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Sample records for design multicenter trial

  1. Variation among institutional review boards in evaluating the design of a multicenter randomized trial

    PubMed Central

    Stark, AR; Tyson, JE; Hibberd, PL

    2010-01-01

    Objective The objective of the study was to examine the variation among institutional review boards (IRBs) in evaluation of the study design of a multicenter trial. Study Design We assessed the first written response of local IRBs to each site investigator for a multicenter trial of vitamin A supplementation in extremely low birth weight (ELBW) infants performed by the National Institute of Child Health and Human Development Neonatal Research Network. Each author of this paper independently reviewed and categorized IRB concerns as major, minor or none, according to the predefined criteria. Result Initially, 9 of 18 IRBs withheld approval because of at least one major concern. These concerns reflected difficulties in evaluating specific scientific issues for the design of the trial, including its justification, enrollment criteria, control and experimental therapies, co-interventions, toxicity assessment, outcome monitoring and informed consent. Conclusion The difficulty in assessing appropriate trial design for the specific hypothesis under investigation resulted in considerable variability in the evaluation by local IRBs. PMID:19798046

  2. Challenges in the Design and Implementation of The Multicenter Uveitis Steroid Treatment (MUST) Trial – Lessons for Comparative Effectiveness Trials

    PubMed Central

    Holbrook, Janet T.; Kempen, John H.; Prusakowski, Nancy A.; Altaweel, Michael M.; Jabs, Douglas A

    2013-01-01

    Background Randomized clinical trials are an important component of comparative effectiveness (CE) research because they are the optimal design for head-to-head comparisons of different treatment options. Purpose To describe decisions made in the design of the Multicenter Uveitis Steroid Treatment (MUST) Trial to ensure that the results would be widely generalizable. Methods Review of design and implementation decisions and their rationale for the trial. Results The MUST Trial is a multicenter randomized controlled comparative effectiveness trial evaluating a novel local therapy (intraocular fluocinolone acetonide implant) versus the systemic therapy standard of care for noninfectious uveitis. Decisions made in protocol design in order to broaden enrollment included allowing patients with very poor vision and media opacity to enroll and including clinical sites outside the US. The treatment protocol was designed to follow standard care. The primary outcome, visual acuity, is important to patients and can be evaluated in all eyes with uveitis. Other outcomes include patient-reported visual function, quality of life, and disease and treatment related complications. Limitations The trial population is too small for subgroup analyses that are of interest and the trial is being conducted at tertiary medical centers. Conclusion CE trials require greater emphasis on generalizability than many RCTs but otherwise face similar challenges for design choices as any RCT. The increase in heterogeneity in patients and treatment required to ensure generalizability can be balanced with a rigorous approach to implementation, outcome assessment and statistical design. This approach requires significant resources that may limit implementation in many RCTs, especially in clinical practice settings. PMID:21994128

  3. The Multicenter Uveitis Steroid Treatment (MUST) Trial: Rationale, Design and Baseline Characteristics

    PubMed Central

    2010-01-01

    Purpose To describe the design and methods of the Multicenter Uveitis Steroid Treatment (MUST) Trial, and the baseline characteristics of enrolled patients. Design Baseline data from a 1:1 randomized, parallel treatment design clinical trial at 23 clinical centers comparing systemic corticosteroid therapy (and immunosuppression when indicated) to fluocinolone acetonide implant placement. Methods Eligible patients have active or recently active non-infectious intermediate, posterior, or panuveitis. The study design had 90% power (two-sided type I error rate=0.05) to detect a 7.5 letter (1.5 line) difference between groups in the mean visual acuity change between baseline and two years. Secondary outcomes include ocular and systemic complications of therapy and quality of life. Baseline characteristics include demographic and clinical characteristics, quality of life, and reading center gradings of lens and fundus photos, optical coherence tomography images, and fluorescein angiograms. Results Over three years, 255 patients were enrolled (481 eyes with uveitis). At baseline, 50% of eyes with uveitis had best-corrected visual acuity worse than 20/40 (16% worse than 20/200), with a similar distribution of reduced visual acuity for intermediate uveitis and posterior or panuveitis cases. Structural complications, including macular edema (36%) and epiretinal membrane (48%), were common. Conclusions The MUST Trial will compare fluocinolone acetonide implant versus systemic therapy for management of intermediate, posterior and panuveitis. Patients with intermediate, posterior, or panuveitis enrolled in the trial had a high burden of reduced visual acuity, cataract, macular edema and epiretinal membrane; overall quality of life was lower than expected based on visual acuity. PMID:20097325

  4. A Bayesian Approach to Multicenter Trials and Metaanalysis.

    ERIC Educational Resources Information Center

    Berry, Donald A.

    The use of a Bayesian approach in evaluating data from clinical trials with many treatment centers and from many studies is discussed. The main distinction between a metaanalysis and an analysis of a multicenter trial is that different studies may have very different designs, while the centers in a multicenter trial usually follow the same…

  5. Impact of the Patient-Reported Outcomes Management Information System (PROMIS) upon the design and operation of multi-center clinical trials: a qualitative research study.

    PubMed

    Eisenstein, Eric L; Diener, Lawrence W; Nahm, Meredith; Weinfurt, Kevin P

    2011-12-01

    New technologies may be required to integrate the National Institutes of Health's Patient Reported Outcome Management Information System (PROMIS) into multi-center clinical trials. To better understand this need, we identified likely PROMIS reporting formats, developed a multi-center clinical trial process model, and identified gaps between current capabilities and those necessary for PROMIS. These results were evaluated by key trial constituencies. Issues reported by principal investigators fell into two categories: acceptance by key regulators and the scientific community, and usability for researchers and clinicians. Issues reported by the coordinating center, participating sites, and study subjects were those faced when integrating new technologies into existing clinical trial systems. We then defined elements of a PROMIS Tool Kit required for integrating PROMIS into a multi-center clinical trial environment. The requirements identified in this study serve as a framework for future investigators in the design, development, implementation, and operation of PROMIS Tool Kit technologies.

  6. Impact of the Patient-Reported Outcomes Management Information System (PROMIS) upon the Design and Operation of Multi-center Clinical Trials: a Qualitative Research Study

    PubMed Central

    Diener, Lawrence W.; Nahm, Meredith; Weinfurt, Kevin P.

    2013-01-01

    New technologies may be required to integrate the National Institutes of Health’s Patient Reported Outcome Management Information System (PROMIS) into multi-center clinical trials. To better understand this need, we identified likely PROMIS reporting formats, developed a multi-center clinical trial process model, and identified gaps between current capabilities and those necessary for PROMIS. These results were evaluated by key trial constituencies. Issues reported by principal investigators fell into two categories: acceptance by key regulators and the scientific community, and usability for researchers and clinicians. Issues reported by the coordinating center, participating sites, and study subjects were those faced when integrating new technologies into existing clinical trial systems. We then defined elements of a PROMIS Tool Kit required for integrating PROMIS into a multi-center clinical trial environment. The requirements identified in this study serve as a framework for future investigators in the design, development, implementation, and operation of PROMIS Tool Kit technologies. PMID:20703765

  7. Minocycline and celecoxib as adjunctive treatments for bipolar depression: a study protocol for a multicenter factorial design randomized controlled trial

    PubMed Central

    Husain, Muhammad I; Chaudhry, Imran B; Hamirani, Munir M; Minhas, Fareed A; Kazmi, Ajmal; Hodsoll, John; Haddad, Peter M; Deakin, John FW; Husain, Nusrat; Young, Allan H

    2017-01-01

    Background Evidence suggests that the use of anti-inflammatory agents may improve depressive symptoms in patients with bipolar affective disorder. However, there are few well-designed clinical trials demonstrating the efficacy of these newer treatment strategies. Patients and methods This is a multicenter, 3-month, randomized, placebo-controlled, double-blind, factorial design trial of minocycline and/or celecoxib added to TAU for the treatment of depressive symptoms in patients experiencing a DSM-5 bipolar I or II disorder and a current major depressive episode. A total of 240 participants will undergo screening and randomization followed by four assessment visits. The primary outcome measure will be mean change from baseline to week 12 on the Hamilton Depression Scale scores. Clinical assessments using the Clinical Global Impression scale, Patient Health Questionnaire-9, and the Generalized Anxiety Disorder 7-item scale will be carried out at every visit as secondary outcomes. Side-effect checklists will be used to monitor the adverse events at each visit. Complete blood count and plasma C-reactive protein will be measured at baseline and at the end of the treatment. Minocycline will be started at 100 mg once daily and increased to 200 mg at 2 weeks. Celecoxib will be started at 200 mg once daily and increased to 400 mg at 2 weeks. Discussion Anti-inflammatory agents have been shown to be potentially efficacious in the treatment of depressive symptoms. The aim of this study is to determine whether the addition of minocycline and/or celecoxib to TAU improves depressive symptoms in patients with bipolar affective disorder. PMID:28031712

  8. Diagnosis of Basal Cell Carcinoma by Reflectance Confocal Microscopy: Study Design and Protocol of a Randomized Controlled Multicenter Trial

    PubMed Central

    Alkemade, Hans A.C; Maessen-Visch, Birgitte; Hendriks, Jan C.M; van Erp, Piet E.J; Adang, Eddy M.M; Gerritsen, Marie-Jeanne P

    2016-01-01

    Background Skin cancer, including basal cell carcinoma (BCC), has become a major health care problem. The limitations of a punch biopsy (at present the gold standard) as diagnostic method together with the increasing incidence of skin cancer point out the need for more accurate, cost-effective, and patient friendly diagnostic tools. In vivo reflectance confocal microscopy (RCM) is a noninvasive imaging technique that has great potential for skin cancer diagnosis. Objective To investigate whether in vivo RCM can correctly identify the subtype of BCC and to determine the cost-effectiveness of RCM compared with punch biopsy (usual care). Study design: Randomized controlled multicenter trial. Methods On the basis of 80% power and an alpha of 0.05, 329 patients with lesions clinically suspicious for BCC will be included in this study. Patients will be randomized for RCM or for a punch biopsy (usual care). When a BCC is diagnosed, surgical excision will follow and a follow-up visit will be planned 3 months later. Several questionnaires will be filled in (EQ-5D, EQ-5D VAS, iMTA PCQ, and TSQM-9). We will perform statistical analysis, cost-effectiveness, and patient outcome analysis after data collection. Results This research started in January 2016 and is ethically approved. We expect to finish this study at the end of 2018. Conclusions In this study, we will investigate whether RCM is at least as good in identifying BCC subtypes as conventional pathological investigation of skin biopsies. Anticipating that RCM is found to be a cost-effective alternative, it saves on direct medical consumption like labor of the pathologist and other medical personnel as well as materials related to treatment failure with at least equal effectiveness. Trial Registration Clinicaltrials.gov NCT02623101; https://clinicaltrials.gov/ct2/show/NCT02623101 (Archived by WebCite at http://www.webcitation.org/6id54WQa2) PMID:27363577

  9. The design and rationale of a multi-center clinical trial comparing two strategies for control of systolic blood pressure: The Systolic Blood Pressure Intervention Trial (SPRINT)

    PubMed Central

    2014-01-01

    Background High blood pressure is an important public health concern because it is highly prevalent and a risk factor for adverse health outcomes, including coronary heart disease, stroke, decompensated heart failure, chronic kidney disease, and decline in cognitive function. Observational studies show a progressive increase in risk associated with blood pressure above 115/75 mm Hg. Prior research has shown that reducing elevated systolic blood pressure lowers the risk of subsequent clinical complications from cardiovascular disease. However, the optimal systolic blood pressure to reduce blood pressure-related adverse outcomes is unclear, and the benefit of treating to a level of systolic blood pressure well below 140 mm Hg has not been proven in a large, definitive clinical trial. Purpose To describe the design considerations of the Systolic Blood Pressure Intervention Trial (SPRINT) and the baseline characteristics of trial participants. Methods SPRINT is a multi-center, randomized, controlled trial that compares two strategies for treating systolic blood pressure: one targets the standard target of <140 mm Hg, and the other targets a more intensive target of <120 mm Hg. Enrollment focused on volunteers of age ≥50 years (no upper limit) with an average baseline systolic blood pressure ≥130 mm Hg and evidence of cardiovascular disease, chronic kidney disease, 10-year Framingham cardiovascular disease risk score ≥15%, or age ≥75 years. SPRINT recruitment also targeted three pre-specified subgroups: participants with chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73m2), participants with a history of cardiovascular disease, and participants 75 years of age or older. The primary outcome is first occurrence of a myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular disease death. Secondary outcomes include all-cause mortality, decline in kidney function or development of end-stage renal disease

  10. Rationale and study design of ViPS – variable pressure support for weaning from mechanical ventilation: study protocol for an international multicenter randomized controlled open trial

    PubMed Central

    2013-01-01

    Background In pressure support ventilation (PSV), a non-variable level of pressure support is delivered by the ventilator when triggered by the patient. In contrast, variable PSV delivers a level of pressure support that varies in a random fashion, introducing more physiological variability to the respiratory pattern. Experimental studies show that variable PSV improves gas exchange, reduces lung inflammation and the mean pressure support, compared to non-variable PSV. Thus, it can theoretically shorten weaning from the mechanical ventilator. Methods/design The ViPS (variable pressure support) trial is an international investigator-initiated multicenter randomized controlled open trial comparing variable vs. non-variable PSV. Adult patients on controlled mechanical ventilation for more than 24 hours who are ready to be weaned are eligible for the study. The randomization sequence is blocked per center and performed using a web-based platform. Patients are randomly assigned to one of the two groups: variable PSV or non-variable PSV. In non-variable PSV, breath-by-breath pressure support is kept constant and targeted to achieve a tidal volume of 6 to 8 ml/kg. In variable PSV, the mean pressure support level over a specific time period is targeted at the same mean tidal volume as non-variable PSV, but individual levels vary randomly breath-by-breath. The primary endpoint of the trial is the time to successful weaning, defined as the time from randomization to successful extubation. Discussion ViPS is the first randomized controlled trial investigating whether variable, compared to non-variable PSV, shortens the duration of weaning from mechanical ventilation in a mixed population of critically ill patients. This trial aims to determine the role of variable PSV in the intensive care unit. Trial registration clinicaltrials.gov NCT01769053 PMID:24176188

  11. Multicenter Clinical Trial of Keratin Biomaterial for Peripheral Nerve Regeneration

    DTIC Science & Technology

    2015-12-01

    Award Number: W81XWH-10-1-0894 TITLE: Multicenter Clinical Trial of Keratin Biomaterial for Peripheral Nerve Regeneration PRINCIPAL...DATES COVERED 15Sep2010 - 14Sep2015 4. TITLE AND SUBTITLE Multicenter Clinical Trial of Keratin Biomaterial for 5a. CONTRACT NUMBER W81XWH-10-1-0894... clinical trial was to be initiated as soon as the FDA provided an IND for the keratin biomaterial hydrogel. However, due to delays in the FDA approval

  12. Assessment of a Standardized Pre-Operative Telephone Checklist Designed to Avoid Late Cancellation of Ambulatory Surgery: The AMBUPROG Multicenter Randomized Controlled Trial

    PubMed Central

    Marchand-Maillet, Florence; Baron, Gabriel; Douard, Richard; Béthoux, Jean-Pierre

