenter, parallel-group study.

PubMed

Gong, Zijian; Lai, Wei; Zhao, Guang; Wang, Xuemin; Zheng, Min; Li, Li; Yang, Qingqi; Dang, Yuping; Liu, Lunfei; Zou, Ying

2015-06-01

This study aimed to determine the efficacy and safety of fluocinolone acetonide, hydroquinone, and tretinoin (FAHT) cream for the treatment of moderate and severe facial melasma. The primary objective was assessment of clinical efficacy, instrumental measured efficacy, and integral therapeutic efficacy at the end of weeks 4 and 8. A total of 233 subjects were randomly allocated (1:1 ratio) to receive topically administered FAHT cream (n = 117) or placebo (n = 116) once nightly for 8 weeks. Observed side effects were documented throughout. In the per protocol set (PPS; those subjects who met all requirements of the protocol), the integral therapeutic efficacy rate of FAHT cream on moderate and severe melasma was 68.57% (vs. placebo, 0.94%), the clinical effective rate of FAHT cream was 74.29 % (vs. placebo, 0.94%), and the instrumental measure efficacy of FAHT cream was 71.43% (vs. placebo, 6.60%). The difference in efficacy between the two groups was statistically significant (p < 0.001). In the full analysis set (FAS; the PPS and those subjects who were lost to follow-up but received at least one study treatment), the integral therapeutic efficacy rate of FAHT cream was 64.60% (vs. placebo, 0.88%), the clinical effective rate of FAHT cream was 69.91% (vs. placebo, 0.88%), and the instrumental measure efficacy of FAHT cream was 69.03 % (vs. placebo, 7.08%). The difference in efficacy between the two groups was statistically significant (p < 0.001). Of 113 subjects in the FAHT group, 34 (30.1%) reported adverse effects. Most of the pathological adverse effects were mild and resolved with either continuous treatment or discontinuation. Of 113 subjects in the placebo group, three (2.6%) reported mild adverse effects. No severe adverse effects or other abnormal clinical results were associated with the study treatment. FAHT cream is efficacious, well tolerated, and has a high margin of safety for the treatment of moderate and severe melasma in the Chinese population.

Individualized homeopathic treatment and fluoxetine for moderate to severe depression in peri- and postmenopausal women (HOMDEP-MENOP study): a randomized, double-dummy, double-blind, placebo-controlled trial.

PubMed

Macías-Cortés, Emma Del Carmen; Llanes-González, Lidia; Aguilar-Faisal, Leopoldo; Asbun-Bojalil, Juan

2015-01-01

Perimenopausal period refers to the interval when women's menstrual cycles become irregular and is characterized by an increased risk of depression. Use of homeopathy to treat depression is widespread but there is a lack of clinical trials about its efficacy in depression in peri- and postmenopausal women. The aim of this study was to assess efficacy and safety of individualized homeopathic treatment versus placebo and fluoxetine versus placebo in peri- and postmenopausal women with moderate to severe depression. A randomized, placebo-controlled, double-blind, double-dummy, superiority, three-arm trial with a 6 week follow-up study was conducted. The study was performed in a public research hospital in Mexico City in the outpatient service of homeopathy. One hundred thirty-three peri- and postmenopausal women diagnosed with major depression according to DSM-IV (moderate to severe intensity) were included. The outcomes were: change in the mean total score among groups on the 17-item Hamilton Rating Scale for Depression, Beck Depression Inventory and Greene Scale, after 6 weeks of treatment, response and remission rates, and safety. Efficacy data were analyzed in the intention-to-treat population (ANOVA with Bonferroni post-hoc test). After a 6-week treatment, homeopathic group was more effective than placebo by 5 points in Hamilton Scale. Response rate was 54.5% and remission rate, 15.9%. There was a significant difference among groups in response rate definition only, but not in remission rate. Fluoxetine-placebo difference was 3.2 points. No differences were observed among groups in the Beck Depression Inventory. Homeopathic group was superior to placebo in Greene Climacteric Scale (8.6 points). Fluoxetine was not different from placebo in Greene Climacteric Scale. Homeopathy and fluoxetine are effective and safe antidepressants for climacteric women. Homeopathy and fluoxetine were significantly different from placebo in response definition only. Homeopathy, but not fluoxetine, improves menopausal symptoms scored by Greene Climacteric Scale. ClinicalTrials.gov NCT01635218. https://clinicaltrials.gov/ct2/show/NCT01635218 [corrected].

Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories.

PubMed

Kishimoto, T; Chawla, J M; Hagi, K; Zarate, C A; Kane, J M; Bauer, M; Correll, C U

2016-05-01

Ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists (NMDAR antagonists) recently demonstrated antidepressant efficacy for the treatment of refractory depression, but effect sizes, trajectories and possible class effects are unclear. We searched PubMed/PsycINFO/Web of Science/clinicaltrials.gov until 25 August 2015. Parallel-group or cross-over randomized controlled trials (RCTs) comparing single intravenous infusion of ketamine or a non-ketamine NMDAR antagonist v. placebo/pseudo-placebo in patients with major depressive disorder (MDD) and/or bipolar depression (BD) were included in the analyses. Hedges' g and risk ratios and their 95% confidence intervals (CIs) were calculated using a random-effects model. The primary outcome was depressive symptom change. Secondary outcomes included response, remission, all-cause discontinuation and adverse effects. A total of 14 RCTs (nine ketamine studies: n = 234; five non-ketamine NMDAR antagonist studies: n = 354; MDD = 554, BD = 34), lasting 10.0 ± 8.8 days, were meta-analysed. Ketamine reduced depression significantly more than placebo/pseudo-placebo beginning at 40 min, peaking at day 1 (Hedges' g = -1.00, 95% CI -1.28 to -0.73, p < 0.001), and loosing superiority by days 10-12. Non-ketamine NMDAR antagonists were superior to placebo only on days 5-8 (Hedges' g = -0.37, 95% CI -0.66 to -0.09, p = 0.01). Compared with placebo/pseudo-placebo, ketamine led to significantly greater response (40 min to day 7) and remission (80 min to days 3-5). Non-ketamine NMDAR antagonists achieved greater response at day 2 and days 3-5. All-cause discontinuation was similar between ketamine (p = 0.34) or non-ketamine NMDAR antagonists (p = 0.94) and placebo. Although some adverse effects were more common with ketamine/NMDAR antagonists than placebo, these were transient and clinically insignificant. A single infusion of ketamine, but less so of non-ketamine NMDAR antagonists, has ultra-rapid efficacy for MDD and BD, lasting for up to 1 week. Development of easy-to-administer, repeatedly given NMDAR antagonists without risk of brain toxicity is of critical importance.

Vedolizumab as induction and maintenance therapy for ulcerative colitis.

PubMed

Feagan, Brian G; Rutgeerts, Paul; Sands, Bruce E; Hanauer, Stephen; Colombel, Jean-Frédéric; Sandborn, William J; Van Assche, Gert; Axler, Jeffrey; Kim, Hyo-Jong; Danese, Silvio; Fox, Irving; Milch, Catherine; Sankoh, Serap; Wyant, Tim; Xu, Jing; Parikh, Asit

2013-08-22

Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis. We conducted two integrated randomized, double-blind, placebo-controlled trials of vedolizumab in patients with active disease. In the trial of induction therapy, 374 patients (cohort 1) received vedolizumab (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2, with disease evaluation at week 6. In the trial of maintenance therapy, patients in either cohort who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. A response was defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6 to 31.7; P<0.001). At week 52, 41.8% of patients who continued to receive vedolizumab every 8 weeks and 44.8% of patients who continued to receive vedolizumab every 4 weeks were in clinical remission (Mayo Clinic score ≤2 and no subscore >1), as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [95% CI, 14.9 to 37.2; P<0.001] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [95% CI, 17.9 to 40.4; P<0.001]). The frequency of adverse events was similar in the vedolizumab and placebo groups. Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 ClinicalTrials.gov number, NCT00783718.).

The role of thalidomide and placebo for the treatment of cancer-related anorexia-cachexia symptoms: results of a double-blind placebo-controlled randomized study.

PubMed

Yennurajalingam, Sriram; Willey, Jie S; Palmer, J Lynn; Allo, Julio; Del Fabbro, Egidio; Cohen, Evan N; Tin, Sanda; Reuben, James M; Bruera, Eduardo

2012-10-01

To determine the effects of thalidomide and placebo on anorexia-cachexia and its related symptoms, body composition, resting metabolic rate, and serum cytokines and their receptors in patients with advanced cancer. Included in the study were patients with advanced cancer with weight loss greater than 5% in 6 months and who reported anorexia, fatigue, and one of the following: anxiety, depression, or sleep disturbances. Patients on chemotherapy within 2 weeks prior or during the study were excluded from the study. Patients were randomly assigned to either 100 mg thalidomide or placebo once a day for 14 days. The Edmonton Symptom Assessment Scale (ESAS), Functional Assessment of Anorexia/Cachexia Therapy (FAACT), Functional Assessment of Cancer Illness Therapy (FACIT-F), Hospital Anxiety Depression Scale (HADS) Pittsburgh Sleep Quality Index (PSQI) were utilized, and in addition body composition, Resting Energy Expenditure (REE), and serum cytokine levels were assessed. Of the 31 patients entered in the study, 15 were assigned to the thalidomide group and 16 to the placebo group. However only 21/31 patients were able to complete the study. Compared with their baseline values, both the thalidomide and the placebo groups showed significant reduction in cytokines. Tumor necrosis factor (TNF)-α (p=0.04) and its receptors TNFR1 (p=0.04), TNFR2 (p=0.04), and interleukin (IL)-8 (p=0.04) were statistically significant in the thalidomide group. In the placebo group, TNF-α (p=0.008), TNFR1 (p=0.005), TNFR2 (p=0.005), IL-RA (p=0.005), IL-6 (p=0.005), and IL-8 (p=0.005) were statistically significant. However, improvement in these symptoms and cytokine levels were not significantly different in the thalidomide group compared with the placebo group. None of the patients withdrew from the study because of toxicity of either thalidomide or placebo. Based on the poor accrual rate and attrition observed in this study, it is important that future research on thalidomide as a treatment for cancer-related anorexia-cachexia symptoms (ACS) in patients with advanced cancer use less stringent entry criteria and less exhaustive outcome measures.

Efficacy of Febuxostat for Slowing the GFR Decline in Patients With CKD and Asymptomatic Hyperuricemia: A 6-Month, Double-Blind, Randomized, Placebo-Controlled Trial.