    2016-01-01

    Objectives To assess the impact of a standardized pre-operative telephone checklist on the rate of late cancellations of ambulatory surgery (AMBUPROG trial). Design Multicenter, two-arm, parallel-group, open-label randomized controlled trial. Setting 11 university hospital ambulatory surgery units in Paris, France. Participants Patients scheduled for ambulatory surgery and able to be reached by telephone. Intervention A 7-item checklist designed to prevent late cancellation, available in five languages and two versions (for children and adults), was administered between 7 and 3 days before the planned date of surgery, by an automated phone system or a research assistant. The control group received standard management alone. Main Outcome Measures Rate of cancellation on the day of surgery or the day before. Results The study population comprised 3900 patients enrolled between November 2012 and September 2013: 1950 patients were randomized to the checklist arm and 1950 patients to the control arm. The checklist was administered to 68.8% of patients in the intervention arm, 1002 by the automated phone system and 340 by a research assistant. The rate of late cancellation did not differ significantly between the checklist and control arms (109 (5.6%) vs. 113 (5.8%), adjusted odds ratio [95% confidence interval] = 0.91 [0.65–1.29], (p = 0.57)). Checklist administration revealed that 355 patients (28.0%) had not undergone tests ordered by the surgeon or anesthetist, and that 254 patients (20.0%) still had questions concerning the fasting state. Conclusions A standardized pre-operative telephone checklist did not avoid late cancellations of ambulatory surgery but enabled us to identify several frequent causes. Trial Registration ClinicalTrials.gov NCT01732159 PMID:26829478

  13. Multicenter Clinical Trial of Keratin Biomaterial for Peripheral Nerve Regeneration

    DTIC Science & Technology

    2014-10-01

    AD_________________ Award Number: W81XWH-10-1-0894 TITLE: Multicenter Clinical Trial of Keratin Biomaterial for Peripheral Nerve Regeneration...DATES COVERED 15 Sep 2013 - 14 Sep 2014 4. TITLE AND SUBTITLE Multicenter Clinical Trial of Keratin Biomaterial for 5a. CONTRACT NUMBER Peripheral...has developed a keratin biomaterial hydrogel that can be used as luminal filler in nerve guidance conduits to facilitate nerve regeneration

  14. Non-invasive cardiac assessment in high risk patients (The GROUND study): rationale, objectives and design of a multi-center randomized controlled clinical trial

    PubMed Central

    de Vos, Alexander M; Rutten, Annemarieke; van de Zaag-Loonen, Hester J; Bots, Michiel L; Dikkers, Riksta; Buiskool, Robert A; Mali, Willem P; Lubbers, Daniel D; Mosterd, Arend; Prokop, Mathias; Rensing, Benno J; Cramer, Maarten J; van Es, H Wouter; Moll, Frans L; van de Pavoordt, Eric D; Doevendans, Pieter A; Velthuis, Birgitta K; Mackaay, Albert J; Zijlstra, Felix; Oudkerk, Matthijs

    2008-01-01

    Background Peripheral arterial disease (PAD) is a common disease associated with a considerably increased risk of future cardiovascular events and most of these patients will die from coronary artery disease (CAD). Screening for silent CAD has become an option with recent non-invasive developments in CT (computed tomography)-angiography and MR (magnetic resonance) stress testing. Screening in combination with more aggressive treatment may improve prognosis. Therefore we propose to study whether a cardiac imaging algorithm, using non-invasive imaging techniques followed by treatment will reduce the risk of cardiovascular disease in PAD patients free from cardiac symptoms. Design The GROUND study is designed as a prospective, multi-center, randomized clinical trial. Patients with peripheral arterial disease, but without symptomatic cardiac disease will be asked to participate. All patients receive a proper risk factor management before randomization. Half of the recruited patients will enter the 'control group' and only undergo CT calcium scoring. The other half of the recruited patients (index group) will undergo the non invasive cardiac imaging algorithm followed by evidence-based treatment. First, patients are submitted to CT calcium scoring and CT angiography. Patients with a left main (or equivalent) coronary artery stenosis of > 50% on CT will be referred to a cardiologist without further imaging. All other patients in this group will undergo dobutamine stress magnetic resonance (DSMR) testing. Patients with a DSMR positive for ischemia will also be referred to a cardiologist. These patients are candidates for conventional coronary angiography and cardiac interventions (coronary artery bypass grafting (CABG) or percutaneous cardiac interventions (PCI)), if indicated. All participants of the trial will enter a 5 year follow up period for the occurrence of cardiovascular events. Sequential interim analysis will take place. Based on sample size calculations about

  15. Minimally invasive 'step-up approach' versus maximal necrosectomy in patients with acute necrotising pancreatitis (PANTER trial): design and rationale of a randomised controlled multicenter trial [ISRCTN38327949

    PubMed Central

    Besselink, Marc GH; van Santvoort, Hjalmar C; Nieuwenhuijs, Vincent B; Boermeester, Marja A; Bollen, Thomas L; Buskens, Erik; Dejong, Cornelis HC; van Eijck, Casper HJ; van Goor, Harry; Hofker, Sijbrand S; Lameris, Johan S; van Leeuwen, Maarten S; Ploeg, Rutger J; van Ramshorst, Bert; Schaapherder, Alexander FM; Cuesta, Miguel A; Consten, Esther CJ; Gouma, Dirk J; van der Harst, Erwin; Hesselink, Eric J; Houdijk, Lex PJ; Karsten, Tom M; van Laarhoven, Cees JHM; Pierie, Jean-Pierre EN; Rosman, Camiel; Bilgen, Ernst Jan Spillenaar; Timmer, Robin; van der Tweel, Ingeborg; de Wit, Ralph J; Witteman, Ben JM; Gooszen, Hein G

    2006-01-01

    Background The initial treatment of acute necrotizing pancreatitis is conservative. Intervention is indicated in patients with (suspected) infected necrotizing pancreatitis. In the Netherlands, the standard intervention is necrosectomy by laparotomy followed by continuous postoperative lavage (CPL). In recent years several minimally invasive strategies have been introduced. So far, these strategies have never been compared in a randomised controlled trial. The PANTER study (PAncreatitis, Necrosectomy versus sTEp up appRoach) was conceived to yield the evidence needed for a considered policy decision. Methods/design 88 patients with (suspected) infected necrotizing pancreatitis will be randomly allocated to either group A) minimally invasive 'step-up approach' starting with drainage followed, if necessary, by videoscopic assisted retroperitoneal debridement (VARD) or group B) maximal necrosectomy by laparotomy. Both procedures are followed by CPL. Patients will be recruited from 20 hospitals, including all Dutch university medical centres, over a 3-year period. The primary endpoint is the proportion of patients suffering from postoperative major morbidity and mortality. Secondary endpoints are complications, new onset sepsis, length of hospital and intensive care stay, quality of life and total (direct and indirect) costs. To demonstrate that the 'step-up approach' can reduce the major morbidity and mortality rate from 45 to 16%, with 80% power at 5% alpha, a total sample size of 88 patients was calculated. Discussion The PANTER-study is a randomised controlled trial that will provide evidence on the merits of a minimally invasive 'step-up approach' in patients with (suspected) infected necrotizing pancreatitis. PMID:16606471

  16. Rationale and design of the Clinical Evaluation of Magnetic Resonance Imaging in Coronary heart disease 2 trial (CE-MARC 2): A prospective, multicenter, randomized trial of diagnostic strategies in suspected coronary heart disease

    PubMed Central

    Ripley, David P.; Brown, Julia M.; Everett, Colin C.; Bijsterveld, Petra; Walker, Simon; Sculpher, Mark; McCann, Gerry P.; Berry, Colin; Plein, Sven; Greenwood, John P.

    2015-01-01

    Background A number of investigative strategies exist for the diagnosis of coronary heart disease (CHD). Despite the widespread availability of noninvasive imaging, invasive angiography is commonly used early in the diagnostic pathway. Consequently, approximately 60% of angiograms reveal no evidence of obstructive coronary disease. Reducing unnecessary angiography has potential financial savings and avoids exposing the patient to unnecessary risk. There are no large-scale comparative effectiveness trials of the different diagnostic strategies recommended in international guidelines and none that have evaluated the safety and efficacy of cardiovascular magnetic resonance. Trial Design CE-MARC 2 is a prospective, multicenter, 3-arm parallel group, randomized controlled trial of patients with suspected CHD (pretest likelihood 10%-90%) requiring further investigation. A total of 1,200 patients will be randomized on a 2:2:1 basis to receive 3.0-T cardiovascular magnetic resonance–guided care, single-photon emission computed tomography–guided care (according to American College of Cardiology/American Heart Association appropriate-use criteria), or National Institute for Health and Care Excellence guidelines–based management. The primary (efficacy) end point is the occurrence of unnecessary angiography as defined by a normal (>0.8) invasive fractional flow reserve. Safety of each strategy will be assessed by 3-year major adverse cardiovascular event rates. Cost-effectiveness and health-related quality-of-life measures will be performed. Conclusions The CE-MARC 2 trial will provide comparative efficacy and safety evidence for 3 different strategies of investigating patients with suspected CHD, with the intension of reducing unnecessary invasive angiography rates. Evaluation of these management strategies has the potential to improve patient care, health-related quality of life, and the cost-effectiveness of CHD investigation. PMID:25497243

  17. Transluminal endoscopic step-up approach versus minimally invasive surgical step-up approach in patients with infected necrotising pancreatitis (TENSION trial): design and rationale of a randomised controlled multicenter trial [ISRCTN09186711

    PubMed Central

    2013-01-01

    Background Infected necrotising pancreatitis is a potentially lethal disease that nearly always requires intervention. Traditionally, primary open necrosectomy has been the treatment of choice. In recent years, the surgical step-up approach, consisting of percutaneous catheter drainage followed, if necessary, by (minimally invasive) surgical necrosectomy has become the standard of care. A promising minimally invasive alternative is the endoscopic transluminal step-up approach. This approach consists of endoscopic transluminal drainage followed, if necessary, by endoscopic transluminal necrosectomy. We hypothesise that the less invasive endoscopic step-up approach is superior to the surgical step-up approach in terms of clinical and economic outcomes. Methods/Design The TENSION trial is a randomised controlled, parallel-group superiority multicenter trial. Patients with (suspected) infected necrotising pancreatitis with an indication for intervention and in whom both treatment modalities are deemed possible, will be randomised to either an endoscopic transluminal or a surgical step-up approach. During a 4 year study period, 98 patients will be enrolled from 24 hospitals of the Dutch Pancreatitis Study Group. The primary endpoint is a composite of death and major complications within 6 months following randomisation. Secondary endpoints include complications such as pancreaticocutaneous fistula, exocrine or endocrine pancreatic insufficiency, need for additional radiological, endoscopic or surgical intervention, the need for necrosectomy after drainage, the number of (re-)interventions, quality of life, and total direct and indirect costs. Discussion The TENSION trial will answer the question whether an endoscopic step-up approach reduces the combined primary endpoint of death and major complications, as well as hospital stay and related costs compared with a surgical step-up approach in patients with infected necrotising pancreatitis. PMID:24274589

  18. Curved versus Straight Stem Uncemented Total Hip Arthroplasty Osteoarthritis Multicenter trial (CUSTOM): design of a prospective blinded randomised controlled multicentre trial

    PubMed Central

    van Beers, Loes W A H; van Oldenrijk, Jakob; Scholtes, Vanessa A B; Geerdink, Carel H; Niers, Bob B A M; Runne, Wouter; Bhandari, Mohit; Poolman, Rudolf W

    2016-01-01

    Introduction Answering the demands of an increasingly young and active patient population, recent developments in total hip arthroplasty (THA) have shifted towards minimising tissue damage. The Collum Femoris Preserving (CFP) stem was developed to preserve the trochanteric region of the femur, which potentially preserves the insertion of the gluteus musculature. This might accelerate early postoperative rehabilitation and improve functional outcome. Currently the functional results of the CFP stem have not been compared with conventional straight stems in a randomised controlled trial (RCT). The primary purpose of this trial is to compare the functional result of CFP stem THA with conventional uncemented straight stem THA, measured by the Dutch Hip disability and Osteoarthritis Outcome Score (HOOS) at 3-month follow-up. Methods A prospective blinded multicentre RCT will be performed. We aim to recruit 150 patients. The patients will be randomly allocated to a THA with a straight or a curved stem. All patients, research assistants, clinical assessors and investigators will be blinded for the type of prosthesis for 5 years. Clinical assessments and roentgenograms will be taken preoperative, at 6 weeks after surgery, at 1, 2, 3, 4 and 5 years after surgery. Patient reported outcome measures (PROMs) will be obtained at the same follow-up moments. In addition, the PROMs will also be sent to the patients at 3 and 6 months after surgery. The HOOS at 3-month follow-up will be our primary outcome. Ethics and dissemination This trial will be performed in accordance with the Declaration of Helsinki. A local ethics committee has approved this trial. Written informed consent will be obtained from all participating patients. All serious adverse events will be reported to the ethics committee. Results Results will be submitted for publication to an orthopaedics related journal. Trial registration number NTR1560. PMID:27009147

  19. The Joys of Clinical Trials: A Case Study of a Multicenter Pharmaceutical Trial.

    ERIC Educational Resources Information Center

    Soronson, Bryan M.; Shaw, Diana V.

    1994-01-01

    A discussion of clinical trials in the pharmaceutical industry describes typical processes and administrative issues, then presents a case in which a foreign pharmaceutical company negotiated with a university for sponsorship of a multicenter clinical trial of a new drug therapy. Problems and important considerations in clinical trials are…

  20. [Multicenter trial for sudden hearing loss therapy - planning and concept].

    PubMed

    Plontke, S K; Girndt, M; Meisner, C; Probst, R; Oerlecke, I; Richter, M; Steighardt, J; Dreier, G; Weber, A; Baumann, I; Plößl, S; Löhler, J; Laszig, R; Werner, J A; Rahne, T

    2016-04-01

    Systemic steroids are widely used worldwide as a standard of care for primary therapy of idiopathic sudden sensorineural hearing loss (ISSHL). The German ISSHL guideline recommends high-dose steroids for primary therapy of ISSHL, without evidence from randomized controlled trials (RCTs). The rationale for the treatment of ISSHL using high dose steroids is only based on retrospective cohort studies.This article describes the planning and initiation of a multicenter, national, randomized, controlled clinical trial entitled Efficacy and safety of high dose glucocorticosteroid treatment for idiopathic sudden sensorineural hearing loss - a three-armed, randomized, triple-blind, multicenter trial (HODOKORT). This clinical trial aims to compare standard dose with two types of high-dose steroids for primary systemic therapy with respect to their efficacy in improving hearing, and thus communication ability, in patients with idiopathic sudden sensorineural hearing loss.This study is funded by the "Clinical Trials with High Patient Relevance" research program in the health research framework of the German Federal Ministry of Education and Research. It is one of two studies by the German Study Center of Clinical Trials of the German Society of Otorhinolaryngology, Head and Neck Surgery (DSZ-HNO). Planning and initiation was done in cooperation with the DSZ-HNO, the Coordination Center of Clinical Trials of the Martin-Luther-University Halle-Wittenberg, and the Study Center of the University Hospital Freiburg.

  1. MAIN ETHICAL BREACHES IN MULTICENTER CLINICAL TRIALS REGULATIONS OF TURKEY

    PubMed Central

    Ekmekci, P. Elif

    2017-01-01

    Turkey has been a growing market for multicenter clinical trials for the last ten years and is considered among the top ten countries in terms of potential study subject populations. The objective of increasing the share of Turkey in multicenter clinical trials is strongly supported. This ambitious goal of Turkey raises the need to have regulations in compliance with other leading countries conducting clinical trials. The latest published Turkish regulations on clinical trials are structured in compliance with the International Conference on Harmonization (ICH) Guidelines and in harmony with the regulations of other leading countries in clinical research, such as the US. There are still flaws in Turkish regulation with the risk of violating human subjects’ rights and issues with responsible conduct of research. The aim of this article is to compare Turkish clinical trials regulations with those of the US, to determine if there exists any incompatibility between the countries’ regulations and, if so, how to ameliorate these. The main flaws in Turkish clinical trials regulations are identified as follows: lack of definition of the term “human subject; absence of explicit referral to the unacceptability of Conflict of Interest (COI) and taking measures to avoid it; exiguity of emphasis on plurality of the IRB members; nonexistence of a clear expression that this is research; and clinical equipoise, regarding the treatment of the existing clinical problem and lack of integration with international accreditation systems for Institutional Review Boards.

  2. Using Vascular Quality Initiative as a Platform for Organizing Multicenter, Prospective, Randomized Clinical Trials: OVERPAR Trial

    PubMed Central

    Eslami, Mohammad H.; Doros, Gheorghe; Goodney, Philip P.; Elderup-Jorgenson, Jens; Cronenwett, Jack L.; Malikova, Marina; Farber, Alik

    2014-01-01

    Background We describe the organization of a prospective, randomized, multicenter trial comparing the effectiveness of open popliteal artery aneurysm repair (OPAR) and endovascular popliteal artery aneurysm repair (EPAR) of asymptomatic popliteal artery aneurysms (PAAs) as an example for how to use the Vascular Quality Initiative (VQI) framework. Given that many centers participate in the VQI, this model can be used to perform multicenters’ prospective trials on very modest budget. Methods VQI prospectively collects data on many vascular procedures. These data include many important perioperative, intraoperative, and postoperative details regarding both patients and their procedures. We describe a study where minimal changes to the collected data by participating centers can provide level-1 evidence regarding a significant clinical question. Data will be collected using modified VQI forms within the existing VQI data reporting structure. We plan to enroll 148 patients with asymptomatic PAAs into the open and endovascular surgery cohorts. Patients from participating VQI centers will be randomized 1:1 to either OPAR or EPAR and will be followed for an average of 2.5 years. Our primary hypothesis is that major adverse limb event–free survival is lower in the EPAR cohort and that EPAR is associated with more secondary interventions, improved quality of life, and decreased length of stay. The budget for this trial is fixed at $10,000/year for the course of the study, and the trial is judged to be feasible because of the functionality of the VQI platform. Conclusions Using the existing VQI infrastructure, Open versus Endovascular Repair of Popliteal Artery Aneurysm will provide level 1 data for PAA treatment on a modest budget. The proposed trial has an adequately powered comparative design that will use objective performance goals to describe limb-related morbidity and procedural reintervention rates. PMID:25311746

  3. Clinical trial design and rationale of the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) investigational device exemption clinical study protocol.

    PubMed

    Heatley, Gerald; Sood, Poornima; Goldstein, Daniel; Uriel, Nir; Cleveland, Joseph; Middlebrook, Don; Mehra, Mandeep R

    2016-04-01

    The HeartMate 3 left ventricular assist system (LVAS; St. Jude Medical, Inc., formerly Thoratec Corporation, Pleasanton, CA) was recently introduced into clinical trials for durable circulatory support in patients with medically refractory advanced-stage heart failure. This centrifugal, fully magnetically levitated, continuous-flow pump is engineered with the intent to enhance hemocompatibility and reduce shear stress on blood elements, while also possessing intrinsic pulsatility. Although bridge-to-transplant (BTT) and destination therapy (DT) are established dichotomous indications for durable left ventricular assist device (LVAD) support, clinical practice has challenged the appropriateness of these designations. The introduction of novel LVAD technology allows for the development of clinical trial designs to keep pace with current practices. The prospective, randomized Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) clinical trial aims to evaluate the safety and effectiveness of the HeartMate 3 LVAS by demonstrating non-inferiority to the HeartMate II LVAS (also St. Jude Medical, Inc.). The innovative trial design includes patients enrolled under a single inclusion and exclusion criteria , regardless of the intended use of the device, with outcomes ascertained in the short term (ST, at 6 months) and long term (LT, at 2 years). This adaptive trial design includes a pre-specified safety phase (n = 30) analysis. The ST cohort includes the first 294 patients and the LT cohort includes the first 366 patients for evaluation of the composite primary end-point of survival to transplant, recovery or LVAD support free of debilitating stroke (modified Rankin score >3), or re-operation to replace the pump. As part of the adaptive design, an analysis by an independent statistician will determine whether sample size adjustment is required at pre-specified times during the study. A further 662

  4. A Multicenter, Prospective Study to Evaluate the Use of Contrast Stress Echocardiography in Early Menopausal Women at Risk for Coronary Artery Disease: Trial Design and Baseline Findings

    PubMed Central

    Abdelmoneim, Sahar S.; Bernier, Mathieu; Hagen, Mary E.; Eifert-Rain, Susan; Bott-Kitslaar, Dalene; Wilansky, Susan; Castello, Ramon; Bhat, Gajanan; Pellikka, Patricia A.; Best, Patricia J. M.; Hayes, Sharonne N.

    2013-01-01

    Abstract Aims This multisite prospective trial, Stress Echocardiography in Menopausal Women At Risk for Coronary Artery Disease (SMART), aimed to evaluate the prognostic value of contrast stress echocardiography (CSE), coronary artery calcification (CAC), and cardiac biomarkers for prediction of cardiovascular events after 2 and 5 years in early menopausal women experiencing chest pain symptoms or risk factors. This report describes the study design, population, and initial test results at study entry. Methods From January 2004 through September 2007, 366 early menopausal women (age 54±5 years, Framingham risk score 6.51%±4.4 %, range 1%–27%) referred for stress echocardiography were prospectively enrolled. Image quality was enhanced with an ultrasound contrast agent. Tests for cardiac biomarkers [high-sensitivity C-reactive protein (hsCRP), atrial natriuretic protein (ANP), brain natriuretic protein (BNP), endothelin (ET-1)] and cardiac computed tomography (CT) for CAC were performed. Results CSE (76% exercise, 24% dobutamine) was abnormal in 42 women (11.5%), and stress electrocardiogram (ECG) was positive in 22 women (6%). Rest BNP correlated weakly with stress wall motion score index (WMSI) (r=0.189, p<0.001). Neither hsCRP, ANP, endothelin, nor CAC correlated with stress WMSI. Predictors of abnormal CSE were body mass index (BMI), diabetes mellitus, family history of premature coronary artery disease (CAD), and positive stress ECG. Twenty-four women underwent clinically indicated coronary angiography (CA); 5 had obstructive (≥50%), 15 had nonobstructive (10%–49%), and 4 had no epicardial CAD. Conclusions The SMART trial is designed to assess the prognostic value of CSE in early menopausal women. Independent predictors of positive CSE were BMI, diabetes mellitus, family history of premature CAD, and positive stress ECG. CAC scores and biomarkers (with the exception of rest BNP) were not correlated with CSE results. We await the follow-up data. PMID

  5. Multicenter randomized trial of cell therapy in cardiopathies – MiHeart Study

    PubMed Central

    Tura, Bernardo R; Martino, Helena F; Gowdak, Luis H; dos Santos, Ricardo Ribeiro; Dohmann, Hans F; Krieger, José E; Feitosa, Gilson; Vilas-Boas, Fábio; Oliveira, Sérgio A; Silva, Suzana A; Bozza, Augusto Z; Borojevic, Radovan; de Carvalho, Antonio C Campos

    2007-01-01

    Background Cardiovascular diseases are the major cause of death in the world. Current treatments have not been able to reverse this scenario, creating the need for the development of new therapies. Cell therapies have emerged as an alternative for cardiac diseases of distinct causes in experimental animal studies and more recently in clinical trials. Method/Design We have designed clinical trials to test for the efficacy of autologous bone marrow derived mononuclear cell therapies in four different cardiopathies: acute and chronic ischemic heart disease, and Chagasic and dilated cardiomyopathy. All trials are multicenter, randomized, double-blind and placebo controlled. In each trial 300 patients will be enrolled and receive optimized therapy for their specific condition. Additionally, half of the patients will receive the autologous bone marrow cells while the other half will receive placebo (saline with 5% autologous serum). For each trial there are specific inclusion and exclusion criteria and the method for cell delivery is intramyocardial for the chronic ischemic heart disease and intracoronary for all others. Primary endpoint for all studies will be the difference in ejection fraction (determined by Simpson's rule) six and twelve months after intervention in relation to the basal ejection fraction. The main hypothesis of this study is that the patients who receive the autologous bone-marrow stem cell implant will have after a 6 month follow-up a mean increase of 5% in absolute left ventricular ejection fraction in comparison with the control group. Discussion Many phase I clinical trials using cell therapy for cardiac diseases have already been performed. The few randomized studies have yielded conflicting results, rendering necessary larger well controlled trials to test for efficacy of cell therapies in cardiopathies. The trials registration numbers at the NIH registry are the following: Chagasic cardiomyopathy (NCT00349271), dilated cardiomyopathy (NCT

  6. Limiting loss to follow-up in a multicenter randomized trial in orthopedic surgery.

    PubMed

    Sprague, Sheila; Leece, Pamela; Bhandari, Mohit; Tornetta, Paul; Schemitsch, Emil; Swiontkowski, Marc F

    2003-12-01

    Even the best-designed, randomized controlled trials suffer when patients are lost to follow-up. Incomplete follow-up biases the results of a trial when patients who drop out are different from those who complete follow-up. This is exaggerated further when there are differential dropout rates between study groups. Previous randomized controlled trials in orthopedic trauma have reported up to 28% loss to follow-up. Only by striving to achieve a 0% loss to follow-up rate can we be certain that this type of bias does not affect our results. In our ongoing multicenter, randomized controlled trial comparing reamed and nonreamed intramedullary nailing of tibial shaft fractures, we have implemented several innovative strategies to minimize loss to follow-up. The exclusion criteria and consent process are designed to minimize losses. Study staff are carefully trained in communication and negotiation with patients. Additionally, a central methods center monitors all patient follow-up and aids in finding lost patients. Through these primary, secondary, and tertiary interventions, we have achieved 94% complete 1-year follow-up for the first 440 patients enrolled in the trial. Eleven patients withdrew consent, and we are unable to locate 17 patients. We have successfully minimized the loss to follow-up rate in our trial by incorporating innovative prevention and retention strategies into its design and conduct. Through planning, organization, and committing time and resources to minimizing loss to follow-up, other orthopedic trauma trials can hope to achieve the same high rates of follow-up.

  7. Laparoscopic versus open adhesiolysis for small bowel obstruction - a multicenter, prospective, randomized, controlled trial

    PubMed Central

    2014-01-01

    Background Laparoscopic adhesiolysis is emerging as an alternative for open surgery in adhesive small bowel obstruction. Retrospective studies suggest that laparoscopic approach shortens hospital stay and reduces complications in these patients. However, no prospective, randomized, controlled trials comparing laparoscopy to open surgery have been published. Methods/Design This is a multicenter, prospective, open label, randomized, controlled trial comparing laparoscopic adhesiolysis to open surgery in patients with computed-tomography diagnosed adhesive small bowel obstruction that is not resolving with conservative management. The primary study endpoint is the length of postoperative hospital stay in days. Sample size was estimated based on preliminary retrospective cohort, which suggested that 102 patients would provide 80% power to detect a difference of 2.5 days in the length of postoperative hospital stay with significance level of 0.05. Secondary endpoints include passage of stool, commencement of enteral nutrition, 30-day mortality, complications, postoperative pain, and the length of sick leave. Tertiary endpoints consist of the rate of ventral hernia and the recurrence of small bowel obstruction during long-term follow-up. Long-term follow-up by letter or telephone interview will take place at 1, 5, and 10 years. Discussion To the best of our knowledge, this trial is the first one aiming to provide level Ib evidence to assess the use of laparoscopy in the treatment of adhesive small bowel obstruction. Trial registration ClinicalTrials.gov identifier: NCT01867528. Date of registration May 26th 2013. PMID:25306234

  8. Acupuncture as prophylaxis for menstrual-related migraine: study protocol for a multicenter randomized controlled trial

    PubMed Central

    2013-01-01

    Background Menstrual-related migraine is a common form of migraine affecting >50% of female migraineurs. Acupuncture may be a choice for menstrual-related migraine, when pharmacological prophylaxis is not suitable. However, the efficacy of acupuncture has not been confirmed. We design and perform a randomized controlled clinical trial to evaluate the efficacy of acupuncture compared with naproxen in menstrual-related migraine patients. Methods/Design This is a multicenter, single blind, randomized controlled clinical trial. A total of 184 participants will be randomly assigned to two different groups. Participants will receive verum acupuncture and placebo medicine in the treatment group, while participants in the control group will be treated with sham acupuncture and medicine (Naproxen Sustained Release Tablets). All treatments will be given for 3 months (menstrual cycles). The primary outcome measures are the change of migraine days inside the menstrual cycle and the proportion of responders (defined as the proportion of patients with at least a 50% reduction in the number of menstrual migraine days). The secondary outcome measures are the change of migraine days outside the menstrual cycle, duration of migraine attack, the Visual Analogue Scale (VAS), and intake of acute medication. The assessment will be made at baseline (before treatment), 3 months (menstrual cycles), and 4 months (menstrual cycles) after the first acupuncture session. Discussion The results of this trial will be helpful to supply the efficacy of acupuncture for menstrual-related migraine prophylaxis. Trial registration ISRCTN: ISRCTN57133712 PMID:24195839

  9. Fluid Lavage of Open Wounds (FLOW): design and rationale for a large, multicenter collaborative 2 × 3 factorial trial of irrigating pressures and solutions in patients with open fractures

    PubMed Central

    2010-01-01

    Background Open fractures frequently result in serious complications for patients, including infections, wound healing problems, and failure of fracture healing, many of which necessitate subsequent operations. One of the most important steps in the initial management of open fractures is a thorough wound irrigation and debridement to remove any contaminants. There is, however, currently no consensus regarding the optimal approach to irrigating open fracture wounds during the initial operative procedure. The selection of both the type of irrigating fluid and the pressure of fluid delivery remain controversial. The primary objective of this study is to investigate the effects of irrigation solutions (soap vs. normal saline) and pressure (low vs. high; gravity flow vs. high; low vs. gravity flow) on re-operation within one year among patients with open fractures. Methods/Design The FLOW study is a multi-center, randomized controlled trial using a 2 × 3 factorial design. Surgeons at clinical sites in North America, Europe, Australia, and Asia will recruit 2 280 patients who will be centrally randomized into one of the 6 treatment arms (soap + low pressure; soap + gravity flow pressure; soap + high pressure; saline + low pressure; saline + gravity flow pressure; saline + high pressure). The primary outcome of the study is re-operation to promote wound or bone healing, or to treat an infection. This composite endpoint of re-operation includes a narrow spectrum of patient-important procedures: irrigation and debridement for infected wound, revision and closure for wound dehiscence, wound coverage procedures for infected or necrotic wound, bone grafts or implant exchange procedures for established nonunion in patients with postoperative fracture gaps less than 1 cm, intramedullary nail dynamizations in the operating room, and fasciotomies for compartment syndrome. Patients, outcome adjudicators, and data analysts will be blinded. We will compare rates of re-operation at

  10. Malignant Peripheral Nerve Sheath Tumors in Neurofibromatosis Type 1: A Multicenter Project With 3 Clinical Trials

    DTIC Science & Technology

    2006-06-01

    Tumors in Neurofibromatosis Type 1: A Multicenter Project with 3 Clinical Trials PRINCIPAL INVESTIGATOR: David Viskochil, M.D., Ph.D...Trials 5b. GRANT NUMBER W81XWH-04-1-0502 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) David Viskochil, M.D., Ph.D. 5d. PROJECT...submission of a clinical trial for neoadjuvant chemotherapy in MPNST (DAMD-NF043129; PI- David Viskochil). This proposal was not funded, however it was

  11. Proposal for a "phase II" multicenter trial model for preclinical new antiepilepsy therapy development.

    PubMed

    O'Brien, Terence J; Ben-Menachem, Elinor; Bertram, Edward H; Collins, Stephen D; Kokaia, Merab; Lerche, Holger; Klitgaard, Henrik; Staley, Kevin J; Vaudano, Elisabetta; Walker, Matthew C; Simonato, Michele

    2013-08-01

    There is a pressing need to address the current major gaps in epilepsy treatment, in particular drug-resistant epilepsy, antiepileptogenic therapies, and comorbidities. A major concern in the development of new therapies is that current preclinical testing is not sufficiently predictive for clinical efficacy. Methodologic limitations of current preclinical paradigms may partly account for this discrepancy. Here we propose and discuss a strategy for implementing a "phase II" multicenter preclinical drug trial model based on clinical phase II/III studies designed to generate more rigorous preclinical data for efficacy. The goal is to improve the evidence resulting from preclinical studies for investigational new drugs that have shown strong promise in initial preclinical "phase I" studies. This should reduce the risk for expensive clinical studies in epilepsy and therefore increase the appeal for funders (industry and government) to invest in their clinical development.