PubMed

Sircar, Dipankar; Chatterjee, Soumya; Waikhom, Rajesh; Golay, Vishal; Raychaudhury, Arpita; Chatterjee, Suparna; Pandey, Rajendra

2015-12-01

Hyperuricemia is a putative risk factor for the progression of chronic kidney disease (CKD). We hypothesized that control of asymptomatic hyperuricemia may slow disease progression in CKD. This was a single-center, double-blind, randomized, parallel-group, placebo-controlled study. Eligible participants were adults from Eastern India aged 18 to 65 years with CKD stages 3 and 4, with asymptomatic hyperuricemia. The intervention group received febuxostat, 40mg, once daily for 6 months, while the placebo group received placebo; both groups were followed up for 6 months. The primary outcome was the proportion of patients showing a >10% decline in estimated glomerular filtration rate (eGFR) from baseline in the febuxostat and placebo groups. Secondary outcomes included changes in eGFRs in the 2 groups from baseline and at the end of the study period. 45 patients in the febuxostat group and 48 in the placebo group were analyzed. Mean eGFR in the febuxostat group showed a nonsignificant increase from 31.5±13.6 (SD) to 34.7±18.1mL/min/1.73m(2) at 6 months. With placebo, mean eGFR decreased from a baseline of 32.6±11.6 to 28.2±11.5mL/min/1.73m(2) (P=0.003). The difference between groups was 6.5 (95% CI, 0.08-12.81) mL/min/1.73m(2) at 6 months (P=0.05). 17 of 45 (38%) participants in the febuxostat group had a >10% decline in eGFR over baseline compared with 26 of 48 (54%) from the placebo group (P<0.004). Limitations of this study included small numbers of patients and short follow-up, and ∼10% of the randomly assigned population dropped out prior to completion. Febuxostat slowed the decline in eGFR in CKD stages 3 and 4 compared to placebo. Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Correction of Abdominal Distention by Biofeedback-Guided Control of Abdominothoracic Muscular Activity in a Randomized, Placebo-Controlled Trial.

PubMed

Barba, Elizabeth; Accarino, Anna; Azpiroz, Fernando

2017-12-01

Abdominal distention is produced by abnormal somatic postural tone. We developed an original biofeedback technique based on electromyography-guided control of abdominothoracic muscular activity. We performed a randomized, placebo-controlled study to demonstrate the superiority of biofeedback to placebo for the treatment of abdominal distention. At a referral center in Spain, we enrolled consecutive patients with visible abdominal distention who fulfilled the Rome III criteria for functional intestinal disorders (47 women, 1 man; 21-74 years old); 2 patients assigned to the placebo group withdrew and 2 patients assigned to biofeedback were not valid for analysis. Abdominothoracic muscle activity was recorded by electromyography. The patients in the biofeedback group were shown the signal and instructed to control muscle activity, whereas patients in the placebo received no instructions and were given oral simethicone. Each patient underwent 3 sessions over a 10-day period. The primary outcomes were subjective sensation of abdominal distention, measured by graphic rating scales for 10 consecutive days before and after the intervention. Patients in the biofeedback group effectively learned to reduce intercostal activity (by a mean 45% ± 3%), but not patients in the placebo group (reduced by a mean 5% ± 2%; P < .001). Patients in the biofeedback group learned to increase anterior wall muscle activity (by a mean 101% ± 10%), but not in the placebo group (decreased by a mean 4% ± 2%; P < .001). Biofeedback resulted in a 56% ± 1% reduction of abdominal distention (from a mean score of 4.6 ± 0.2 to 2.0 ± 0.2), whereas patients in the placebo group had a reduction of only 13% ± 8% (from a mean score of 4.7 ± 0.1 to 4.1 ± 0.4) (P < .001). In a randomized trial of patients with a functional intestinal disorder, we found that abdominal distention can be effectively corrected by biofeedback-guided control of abdominothoracic muscular activity, compared with placebo. ClincialTrials.gov no: NCT01205100. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Oral Aripiprazole as Maintenance Treatment in Adolescent Schizophrenia: Results From a 52-Week, Randomized, Placebo-Controlled Withdrawal Study.

PubMed

Correll, Christoph U; Kohegyi, Eva; Zhao, Cathy; Baker, Ross A; McQuade, Robert; Salzman, Phyllis M; Sanchez, Raymond; Nyilas, Margaretta; Carson, William

2017-09-01

To evaluate the efficacy, safety, and tolerability of aripiprazole, a dopamine D 2 receptor partial agonist, as maintenance treatment in adolescent outpatients with schizophrenia. This was a multicenter, double-blind, placebo-controlled, randomized withdrawal design trial. Participants 13 to 17 years of age with a diagnosis of schizophrenia (DSM-IV-TR) were first cross-titrated from their other oral antipsychotic(s) (4-6 weeks), then stabilized (7-21 weeks) on oral aripiprazole 10 to 30 mg/d, and finally randomized 2:1 to continuation of oral aripiprazole or to placebo in a double-blind maintenance phase (≤52 weeks). The primary endpoint was time from randomization to exacerbation of psychotic symptoms/impending relapse. Safety and tolerability were assessed. Of 201 enrolled participants, 146 were randomized to aripiprazole (n = 98) or placebo (n = 48) in the double-blind maintenance phase. Treatment with aripiprazole was associated with a significantly longer time to exacerbation of psychotic symptoms/impending relapse compared with placebo (hazard ratio, 0.46 [95% CI = 0.24-0.88]; p = .016). Aripiprazole was associated with lower rates of serious treatment-emergent adverse events (TEAEs) versus placebo (3.1% versus 12.5%; p = .059) and severe TEAEs (2.0% versus 10.4%; p = .039). The rate of discontinuation due to TEAEs was lower with aripiprazole versus placebo (20.4% versus 39.6%, p = .014; number-needed-to-harm = 5.1). The incidences of extrapyramidal symptoms, weight gain, and somnolence were similar or lower with aripiprazole than with placebo, and no TEAEs related to elevated serum prolactin were reported. Based on Tanner staging, 27.6% of participants treated with aripiprazole and 16.7% of those who received placebo progressed one or two stages from baseline. Aripiprazole was observed to be safe and effective for the maintenance treatment of adolescents with schizophrenia. Efficacy and Safety Study of Oral Aripiprazole in Adolescents With Schizophrenia; http://clinicaltrials.gov/; NCT01149655. Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Effects of a Standardized Bacopa monnieri Extract on Cognitive Performance, Anxiety, and Depression in the Elderly: A Randomized, Double-Blind, Placebo-Controlled Trial

PubMed Central

Gregory, William L.; Leo, Michael; Kraemer, Dale; Bone, Kerry; Oken, Barry

2008-01-01

Abstract Objectives Study aims were to evaluate effects of Bacopa monnieri whole plant standardized dry extract on cognitive function and affect and its safety and tolerability in healthy elderly study participants. Design The study was a randomized, double-blind, placebo-controlled clinical trial with a placebo run-in of 6 weeks and a treatment period of 12 weeks. Setting/location Volunteers were recruited from the community to a clinic in Portland, Oregon by public notification. Subjects Fifty-four (54) participants, 65 or older (mean 73.5 years), without clinical signs of dementia, were recruited and randomized to Bacopa or placebo. Forty-eight (48) completed the study with 24 in each group. Interventions Standardized B. monnieri extract 300 mg/day or a similar placebo tablet orally for 12 weeks. Outcome measures The primary outcome variable was the delayed recall score from the Rey Auditory Verbal Learning Test (AVLT). Other cognitive measures were the Stroop Task assessing the ability to ignore irrelevant information, the Divided Attention Task (DAT), and the Wechsler Adult Intelligence Scale (WAIS) letter-digit test of immediate working memory. Affective measures were the State-Trait Anxiety Inventory, Center for Epidemiologic Studies Depression scale (CESD)-10 depression scale, and the Profile of Mood States. Vital signs were also monitored. Results Controlling for baseline cognitive deficit using the Blessed Orientation–Memory–Concentration test, Bacopa participants had enhanced AVLT delayed word recall memory scores relative to placebo. Stroop results were similarly significant, with the Bacopa group improving and the placebo group unchanged. CESD-10 depression scores, combined state plus trait anxiety scores, and heart rate decreased over time for the Bacopa group but increased for the placebo group. No effects were found on the DAT, WAIS digit task, mood, or blood pressure. The dose was well tolerated with few adverse events (Bacopa n = 9, placebo n = 10), primarily stomach upset. Conclusions This study provides further evidence that B. monnieri has potential for safely enhancing cognitive performance in the aging. PMID:18611150

Individualized Homeopathic Treatment and Fluoxetine for Moderate to Severe Depression in Peri- and Postmenopausal Women (HOMDEP-MENOP Study): A Randomized, Double-Dummy, Double-Blind, Placebo-Controlled Trial

PubMed Central

Macías-Cortés, Emma del Carmen; Llanes-González, Lidia; Aguilar-Faisal, Leopoldo; Asbun-Bojalil, Juan

2015-01-01

Background Perimenopausal period refers to the interval when women's menstrual cycles become irregular and is characterized by an increased risk of depression. Use of homeopathy to treat depression is widespread but there is a lack of clinical trials about its efficacy in depression in peri- and postmenopausal women. The aim of this study was to assess efficacy and safety of individualized homeopathic treatment versus placebo and fluoxetine versus placebo in peri- and postmenopausal women with moderate to severe depression. Methods/Design A randomized, placebo-controlled, double-blind, double-dummy, superiority, three-arm trial with a 6 week follow-up study was conducted. The study was performed in a public research hospital in Mexico City in the outpatient service of homeopathy. One hundred thirty-three peri- and postmenopausal women diagnosed with major depression according to DSM-IV (moderate to severe intensity) were included. The outcomes were: change in the mean total score among groups on the 17-item Hamilton Rating Scale for Depression, Beck Depression Inventory and Greene Scale, after 6 weeks of treatment, response and remission rates, and safety. Efficacy data were analyzed in the intention-to-treat population (ANOVA with Bonferroni post-hoc test). Results After a 6-week treatment, homeopathic group was more effective than placebo by 5 points in Hamilton Scale. Response rate was 54.5% and remission rate, 15.9%. There was a significant difference among groups in response rate definition only, but not in remission rate. Fluoxetine-placebo difference was 3.2 points. No differences were observed among groups in the Beck Depression Inventory. Homeopathic group was superior to placebo in Greene Climacteric Scale (8.6 points). Fluoxetine was not different from placebo in Greene Climacteric Scale. Conclusion Homeopathy and fluoxetine are effective and safe antidepressants for climacteric women. Homeopathy and fluoxetine were significantly different from placebo in response definition only. Homeopathy, but not fluoxetine, improves menopausal symptoms scored by Greene Climacteric Scale. Trial Registration ClinicalTrials.gov NCT01635218 Protocol Publication http://www.trialsjournal.com/content/14/1/105. PMID:25768800

A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients: a high-dose study.