  12. Design of clinical trials.

    PubMed

    Rollo, David; Machado, Sanjay; Ceschin, Mauro

    2010-09-01

    Clinical trial design for nuclear medicine diagnostic imaging radiopharmaceuticals must include a design for preclinical safety studies. These studies should establish that the investigational product (IP) does not have a toxic effect. As a further requirement, radiopharmaceutical clinical trials include a human study (phase 1) that provides biodistribution, pharmacokinetics, and radiation dosimetry information. These studies demonstrate to the Food and Drug Administration that the IP either meets or exceeds the toxicology and radiation exposure safety limits. Satisfying this requirement can result in the Food and Drug Administration approving the performance of late-phase (phase 2/3) clinical trials that are designed to validate the clinical efficacy of the diagnostic imaging agent in patients who have a confirmed diagnosis for the intended application. Emphasis is placed on the most typical trial design for diagnostic imaging agents that use a comparator to demonstrate that the new IP is similar in efficacy to an established standard comparator. Such trials are called equivalence, or noninferiority, trials that attempt to show that the new IP is not less effective than the comparator by more than a statistically defined amount. Importantly, the trial design must not inappropriately favor one diagnostic imaging agent over the other. Bias is avoided by the use of a core laboratory with expert physicians who are not involved in the trial for interpreting and objectively scoring the image sets obtained at the clinical trial sites. Clinical trial design must also follow Good Clinical Practice (GCP) guidelines. GCP stipulates the clinical trial process, including protocol and Case Report Form design, analyses planning, as well as analyzing and preparing interim and final clinical trial/study reports.

  13. [CLINICAL TRIAL DESIGN].

    PubMed

    Morita, Satoshi

    2016-01-01

    Clinical trials/research are conducted to examine the clinical questions of practicing physicians. It is important to design trials appropriately in advance, taking their feasibility into account. A randomized, controlled trial is the ultimate design for treatment comparisons at the final confirmatory stage. However, randomized trials do not necessarily provide all answers to clinical questions. This article summarizes fundamental points of clinical trial design and the important role of randomization and contrasts superiority and noninferiority trials. In addition, it focuses on propensity score matching, a useful method to compare two treatment arms, especially in the context where randomization is infeasible. The propensity score-matching method is increasingly used in surgical clinical research.

  14. A Double-Blind, Double-Dummy, Flexible-Design Randomized Multicenter Trial: Early Safety of Single- Versus Divided-Dose Rabbit Anti-Thymocyte Globulin Induction in Renal Transplantation.

    PubMed

    Stevens, R B; Wrenshall, L E; Miles, C D; Farney, A C; Jie, T; Sandoz, J P; Rigley, T H; Osama Gaber, A

    2016-06-01

    A previous nonblinded, randomized, single-center renal transplantation trial of single-dose rabbit anti-thymocyte globulin induction (SD-rATG) showed improved efficacy compared with conventional divided-dose (DD-rATG) administration. The present multicenter, double-blind/double-dummy STAT trial (Single dose vs. Traditional Administration of Thymoglobulin) evaluated SD-rATG versus DD-rATG induction for noninferiority in early (7-day) safety and tolerability. Ninety-five patients (randomized 1:1) received 6 mg/kg SD-rATG or 1.5 mg/kg/dose DD-rATG, with tacrolimus-mycophenolate maintenance immunosuppression. The primary end point was a composite of fever, hypoxia, hypotension, cardiac complications, and delayed graft function. Secondary end points included 12-month patient survival, graft survival, and rejection. Target enrollment was 165 patients with an interim analysis scheduled after 80 patients. Interim analysis showed primary end point noninferiority of SD-rATG induction (p = 0.6), and a conditional probability of <1.73% of continued enrollment producing a significant difference (futility analysis), leading to early trial termination. Final analysis (95 patients) showed no differences in occurrence of primary end point events (p = 0.58) or patients with no, one, or more than one event (p = 0.81), or rejection, graft, or patient survival (p = 0.78, 0.47, and 0.35, respectively). In this rigorously blinded trial in adult renal transplantation, we have shown SD-rATG induction to be noninferior to DD-rATG induction in early tolerability and equivalent in 12-month safety. (Clinical Trials.gov #NCT00906204.).

  15. Multicenter Clinical Trial of the Nucleus® Hybrid™ S8 Cochlear Implant: Final Outcomes

    PubMed Central

    Gantz, Bruce J; Dunn, Camille; Oleson, Jacob; Hansen, Marlan; Parkinson, Aaron; Turner, Christopher

    2015-01-01

    Objective The concept expanding electrical speech processing to those with more residual acoustic hearing with a less invasive shorter cochlear implant has been ongoing since 1999. A multi-center study of the Nucleus Hybrid S8 CI took place between 2002–11. This report describes the final outcomes of this clinical trial. Study Design Multi-Center longitudinal single subject design Methods Eighty-seven subjects received a Nucleus® Hybrid™ S8 implant in their poorer ear. Speech perception in quiet (CNC words) and in noise (BKB-SIN) was collected pre- and post-operatively at 3, 6, and 12 months. Subjective questionnaire data using the APHAB was also collected. Results Some level of hearing preservation was accomplished in 98% subjects with 90% maintaining a functional low-frequency pure-tone average (LFPTA) at initial activation. By 12 months, 5 subjects had total hearing loss and 80% of subjects maintained functional hearing. CNC words demonstrated that 82.5% and 87.5% of subjects had significant improvements in the Hybrid and Combined conditions. The majority of had improvements with BKB-SIN. Results also indicated that as long as subjects maintained at least a severe LFPTA, there was significant improvement in speech understanding. Furthermore, all subjects reported positive improvements in hearing in three of the 4 subscales of the APHAB. Conclusion The concept of hybrid speech processing has significant advantages for subjects with residual low-frequency hearing. In this study, the Nucleus® Hybrid™ S8 provided improved word understanding in quiet and noise. Additionally, there appears to be stability of the residual hearing after initial activation of the device. Level of evidence 2c PMID:26756395

  16. Prefrontal transcranial direct current stimulation (tDCS) as treatment for major depression: study design and methodology of a multicenter triple blind randomized placebo controlled trial (DepressionDC).

    PubMed

    Padberg, Frank; Kumpf, Ulrike; Mansmann, Ulrich; Palm, Ulrich; Plewnia, Christian; Langguth, Berthold; Zwanzger, Peter; Fallgatter, Andreas; Nolden, Jana; Burger, Max; Keeser, Daniel; Rupprecht, Rainer; Falkai, Peter; Hasan, Alkomiet; Egert, Silvia; Bajbouj, Malek

    2017-02-28

    Transcranial direct current stimulation (tDCS) has been proposed as novel treatment for major depressive disorder (MDD) based on clinical pilot studies as well as randomized controlled monocentric trials. The DepressionDC trial is a triple-blind (blinding of rater, operator and patient), randomized, placebo controlled multicenter trial investigating the efficacy and safety of prefrontal tDCS used as additive treatment in MDD patients who have not responded to selective serotonin reuptake inhibitors (SSRI). At 5 study sites, 152 patients with MDD receive a 6-weeks treatment with active tDCS (anode F3 and cathode F4, 2 mA intensity, 30 min/day) or sham tDCS add-on to a stable antidepressant medication with an SSRI. Follow-up visits are at 3 and 6 months after the last tDCS session. The primary outcome measure is the change of the Montgomery-Asberg Depression Rating Scale (MADRS) scores at week 6 post-randomisation compared to baseline. Secondary endpoints also cover other psychopathological domains, and a comprehensive safety assessment includes measures of cognition. Patients undergo optional investigations comprising genetic testing and functional magnetic resonance imaging (fMRI) of structural and functional connectivity. The study uses also an advanced tDCS technology including standard electrode positioning and recording of technical parameters (current, impedance, voltage) in every tDCS session. Aside reporting the study protocol here, we present a novel approach for monitoring technical parameters of tDCS which will allow quality control of stimulation and further analysis of the interaction between technical parameters and clinical outcome. The DepressionDC trial will hopefully answer the important clinical question whether prefrontal tDCS is a safe and effective antidepressant intervention in patients who have not sufficiently responded to SSRIs.

  17. Does Quality of Radiation Therapy Predict Outcomes of Multicenter Cooperative Group Trials? A Literature Review

    SciTech Connect

    Fairchild, Alysa; Straube, William; Laurie, Fran; Followill, David

    2013-10-01

    Central review of radiation therapy (RT) delivery within multicenter clinical trials was initiated in the early 1970s in the United States. Early quality assurance publications often focused on metrics related to process, logistics, and timing. Our objective was to review the available evidence supporting correlation of RT quality with clinical outcomes within cooperative group trials. A MEDLINE search was performed to identify multicenter studies that described central subjective assessment of RT protocol compliance (quality). Data abstracted included method of central review, definition of deviations, and clinical outcomes. Seventeen multicenter studies (1980-2012) were identified, plus one Patterns of Care Study. Disease sites were hematologic, head and neck, lung, breast, and pancreas. Between 0 and 97% of treatment plans received an overall grade of acceptable. In 7 trials, failure rates were significantly higher after inadequate versus adequate RT. Five of 9 and 2 of 5 trials reported significantly worse overall and progression-free survival after poor-quality RT, respectively. One reported a significant correlation, and 2 reported nonsignificant trends toward increased toxicity with noncompliant RT. Although more data are required, protocol-compliant RT may decrease failure rates and increase overall survival and likely contributes to the ability of collected data to answer the central trial question.

  18. Laparoscopy Assisted versus Open Distal Gastrectomy with D2 Lymph Node Dissection for Advanced Gastric Cancer: Design and Rationale of a Phase II Randomized Controlled Multicenter Trial (COACT 1001)

    PubMed Central

    Nam, Byung Ho; Reim, Daniel; Eom, Bang Wool; Yu, Wan Sik; Park, Young Kyu; Ryu, Keun Won; Lee, Young Joon; Yoon, Hong Man; Lee, Jun Ho; Jeong, Oh; Jeong, Sang Ho; Lee, Sang Eok; Lee, Sang Ho; Yoon, Ki Young; Seo, Kyung Won; Chung, Ho Young; Kwon, Oh Kyoung; Kim, Tae Bong; Lee, Woon Ki; Park, Seong Heum; Sul, Ji-Young; Yang, Dae Hyun; Lee, Jong Seok

    2013-01-01

    Purpose Laparoscopy-assisted distal gastrectomy for early gastric cancer has gained acceptance and popularity worldwide. However, laparoscopy-assisted distal gastrectomy for advanced gastric cancer is still controversial. Therefore, we propose this prospective randomized controlled multi-center trial in order to evaluate the safety and feasibility of laparoscopy assisted D2-gastrectomy for advanced stage gastric cancer. Materials and Methods Patients undergoing distal gastrectomy for advanced gastric cancer staged cT2/3/4 cN0/1/2/3a cM0 by endoscopy and computed tomography are eligible for enrollment after giving their informed consent. Patients will be randomized either to laparoscopy-assisted distal gastrectomy or open distal gastrectomy. Sample size calculation revealed that 102 patients are to be included per treatment arm. The primary endpoint is the non-compliance rate of D2 dissection; relevant secondary endpoints are three-year disease free survival, surgical and postoperative complications, hospital stay and unanimity rate of D2 dissection evaluated by reviewing the intraoperative video documentation. Discussion Oncologic safety is the major concern regarding laparoscopy-assisted distal gastrectomy for advanced gastric cancer. Therefore, the non-compliance rate of clearing the N2 area was chosen as the most important parameter for the technical feasibility of the laparoscopic procedure. Furthermore, surgical quality will be carefully reviewed, that is, three independent experts will review the video records and score with a check list. For a long-term result, disease free survival is considered a secondary endpoint for this trial. This study will offer promising evidence of the feasibility and safety of Laparoscopy-assisted distal gastrectomy for advanced gastric cancer.Trial Registration: NCT01088204 (international), NCCCTS-09-448 (Korea). PMID:24156036

  19. Multicenter clinical trials in sepsis: understanding the big picture and building a successful operation at your hospital.

    PubMed

    Dellinger, R Phillip; Schorr, Christa; Trzeciak, Stephen

    2011-03-01

    Only through adequately designed and adequately conducted clinical trials can new treatments be found for the benefit of the septic patient. Over the past 20 years, tens of thousands of patients have been enrolled in sepsis clinical trials with little success. These efforts, however, have not been without worth. Much has been learned and the knowledge gained has changed our approach to trial design in this very difficult field. Animal studies are better designed to match the clinical picture of severe sepsis. Phase II studies are more carefully engineered to answer questions about the most suitable target population and end points. Trial conduct likely benefits from use of CROs and a CCC. The future of clinical trials may include more standardization of sepsis management across investigative sites. Before the decision is made to become an investigative site in a multicenter industry-sponsored clinical trial in sepsis or severe sepsis, it is important to recognize what is required to succeed. Once these key-to-success elements are in place, members of the investigative team are more likely to realize the satisfaction and career growth from becoming a successful site. The most professional satisfaction comes from the knowledge of contributing to original science in the field of the sepsis.

  20. Innovative Clinical Trial Designs

    PubMed Central

    Lavori, Philip W.

    2015-01-01

    Whereas the 20th-century health care system sometimes seemed to be inhospitable to and unmoved by experimental research, its inefficiency and unaffordability have led to reforms that foreshadow a new health care system. We point out certain opportunities and transformational needs for innovations in study design offered by the 21st-century health care system, and describe some innovative clinical trial designs and novel design methods to address these needs and challenges. PMID:26140056

  1. Multicenter Australian trial of islet transplantation: improving accessibility and outcomes.

    PubMed

    O'Connell, P J; Holmes-Walker, D J; Goodman, D; Hawthorne, W J; Loudovaris, T; Gunton, J E; Thomas, H E; Grey, S T; Drogemuller, C J; Ward, G M; Torpy, D J; Coates, P T; Kay, T W

    2013-07-01

    Whilst initial rates of insulin independence following islet transplantation are encouraging, long-term function using the Edmonton Protocol remains a concern. The aim of this single-arm, multicenter study was to evaluate an immunosuppressive protocol of initial antithymocyte globulin (ATG), tacrolimus and mycophenolate mofetil (MMF) followed by switching to sirolimus and MMF. Islets were cultured for 24 h prior to transplantation. The primary end-point was an HbA1c of <7% and cessation of severe hypoglycemia. Seventeen recipients were followed for ≥ 12 months. Nine islet preparations were transported interstate for transplantation. Similar outcomes were achieved at all three centers. Fourteen of the 17 (82%) recipients achieved the primary end-point. Nine (53%) recipients achieved insulin independence for a median of 26 months (range 7-39 months) and 6 (35%) remain insulin independent. All recipients were C-peptide positive for at least 3 months. All subjects with unstimulated C-peptide >0.2 nmol/L had cessation of severe hypoglycemia. Nine of the 17 recipients tolerated switching from tacrolimus to sirolimus with similar graft outcomes. There was a small but significant reduction in renal function in the first 12 months. The combination of islet culture, ATG, tacrolimus and MMF is a viable alternative for islet transplantation.