PubMed

Aronne, L J; Tonstad, S; Moreno, M; Gantz, I; Erondu, N; Suryawanshi, S; Molony, C; Sieberts, S; Nayee, J; Meehan, A G; Shapiro, D; Heymsfield, S B; Kaufman, K D; Amatruda, J M

2010-05-01

To evaluate the efficacy, safety and tolerability of taranabant in obese and overweight patients. Double-blind, randomized, placebo-controlled study. Patients were >or=18 years old, with body mass index of 27-43 kg m(-2), and 51% with metabolic syndrome (MS) randomized to placebo (N=417) or taranabant 2 mg (N=414), 4 mg (N=415) or 6 mg (N=1256) for 104 weeks. Key efficacy measurements included body weight, waist circumference (WC), lipid and glycemic end points. On the basis of risk/benefit assessments, the 6-mg dose was discontinued during year 1 (patients on 6 mg were down-dosed to 2 mg or placebo) and the 4-mg dose was discontinued during year 2 (patients on 4 mg were down-dosed to 2 mg). Changes from baseline in body weight at week 52 (all-patients-treated population, last observation carried forward analysis) were -2.6, -6.6 and -8.1 kg, respectively, for placebo and taranabant 2 and 4 mg (both doses P<0.001 vs placebo). For patients who completed year 1, changes from baseline in body weight at week 104 were -1.4, -6.4 and -7.6 kg for placebo and taranabant 2 and 4 mg, respectively (both doses P<0.001 vs placebo). The proportions of patients at weeks 52 and 104 who lost at least 5 and 10% of their baseline body weight were significantly higher and the proportions of patients who met criteria for MS were significantly lower for taranabant 2 and 4 mg vs placebo. The incidence of adverse experiences classified in the gastrointestinal, nervous, psychiatric, cutaneous and vascular organ systems were generally observed to be dose related with taranabant vs placebo. Taranabant at the 2- and 4-mg dose was effective in achieving clinically significant weight loss over 2 years and was associated with dose-related increases in adverse experiences. On the basis of these and other data, an assessment was made that the overall safety and efficacy profile of taranabant did not support its further development for the treatment of obesity.

The safety profile of parecoxib for the treatment of postoperative pain: a pooled analysis of 28 randomized, double-blind, placebo-controlled clinical trials and a review of over 10 years of postauthorization data

PubMed Central

Schug, Stephan A; Parsons, Bruce; Li, Chunming; Xia, Feng

2017-01-01

Background Nonselective, nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors are associated with safety issues including cardiovascular, renal, and gastrointestinal (GI) events. Objective To examine the safety of parecoxib, a COX-2 inhibitor, for the management of postoperative pain. Design Pooled analysis of 28 placebo-controlled trials of parecoxib and review of postauthorization safety data. Main outcome measures Prespecified safety events commonly associated with COX-2 inhibitors and/or NSAIDs. In the clinical trial analysis, the frequency of each event was compared between treatment groups using a chi-square test. In the postauthorization review, the number of confirmed cases, along with outcome, was presented for each event. Results In the clinical trial analysis, GI-related events occurred in ~0.2% of patients in the parecoxib and placebo groups. Renal failure and impairment was similar between parecoxib (1.0%) and placebo (0.9%). The occurrence of arterial (parecoxib=0.3%; placebo=0.2%) and venous (parecoxib=0.2%; placebo=0.1%) cardiovascular embolic and thrombotic events was similar between groups. Hypersensitivity reactions including anaphylactic reactions (parecoxib=8.7%; placebo=8.6%), hypotension (parecoxib=2.6%; placebo=2.1%), angioedema (parecoxib=2.5%; placebo=2.8%), and severe cutaneous adverse reactions (0% in both groups) were similar between groups. Incision site or other skin/tissue infections occurred in <0.1% of patients in both groups. The occurrence of these events (total reports/serious reports) in the postauthorization database, based on 69,567,300 units of parecoxib, was as follows: GI ulceration-related events (35/35), renal failure and impairment (77/68), cardiovascular embolic and thrombotic events (66/64), hypersensitivity reactions including hypotension-related events (32/25) and severe cutaneous adverse events (17/17), and masking signs of inflammation (18/18). A majority of reported outcomes were classified as recovered or recovering. Conclusions Potentially serious safety events occur infrequently with parecoxib, which high-lights its safety in patients with postoperative pain. PMID:29066931

The safety profile of parecoxib for the treatment of postoperative pain: a pooled analysis of 28 randomized, double-blind, placebo-controlled clinical trials and a review of over 10 years of postauthorization data.

PubMed

Schug, Stephan A; Parsons, Bruce; Li, Chunming; Xia, Feng

2017-01-01

Nonselective, nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors are associated with safety issues including cardiovascular, renal, and gastrointestinal (GI) events. To examine the safety of parecoxib, a COX-2 inhibitor, for the management of postoperative pain. Pooled analysis of 28 placebo-controlled trials of parecoxib and review of postauthorization safety data. Prespecified safety events commonly associated with COX-2 inhibitors and/or NSAIDs. In the clinical trial analysis, the frequency of each event was compared between treatment groups using a chi-square test. In the postauthorization review, the number of confirmed cases, along with outcome, was presented for each event. In the clinical trial analysis, GI-related events occurred in ~0.2% of patients in the parecoxib and placebo groups. Renal failure and impairment was similar between parecoxib (1.0%) and placebo (0.9%). The occurrence of arterial (parecoxib=0.3%; placebo=0.2%) and venous (parecoxib=0.2%; placebo=0.1%) cardiovascular embolic and thrombotic events was similar between groups. Hypersensitivity reactions including anaphylactic reactions (parecoxib=8.7%; placebo=8.6%), hypotension (parecoxib=2.6%; placebo=2.1%), angioedema (parecoxib=2.5%; placebo=2.8%), and severe cutaneous adverse reactions (0% in both groups) were similar between groups. Incision site or other skin/tissue infections occurred in <0.1% of patients in both groups. The occurrence of these events (total reports/serious reports) in the postauthorization database, based on 69,567,300 units of parecoxib, was as follows: GI ulceration-related events (35/35), renal failure and impairment (77/68), cardiovascular embolic and thrombotic events (66/64), hypersensitivity reactions including hypotension-related events (32/25) and severe cutaneous adverse events (17/17), and masking signs of inflammation (18/18). A majority of reported outcomes were classified as recovered or recovering. Potentially serious safety events occur infrequently with parecoxib, which high-lights its safety in patients with postoperative pain.

Summary of anti-malarial prophylactic efficacy of tafenoquine from three placebo-controlled studies of residents of malaria-endemic countries.

PubMed

Dow, Geoffrey S; Liu, Jun; Lin, Gina; Hetzell, Brian; Thieling, Sarah; McCarthy, William F; Tang, Douglas; Smith, Bryan

2015-11-26

Tafenoquine is a long half-life primaquine analog being developed for malaria prophylaxis. The US Army recently performed a unified analysis of efficacy in preparation for a regulatory submission, utilizing legacy data from three placebo-controlled studies conducted in the late 1990s and early 2000s. The subjects were residents of Africa who were naturally exposed to Plasmodium falciparum for 12-26 weeks. The prophylactic efficacy of tafenoquine and mefloquine (included in some studies as a comparator) was calculated using incidence density among subjects who had completed the three-day loading doses of study drug, had at least one maintenance dose and had at least one blood smear assessed during the prophylactic period. The three placebo-controlled studies were analysed separately and then in two pooled analyses: one for tafenoquine versus placebo (three studies) and one for tafenoquine and mefloquine versus placebo (two studies). The pooled protective efficacy (PE) of a tafenoquine regimen with three daily loading doses plus weekly maintenance at 200-mg for 10 weeks or longer (referred to as 200-mg weekly hereafter) relative to placebo in three placebo-controlled studies was 93.1 % [95 % confidence interval (CI) 89.1-95.6 %; total N = 492]. The pooled PEs of regimens of tafenoquine 200-mg weekly and mefloquine 250-mg weekly relative to placebo in two placebo-controlled studies (total N = 519) were 93.5 % (95 % CI 88.6-96.2 %) and 94.5 % (95 % CI 88.7-97.3 %), respectively. Three daily loading plus weekly maintenance doses of 50- and 100-mg, but not 25-mg, exhibited similar PEs. The PEs of tafenoquine regimens of a three-day loading dose at 400-mg with and without follow-up weekly maintenance doses at 400-mg were 93.7 % (95 % CI 85.4-97.3 %) and 81.0 % (95 % CI 66.8-89.1 %), respectively. Tafenoquine provided the same level of prophylactic efficacy as mefloquine in residents of Africa. These data support the prophylactic efficacy of tafenoquine and mefloquine that has already been demonstrated in the intended malaria naive population.

Does 3-Day Course of Oral Amoxycillin Benefit Children of Non-Severe Pneumonia with Wheeze: A Multicentric Randomised Controlled Trial

PubMed Central

Awasthi, Shally; Agarwal, Girdhar; Kabra, Sushil K.; Singhi, Sunit; Kulkarni, Madhuri; More, Vaishali; Niswade, Abhimanyu; Pillai, Raj Mohan; Luke, Ravi; Srivastava, Neeraj M.; Suresh, Saradha; Verghese, Valsan P.; Raghupathy, P.; Lodha, R.; Walter, Stephen D.

2008-01-01

Background WHO-defined pneumonias, treated with antibiotics, are responsible for a significant proportion of childhood morbidity and mortality in the developing countries. Since substantial proportion pneumonias have a viral etiology, where children are more likely to present with wheeze, there is a concern that currently antibiotics are being over-prescribed for it. Hence the current trial was conducted with the objective to show the therapeutic equivalence of two treatments (placebo and amoxycillin) for children presenting with non-severe pneumonia with wheeze, who have persistent fast breathing after nebulisation with salbutamol, and have normal chest radiograph. Methodology This multi-centric, randomised placebo controlled double blind clinical trial intended to investigate equivalent efficacy of placebo and amoxicillin and was conducted in ambulatory care settings in eight government hospitals in India. Participants were children aged 2–59 months of age, who received either oral amoxycillin (31–54 mg/Kg/day, in three divided doses for three days) or placebo, and standard bronchodilator therapy. Primary outcome was clinical failure on or before day- 4. Principal Findings We randomized 836 cases in placebo and 835 in amoxycillin group. Clinical failures occurred in 201 (24.0%) on placebo and 166 (19.9%) on amoxycillin (risk difference 4.2% in favour of antibiotic, 95% CI: 0.2 to 8.1). Adherence for both placebo and amoxycillin was >96% and 98.9% subjects were followed up on day- 4. Clinical failure was associated with (i) placebo treatment (adjusted OR = 1.28, 95% CI: 1.01 to1.62), (ii) excess respiratory rate of >10 breaths per minute (adjusted OR = 1.51, 95% CI: 1.19, 1.92), (iii) vomiting at enrolment (adjusted OR = 1.49, 95% CI: 1.13, 1.96), (iv) history of use of broncho-dilators (adjusted OR = 1.71, 95% CI: 1.30, 2.24) and (v) non-adherence (adjusted OR = 8.06, 95% CI: 4.36, 14.92). Conclusions Treating children with non-severe pneumonia and wheeze with a placebo is not equivalent to treatment with oral amoxycillin. Trial Registration ClinicalTrials.gov NCT00407394 PMID:18431478

A randomized, placebo-controlled trial of nandrolone decanoate in human immunodeficiency virus-infected men with mild to moderate weight loss with recombinant human growth hormone as active reference treatment.

PubMed

Storer, Thomas W; Woodhouse, Linda J; Sattler, Fred; Singh, Atam B; Schroeder, E Todd; Beck, Keith; Padero, MaClara; Mac, Phong; Yarasheski, Kevin E; Geurts, Paul; Willemsen, Arnold; Harms, Marloes K; Bhasin, Shalender

2005-08-01

We compared the effectiveness of a biweekly regimen of 150 mg nandrolone with placebo in HIV-infected men with mild to moderate weight loss and contrasted its effects against a Food and Drug Administration-approved regimen of recombinant human (rh)GH. In this placebo-controlled, randomized, 12-wk trial, placebo and nandrolone (150 mg im biweekly) were administered double blind, and rhGH (6 mg sc daily) was administered in an open-label manner. Participants were HIV-infected men with 5-15% weight loss over 6 months and on stable antiretroviral therapy for more than 12 wk. Lean body mass (LBM), muscle performance, physical function, endurance, hormone levels, insulin sensitivity, sexual function, quality of life, and appetite were assessed at baseline and after 12 wk. Nandrolone administration was associated with a greater increase in LBM (+1.6 +/- 0.3 kg) by dual-energy x-ray absorptiometry scan than placebo (+0.4 +/- 0.3 kg; P < 0.05); however, the change in LBMs with nandrolone was not significantly different from rhGH (+2.5 +/- 0.3 kg). Nandrolone administration was also associated with significantly greater gains in fat-free mass (+1.6 +/- 0.3 kg), body cell mass (+1.0 +/- 0.2 kg), and intracellular water (+0.9 +/- 0.2 kg) than placebo; these changes in the nandrolone group were not significantly different from the rhGH group. rhGH administration was associated with greater loss of whole body fat mass and higher frequency of drug-related adverse effects and treatment discontinuations than nandrolone and placebo and a greater increase in extracellular water than nandrolone. Nandrolone treatment was associated with greater improvements in perception of health than rhGH and sexual function than placebo. The cachexia/anorexia scores, health care resource use, and insulin sensitivity did not significantly change. We conclude that nandrolone is superior to placebo and not significantly different from a Food and Drug Administration-approved regimen of rhGH in improving lean body mass in HIV-infected men with mild to moderate weight loss.

Ferric citrate hydrate for the treatment of hyperphosphatemia in nondialysis-dependent CKD.

PubMed

Yokoyama, Keitaro; Hirakata, Hideki; Akiba, Takashi; Fukagawa, Masafumi; Nakayama, Masaaki; Sawada, Kenichi; Kumagai, Yuji; Block, Geoffrey A

2014-03-01

Ferric citrate hydrate is a novel iron-based phosphate binder being developed for hyperphosphatemia in patients with CKD. A phase 3, multicenter, randomized, double blind, placebo-controlled study investigated the efficacy and safety of ferric citrate hydrate in nondialysis-dependent patients with CKD. Starting in April of 2011, 90 CKD patients (eGFR=9.21±5.72 ml/min per 1.73 m(2)) with a serum phosphate≥5.0 mg/dl were randomized 2:1 to ferric citrate hydrate or placebo for 12 weeks. The primary end point was change in serum phosphate from baseline to the end of treatment. Secondary end points included the percentage of patients achieving target serum phosphate levels (2.5-4.5 mg/dl) and change in fibroblast growth factor-23 at the end of treatment. The mean change in serum phosphate was -1.29 mg/dl (95% confidence interval, -1.63 to -0.96 mg/dl) in the ferric citrate hydrate group and 0.06 mg/dl (95% confidence interval, -0.20 to 0.31 mg/dl) in the placebo group (P<0.001 for difference between groups). The percentage of patients achieving target serum phosphate levels was 64.9% in the ferric citrate hydrate group and 6.9% in the placebo group (P<0.001). Fibroblast growth factor-23 concentrations were significantly lower in patients treated with ferric citrate hydrate versus placebo (change from baseline [median], -142.0 versus 67.0 pg/ml; P<0.001). Ferric citrate hydrate significantly increased serum iron, ferritin, and transferrin saturation compared with placebo (P=0.001 or P<0.001). Five patients discontinued active treatment because of treatment-emergent adverse events with ferric citrate hydrate treatment versus one patient with placebo. Overall, adverse drug reactions were similar in patients receiving ferric citrate hydrate or placebo, with gastrointestinal disorders occurring in 30.0% of ferric citrate hydrate patients and 26.7% of patients receiving placebo. In patients with nondialysis-dependent CKD, 12-week treatment with ferric citrate hydrate resulted in significant reductions in serum phosphate and fibroblast growth factor-23 while simultaneously increasing serum iron parameters.

Phase 3 randomized study of the efficacy and safety of inhaled dry powder mannitol for the symptomatic treatment of non-cystic fibrosis bronchiectasis.

PubMed

Bilton, Diana; Daviskas, Evangelia; Anderson, Sandra D; Kolbe, John; King, Gregory; Stirling, Rob G; Thompson, Bruce R; Milne, David; Charlton, Brett

2013-07-01

Inhaled dry powder mannitol enhanced mucus clearance and improved quality of life over 2 weeks in non-cystic fibrosis bronchiectasis. This study's objective was to investigate the efficacy and safety of dry powder mannitol over 12 weeks. Patients with bronchiectasis confirmed by high-resolution CT (HRCT) scan, aged 15 to 80 years, with FEV1≥50% predicted and ≥1 L participated in a randomized, placebo-controlled, double-blind study. Patients with a negative mannitol provocation test were randomized to inhale 320 mg mannitol (n=231) or placebo (n=112) bid for 12 weeks. To further assess safety, the same mannitol dose/frequency was administered to a patient subset in an open-label extension over 52 weeks. Primary end points were changes from baseline at 12 weeks in 24-h sputum weight and St. George's Respiratory Questionnaire (SGRQ) score. There was a significant difference of 4.3 g in terms of change in sputum weight over 12 weeks (95% CI, 1.64-7.00; P=.002) between mannitol and placebo; however, this was largely driven by a decrease in sputum weight in the placebo group. This was associated, in turn, with more antibiotic use in the placebo group (50 of 112 [45%]) than in the inhaled mannitol group (85 of 231 [37%]). There was no statistical difference between the groups (P=.304) in total SGRQ score (mannitol, -3.4 points [95% CI, -4.81 to -1.94] vs placebo, -2.1 points [95% CI, -4.12 to -0.09]). In a subgroup study (n=82), patients receiving mannitol showed less small airway mucus plugging on HRCT scan at 12 weeks compared with patients receiving placebo (P=.048). Compliance rates were high, and mannitol was well tolerated with adverse events similar to those of placebo. Because the difference in sputum weights appears to be associated with increased antibiotic use in the placebo group, a larger controlled study is now required to investigate the long-term mannitol effect on pulmonary exacerbations and antibiotic use. ClinicalTrials.gov; No.: NCT0027753; URL: www.clinicaltrials.gov.

Novel sublingual low-dose zolpidem tablet reduces latency to sleep onset following spontaneous middle-of-the-night awakening in insomnia in a randomized, double-blind, placebo-controlled, outpatient study.

PubMed

Roth, Thomas; Krystal, Andrew; Steinberg, Frank J; Singh, Nikhilesh N; Moline, Margaret

2013-02-01

To evaluate efficacy and safety of 3.5-mg zolpidem tartrate sublingual tablets (ZST) on latency to sleep onset after middle-of-the-night (MOTN) awakenings in patients with insomnia characterized by difficulty returning to sleep after MOTN awakenings. Multicenter randomized, double-blind, placebo-controlled, parallel-group. Outpatient. There were 295 adults (median age 43 y; 68.1% female) with primary insomnia and difficulty returning to sleep after MOTN awakenings (three or more MOTN awakenings/wk during screening). After a 2-wk, single-blind placebo eligibility period, participants were randomized 1:1 to as-needed MOTN dosing with 3.5 mg ZST or placebo for 28 nights. An interactive voice response system determined if the study drug could be taken and recorded sleep/wake efficacy measures. ZST significantly (P < 0.0001) decreased latency to sleep onset over 4 wk (baseline 68.1 min; ZST 38.2 min) compared with placebo (baseline 69.4 min; placebo 56.4 min). Ratings of morning sleepiness/alertness significantly (P = 0.0041) favored the ZST group on nights medication was taken but not on other nights. Participants in the ZST group took the study drug on 62% of nights during the 4 wk; members of the placebo group took study medication on 64% of nights. Adverse events were generally mild and at the same rate (19.3% of participants) in both groups. There were no treatment-related serious adverse events (SAEs), and one adverse event-related study discontinuation from the placebo group. Dosing/week did not increase across the study. 3.5 mg ZST used as needed significantly reduced latency to return to sleep in comparison with placebo in these patients with insomnia. Sleep quality was improved, and morning sleepiness/alertness scores also improved. ZST was well tolerated. These data demonstrate the utility of a sleep-promoting agent when used as needed in the MOTN. NCT00466193: "A Study of Zolpidem Tartrate Tablet in Adult Patients with Insomnia" http://www.clinicaltrials.gov/ct2/show/NCT00466193?spons=%22Transcept+Pharmaceuticals%22&spons_ex=Y&rank=2

Rotigotine transdermal patch in Chinese patients with advanced Parkinson's disease: A randomized, double-blind, placebo-controlled pivotal study.

PubMed

Zhang, Zhen-Xin; Liu, Chun-Feng; Tao, En-Xiang; Shao, Ming; Liu, Yi-Ming; Wang, Jian; Asgharnejad, Mahnaz; Xue, Hai-Bo; Surmann, Erwin; Bauer, Lars

2017-11-01

Rotigotine was demonstrated to be efficacious and well-tolerated in three placebo-controlled studies (CLEOPATRA-PD/PREFER/SP921) of patients with advanced-stage Parkinson's disease (PD), most of whom were Caucasian. This multicenter phase 3 study (SP1037; NCT01646255) was the first to investigate the efficacy and safety of rotigotine in Chinese patients with advanced-stage PD. Chinese patients with PD, inadequately controlled on levodopa (stable dose ≥200 mg/day), with ≥2.5 h/day "off" time, and Hoehn & Yahr stage 2-4, were randomized 1:1 to receive transdermal rotigotine or placebo, titrated over ≤7 weeks, maintained at optimal/maximum dose (4-16 mg/24 h) for 12 weeks. Primary efficacy variable: mean change in absolute "off" time (according to patient diaries) from baseline to end of maintenance. Safety variables included adverse events (AEs) and discontinuations due to AEs. 346 patients were randomized and 89.9% completed the study (87.8% placebo; 92.0% rotigotine). All were Chinese (58.7% male; mean ± SD age: 62.2 ± 8.9 years; mean ± SD time since PD diagnosis: 6.62 ± 3.70 years). Rotigotine significantly reduced "off" time vs placebo (LS mean [95% CI] treatment difference: -1.20 h/day [-1.83, -0.57]; p = 0.0002), and resulted in more responders (≥30% decrease in "off" time: 36.9% placebo; 48.8% rotigotine; p = 0.0269). AEs were reported for 86 (50.0%) placebo- and 103 (59.2%) rotigotine-treated patients; 15 discontinued due to AEs (placebo 7; rotigotine 8). The most common AEs (≥5%) were dizziness, nausea, pruritus, and dyskinesia. Rotigotine was efficacious in Chinese patients with advanced-stage PD as add-on therapy to levodopa, significantly reducing "off" time vs placebo; the treatment difference was similar to that observed in previous studies of mainly Caucasian patients. Rotigotine was generally well-tolerated and had a similar AE profile to those observed in previous studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Once daily controlled-release pregabalin in the treatment of patients with fibromyalgia: a phase III, double-blind, randomized withdrawal, placebo-controlled study.