  2. Dairy-Rich Diets Augment Fat Loss on an Energy-Restricted Diet: A Multicenter Trial

    PubMed Central

    Zemel, Michael B.; Teegarden, Dorothy; Loan, Marta Van; Schoeller, Dale A.; Matkovic, Velimir; Lyle, Roseann M.; Craig, Bruce A.

    2009-01-01

    A 12-week randomized controlled multi-center clinical trial was conducted in 106 overweight and obese adults. Diets were designed to produce a 2,093 kJ/day energy deficit with either low calcium (LC; ~600 mg/day), high calcium (HC; ~1,400 mg/day), or high dairy (HD; three dairy servings, diet totaling ~1,400 mg/day). Ninety-three subjects completed the trial, and 68 met all a priori weekly compliance criteria. Both HC and HD contained comparable levels of calcium, but HC was only ~30% as effective as HD in suppressing 1,25-(OH)2D and exerted no significant effects on weight loss or body composition compared to LC. In the group that met compliance criteria, HD resulted in ~two-fold augmentation of fat loss compared to LC and HC (HD: -4.43 ± 0.53 kg; LC: -2.69 ± 0.0.53 kg; HC: -2.23 ± 0.73kg, p < 0.025); assessment of all completers and an intent-to-treat analysis produced similar trends. HD augmentated central (trunk) fat loss (HD: -2.38 ± 0.30 kg; HC: -1.42 ± 0.30 kg; LC: -1.36 ± 0.42 kg, p < 0.05) and waist circumference (HD: -7.65 ± 0.75 cm; LC: -4.92 ± 0.74 cm; LC: -4.95 ± 1.05 cm, p < 0.025). Similar effects were noted among all subjects completing the study and in an intent-to-treat analysis. These data indicate that dairy-rich diets augment weight loss by targeting the fat compartment during energy restriction. PMID:22253969

  3. Family Presence during Resuscitation: A Qualitative Analysis from a National Multicenter Randomized Clinical Trial

    PubMed Central

    De Stefano, Carla; Normand, Domitille; Jabre, Patricia; Azoulay, Elie; Kentish-Barnes, Nancy; Lapostolle, Frederic; Baubet, Thierry; Reuter, Paul-Georges; Javaud, Nicolas; Borron, Stephen W.; Vicaut, Eric; Adnet, Frederic

    2016-01-01

    Background The themes of qualitative assessments that characterize the experience of family members offered the choice of observing cardiopulmonary resuscitation (CPR) of a loved one have not been formally identified. Methods and Findings In the context of a multicenter randomized clinical trial offering family members the choice of observing CPR of a patient with sudden cardiac arrest, a qualitative analysis, with a sequential explanatory design, was conducted. The aim of the study was to understand family members’ experience during CPR. All participants were interviewed by phone at home three months after cardiac arrest. Saturation was reached after analysis of 30 interviews of a randomly selected sample of 75 family members included in the trial. Four themes were identified: 1- choosing to be actively involved in the resuscitation; 2- communication between the relative and the emergency care team; 3- perception of the reality of the death, promoting acceptance of the loss; 4- experience and reactions of the relatives who did or did not witness the CPR, describing their feelings. Twelve sub-themes further defining these four themes were identified. Transferability of our findings should take into account the country-specific medical system. Conclusions Family presence can help to ameliorate the pain of the death, through the feeling of having helped to support the patient during the passage from life to death and of having participated in this important moment. Our results showed the central role of communication between the family and the emergency care team in facilitating the acceptance of the reality of death. PMID:27253993

  4. Central coordination as an alternative for local coordination in a multicenter randomized controlled trial: the FAITH trial experience

    PubMed Central

    2012-01-01

    Background Surgeons in the Netherlands, Canada and the US participate in the FAITH trial (Fixation using Alternative Implants for the Treatment of Hip fractures). Dutch sites are managed and visited by a financed central trial coordinator, whereas most Canadian and US sites have local study coordinators and receive per patient payment. This study was aimed to assess how these different trial management strategies affected trial performance. Methods Details related to obtaining ethics approval, time to trial start-up, inclusion, and percentage completed follow-ups were collected for each trial site and compared. Pre-trial screening data were compared with actual inclusion rates. Results Median trial start-up ranged from 41 days (P25-P75 10-139) in the Netherlands to 232 days (P25-P75 98-423) in Canada (p = 0.027). The inclusion rate was highest in the Netherlands; median 1.03 patients (P25-P75 0.43-2.21) per site per month, representing 34.4% of the total eligible population. It was lowest in Canada; 0.14 inclusions (P25-P75 0.00-0.28), representing 3.9% of eligible patients (p < 0.001). The percentage completed follow-ups was 83% for Canadian and Dutch sites and 70% for US sites (p = 0.217). Conclusions In this trial, a central financed trial coordinator to manage all trial related tasks in participating sites resulted in better trial progression and a similar follow-up. It is therefore a suitable alternative for appointing these tasks to local research assistants. The central coordinator approach can enable smaller regional hospitals to participate in multicenter randomized controlled trials. Circumstances such as available budget, sample size, and geographical area should however be taken into account when choosing a management strategy. Trial Registration ClinicalTrials.gov: NCT00761813 PMID:22225733

  5. Management of Pneumothorax in Emergency Medicine Departments: Multicenter Trial

    PubMed Central

    Ince, Abdulkadir; Ozucelik, Dogac Niyazi; Avci, Akkan; Nizam, Ozgur; Dogan, Halil; Topal, Mehmet Ali

    2013-01-01

    Background: Pneumothorax is common and life-threatening clinical condition which may require emergency treatment in Emergency Medicine Departments. Objectives: We aimed to reveal the epidemiological analysis of the patients admitted to the Emergency Department with pneumothorax. Material and Methods: This case-control and multi-center study was conducted in the patients treated with the diagnosis of pneumothorax between 01.01.2010-31.12.2010. Patient data were collected from hospital automation system. According to the etiology of the pneumothorax, study groups were arranged like spontaneous pneumothorax and traumatic pneumothorax. Results: 82.2% (n = 106) of patients were male and 17.8% (n = 23) of patients were female and mean age were 31.3 ± 20,2 (Minimum: 1, Maximum: 87). 68.2% (n = 88) of patients were spontaneous pneumothorax (61.36%, n=79 were primary spontaneous pneumothorax) and 31.8% (n = 41) of patients were traumatic pneumothorax (21.95% were iatrogenic pneumothorax). Main complaint is shortness of breath (52.3%, n=67) and 38% (n=49) of patients were smokers. Posteroanterior (PA) Chest X-Ray has been enough for 64.3% (n = 83) of the patients' diagnosis. Tube thoracostomy is applied to 84.5% (n = 109) of patients and surgery is applied to 9.3% (n = 12) of patients and 6.2% (n = 8) of patients were discharged with conservative treatment. Spontaneous pneumothorax showed statistically significant high recurrence compared with traumatic pneumothorax (P = 0.007). 4.65% of (n = 6) patients died. The average age of those who died (9.3 ± 19.9), statistically were significantly lower the mean age of living patients (32.4 ± 19.7) (t test, P = 0,006). 83.33% of the patients who died were neonatals and in the 0-1 years age group, and five of these patients were secondary spontaneous pneumothorax, and one of these patients were iatrogenic pneumothorax due to mechanical ventilation. Conclusions: Pneumothorax in adults can be treated by tube thoracostomy or

  6. Technical success from endovascular aneurysm repair in the post-marketing era: a multicenter prospective trial.

    PubMed

    Naslund, Thomas C; Becker, Stacey Y

    2003-01-01

    Evaluation of post-marketing success with the Ancure Endovascular Graft (AEG) was accomplished by review of a multicenter, prospective trial involving 46 centers and 163 patients. A second cohort of patients (n = 350) treated with the AEG under a controlled-use interval prior to the prospective trial was simultaneously evaluated. Technical success in both groups of patients (96.9% and 97.4%, respectively) was similar to what was reported in pre-market clinical trials. Operative implantation complications unique to the AEG included graft limb stenosis/occlusion in 35.6 and 31.4%, contralateral pull wire being caught on hooks in 33.7 and 28%, failure to seal (type I endoleak) in 17.2 and 18.3%, jacket guard being stuck in 12.9 and 11%, contralateral wire being stuck in 6.8 and 7.1%, high jacket retraction force in 16 and 8.5%, and inability to retract jacket in 1.8 and 0.5% of patients involved in the multicenter trial and controlled-use interval, respectively. One of four patients undergoing conversion in the prospective trial had graft misdeployment as a mode of failure. Three were converted for access failure. The 30-day mortality rate in the prospective trial was 3.7%. Interventions to resolve implantation-related events included stenting, guide catheter manipulations, wire exchanges, and delivery catheter disassembly. These interventions were successful in virtually every case. Open surgical procedures were not needed to correct these operative problems. Results from this study demonstrate excellent technical success with the AEG in the post-market era. Interventions to resolve implantation complications, when utilized, are highly successful in facilitating AEG implantation and providing technical success.

  7. Treatment of limited stage follicular lymphoma with Rituximab immunotherapy and involved field radiotherapy in a prospective multicenter Phase II trial-MIR trial

    PubMed Central

    2011-01-01

    Background The optimal treatment of early stage follicular Lymphoma is a matter of debate. Radiation therapy has frequently been applied with a curative approach beside watchful waiting. Involved field, extended field and total nodal radiation techniques are used in various protocols, but the optimal radiation field still has to be defined. Follicular lymphoma is characterized by stable expression of the CD20 antigen on the tumour cells surface. The anti CD20 antibody Rituximab (Mabthera®) has shown to be effective in systemic therapy of FL in primary treatment, relapse and maintenance therapy. Methods/design The MIR (Mabthera® and Involved field Radiation) study is a prospective multicenter trial combining systemic treatment with the anti CD20 antibody Rituximab (Mabthera®) in combination with involved field radiotherapy (30 - 40 Gy). This trial aims at testing the combination's efficacy and safety with an accrual of 85 patients. Primary endpoint of the study is progression free survival. Secondary endpoints are response rate to Rituximab, complete remission rate at week 18, relapse rate, relapse pattern, relapse free survival, overall survival, toxicity and quality of life. Discussion The trial evaluates the efficacy of Rituximab to prevent out-filed recurrences in early stage nodal follicular lymphoma and the safety of the combination of Rituximab and involved field radiotherapy. It also might show additional risk factors for a later recurrence (e.g. remission state after Rituximab only). Trial Registration ClinicalTrials (NCT): NCT00509184 PMID:21352561

  8. A multicenter, randomized controlled trial of immediate total-body CT scanning in trauma patients (REACT-2)

    PubMed Central

    2012-01-01

    Background Computed tomography (CT) scanning has become essential in the early diagnostic phase of trauma care because of its high diagnostic accuracy. The introduction of multi-slice CT scanners and infrastructural improvements made total-body CT scanning technically feasible and its usage is currently becoming common practice in several trauma centers. However, literature provides limited evidence whether immediate total-body CT leads to better clinical outcome then conventional radiographic imaging supplemented with selective CT scanning in trauma patients. The aim of the REACT-2 trial is to determine the value of immediate total-body CT scanning in trauma patients. Methods/design The REACT-2 trial is an international, multicenter randomized clinical trial. All participating trauma centers have a multi-slice CT scanner located in the trauma room or at the Emergency Department (ED). All adult, non-pregnant, severely injured trauma patients according to predefined criteria will be included. Patients in whom direct scanning will hamper necessary cardiopulmonary resuscitation or who require an immediate operation because of imminent death (both as judged by the trauma team leader) are excluded. Randomization will be computer assisted. The intervention group will receive a contrast-enhanced total-body CT scan (head to pelvis) during the primary survey. The control group will be evaluated according to local conventional trauma imaging protocols (based on ATLS guidelines) supplemented with selective CT scanning. Primary outcome will be in-hospital mortality. Secondary outcomes are differences in mortality and morbidity during the first year post trauma, several trauma work-up time intervals, radiation exposure, general health and quality of life at 6 and 12 months post trauma and cost-effectiveness. Discussion The REACT-2 trial is a multicenter randomized clinical trial that will provide evidence on the value of immediate total-body CT scanning during the primary

  9. Current situation of asthma-COPD overlap syndrome (ACOS) in Chinese patients older than 40 years with airflow limitation: rationale and design for a multicenter, cross-sectional trial (study protocol)

    PubMed Central

    Yao, Wanzhen; Cai, Baiqiang; Chen, Ping; Ling, Xia; Shang, Hongyan

    2016-01-01

    Background Asthma and chronic obstructive pulmonary disease (COPD) are the frequently occurring chronic airway diseases, and the overlapping syndrome observed in the majority of patients has been recently defined as asthma-COPD overlap syndrome (ACOS) by the Global Initiative for Chronic Obstructive Lung (GOLD, 2014) and Global initiative for Asthma (GINA, 2015). The proportion, features, and clinical practice of ACOS still remain elusive in China. We are conducting this multicenter, cross-sectional, observational study (NCT02600221) to investigate the distributions of chronic obstructive diseases in patients >40 years of age with chronic airflow limitation in China along with determination of the main clinical practice and features of these diseases. The study will also explore the factors that may influence the exacerbations and severity of ACOS in Chinese patients (>40 years of age). Methods A total of 2,000 patients (age, ≥40 years; either sex) who are clinically diagnosed as having asthma, COPD/chronic bronchitis/emphysema, or ACOS for at least 12 months with airflow limitation [post-bronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC): <0.7] will be enrolled from approximately 20 sites in China between December 2015 and December 2016. The proportion of ACOS among patients older than 40 years based on GINA 2015 and GOLD 2014 definitions is the primary variable. Following were the secondary variables: the proportions of COPD and asthma among the patients, distributions of the severity of airflow limitation, distribution of groups according to GOLD 2011 group definition (A, B, C, D), and the distribution of medication by drug class in patients with ACOS, asthma, and COPD. Acute exacerbation history, hospitalization, and severity of ACOS as evaluated using COPD Assessment Test, Asthma Control Questionnaire-5, and Modified British Medical Research Council in patients with ACOS were also assessed. Implications This will be the

  10. A Multicenter Trial Defining a Serum Protein Signature Associated with Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Gerdtsson, Anna S.; Malats, Núria; Säll, Anna; Real, Francisco X.; Porta, Miquel; Skoog, Petter; Persson, Helena; Wingren, Christer; Borrebaeck, Carl A. K.

    2015-01-01

    Background. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with rapid tumor progression and poor prognosis. This study was motivated by the lack of sensitive and specific PDAC biomarkers and aimed to identify a diagnostic, serum protein signature for PDAC. Methods. To mimic a real life test situation, a multicenter trial comprising a serum sample cohort, including 338 patients with either PDAC or other pancreatic diseases (OPD) and controls with nonpancreatic conditions (NPC), was analyzed on 293-plex recombinant antibody microarrays targeting immunoregulatory and cancer-associated antigens. Results. Serum samples collected from different hospitals were analyzed and showed that (i) sampling from five different hospitals could not be identified as a preanalytical variable and (ii) a multiplexed biomarker signature could be identified, utilizing up to 10 serum markers that could discriminate PDAC from controls, with sensitivities and specificities in the 91–100% range. The first protein profiles associated with the location of the primary tumor in the pancreas could also be identified. Conclusions. The results demonstrate that robust enough serum signatures could be identified in a multicenter trial, potentially contributing to the development of a multiplexed biomarker immunoassay for improved PDAC diagnosis. PMID:26587286

  11. Reconstruction of Peri-implant Osseous Defects: A Multicenter Randomized Trial.

    PubMed

    Jepsen, K; Jepsen, S; Laine, M L; Anssari Moin, D; Pilloni, A; Zeza, B; Sanz, M; Ortiz-Vigon, A; Roos-Jansåker, A M; Renvert, S

    2016-01-01

    There is a paucity of data for the effectiveness of reconstructive procedures in the treatment of peri-implantitis. The objective of this study was to compare reconstruction of peri-implant osseous defects with open flap debridement (OFD) plus porous titanium granules (PTGs) compared with OFD alone. Sixty-three patients (36 female, 27 male; mean age 58.4 y [SD 12.3]), contributing one circumferential peri-implant intraosseous defect, were included in a multinational, multicenter randomized trial using a parallel-group design. After OFD and surface decontamination using titanium brushes and hydrogen peroxide, 33 defects received PTGs. The implants were not submerged. All patients received adjunctive perioperative systemic antibiotics. The primary outcome variable (defect fill) was assessed on digitalized radiographs. Clinical measurements of probing depth (PPD), bleeding on probing (BoP), suppuration, and plaque were taken by blinded examiners. After 12 mo, the test group (OFD plus PTG) showed a mean radiographic defect fill (mesial/distal) of 3.6/3.6 mm compared with 1.1/1.0 in the control group (OFD). Differences were statistically significant in favor of the test group (P < 0.0001). The OFD plus PTG group showed a mean reduction in PPD of 2.8 mm compared with 2.6 mm in the OFD group. BoP was reduced from 89.4% to 33.3% and from 85.8% to 40.4% for the test and control groups, respectively. There was no significant difference in complete resolution of peri-implantitis (PPD ≤4 mm and no BoP at six implant sites and no further bone loss), because this finding was accomplished at 30% of implants in the test group and 23% of implants in the control group. Reconstructive surgery using PTGs resulted in significantly enhanced radiographic defect fill compared with OFD. However, limitations in the lack of ability to discern biomaterial from osseous tissue could not be verified to determine new bone formation. Similar improvements according to clinical measures were

  12. Interventions to Increase Enrollment in a Large Multicenter Phase 3 Trial of Carotid Stenting versus Endarterectomy

    PubMed Central

    Longbottom, Mary E.; Roberts, Jamie N.; Tom, MeeLee; Hughes, Susan E.; Howard, Virginia J.; Sheffet, Alice J.; Meschia, James F.; Brott, Thomas G.

    2012-01-01

    Background Randomized clinical trials often encounter slow enrollment. Failing to meet sample size requirements has scientific, financial, and ethical implications. Aims We report interventions used to accelerate recruitment in a large multicenter clinical trial that was not meeting prespecified enrollment commitments. Methods The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) began randomization in December 2000. To accelerate enrollment, multiple recruitment tactics were initiated, which included expanding the number of sites; hiring a Recruitment Director (May 2003); broadening eligibility criteria (April 2005); branding with a study logo, website, and recruitment materials; increasing site visits by study leadership; sending emails to the site teams after every enrollment; distributing electronic newsletters; and implementing investigator and coordinator conferences. Results From December 2000 through May 2003, 14 sites became active (54 patients randomized); from June 2003 through April 2005, 44 sites were added (404 patients randomized); and from May 2005 through July 2008, 54 sites were added (2044 patients randomized). During these time intervals, the number of patients enrolled per site per year was 1.5, 3.6, and 5.6. For the single years 2004 to 2008, the mean monthly randomization rates per year were 19.7, 38.1, 56.4, 53.0, and 54.7 (annualized), respectively. Enrollment was highest after recruitment tactics were implemented: 677 patients in 2006, 636 in 2007, and 657 in 2008 (annualized). The prespecified sample size of 2502 patients, 47% asymptomatic, was accomplished July 2008. Conclusions Aggressive recruitment tactics and investment in a full-time Recruitment Director who can lead implementation may be effective in accelerating recruitment in multicenter trials. PMID:22631861

  13. Factors Influencing Medical Student Attrition and Their Implications in a Large Multi-Center Randomized Education Trial

    ERIC Educational Resources Information Center

    Kalet, A.; Ellaway, R. H.; Song, H. S.; Nick, M.; Sarpel, U.; Hopkins, M. A.; Hill, J.; Plass, J. L.; Pusic, M. V.

    2013-01-01

    Participant attrition may be a significant threat to the generalizability of the results of educational research studies if participants who do not persist in a study differ from those who do in ways that can affect the experimental outcomes. A multi-center trial of the efficacy of different computer-based instructional strategies gave us the…

  14. Methodologic issues in terminating enrollment of a subgroup of patients in a multicenter randomized trial.

    PubMed

    Lee, Shing M; Wise, Robert; Sternberg, Alice L; Tonascia, James; Piantadosi, Steven

    2004-01-01

    The National Emphysema Treatment Trial (NETT) was a multicenter randomized controlled trial comparing medical treatment plus lung-volume-reduction surgery (LVRS) to medical treatment alone for the treatment of severe emphysema. The primary outcomes specified for the trial were mortality from all causes and change in functional status as indicated by the change in maximum exercise capacity measured two years after randomization. A secondary objective of the trial was to define criteria to identify subgroups of patients at risk of harm or benefit from LVRS. Stopping guidelines for safety and efficacy based on 30-day mortality and a combination of overall mortality and functional status at two years were specified at the inception of the trial. Although specific subgroups of patients likely to benefit were not identified in advance, several clinical factors were specified as likely to be important in defining subgroups with differential outcome. In May 2001, with 40% of expected deaths accrued, the Data and Safety Monitoring Board determined that a subgroup of patients was at significantly higher risk of 30-day mortality from LVRS without counterbalancing evidence of functional benefit, and recommended that the protocol be modified to exclude further randomization of such patients. The trial's sponsor, the National Heart, Lung and Blood Institute, accepted the recommendation, which was rapidly communicated to participating clinics. This paper describes the operational aspects of identification of the subgroup and implementation of the recommendation to continue the trial, but to terminate enrollment of new patients in the subgroup. These aspects include notification of the investigators, the institutional review boards, the Research Group, the patients and the medical community. We also describe the repercussions of the publication and the misinterpretations of the results based on media coverage.

  15. Quantitative analysis of tomographic stress thallium-201 myocardial scintigrams: a multicenter trial.

    PubMed

    Van Train, K F; Maddahi, J; Berman, D S; Kiat, H; Areeda, J; Prigent, F; Friedman, J

    1990-07-01

    The accuracy of the previously developed and validated Cedars-Sinai Medical Center (CSMC) computer program for quantitative analysis of thallium-201 (201TI) stress myocardial tomograms was assessed in a multicenter trial consisting of 242 patients with coronary angiography and 76 with a low likelihood (LL) of coronary artery disease (CAD) involving various cameras, computers, and operators. The program utilized gender-matched normal limits developed from 35 LL patients at CSMC. The multicenter results as compared to those of 168 patients from CSMC were not significantly different with respect to the overall sensitivities (94% versus 95%) and specificities (44% versus 56%) for identification of CAD and normalcy rates which were determined in LL patients (82% for both) and with respect to identification of individual diseased arteries. The results indicate that our method for quantifying tomographic 201TI stress scintigrams utilizing standard normal limits can be applied at other institutions by different operators, using a variety of cameras and computers, with similar accuracy to that currently obtained at our institution.

  16. The effectiveness of video interaction guidance in parents of premature infants: A multicenter randomised controlled trial

    PubMed Central

    2012-01-01

    Background Studies have consistently found a high incidence of neonatal medical problems, premature births and low birth weights in abused and neglected children. One of the explanations proposed for the relation between neonatal problems and adverse parenting is a possible delay or disturbance in the bonding process between the parent and infant. This hypothesis suggests that due to neonatal problems, the development of an affectionate bond between the parent and the infant is impeded. The disruption of an optimal parent-infant bond -on its turn- may predispose to distorted parent-infant interactions and thus facilitate abusive or neglectful behaviours. Video Interaction Guidance (VIG) is expected to promote the bond between parents and newborns and is expected to diminish non-optimal parenting behaviour. Methods/design This study is a multi-center randomised controlled trial to evaluate the effectiveness of Video Interaction Guidance in parents of premature infants. In this study 210 newborn infants with their parents will be included: n = 70 healthy term infants (>37 weeks GA), n = 70 moderate term infants (32–37 weeks GA) which are recruited from maternity wards of 6 general hospitals and n = 70 extremely preterm infants or very low birth weight infants (<32 weeks GA) recruited by the NICU of 2 specialized hospitals. The participating families will be divided into 3 groups: a reference group (i.e. full term infants and their parents, receiving care as usual), a control group (i.e. premature infants and their parents, receiving care as usual) and an intervention group (i.e. premature infants and their parents, receiving VIG). The data will be collected during the first six months after birth using observations of parent-infant interactions, questionnaires and semi-structured interviews. Primary outcomes are the quality of parental bonding and parent-infant interactive behaviour. Parental secondary outcomes are (posttraumatic) stress symptoms

  17. Rationale and design of the RIACT–study: a multi-center placebo controlled double blind study to test the efficacy of RItuximab in Acute Cellular tubulointerstitial rejection with B-cell infiltrates in renal Transplant patients: study protocol for a randomized controlled trial

    PubMed Central

    2012-01-01

    Background Acute kidney allograft rejection is a major cause for declining graft function and has a negative impact on the long-term graft survival. The majority (90%) of acute rejections are T-cell mediated and, therefore, the anti-rejection therapy targets T-cell-mediated mechanisms of the rejection process. However, there is increasing evidence that intragraft B-cells are also important in the T-cell-mediated rejections. First, a significant proportion of patients with acute T-cell-mediated rejection have B-cells present in the infiltrates. Second, the outcome of these patients is inferior, which has been related to an inferior response to the conventional anti-rejection therapy. Third, treatment of these patients with an anti-CD20 antibody (rituximab) improves the allograft outcome as reported in single case observations and in one small study. Despite the promise of these observations, solid evidence is required before incorporating this treatment option into a general treatment recommendation. Methods/Design The RIACT study is designed as a randomized, double-blind, placebo-controlled, parallel group multicenter Phase III study. The study examines whether rituximab, in addition to the standard treatment with steroid-boli, leads to an improved one-year kidney allograft function, compared to the standard treatment alone in patients with acute T-cell mediated tubulointerstitial rejection and significant B-cell infiltrates in their biopsies. A total of 180 patients will be recruited. Discussion It is important to clarify the relevance of anti-B cell targeting in T-cell mediated rejection and answer the question whether this novel concept should be incorporated in the conventional anti-rejection therapy. Trial registration Clinical trials gov. number: NCT01117662 PMID:23101480

  18. Challenges in conducting multicenter, multicultural, and multilingual trials: a view from the literature and real-life experience reports.

    PubMed

    Hanson, Beate; De Faoite, Diarmuid

    2013-01-01

    A trend toward international multicenter clinical trials in the medical device industry is helping to increase recruitment figures and to improve the generalizability of results, among other factors. However, working globally creates its own unique set of problems, which are rarely discussed in the literature. This article considers these issues from multicenter, multicultural, and multilingual perspectives. A multicenter study implies a replication of work to coordinate research sites that are working under different regulations. Standardizing elements of the clinical trial is essential for proper comparison of results. Multicultural differences manifest themselves in different forms in international clinical research. However, the impact of culture on a study's success is a real issue, particularly when patient-reported outcomes form part of the trial. A trial that is conducted globally obviously requires the use of local language material, but this element is fraught with the possibility of mistranslation and misunderstanding. In this article, we also examine the composition of a research team and how to keep everyone involved in a global clinical trial both informed and enthused about a trial that may last several years. Examples from our own clinical investigations are reported throughout this article.

  19. A Guide on Organizing a Multicenter Clinical Trial: the WRIST study group

    PubMed Central

    Chung, Kevin C.; Song, Jae W.

    2010-01-01

    Multicenter clinical trials (MCCTs) are an important research tool. Planning a MCCT is a long and arduous task that requires substantial preparation time. In this guide, we discuss the steps to plan a MCCT. A pre-planning phase, which involves formulating and refining a research question and conducting pilot studies, is detailed as well as the planning phase, which involves the acquisition of funding to support the coordination and preparation of a MCCT, culminating in the submission of an R01 grant. An essential asset to planning a MCCT is the fluidity with which all collaborators work together towards a common vision. The philosophy among collaborators should be consensus and commitment and is emphasized by the development of a consensus-assisted study protocol and the recruitment of centers and co-investigators who are dedicated, collaborative and selfless in this team effort to achieve goals that cannot be reached by a single center effort. PMID:20375760

  20. Reliable surrogate outcome measures in multicenter clinical trials of Duchenne muscular dystrophy.

    PubMed

    Mayhew, Jill E; Florence, Julaine M; Mayhew, Thomas P; Henricson, Erik K; Leshner, Robert T; McCarter, Robert J; Escolar, Diana M

    2007-01-01

    We studied the reliability of a series of endpoints in an evaluation of subjects with Duchenne muscular dystrophy (DMD). The endpoints included quantitative muscle tests (QMTs), timed function tests, forced vital capacity (FVC), and manual muscle tests (MMT). Thirty-one ambulatory subjects with DMD (mean age 8.9 years; range 5-16 years) were evaluated at eight sites by 15 newly trained evaluators as a test of interrater reliability of outcome measures. Both total QMT score [intraclass correlation coefficient (ICC) 0.96] and individual QMT assessments (ICC 0.85-0.96) were highly reliable. Forced vital capacity and all timed function tests were also highly reliable (ICC 0.97-0.99). MMT was the least reliable assessment method (ICC 0.61). These data suggest that primary surrogate outcome measures in large multicenter clinical trials in DMD should use QMT, FVC, or time function tests to obtain maximum power and greatest sensitivity.

  1. Evaluation of the Informed Consent Process of a Multicenter Tuberculosis Treatment Trial

    PubMed Central

    Chapman, Kimberley N.; Pevzner, Eric; Mangan, Joan M.; Breese, Peter; Lamunu, Dorcas; Shrestha-Kuwahara, Robin; Nakibali, Joseph G.; Goldberg, Stefan V.