PubMed

Arnold, Lesley M; Arsenault, Pierre; Huffman, Cynthia; Patrick, Jeffrey L; Messig, Michael; Chew, Marci L; Sanin, Luis; Scavone, Joseph M; Pauer, Lynne; Clair, Andrew G

2014-10-01

Safety and efficacy of a once daily controlled-released (CR) formulation of pregabalin was evaluated in patients with fibromyalgia using a placebo-controlled, randomized withdrawal design. This multicenter study included 6 week single-blind pregabalin CR treatment followed by 13 week double-blind treatment with placebo or pregabalin CR. The starting dose of 165 mg/day was escalated during the first 3 weeks, up to 495 mg/day based on efficacy and tolerability. Patients with ≥50% reduction in average daily pain score at the end of the single-blind phase were randomized to continue pregabalin CR at the optimized dose (330-495 mg/day) or to placebo. The primary endpoint was time to loss of therapeutic response (LTR), defined as <30% pain reduction relative to single-blind baseline or discontinuation owing to lack of efficacy or adverse event (AE). Secondary endpoints included measures of pain severity, global assessment, functional status, tiredness/fatigue, and sleep. ClinicalTrials.gov NCT01271933. A total of 441 patients entered the single-blind phase, and 63 were randomized to pregabalin CR and 58 to placebo. The median time to LTR (Kaplan-Meier analysis) was significantly longer in the pregabalin CR group than placebo (58 vs. 22 days, p = 0.02). By trial end, 34/63 (54.0%) pregabalin CR and 41/58 (70.7%) placebo patients experienced LTR. Significantly more patients reported 'benefit from treatment' (Benefit, Satisfaction, and Willingness to Continue Scale) in the pregabalin CR group; no other secondary endpoints were statistically significant. Most AEs were mild to moderate in severity (most frequent: dizziness, somnolence). The percentage of pregabalin CR patients discontinuing because of AEs was 12.2% and 4.8% in the single-blind and double-blind phases, respectively (placebo, 0%). Time to LTR was significantly longer with pregabalin CR versus placebo in fibromyalgia patients who initially showed improvement with pregabalin CR, indicating maintenance of response. Pregabalin CR was well tolerated in most patients. Generalizability may be limited by study duration and selective population.

Recurrent urinary tract infection and urinary Escherichia coli in women ingesting cranberry juice daily: a randomized controlled trial.

PubMed

Stapleton, Ann E; Dziura, James; Hooton, Thomas M; Cox, Marsha E; Yarova-Yarovaya, Yuliya; Chen, Shu; Gupta, Kalpana

2012-02-01

To compare the time to urinary tract infection (UTI) and the rates of asymptomatic bacteriuria and urinary P-fimbriated Escherichia coli during a 6-month period in women ingesting cranberry vs placebo juice daily. Premenopausal women with a history of recent UTI were enrolled from November 16, 2005, through December 31, 2008, at 2 centers and randomized to 1 of 3 arms: 4 oz of cranberry juice daily, 8 oz of cranberry juice daily, or placebo juice. Time to UTI (symptoms plus pyuria) was the main outcome. Asymptomatic bacteriuria, adherence, and adverse effects were assessed at monthly visits. A total of 176 participants were randomized (120 to cranberry juice and 56 to placebo) and followed up for a median of 168 days. The cumulative rate of UTI was 0.29 in the cranberry juice group and 0.37 in the placebo group (P=.82). The adjusted hazard ratio for UTI in the cranberry juice group vs the placebo group was 0.68 (95% confidence interval, 0.33-1.39; P=.29). The proportion of women with P-fimbriated urinary E coli isolates during the intervention phase was 10 of 23 (43.5%) in the cranberry juice group and 8 of 10 (80.0%) in the placebo group (P=.07). The mean dose adherence was 91.8% and 90.3% in the cranberry juice group vs the placebo group. Minor adverse effects were reported by 24.2% of those in the cranberry juice group and 12.5% in the placebo group (P=.07). Cranberry juice did not significantly reduce UTI risk compared with placebo. The potential protective effect we observed is consistent with previous studies and warrants confirmation in larger, well-powered studies of women with recurrent UTI. The concurrent reduction in urinary P-fimbriated E coli strains supports the biological plausibility of cranberry activity. clinicaltrials.gov Identifier: NCT00128128. Copyright © 2012 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study.

PubMed

Kudo, Masatoshi; Cheng, Ann-Lii; Park, Joong-Won; Park, Jae Hyung; Liang, Po-Chin; Hidaka, Hisashi; Izumi, Namiki; Heo, Jeong; Lee, Youn Jae; Sheen, I-Shyan; Chiu, Chang-Fang; Arioka, Hitoshi; Morita, Satoshi; Arai, Yasuaki

2018-01-01

Orantinib is an oral multi-kinase inhibitor. This study was done to evaluate the efficacy of orantinib combined with conventional transcatheter arterial chemoembolisation (cTACE) in patients with unresectable hepatocellular carcinoma. This randomised, double-blind, placebo-controlled, phase 3 study was done at 75 sites in Japan, South Korea, and Taiwan. Patients with unresectable hepatocellular carcinoma, no extra-hepatic tumour spread, and Child-Pugh score of 6 or less were randomly assigned (1:1) by interactive web response system using a computer-generated sequence to receive orantinib or placebo, within 28 days of cTACE. Randomisation was stratified by region, Child-Pugh score (5 vs 6), alpha fetoprotein concentrations (<400 ng/mL vs ≥400 ng/mL), and size of the largest lesion (≤50 mm vs >50 mm). Orantinib at 200 mg, twice per day, or placebo was given orally until TACE failure or unacceptable toxicity. The patients, investigators, and study personnel were masked to treatment assignment. The primary endpoint was overall survival, analysed in the full analysis set (patients who had received at least one dose of study drug). This study is registered at ClinicalTrials.gov, number NCT01465464, and has been terminated. Between Dec 10, 2010, and Nov 21, 2013, 889 patients were randomly assigned to receive either orantinib (445 patients; 444 treated) or placebo (444 patients; all treated). The study was ended at interim analysis for futility evaluation. Median follow-up was 17·3 months (IQR 11·3-26·4). There was no improvement in overall survival with orantinib compared with placebo (median 31·1 months [95% CI 26·5-34·5] vs 32·3 months [28·4-not reached]; hazard ratio 1·090, 95% CI 0·878-1·352; p=0·435). The main adverse events in the orantinib group were oedema, ascites, and elevation of aspartate and alanine aminotransferases. The most frequent adverse events of grade 3 or worse in the orantinib group included elevated aspartate aminotransferase (189 [43%] patients in the oratinib group, 161 [36%] patients in the placebo group), elevated alanine aminotransferase (150 [34%] patients in the oratinib group, 132 (30%) patients in the placebo group), and hypertension (47 [11%] patients in the oratinib group, 39 [9%] patients in the placebo group). Serious adverse events were reported in 200 (45%) patients in the orantinib group and 134 (30%) patients in the placebo group. Orantinib combined with cTACE did not improve overall survival in patients with unresectable hepatocellular carcinoma. Taiho Pharmaceutical. Copyright © 2018 Elsevier Ltd. All rights reserved.

Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial.

PubMed

San-Miguel, Jesús F; Hungria, Vania T M; Yoon, Sung-Soo; Beksac, Meral; Dimopoulos, Meletios A; Elghandour, Ashraf; Jedrzejczak, Wieslaw W; Günther, Andreas; Nakorn, Thanyaphong N; Siritanaratkul, Noppadol; Schlossman, Robert L; Hou, Jian; Moreau, Philippe; Lonial, Sagar; Lee, Jae H; Einsele, Hermann; Sopala, Monika; Bengoudifa, Bourras-Rezki; Binlich, Florence; Richardson, Paul G

2016-11-01

Panobinostat plus bortezomib and dexamethasone significantly increased median progression-free survival compared with placebo plus bortezomib and dexamethasone in the phase 3 PANORAMA 1 trial. Here, we present the final overall survival analysis for this trial. PANORAMA 1 is a randomised, placebo-controlled, double-blind, phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma with one to three previous treatments. Patients were randomly assigned (1:1) to receive panobinostat (20 mg orally) or placebo, with bortezomib (1·3 mg/m 2 intravenously) and dexamethasone (20 mg orally), over two distinct treatment phases. In treatment phase 1 (eight 3-week cycles), patients received: panobinostat or placebo on days 1, 3, 5, 8, 10, and 12; bortezomib on days 1, 4, 8, and 11; and dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. During treatment phase 2 (four 6-week cycles with a 2 weeks on, 1 week off schedule), panobinostat or placebo was given three times a week, bortezomib was administered once a week, and dexamethasone was given on the days of and following bortezomib administration. The primary endpoint was progression-free survival; overall survival was a key secondary endpoint. This study is registered at ClinicalTrials.gov, NCT01023308. Between Jan 21, 2010, and Feb 29, 2012, 768 patients were enrolled into the study and randomly assigned to receive either panobinostat (n=387) or placebo (n=381), plus bortezomib and dexamethasone. At data cutoff (June 29, 2015), 415 patients had died. Median overall survival was 40·3 months (95% CI 35·0-44·8) in those who received panobinostat, bortezomib, and dexamethasone versus 35·8 months (29·0-40·6) in those who received placebo, bortezomib, and dexamethasone (hazard ratio [HR] 0·94, 95% CI 0·78-1·14; p=0·54). Of patients who had received at least two previous regimens including bortezomib and an immunomodulatory drug, median overall survival was 25·5 months (95% CI 19·6-34·3) in 73 patients who received panobinostat, bortezomib, and dexamethasone versus 19·5 months (14·1-32·5) in 74 who received placebo (HR 1·01, 95% CI 0·68-1·50). The overall survival benefit with panobinostat over placebo with bortezomib and dexamethasone was modest. However, optimisation of the regimen could potentially prolong treatment duration and improve patients' outcomes, although further trials will be required to confirm this. Novartis Pharmaceuticals. Copyright © 2016 Elsevier Ltd. All rights reserved.

Trial of Tocilizumab in Giant-Cell Arteritis.