    2016-01-01

    and challenges were identified in obtaining consent in a large, international multicenter trial and provided insights for a more robust assessment of the consent process in future trials. PMID:28317002

  2. Results of a prospective multicenter trial evaluating the ePTFE peritoneal onlay laparoscopic inguinal hernioplasty.

    PubMed

    Toy, F K; Moskowitz, M; Smoot, R T; Pleatman, M; Bagdasarian, A; Polito, W; Carey, S D; Schatz, R; Janes, K; Zipser, M E

    1996-12-01

    A 2.8-year prospective multicenter trial was conducted to evaluate the ePTFE peritoneal onlay laparoscopic inguinal hernioplasty. A total of 441 inguinal hernias were repaired in 351 patients (326 male; 25 female). Two hundred twenty-six of the hernias were direct, 185 indirect, 4 femoral, 26 pantaloon, 90 bilateral, and 92 recurrent. Standardized data collection forms were used and submitted for centralized data analysis. For the hernioplasty, Cooper's ligament was exposed and an 8 cm x 12 cm x 1 mm GORE-TEX Soft Tissue Patch was stapled circumferentially to Cooper's ligament and the endoabdominal fascia. Patients were followed at 1 week, 6 months, 1 year, and then annually. Three-month intervals were used as needed. There was a mean follow-up of 447 days, with 21% of the total repairs followed for more than 2 years and 56% for more than a year. The overall follow-up rate was 95.5%. The operative and postoperative complication rates were 0.45% and 8%, respectively. There were 17 recurrent hernias (3.8%). The range of experience among the investigators was 13 to 168 hernioplasties. With the completion of 25 cases per investigator, the recurrence rate fell to 0.39%. Postoperative analgesia averaged a 24-hr supply of medication; 12.2% of patients required no analgesia. Convalescence averaged 5.4 days, and return to work averaged 7.7 days. This multicenter trial demonstrates that the ePTFE laparoscopic peritoneal onlay inguinal hernioplasty is a safe and dependable repair, especially after the initial learning curve is surmounted.

  3. Esthetic outcomes in relation to implant-abutment interface design following a standardized treatment protocol in a multicenter randomized controlled trial--a cohort of 12 cases at 1-year follow-up.

    PubMed

    McGuire, Michael K; Scheyer, Todd; Ho, Daniel K; Stanford, Clark M; Feine, Jocelyne S; Cooper, Lyndon F

    2015-01-01

    The design of an implant-abutment interface may have an impact on the peri-implant soft tissue esthetics. In an ongoing randomized controlled trial (RCT) with 141 participants, the authors evaluated the peri-implant tissue responses around three different implant-abutment interface designs used to replace single teeth in the esthetic zone. The aim of this report is to describe the treatment protocol utilized in this ongoing RCT by (1) demonstrating in detail a clinical case treated under this protocol and (2) reporting peri-implant soft tissue responses in a cohort of 12 representative cases from the RCT at 1-year follow-up. Male and female adults requiring single implants in the anterior maxilla were enrolled in the RCT according to the study protocol. Five months following any required extraction and/or socket bone grafting/ridge augmentation, one of the following three implant-abutment interfaces was placed and immediately provisionalized: (1) conical interface (CI; OsseoSpeed, Dentsply Implants), n = 4; (2) flat-to-flat interface (FI; NobelSpeedy Replace, Nobel Biocare), n = 4; or (3) platform-switch interface (PS; NanoTite Certain Prevail, Biomet 3i), n = 4. Twelve weeks later, definitive crowns were delivered. Throughout the treatment, peri-implant buccal gingival zenith height and mesial/distal papilla height were measured on stereotactic device photographs, and pink esthetic scores (PES) were determined. The demographics of the participants in each of the three implant-abutment interface groups were very similar. All 12 study sites had ideal ridge form with a minimum width of 5.5 mm following implant site development performed according to the described treatment protocol. Using this treatment protocol for single-tooth replacement in the anterior maxilla, the clinicians were able to obtain esthetic peri-implant soft tissue outcomes with all three types of implant-abutment interface designs at 1-year follow-up as shown by the Canfield data and PES. The

  4. WIDEN: A tool for medical image management in multicenter clinical trials.

    PubMed

    Chauvie, Stéphane; Biggi, Alberto; Stancu, Alexandru; Cerello, Piergiorgio; Cavallo, Anna; Fallanca, Federico; Ficola, Umberto; Gregianin, Michele; Guerra, Ugo Paolo; Chiaravalloti, Agostino; Schillaci, Orazio; Gallamini, Andrea

    2014-06-01

    Background It has been proposed that in clinical trials in which the therapeutic strategy is driven by functional imaging, central review of the images should be done in real time. Purpose We report our experience with a new tool for image exchange and review, called Web-Based Imaging Diagnosis by Expert Network (WIDEN), which we implemented for the HD0607 prospective multicenter Italian clinical trial in which Hodgkin lymphoma treatment was adapted based on results of an interim positron emission tomography (PET) scan performed after the first two cycles of chemotherapy. Methods We used WIDEN for general management of the clinical trial, site imaging qualification, image exchange, workflow control, blinded independent central review, inter-observer variability assessment, consensus creation, audit, and statistical analysis. Results As of February 2013, the interim PET was available for 512 patients; upon central review, 103 of the scans were judged to be positive and 409 to be negative. The median scan uploading and downloading times were 1 min, 25 s and 1 min, 55 s, respectively; the average and median times for diagnosis exchange were 47 h, 53 min and 37 h, 43 min, respectively. The binary concordance between pairs of reviewers (Cohen's kappa) ranged from 0.72 to 0.85. The 5-point scale concordance among all reviewers (Krippendorf's alpha) was 0.77. Conclusions WIDEN proved to be an effective tool for medical imaging exchange and online review. Data security, simplicity, feasibility, and prompt scan review were demonstrated. Central reviews were completed promptly.

  5. Non-invasive repeated therapeutic stimulation for aphasia recovery: a multilingual, multicenter aphasia trial.

    PubMed

    Thiel, Alexander; Black, Sandra E; Rochon, Elizabeth A; Lanthier, Sylvain; Hartmann, Alexander; Chen, Joyce L; Mochizuki, George; Zumbansen, Anna; Heiss, Wolf-Dieter

    2015-04-01

    Noninvasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) has been used in case series and small randomized controlled trials to improve recovery from poststroke aphasia in combination with speech and language therapy. Results of these studies suggest possible clinical efficacy and an excellent safety profile. Therefore, a larger international multicenter proof-of-concept trial was launched, to directly compare the safety and efficacy of rTMS, tDCS, and sham stimulation as adjuvant therapy to speech and language therapy in subacute poststroke aphasia. In the 4 participating centers, subacute stroke patients with aphasia are randomized between 5 and 30 days after ischemic stroke to either receive rTMS, tDCS, or sham stimulation in combination with a daily 45 minutes speech and language therapy session for 10 days. Efficacy is evaluated at 1 and 30 days after the last of the 10 treatment sessions using 3 outcome measures, validated in all participating languages: Boston naming test, Token test, and verbal fluency test. Additionally, adverse events are recorded to prove safety. In this study, a total of 90 patients will be recruited, and data analysis will be completed in 2016. This is the first multilingual and multinational randomized and controlled trial in poststroke aphasia and if positive, will add an effective new strategy for early stage poststroke aphasia rehabilitation.

  6. Distribution of guidance models for cardiac resynchronization therapy in the setting of multi-center clinical trials

    NASA Astrophysics Data System (ADS)

    Rajchl, Martin; Abhari, Kamyar; Stirrat, John; Ukwatta, Eranga; Cantor, Diego; Li, Feng P.; Peters, Terry M.; White, James A.

    2014-03-01

    Multi-center trials provide the unique ability to investigate novel techniques across a range of geographical sites with sufficient statistical power, the inclusion of multiple operators determining feasibility under a wider array of clinical environments and work-flows. For this purpose, we introduce a new means of distributing pre-procedural cardiac models for image-guided interventions across a large scale multi-center trial. In this method, a single core facility is responsible for image processing, employing a novel web-based interface for model visualization and distribution. The requirements for such an interface, being WebGL-based, are minimal and well within the realms of accessibility for participating centers. We then demonstrate the accuracy of our approach using a single-center pacemaker lead implantation trial with generic planning models.

  7. Treosulfan-Based Conditioning and Hematopoietic Cell Transplantation for Nonmalignant Diseases: A Prospective Multi-Center Trial

    PubMed Central

    Burroughs, Lauri M.; Nemecek, Eneida R.; Torgerson, Troy R.; Storer, Barry E.; Talano, Julie-An; Domm, Jennifer; Giller, Roger H.; Shimamura, Akiko; Delaney, Colleen; Skoda-Smith, Suzanne; Thakar, Monica S.; Baker, K. Scott; Rawlings, David J.; Englund, Janet A.; Flowers, Mary E. D.; Deeg, H. Joachim; Storb, Rainer; Woolfrey, Ann E.

    2015-01-01

    Hematopoietic cell transplantation (HCT) is effective in the treatment of patients with nonmalignant diseases and for many is the only known cure. Conventional myeloablative regimens have been associated with unacceptably high early transplant-related mortality (TRM) particularly in patients with co-morbid conditions. This prospective multicenter trial was designed to determine the safety and engraftment efficacy of treosulfan-based conditioning in patients with nonmalignant diseases. Thirty-one patients received HLA-matched related (n=4) or unrelated (n=27) grafts following conditioning with treosulfan (total dose: 42 g/m2), fludarabine (total dose: 150 mg/m2), ± thymoglobulin (6 mg/kg; n=22). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. All patients engrafted. Day-100 TRM was 0%. With a median follow-up of 2 years, the 2-year survival was 90%. Three patients died of GVHD, recurrent hemophagocytic lymphohistiocytosis, and a surgical complication, respectively. The cumulative incidences of grades II–IV and III–IV acute GVHD at day 100 and chronic GVHD at 2 years were 62%, 10% and 21%, respectively. Patients who received thymoglobulin had a significantly lower incidence of grade III-IV acute GVHD (0% versus 33%; P = 0.005). These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with low toxicity and improved survival in patients with nonmalignant diseases, and support the need for future disease-specific clinical trials. PMID:25196857

  8. Implementation of the exception from informed consent regulations in a large multicenter emergency clinical trials network: the RAMPART experience.

    PubMed

    Silbergleit, Robert; Biros, Michelle H; Harney, Deneil; Dickert, Neal; Baren, Jill

    2012-04-01

    Clinical trials investigating therapies for acutely and critically ill and injured patients in the earliest phases of treatment often can only be performed under regulations allowing for exception from informed consent (EFIC) for emergency research. Implementation of these regulations in multicenter clinical trials involves special challenges and opportunities. The Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART), the first EFIC trial conducted by the Neurological Emergencies Treatment Trials (NETT) network, combined centralized resources and coordination with retention of local control and flexibility to facilitate compliance with the EFIC regulations. Specific methods used by the NETT included common tools for community consultation and public disclosure, sharing of experiences and knowledge, and reporting of aggregate results. Tracking of community consultation and public disclosure activities and feedback facilitates empirical research on EFIC methods in the network and supports quality improvements for future NETT trials. The NETT model used in RAMPART demonstrates how EFIC may be effectively performed in established clinical trial networks.

  9. Efficacy of coupled plasma filtration adsorption (CPFA) in patients with septic shock: A multicenter randomised controlled clinical trial

    PubMed Central

    Livigni, Sergio; Bertolini, Guido; Rossi, Carlotta; Ferrari, Fiorenza; Giardino, Michele; Pozzato, Marco; Remuzzi, Giuseppe

    2014-01-01

    Objectives Coupled plasma filtration adsorption (CPFA, Bellco, Italy), to remove inflammatory mediators from blood, has been proposed as a novel treatment for septic shock. This multicenter, randomised, non-blinded trial compared CPFA with standard care in the treatment of critically ill patients with septic shock. Design Prospective, multicenter, randomised, open-label, two parallel group and superiority clinical trial. Setting 18 Italian adult, general, intensive care units (ICUs). Participants Of the planned 330 adult patients with septic shock, 192 were randomised to either have CPFA added to the standard care, or not. The external monitoring committee excluded eight ineligible patients who were erroneously included. Interventions CPFA was to be performed daily for 5 days, lasting at least 10 h/day. Primary and secondary outcome measures The primary endpoint was mortality at discharge from the hospital at which the patient last stayed. Secondary endpoints were: 90-day mortality, new organ failures and ICU-free days within 30 days. Results There was no statistical difference in hospital mortality (47.3% controls, 45.1% CPFA; p=0.76), nor in secondary endpoints, namely the occurrence of new organ failures (55.9% vs 56.0%; p=0.99) or free-ICU days during the first 30 days (6.8 vs 7.5; p=0.35). The study was terminated on the grounds of futility. Several patients randomised to CPFA were subsequently found to be undertreated. An a priori planned subgroup analysis showed those receiving a CPFA dose >0.18 L/kg/day had a lower mortality compared with controls (OR 0.36, 95% CI 0.13 to 0.99). Conclusions CPFA did not reduce mortality in patients with septic shock, nor did it positively affect other important clinical outcomes. A subgroup analysis suggested that CPFA could reduce mortality, when a high volume of plasma is treated. Owing to the inherent potential biases of such a subgroup analysis, this result can only be viewed as a hypothesis generator and

  10. Design of the multicenter standardized supervised exercise training intervention for the claudication: exercise vs endoluminal revascularization (CLEVER) study.

    PubMed

    Bronas, Ulf G; Hirsch, Alan T; Murphy, Timothy; Badenhop, Dalynn; Collins, Tracie C; Ehrman, Jonathan K; Ershow, Abby G; Lewis, Beth; Treat-Jacobson, Diane J; Walsh, M Eileen; Oldenburg, Niki; Regensteiner, Judith G

    2009-11-01

    The CLaudication: Exercise Vs Endoluminal Revascularization (CLEVER) study is the first randomized, controlled, clinical, multicenter trial that is evaluating a supervised exercise program compared with revascularization procedures to treat claudication. In this report, the methods and dissemination techniques of the supervised exercise training intervention are described. A total of 217 participants are being recruited and randomized to one of three arms: (1) optimal medical care; (2) aortoiliac revascularization with stent; or (3) supervised exercise training. Of the enrolled patients, 84 will receive supervised exercise therapy. Supervised exercise will be administered according to a protocol designed by a central CLEVER exercise training committee based on validated methods previously used in single center randomized control trials. The protocol will be implemented at each site by an exercise committee member using training methods developed and standardized by the exercise training committee. The exercise training committee reviews progress and compliance with the protocol of each participant weekly. In conclusion, a multicenter approach to disseminate the supervised exercise training technique and to evaluate its efficacy, safety and cost-effectiveness for patients with claudication due to peripheral arterial disease (PAD) is being evaluated for the first time in CLEVER. The CLEVER study will further establish the role of supervised exercise training in the treatment of claudication resulting from PAD and provide standardized methods for use of supervised exercise training in future PAD clinical trials as well as in clinical practice.