PubMed

Stone, John H; Tuckwell, Katie; Dimonaco, Sophie; Klearman, Micki; Aringer, Martin; Blockmans, Daniel; Brouwer, Elisabeth; Cid, Maria C; Dasgupta, Bhaskar; Rech, Juergen; Salvarani, Carlo; Schett, Georg; Schulze-Koops, Hendrik; Spiera, Robert; Unizony, Sebastian H; Collinson, Neil

2017-07-27

Giant-cell arteritis commonly relapses when glucocorticoids are tapered, and the prolonged use of glucocorticoids is associated with side effects. The effect of the interleukin-6 receptor alpha inhibitor tocilizumab on the rates of relapse during glucocorticoid tapering was studied in patients with giant-cell arteritis. In this 1-year trial, we randomly assigned 251 patients, in a 2:1:1:1 ratio, to receive subcutaneous tocilizumab (at a dose of 162 mg) weekly or every other week, combined with a 26-week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 weeks or 52 weeks. The primary outcome was the rate of sustained glucocorticoid-free remission at week 52 in each tocilizumab group as compared with the rate in the placebo group that underwent the 26-week prednisone taper. The key secondary outcome was the rate of remission in each tocilizumab group as compared with the placebo group that underwent the 52-week prednisone taper. Dosing of prednisone and safety were also assessed. Sustained remission at week 52 occurred in 56% of the patients treated with tocilizumab weekly and in 53% of those treated with tocilizumab every other week, as compared with 14% of those in the placebo group that underwent the 26-week prednisone taper and 18% of those in the placebo group that underwent the 52-week prednisone taper (P<0.001 for the comparisons of either active treatment with placebo). The cumulative median prednisone dose over the 52-week period was 1862 mg in each tocilizumab group, as compared with 3296 mg in the placebo group that underwent the 26-week taper (P<0.001 for both comparisons) and 3818 mg in the placebo group that underwent the 52-week taper (P<0.001 for both comparisons). Serious adverse events occurred in 15% of the patients in the group that received tocilizumab weekly, 14% of those in the group that received tocilizumab every other week, 22% of those in the placebo group that underwent the 26-week taper, and 25% of those in the placebo group that underwent the 52-week taper. Anterior ischemic optic neuropathy developed in one patient in the group that received tocilizumab every other week. Tocilizumab, received weekly or every other week, combined with a 26-week prednisone taper was superior to either 26-week or 52-week prednisone tapering plus placebo with regard to sustained glucocorticoid-free remission in patients with giant-cell arteritis. Longer follow-up is necessary to determine the durability of remission and safety of tocilizumab. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT01791153 .).

Effects of testosterone supplementation on whole body and regional fat mass and distribution in human immunodeficiency virus-infected men with abdominal obesity.

PubMed

Bhasin, Shalender; Parker, Robert A; Sattler, Fred; Haubrich, Richard; Alston, Beverly; Umbleja, Triin; Shikuma, Cecilia M

2007-03-01

Whole body and abdominal obesity are associated with increased risk of diabetes mellitus and heart disease. The effects of testosterone therapy on whole body and visceral fat mass in HIV-infected men with abdominal obesity are unknown. The objective of this study was to determine the effects of testosterone therapy on intraabdominal fat mass and whole body fat distribution in HIV-infected men with abdominal obesity. IN this multicenter, randomized, placebo-controlled, double-blind trial, 88 HIV-positive men with abdominal obesity (waist-to-hip ratio > 0.95 or mid-waist circumference > 100 cm) and total testosterone 125-400 ng/dl, or bioavailable testosterone less than 115 ng/dl, or free testosterone less than 50 pg/ml on stable antiretroviral regimen, and HIV RNA less than 10,000 copies per milliliter were randomized to receive 10 g testosterone gel or placebo daily for 24 wk. Fat mass and distribution were determined by abdominal computerized tomography and dual energy x-ray absorptiometry during wk 0, 12, and 24. We used an intention-to-treat approach and nonparametric statistical methods. Baseline characteristics were balanced between groups. In 75 subjects evaluated, median percent change from baseline to wk 24 in visceral fat did not differ significantly between groups (testosterone 0.3%, placebo 3.1%, P = 0.75). Total (testosterone -1.5%, placebo 4.3%, P = 0.04) and sc (testosterone-7.2%, placebo 8.1%, P < 0.001) abdominal fat mass decreased in testosterone-treated men, but increased in placebo group. Testosterone therapy was associated with significant decrease in whole body, trunk, and appendicular fat mass by dual energy x-ray absorptiometry (all P < 0.001), whereas whole body and trunk fat increased significantly in the placebo group. The percent of individuals reporting a decrease in abdomen (P = 0.01), neck (P = 0.08), and breast size (P = 0.01) at wk 24 was significantly greater in testosterone-treated than placebo-treated men. Testosterone-treated men had greater increase in lean body mass than placebo (testosterone 1.3%, placebo -0.3, P = 0.02). Plasma insulin, fasting glucose, and total high-density lipoprotein and low-density lipoprotein cholesterol levels did not change significantly. Testosterone therapy was well tolerated. Testosterone therapy in HIV-positive men with abdominal obesity and low testosterone was associated with greater decrease in whole body, total, and sc abdominal fat mass and a greater increase in lean mass compared to placebo. However, changes in visceral fat mass were not significantly different between groups. Further studies are needed to determine testosterone effects on insulin sensitivity and cardiovascular risk.

Dexmedetomidine: a review of its use for sedation in mechanically ventilated patients in an intensive care setting and for procedural sedation.

PubMed

Hoy, Sheridan M; Keating, Gillian M

2011-07-30

Dexmedetomidine (Precedex®), a pharmacologically active dextroisomer of medetomidine, is a selective α(2)-adrenergic receptor agonist. It is indicated in the US for the sedation of mechanically ventilated adult patients in an intensive care setting and in non-intubated adult patients prior to and/or during surgical and other procedures. This article reviews the pharmacological properties, therapeutic efficacy and tolerability of dexmedetomidine in randomized, double-blind, placebo-controlled, multicentre studies in these indications. Post-surgical patients in an intensive care setting receiving dexmedetomidine required less rescue sedation with intravenous propofol or intravenous midazolam to achieve and/or maintain optimal sedation during the assisted ventilation period than placebo recipients, according to two randomized, double-blind, multinational studies. Moreover, significantly more dexmedetomidine than placebo recipients acquired and/or maintained optimal sedation without rescue sedation. Sedation with dexmedetomidine was also effective in terms of the total dose of morphine administered, with dexmedetomidine recipients requiring less morphine than placebo recipients; with regard to patient management, dexmedetomidine recipients were calmer and easier to arouse and manage than placebo recipients. Intravenous dexmedetomidine was effective as a primary sedative in two randomized, double-blind, placebo-controlled, multicentre studies in adult patients undergoing awake fibre-optic intubation or a variety of diagnostic or surgical procedures requiring monitored anaesthesia care. In one study, significantly fewer dexmedetomidine than placebo recipients required rescue sedation with intravenous midazolam to achieve and/or maintain optimal sedation; conversely, in another study, rescue sedation with intravenous midazolam was not required by significantly more dexmedetomidine than placebo recipients. Primary sedation with intravenous dexmedetomidine was also effective in terms of the secondary efficacy endpoints, including the mean total dose of midazolam and fentanyl administered and the percentage of patients requiring further sedation (in addition to dexmedetomidine or placebo and midazolam), with, for the most part, significant between-group differences observed in favour of dexmedetomidine over placebo. In general, no significant differences were observed between the dexmedetomidine and placebo treatment groups in the anaesthesiologists' assessment of ease of intubation, haemodynamic stability, patient cooperation and/or respiratory stability. Intravenous dexmedetomidine is generally well tolerated when utilized in mechanically ventilated patients in an intensive care setting and for procedural sedation in non-intubated patients. Dexmedetomidine is associated with a lower rate of postoperative delirium than midazolam or propofol; it is not associated with respiratory depression. While dexmedetomidine is associated with hypotension and bradycardia, both usually resolve without intervention. Thus, intravenous dexmedetomidine provides a further option as a short-term (<24 hours) primary sedative in mechanically ventilated adult patients in an intensive care setting and in non-intubated adult patients prior to and/or during surgical and other procedures.

Preladenant as an Adjunctive Therapy With Levodopa in Parkinson Disease: Two Randomized Clinical Trials and Lessons Learned.

PubMed

Hauser, Robert A; Stocchi, Fabrizio; Rascol, Olivier; Huyck, Susan B; Capece, Rachel; Ho, Tony W; Sklar, Peter; Lines, Christopher; Michelson, David; Hewitt, David

2015-12-01

Preladenant is an adenosine 2A receptor antagonist that reduced "off" time in a placebo-controlled phase 2b trial in patients with Parkinson disease (PD). We sought to confirm its efficacy in phase 3 trials. To evaluate preladenant as an adjunct to levodopa in patients with PD and motor fluctuations. Two 12-week, phase 3, randomized, placebo-controlled, double-blind trials performed from July 15, 2010, to April 16, 2013. The setting included neurology clinics, clinical research centers, and hospitals in the Americas, the European Union, Eastern Europe, India, and South Africa. Participants included patients with moderate to severe PD taking levodopa who were experiencing motor fluctuations. In trial 1, a total of 778 eligible patients were randomized to the addition of preladenant (2 mg, 5 mg, or 10 mg twice daily), placebo, or rasagiline mesylate (1 mg/d) in a 1:1:1:1:1 ratio. In trial 2, a total of 476 eligible patients were randomized to the addition of preladenant (2 mg or 5 mg twice daily) or placebo in a 1:1:1 ratio. The primary outcome measure was change in off time from baseline to week 12. In trial 1, neither preladenant nor rasagiline was superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were -0.10 hour (95% CI, -0.69 to 0.46 hour) for preladenant 2 mg twice daily, -0.20 hour (95% CI, -0.75 to 0.41 hour) for preladenant 5 mg twice daily, -0.00 hour (95% CI, -0.62 to 0.53 hour) for preladenant 10 mg twice daily, and -0.30 hour (95% CI, -0.90 to 0.26 hour) for rasagiline mesylate 1 mg/d. In trial 2, preladenant was not superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were -0.20 hour (95% CI, -0.72 to 0.35 hour) for preladenant 2 mg twice daily and -0.30 hour (95% CI, -0.86 to 0.21 hour) for preladenant 5 mg twice daily. Preladenant was well tolerated, with the most common adverse event that showed an increase over placebo in both trials being constipation (6%-8% for preladenant vs 1%-3% for placebo). In these phase 3 trials, preladenant did not significantly reduce off time compared with placebo. That the active control rasagiline also failed to demonstrate a significant reduction in off time suggests that issues of study design or conduct may have affected these trials. clinicaltrials.gov Identifier: NCT01155466 and NCT01227265.

Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial.

PubMed

Cummings, Jeffrey L; Lyketsos, Constantine G; Peskind, Elaine R; Porsteinsson, Anton P; Mintzer, Jacobo E; Scharre, Douglas W; De La Gandara, Jose E; Agronin, Marc; Davis, Charles S; Nguyen, Uyen; Shin, Paul; Tariot, Pierre N; Siffert, João

Agitation is common among patients with Alzheimer disease; safe, effective treatments are lacking. To assess the efficacy, safety, and tolerability of dextromethorphan hydrobromide-quinidine sulfate for Alzheimer disease-related agitation. Phase 2 randomized, multicenter, double-blind, placebo-controlled trial using a sequential parallel comparison design with 2 consecutive 5-week treatment stages conducted August 2012-August 2014. Patients with probable Alzheimer disease, clinically significant agitation (Clinical Global Impressions-Severity agitation score ≥4), and a Mini-Mental State Examination score of 8 to 28 participated at 42 US study sites. Stable dosages of antidepressants, antipsychotics, hypnotics, and antidementia medications were allowed. In stage 1, 220 patients were randomized in a 3:4 ratio to receive dextromethorphan-quinidine (n = 93) or placebo (n = 127). In stage 2, patients receiving dextromethorphan-quinidine continued; those receiving placebo were stratified by response and rerandomized in a 1:1 ratio to dextromethorphan-quinidine (n = 59) or placebo (n = 60). The primary end point was change from baseline on the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (scale range, 0 [absence of symptoms] to 12 [symptoms occur daily and with marked severity]). A total of 194 patients (88.2%) completed the study. With the sequential parallel comparison design, 152 patients received dextromethorphan-quinidine and 127 received placebo during the study. Analysis combining stages 1 (all patients) and 2 (rerandomized placebo nonresponders) showed significantly reduced NPI Agitation/Aggression scores for dextromethorphan-quinidine vs placebo (ordinary least squares z statistic, -3.95; P < .001). In stage 1, mean NPI Agitation/Aggression scores were reduced from 7.1 to 3.8 with dextromethorphan-quinidine and from 7.0 to 5.3 with placebo. Between-group treatment differences were significant in stage 1 (least squares mean, -1.5; 95% CI, -2.3 to -0.7; P<.001). In stage 2, NPI Agitation/Aggression scores were reduced from 5.8 to 3.8 with dextromethorphan-quinidine and from 6.7 to 5.8 with placebo. Between-group treatment differences were also significant in stage 2 (least squares mean, -1.6; 95% CI, -2.9 to -0.3; P=.02). Adverse events included falls (8.6% for dextromethorphan-quinidine vs 3.9% for placebo), diarrhea (5.9% vs 3.1% respectively), and urinary tract infection (5.3% vs 3.9% respectively). Serious adverse events occurred in 7.9% with dextromethorphan-quinidine vs 4.7% with placebo. Dextromethorphan-quinidine was not associated with cognitive impairment, sedation, or clinically significant QTc prolongation. In this preliminary 10-week phase 2 randomized clinical trial of patients with probable Alzheimer disease, combination dextromethorphan-quinidine demonstrated clinically relevant efficacy for agitation and was generally well tolerated. clinicaltrials.gov Identifier: NCT01584440.

Modafinil effects on cognitive function in HIV+ patients treated for fatigue: a placebo controlled study.

PubMed

McElhiney, Martin; Rabkin, Judith; Van Gorp, Wilfred; Rabkin, Richard

2010-06-01

Both mild cognitive impairment and fatigue are common among people with HIV/AIDS. This study examined the efficacy of modafinil for HIV+ patients who sought treatment for fatigue in a placebo-controlled double-blind 4-week trial. A battery of standard neuropsychological tests was administered at study entry and Week 4, and change in performance was compared for 59 patients receiving modafinil versus 44 patients receiving placebo. A significant effect on fatigue was observed. In addition, cognitive performance, as measured by a global change score, improved more in the modafinil than in the placebo group although the effect was not specific to any cognitive domain.

Efficacy of bupropion alone and in combination with nicotine gum

PubMed Central

Piper, Megan E.; Federman, E. Belle; McCarthy, Danielle E.; Bolt, Daniel M.; Smith, Stevens S.; Fiore, Michael C.; Baker, Timothy B.

2010-01-01

In this double-blind placebo-controlled smoking cessation treatment study, 608 participants were randomly assigned to receive active bupropion and active 4-mg gum (AA, n = 228), active bupropion and placebo gum (AP, n = 224), or placebo bupropion and placebo gum (PP, n = 156). Relative to the PP group, the AA and AP groups were each significantly more likely to be abstinent at one week, end of treatment and six months, but not twelve months post-quit. After the first week post-quit there were no differences in abstinence rates between the AA and AP groups. There were no significant individual difference variables that moderated outcome beyond one week post-quit. PMID:17763111

Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer's disease psychosis: a phase 2, randomised, placebo-controlled, double-blind study.

PubMed

Ballard, Clive; Banister, Carol; Khan, Zunera; Cummings, Jeffrey; Demos, George; Coate, Bruce; Youakim, James M; Owen, Randall; Stankovic, Srdjan

2018-03-01

Pimavanserin is a selective 5-HT 2A receptor inverse agonist and antagonist approved in the USA for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. No safe or effective pharmacological treatment is approved for psychosis in patients with Alzheimer's disease. Therefore, we aimed to evaluate the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer's disease psychosis. We did a phase 2, randomised, double-blind, placebo-controlled, single-centre (with multiple affiliated nursing home sites across the UK) study. We included participants of either sex who were aged 50 years or older with possible or probable Alzheimer's disease and psychotic symptoms including visual or auditory hallucinations, delusions, or both. Participants were randomly assigned (1:1) to 12 weeks of oral treatment with either pimavanserin (two 17 mg tablets daily) or placebo, with use of permuted block sizes of four and stratified by baseline Mini-Mental State Examination (MMSE) total score (<6 or ≥6) and Neuropsychiatric Inventory-Nursing Home version (NPI-NH) psychosis score (<12 or ≥12). Participants, caregivers, the study sponsor, and study personnel at the clinic site were masked to treatment assignment. The primary endpoint was mean change from baseline to week 6 in the NPI-NH psychosis score for pimavanserin versus placebo in the modified intention-to-treat population. Sustained benefit and safety of pimavanserin were assessed through week 12. This study is registered at ClinicalTrials.gov, number NCT02035553. Between Jan 16, 2014, and Oct 27, 2016, 345 participants across 133 nursing homes were screened, of whom 181 were randomly assigned treatment (n=90 pimavanserin and n=91 placebo). 178 participants were included in the modified intention-to-treat population. Mean total baseline NPI-NH psychosis scores were 9·5 (SD 4·8) for the pimavanserin group and 10·0 (5·6) for the placebo group. Mean change in the NPI-NH psychosis score at week 6 was -3·76 points (SE 0·65) for pimavanserin and -1·93 points (0·63) for placebo (mean difference -1·84 [95% CI -3·64 to -0·04], Cohen's d=-0·32; p=0·045). By week 12, no significant advantage for pimavanserin versus placebo was observed for the overall study population (treatment difference -0·51 [95% CI -2·23 to 1·21]; p=0·561). Common adverse events were falls (21 [23%] of 90 participants in the pimavanserin group vs 21 [23%] of 91 in the placebo group), urinary tract infections (20 [22%] vs 25 [28%]), and agitation (19 [21%] vs 13 [14%]). Eight (9%) participants on pimavanserin and 11 (12%) on placebo discontinued treatment because of adverse events. No detrimental effect was observed on cognition or motor function in either group. Pimavanserin showed efficacy in patients with Alzheimer's disease psychosis at the primary endpoint (week 6) with an acceptable tolerability profile and without negative effect on cognition. Further follow-up to week 12 did not show significant advantage for pimavanserin versus placebo. ACADIA Pharmaceuticals. Copyright © 2018 Elsevier Ltd. All rights reserved.

Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.

PubMed

Bruix, Jordi; Takayama, Tadatoshi; Mazzaferro, Vincenzo; Chau, Gar-Yang; Yang, Jiamei; Kudo, Masatoshi; Cai, Jianqiang; Poon, Ronnie T; Han, Kwang-Hyub; Tak, Won Young; Lee, Han Chu; Song, Tianqiang; Roayaie, Sasan; Bolondi, Luigi; Lee, Kwan Sik; Makuuchi, Masatoshi; Souza, Fabricio; Berre, Marie-Aude Le; Meinhardt, Gerold; Llovet, Josep M

2015-10-01

There is no standard of care for adjuvant therapy for patients with hepatocellular carcinoma. This trial was designed to assess the efficacy and safety of sorafenib versus placebo as adjuvant therapy in patients with hepatocellular carcinoma after surgical resection or local ablation. We undertook this phase 3, double-blind, placebo-controlled study of patients with hepatocellular carcinoma with a complete radiological response after surgical resection (n=900) or local ablation (n=214) in 202 sites (hospitals and research centres) in 28 countries. Patients were randomly assigned (1:1) to receive 400 mg oral sorafenib or placebo twice a day, for a maximum of 4 years, according to a block randomisation scheme (block size of four) using an interactive voice-response system. Patients were stratified by curative treatment, geography, Child-Pugh status, and recurrence risk. The primary outcome was recurrence-free survival assessed after database cut-off on Nov 29, 2013. We analysed efficacy in the intention-to-treat population and safety in randomly assigned patients receiving at least one study dose. The final analysis is reported. This study is registered with ClinicalTrials.gov, number NCT00692770. We screened 1602 patients between Aug 15, 2008, and Nov 17, 2010, and randomly assigned 1114 patients. Of 556 patients in the sorafenib group, 553 (>99%) received the study treatment and 471 (85%) terminated treatment. Of 558 patients in the placebo group, 554 (99%) received the study treatment and 447 (80%) terminated treatment. Median duration of treatment and mean daily dose were 12·5 months (IQR 2·6-35·8) and 577 mg per day (SD 212·8) for sorafenib, compared with 22·2 months (8·1-38·8) and 778·0 mg per day (79·8) for placebo. Dose modification was reported for 497 (89%) of 559 patients in the sorafenib group and 206 (38%) of 548 patients in the placebo group. At final analysis, 464 recurrence-free survival events had occurred (270 in the placebo group and 194 in the sorafenib group). Median follow-up for recurrence-free survival was 8·5 months (IQR 2·9-19·5) in the sorafenib group and 8·4 months (2·9-19·8) in the placebo group. We noted no difference in median recurrence-free survival between the two groups (33·3 months in the sorafenib group vs 33·7 months in the placebo group; hazard ratio [HR] 0·940; 95% CI 0·780-1·134; one-sided p=0·26). The most common grade 3 or 4 adverse events were hand-foot skin reaction (154 [28%] of 559 patients in the sorafenib group vs four [<1%] of 548 patients in the placebo group) and diarrhoea (36 [6%] vs five [<1%] in the placebo group). Sorafenib-related serious adverse events included hand-foot skin reaction (ten [2%]), abnormal hepatic function (four [<1%]), and fatigue (three [<1%]). There were four (<1%) drug-related deaths in the sorafenib group and two (<1%) in the placebo group. Our data indicate that sorafenib is not an effective intervention in the adjuvant setting for hepatocellular carcinoma following resection or ablation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial.

PubMed

Lamas, Gervasio A; Goertz, Christine; Boineau, Robin; Mark, Daniel B; Rozema, Theodore; Nahin, Richard L; Lindblad, Lauren; Lewis, Eldrin F; Drisko, Jeanne; Lee, Kerry L

2013-03-27

Chelation therapy with disodium EDTA has been used for more than 50 years to treat atherosclerosis without proof of efficacy. To determine if an EDTA-based chelation regimen reduces cardiovascular events. Double-blind, placebo-controlled, 2 × 2 factorial randomized trial enrolling 1708 patients aged 50 years or older who had experienced a myocardial infarction (MI) at least 6 weeks prior and had serum creatinine levels of 2.0 mg/dL or less. Participants were recruited at 134 US and Canadian sites. Enrollment began in September 2003 and follow-up took place until October 2011 (median, 55 months). Two hundred eighty-nine patients (17% of total; n=115 in the EDTA group and n=174 in the placebo group) withdrew consent during the trial. Patients were randomized to receive 40 infusions of a 500-mL chelation solution (3 g of disodium EDTA, 7 g of ascorbate, B vitamins, electrolytes, procaine, and heparin) (n=839) vs placebo (n=869) and an oral vitamin-mineral regimen vs an oral placebo. Infusions were administered weekly for 30 weeks, followed by 10 infusions 2 to 8 weeks apart. Fifteen percent discontinued infusions (n=38 [16%] in the chelation group and n=41 [15%] in the placebo group) because of adverse events. The prespecified primary end point was a composite of total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. This report describes the intention-to-treat comparison of EDTA chelation vs placebo. To account for multiple interim analyses, the significance threshold required at the final analysis was P = .036. Qualifying previous MIs occurred a median of 4.6 years before enrollment. Median age was 65 years, 18% were female, 9% were nonwhite, and 31% were diabetic. The primary end point occurred in 222 (26%) of the chelation group and 261 (30%) of the placebo group (hazard ratio [HR], 0.82 [95% CI, 0.69-0.99]; P = .035). There was no effect on total mortality (chelation: 87 deaths [10%]; placebo, 93 deaths [11%]; HR, 0.93 [95% CI, 0.70-1.25]; P = .64), but the study was not powered for this comparison. The effect of EDTA chelation on the components of the primary end point other than death was of similar magnitude as its overall effect (MI: chelation, 6%; placebo, 8%; HR, 0.77 [95% CI, 0.54-1.11]; stroke: chelation, 1.2%; placebo, 1.5%; HR, 0.77 [95% CI, 0.34-1.76]; coronary revascularization: chelation, 15%; placebo, 18%; HR, 0.81 [95% CI, 0.64-1.02]; hospitalization for angina: chelation, 1.6%; placebo, 2.1%; HR, 0.72 [95% CI, 0.35-1.47]). Sensitivity analyses examining the effect of patient dropout and treatment adherence did not alter the results. Among stable patients with a history of MI, use of an intravenous chelation regimen with disodium EDTA, compared with placebo, modestly reduced the risk of adverse cardiovascular outcomes, many of which were revascularization procedures. These results provide evidence to guide further research but are not sufficient to support the routine use of chelation therapy for treatment of patients who have had an MI. clinicaltrials.gov Identifier: NCT00044213.

Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

PubMed

Greenway, Frank L; Fujioka, Ken; Plodkowski, Raymond A; Mudaliar, Sunder; Guttadauria, Maria; Erickson, Janelle; Kim, Dennis D; Dunayevich, Eduardo

2010-08-21

Despite increasing public health concerns regarding obesity, few safe and effective drug treatments are available. Combination treatment with sustained-release naltrexone and bupropion was developed to produce complementary actions in CNS pathways regulating bodyweight. The Contrave Obesity Research I (COR-I) study assessed the effect of such treatment on bodyweight in overweight and obese participants. Men and women aged 18-65 years who had a body-mass index (BMI) of 30-45 kg/m(2) and uncomplicated obesity or BMI 27-45 kg/m(2) with dyslipidaemia or hypertension were eligible for enrolment in this randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 34 sites in the USA. Participants were prescribed mild hypocaloric diet and exercise and were randomly assigned in a 1:1:1 ratio to receive sustained-release naltrexone 32 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB32), sustained-release naltrexone 16 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB16), or matching placebo twice a day, given orally for 56 weeks. The trial included a 3-week dose escalation. Randomisation was done by use of a centralised, computer-generated, web-based system and was stratified by study centre. Co-primary efficacy endpoints at 56 weeks were percentage change in bodyweight and proportion of participants who achieved a decrease in bodyweight of 5% or more. The primary analysis included all randomised participants with a baseline weight measurement and a post-baseline weight measurement while on study drug (last observation carried forward). This study is registered with ClinicalTrials.gov, number NCT00532779. 1742 participants were enrolled and randomised to double-blind treatment (naltrexone 32 mg plus bupropion, n=583; naltrexone 16 mg plus bupropion, n=578; placebo, n=581). 870 (50%) participants completed 56 weeks of treatment (n=296; n=284; n=290, respectively) and 1453 (83%) were included in the primary analysis (n=471; n=471; n=511). Mean change in bodyweight was -1.3% (SE 0.3) in the placebo group, -6.1% (0.3) in the naltrexone 32 mg plus bupropion group (p<0.0001 vs placebo) and -5.0% (0.3) in the naltrexone 16 mg plus bupropion group (p<0.0001 vs placebo). 84 (16%) participants assigned to placebo had a decrease in bodyweight of 5% or more compared with 226 (48%) assigned to naltrexone 32 mg plus bupropion (p<0.0001 vs placebo) and 186 (39%) assigned to naltrexone 16 mg plus bupropion (p<0.0001 vs placebo). The most frequent adverse event in participants assigned to combination treatment was nausea (naltrexone 32 mg plus bupropion, 171 participants [29.8%]; naltrexone 16 mg plus bupropion, 155 [27.2%]; placebo, 30 [5.3%]). Headache, constipation, dizziness, vomiting, and dry mouth were also more frequent in the naltrexone plus bupropion groups than in the placebo group. A transient increase of around 1.5 mm Hg in mean systolic and diastolic blood pressure was followed by a reduction of around 1 mm Hg below baseline in the naltrexone plus bupropion groups. Combination treatment was not associated with increased depression or suicidality events compared with placebo. A sustained-release combination of naltrexone plus bupropion could be a useful therapeutic option for treatment of obesity. Orexigen Therapeutics. Copyright 2010 Elsevier Ltd. All rights reserved.

Effect of Arnica D30 in marathon runners. Pooled results from two double-blind placebo controlled studies.

PubMed

Tveiten, D; Bruset, S

2003-10-01

To examine whether the homeopathic medicine Arnica D30 has an effect on muscle soreness and cell damage after marathon running. The subjects were 82 marathon runners from two separate randomised double-blind placebo controlled trials participating in the Oslo Marathon in 1990 and 1995. Five pills of Arnica D30 or placebo were given morning and evening. Treatment started on the evening before the marathon and continued on day of the race and the three following days. The runners assessed muscular soreness on a visual analogue scale. Muscle enzymes, electrolytes and creatinine were measured before and after the marathon. Muscle soreness immediately after the marathon run was lower in the Arnica group than in the placebo group (P = 0.04). Cell damage measured by enzymes was similar in the Arnica and the placebo group. These pooled results suggest that Arnica D30 has a positive effect on muscle soreness after marathon running, but not on cell damage measured by enzymes.

Power Calculations and Placebo Effect for Future Clinical Trials in Progressive Supranuclear Palsy

PubMed Central

Stamelou, Maria; Schöpe, Jakob; Wagenpfeil, Stefan; Ser, Teodoro Del; Bang, Jee; Lobach, Iryna Y.; Luong, Phi; Respondek, Gesine; Oertel, Wolfgang H.; Boxer, Adam L.; Höglinger, Günter U.

2016-01-01

Background Two recent randomized, placebo-controlled trials of putative disease-modifying agents (davunetide, tideglusib) in progressive supranuclear palsy (PSP) failed to show efficacy, but generated data relevant for future trials. Methods We provide sample size calculations based on data collected in 187 PSP patients assigned to placebo in these trials. A placebo effect was calculated. Results The total PSP-Rating Scale required the least number of patients per group (N = 51) to detect a 50% change in the 1-year progression and 39 when including patients with ≤ 5 years disease duration. The Schwab and England Activities of Daily Living required 70 patients per group and was highly correlated with the PSP-Rating Scale. A placebo effect was not detected in these scales. Conclusions We propose the 1-year PSP-Rating Scale score change as the single primary readout in clinical neuroprotective or disease-modifying trials. The Schwab and England Activities of Daily Living could be used as a secondary outcome. PMID:26948290

Evaluating therapeutic effect in symptoms of moderate-to-severe premenstrual syndrome with Vitex agnus castus (BNO 1095) in Chinese women.

PubMed

Ma, Linlin; Lin, Shouqing; Chen, Rong; Zhang, Ying; Chen, Fengling; Wang, Xiuli

2010-04-01

To assess therapeutic effect of an extract of Vitex agnus castus (VAC, BNO 1095) in premenstrual syndrome (PMS) in Chinese women. It was a prospective, randomised, double-blind, placebo-controlled study carried out in China. Eligible patients were treated with VAC extract or placebo for three cycles. Symptoms were documented with PMS diary (PMSD), a daily rating scale with 17 items. Main efficacy variable was the reduction percentage of 17 symptom score documented in PMSD during the luteal phase of the third treatment cycle. A total of 67 patients were enrolled and randomly assigned to VAC group or placebo group. Of these, 64 patients completed the study (31 vs. 33). All the 17 symptoms showed a significantly greater improvement with VAC than placebo (P < 0.05) except lower abdominal cramping (P > 0.05). Vitex agnus castus is more effective than placebo in the treatment of moderate-to-severe PMS in Chinese women, especially in symptoms of negative effect and insomnia.

[Ethyl chloride aerosol spray for local anesthesia before arterial puncture: randomized placebo-controlled trial].

PubMed

Ballesteros-Peña, Sendoa; Fernández-Aedo, Irrintzi; Vallejo-De la Hoz, Gorka

2017-06-01

To compare the efficacy of an ethyl chloride aerosol spray to a placebo spray applied in the emergency department to the skin to reduce pain from arterial puncture for blood gas analysis. Single-blind, randomized placebo-controlled trial in an emergency department of Hospital de Basurto in Bilbao, Spain. We included 126 patients for whom arterial blood gas analysis had been ordered. They were randomly assigned to receive application of the experimental ethyl chloride spray (n=66) or a placebo aerosol spray of a solution of alcohol in water (n=60). The assigned spray was applied just before arterial puncture. The main outcome variable was pain intensity reported on an 11-point numeric rating scale. The median (interquartile range) pain level was 2 (1-5) in the experimental arm and 2 (1-4.5) in the placebo arm (P=.72). Topical application of an ethyl chloride spray did not reduce pain caused by arterial puncture.