  11. A Phase II Multicenter Trial With Rivaroxaban in the Treatment of Livedoid Vasculopathy Assessing Pain on a Visual Analog Scale

    PubMed Central

    Drabik, Attyla; Hillgruber, Carina

    2014-01-01

    Background Livedoid vasculopathy is an orphan skin disease characterized by recurrent thrombosis of the cutaneous microcirculation. It manifests itself almost exclusively in the ankles, the back of the feet, and the distal part of the lower legs. Because of the vascular occlusion, patients suffer from intense local ischemic pain. Incidence of livedoid vasculopathy is estimated to be around 1:100,000. There are currently no approved treatments for livedoid vasculopathy, making off-label therapy the only option. In Europe, thromboprophylactic treatment with low-molecular-weight heparins has become widely accepted. Objective The aim of this trial is the statistical verification of the therapeutic effects of the anticoagulant rivaroxaban in patients suffering from livedoid vasculopathy. Methods We performed a therapeutic phase IIa trial designed as a prospective, one-armed, multicenter, interventional series of cases with a calculated sample size of 20 patients. The primary outcome is the assessment of local pain on the visual analog scale (VAS) as an intraindividual difference of 2 values between baseline and 12 weeks. Results Enrollment started in December 2012 and was still open at the date of submission. The study is expected to finish in November 2014. Conclusions Livedoid vasculopathy is associated with increased thrombophilia in the cutaneous microcirculation and the continuous use of anticoagulants helps improve the symptoms. The causes of cutaneous infarctions are heterogenous, but ultimately follow the known mechanisms of the coagulation cascade. Rivaroxaban affects the coagulation cascade and inhibits the factor Xa–dependent conversion of prothrombin to thrombin, thereby considerably reducing the risk of thrombosis. Trial Registration Trial Registration EudraCT Number: 2012-000108-13-DE; https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-000108-13 (Archived by WebCite at http://www.webcitation.org/6UCktWVCA); German Clinical

  12. DICOM for Clinical Research: PACS-Integrated Electronic Data Capture in Multi-Center Trials.

    PubMed

    Haak, Daniel; Page, Charles-E; Reinartz, Sebastian; Krüger, Thilo; Deserno, Thomas M

    2015-10-01

    Providing surrogate endpoints in clinical trials, medical imaging has become increasingly important in human-centered research. Nowadays, electronic data capture systems (EDCS) are used but binary image data is integrated insufficiently. There exists no structured way, neither to manage digital imaging and communications in medicine (DICOM) data in EDCS nor to interconnect EDCS with picture archiving and communication systems (PACS). Manual detours in the trial workflow yield errors, delays, and costs. In this paper, requirements for a DICOM-based system interconnection of EDCS and research PACS are analysed. Several workflow architectures are compared. Optimized for multi-center trials, we propose an entirely web-based solution integrating EDCS, PACS, and DICOM viewer, which has been implemented using the open source projects OpenClinica, DCM4CHEE, and Weasis, respectively. The EDCS forms the primary access point. EDCS to PACS interchange is integrated seamlessly on the data and the context levels. DICOM data is viewed directly from the electronic case report form (eCRF), while PACS-based management is hidden from the user. Data privacy is ensured by automatic de-identification and re-labelling with study identifiers. Our concept is evaluated on a variety of 13 DICOM modalities and transfer syntaxes. We have implemented the system in an ongoing investigator-initiated trial (IIT), where five centers have recruited 24 patients so far, performing decentralized computed tomography (CT) screening. Using our system, the chief radiologist is reading DICOM data directly from the eCRF. Errors and workflow processing time are reduced. Furthermore, an imaging database is built that may support future research.

  13. Postprescription review improves in-hospital antibiotic use: a multicenter randomized controlled trial.

    PubMed

    Lesprit, P; de Pontfarcy, A; Esposito-Farese, M; Ferrand, H; Mainardi, J L; Lafaurie, M; Parize, P; Rioux, C; Tubach, F; Lucet, J C

    2015-02-01

    Although review of antibiotic therapy is recommended to optimize antibiotic use, physicians do not always perform it. This trial aimed to evaluate the impact of a systematic postprescription review performed by antimicrobial stewardship program (ASP) infectious disease physicians (IDP) on the quality of in-hospital antibiotic use. A multicenter, prospective, randomized, parallel-group trial using the PROBE (Prospective Randomized Open-label Blinded Endpoint) methodology was conducted in eight surgical or medical wards of four hospitals. Two hundred forty-six patients receiving antibiotic therapy prescribed by ward physicians for less than 24 hours were randomized to receive either a systematic review by the ASP IDP at day 1 and days 3 to 4 (intervention group, n = 123) or no systematic review (usual care, n = 123). The primary outcome measure was appropriateness of antimicrobial therapy, a composite score of appropriateness of antibiotic use at days 3 to 4 and appropriate treatment duration, adjudicated by a blinded committee. Analyses were performed on an intention-to-treat basis. In the intervention group, appropriateness of antimicrobial therapy was more frequent (55/123, 44.7% vs. 35/123, 28.5%; odds ratio 2.03, 95% confidence interval 1.20-3.45). Antibiotic treatment duration was lower in the intervention group (median (interquartile range) 7 (3-9) days vs. 10 (7-12) days; p 0.003). ASP IDP counseling to change therapy was more frequent at days 3 to 4 than at day 1 (114/123; 92.7% vs. 24/123; 19.5%, p <0.001). Clinical outcome was similar between groups. This study suggests that a systematic postprescription antibiotic review performed at days 1 and 3 to 4 results in higher quality of antibiotic use and lower antibiotic duration. This trial was registered at ClinicalTrials.gov (NCT01136200).

  14. Multicenter randomized controlled trial of the management of unresectable malignant mesothelioma proposed by the British Thoracic Society and the British Medical Research Council.

    PubMed

    Girling, David J; Muers, Martin F; Qian, Wendi; Lobban, Dawn

    2002-02-01

    Malignant mesothelioma is almost invariably fatal. The incidence of the disease is rising rapidly in many countries, and there is no generally accepted standard treatment for patients with unresectable disease. According to current British Thoracic Society (BTS) guidelines, patients should be treated with active symptom control (ASC), involving (1) regular follow-up in a specialist clinic; (2) structured assessments of physical, psychological and social problems with appropriate action; (3) rapid involvement of additional specialists; and (4) parallel nursing support. Although many nonrandomized studies have reported tumor responses to anticancer chemotherapy, few have studied palliation and it is not known whether chemotherapy prolongs survival or provides clinically worthwhile palliation with acceptable toxicity when given in addition to ASC. We therefore plan to conduct a multicenter randomized controlled trial comparing (1) ASC alone, (2) ASC plus mitomycin vinblastine and cisplatin (MVP), and (3) ASC plus vinorelbine (N; Navelbine, Pierre Fabre Oncology, Winchester, UK). We chose these chemotherapy regimens because they have been shown in nonrandomized studies to provide good symptom control as recorded by patients. The outcome measures are overall survival, palliation of symptoms, performance status, analgesic usage, toxicity, quality of life, tumor response, and recurrence/progression-free survival. In a preliminary feasibility study, we are assessing the acceptability of the trial design to patients and the suitability of two standard quality-of-life instruments in mesothelioma. Data will help us to decide the final details of the large multicenter trial.

  15. Effectiveness and Safety of Acupuncture for Poststroke Dysphagia: Study Protocol for a Pragmatic Multicenter Nonrandomized Controlled Trial

    PubMed Central

    Guo, Yuan Qi

    2017-01-01

    Background. Dysphagia is one of the most common complications of stroke. Acupuncture is widely employed to treat poststroke dysphagia in East Asia. No evidence is established to support such treatment approach. This proposed study aims to evaluate the effectiveness and safety of acupuncture for the treatment of poststroke dysphagia. Methods and Design. This is a multicenter, pragmatic, single-blinded, nonrandomized controlled clinical trial. A total of 140 eligible patients will be enrolled in the study. Subjects who are eligible in study but refuse to have acupuncture treatment will be put on the no-acupuncture control arm. Both groups of patients will receive standard routine care, while the patients of intervention group will receive add-on standardized acupuncture treatment. Each participant in intervention group will receive a total of 24 sessions of acupuncture treatment (three times per week). The primary outcome measure is the Royal Brisbane Hospital Outcome Measure for Swallowing (RBHOMS). Secondary outcome measures include functional oral intake scale, swallow quality-of-life questionnaire in Chinese version, BMI of the participant, and adverse events. All outcome measures will be assessed at baseline, at the end of acupuncture treatment (month 2), and at two months after treatment (month 4). Ethics and Dissemination. The ethics approval of clinical research study was granted by the Research Ethics Committee of both New Territories East and West Cluster of Hong Kong. Written informed consent will be obtained from all participants and the study will be undertaken according to the ICH-GCP Guidelines. Trial Registration. This trial is registered with chictr.org (registration number: ChiCTR-TRC-12002621 and registration date: 2012-10-26). PMID:28246537

  16. Higher Adenoma Detection Rates with Endocuff-Assisted Colonoscopy – A Randomized Controlled Multicenter Trial

    PubMed Central

    Fitzlaff, Rüdiger; Röming, Hermann; Ameis, Detlev; Heinecke, Achim; Kunsch, Steffen; Ellenrieder, Volker; Ströbel, Philipp; Schepke, Michael; Meister, Tobias

    2014-01-01

    Objectives The Endocuff is a device mounted on the tip of the colonoscope to help flatten the colonic folds during withdrawal. This study aimed to compare the adenoma detection rates between Endocuff-assisted (EC) colonoscopy and standard colonoscopy (SC). Methods This randomized prospective multicenter trial was conducted at four academic endoscopy units in Germany. Participants: 500 patients (235 males, median age 64[IQR 54–73]) for colon adenoma detection purposes were included in the study. All patients were either allocated to EC or SC. The primary outcome measure was the determination of the adenoma detection rates (ADR). Results The ADR significantly increased with the use of the Endocuff compared to standard colonoscopy (35.4%[95% confidence interval{CI} 29–41%] vs. 20.7%[95%CI 15–26%], p<0.0001). Significantly more sessile polyps were detected by EC. Overall procedure time and withdrawal time did not differ. Caecal and ileum intubation rates were similar. No major adverse events occurred in both groups. In multivariate analysis, age (odds ratio [OR] 1.03; 95%[CI] 1.01–1.05), male sex (OR 1.74; 95%CI 1.10–2.73), withdrawal time (OR 1.16; 95%CI 1.05–1.30), procedure time (OR 1.07; 95%CI 1.04–1.10), colon cleanliness (OR 0.60; 95%CI 0.39–0.94) and use of Endocuff (OR 2.09; 95%CI 1.34–3.27) were independent predictors of adenoma detection rates. Conclusions EC increases the adenoma detection rate by 14.7%(95%CI 6.9–22.5%). EC is safe, effective, easy to handle and might reduce colorectal interval carcinomas. Trial Registration ClinicalTrials.gov NCT02034929. PMID:25470133

  17. Albumin Administration in Acute Ischemic Stroke: Safety Analysis of the ALIAS Part 2 Multicenter Trial

    PubMed Central

    Hill, Michael D.; Martin, Renee H.; Palesch, Yuko Y.; Moy, Claudia S.; Tamariz, Diego; Ryckborst, Karla J.; Jones, Elizabeth B.; Weisman, David; Pettigrew, Creed; Ginsberg, Myron D.

    2015-01-01

    Background Albumin treatment of ischemic stroke was associated with cardiopulmonary adverse events in previous studies and a low incidence of intracranial hemorrhage. We sought to describe the neurological and cardiopulmonary adverse events in the ALIAS Part 2 Multicenter Trial. Methods Ischemic stroke patients, aged 18–83 and a baseline NIHSS ≥ 6, were randomized to treatment with ALB or saline control within 5 hours of stroke onset. Neurological adverse events included symptomatic intracranial hemorrhage, hemicraniectomy, neurological deterioration and neurological death. Cardiopulmonary adverse events included pulmonary edema/congestive heart failure, acute coronary syndromes, atrial fibrillation, pneumonia and pulmonary thromboembolism. Results Among 830 patients, neurological and cardiopulmonary adverse events were not differentially associated with poor outcome between ALB and saline control subjects. The rate of symptomatic intracranial hemorrhage in the first 24h was low overall (2.9%, 24/830) but more common in the ALB treated subjects (RR = 2.4, CI95 1.01–5.8). The rate of pulmonary edema/CHF in the first 48h was 7.9% (59/830) and was more common among ALB treated subjects (RR = 10.7, CI95 4.3–26.6); this complication was expected and was satisfactorily managed with mandated diuretic administration and intravenous fluid guidelines. Troponin elevations in the first 48h were common, occurring without ECG change or cardiac symptoms in 52 subjects (12.5%). Conclusions ALB therapy was associated with an increase in symptomatic ICH and pulmonary edema/congestive heart failure but this did not affect final outcomes. Troponin elevation occurs routinely in the first 48 hours after acute ischemic stroke. Trial Registration ClincalTrials.gov NCT00235495 PMID:26325387

  18. Clinical trial design in cancer.

    PubMed

    Mould, R F

    1979-07-01

    The design of clinical trials in cancer is a subject which features reasonably often among FRCR (Part 1) examination questions, and as such should be of more than passing interest to oncologists. It is also a subject which is gaining in relevance since the number of trials is increasing annually due in part to the many chemotherapeutic regimes which are being proposed. This paper which is based on a lecture given in Cambridge at the Hospital Physicists' Association Annual Conference in September 1978, is intended to act as an introduction to clinical trial design. References for further reading are given and, in particular, the extensive report on randomised clinical trials to the Medical Research Council's Leukaemia Steering Committee (Peto et al., 1977, 1978) is recommended.

  19. Rationale and methods of the multicenter randomised trial of a heart failure management programme among geriatric patients (HF-Geriatrics)

    PubMed Central

    2011-01-01

    Background Disease management programmes (DMPs) have been shown to reduce hospital readmissions and mortality in adults with heart failure (HF), but their effectiveness in elderly patients or in those with major comorbidity is unknown. The Multicenter Randomised Trial of a Heart Failure Management Programme among Geriatric Patients (HF-Geriatrics) assesses the effectiveness of a DMP in elderly patients with HF and major comorbidity. Methods/Design Clinical trial in 700 patients aged ≥ 75 years admitted with a primary diagnosis of HF in the acute care unit of eight geriatric services in Spain. Each patient should meet at least one of the following comorbidty criteria: Charlson index ≥ 3, dependence in ≥ 2 activities of daily living, treatment with ≥ 5 drugs, active treatment for ≥ 3 diseases, recent emergency hospitalization, severe visual or hearing loss, cognitive impairment, Parkinson's disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), anaemia, or constitutional syndrome. Half of the patients will be randomly assigned to a 1-year DMP led by a case manager and the other half to usual care. The DMP consists of an educational programme for patients and caregivers on the management of HF, COPD (knowledge of the disease, smoking cessation, immunizations, use of inhaled medication, recognition of exacerbations), diabetes (knowledge of the disease, symptoms of hyperglycaemia and hypoglycaemia, self-adjustment of insulin, foot care) and depression (knowledge of the disease, diagnosis and treatment). It also includes close monitoring of the symptoms of decompensation and optimisation of treatment compliance. The main outcome variables are quality of life, hospital readmissions, and overall mortality during a 12-month follow-up. Discussion The physiological changes, lower life expectancy, comorbidity and low health literacy associated with aging may influence the effectiveness of DMPs in HF. The HF-Geriatrics study will provide direct

  20. Comprehensive rehabilitation with integrative medicine for subacute stroke: A multicenter randomized controlled trial

    PubMed Central

    Fang, Jianqiao; Chen, Lifang; Ma, Ruijie; Keeler, Crystal Lynn; Shen, Laihua; Bao, Yehua; Xu, Shouyu

    2016-01-01

    To determine whether integrative medicine rehabilitation (IMR) that combines conventional rehabilitation (CR) with acupuncture and Chinese herbal medicine has better effects for subacute stroke than CR alone, we conducted a multicenter randomized controlled trial that involved three hospitals in China. Three hundred sixty patients with subacute stroke were randomized into IMR and CR groups. The primary outcome was the Modified Barthel Index (MBI). The secondary outcomes were the National Institutes of Health Stroke Scale (NIHSS), the Fugl-Meyer Assessment (FMA), the mini-mental state examination (MMSE), the Montreal Cognitive Assessment (MoCA), Hamilton’s Depression Scale (HAMD), and the Self-Rating Depression Scale (SDS). All variables were evaluated at week 0 (baseline), week 4 (half-way of intervention), week 8 (after treatment) and week 20 (follow-up). In comparison with the CR group, the IMR group had significantly better improvements (P < 0.01 or P < 0.05) in all the primary and secondary outcomes. There were also significantly better changes from baseline in theses outcomes in the IMR group than in the CR group (P < 0.01). A low incidence of adverse events with mild symptoms was observed in the IMR group. We conclude that conventional rehabilitation combined with integrative medicine is safe and more effective for subacute stroke rehabilitation. PMID:27174221

  1. Hypotony in Patients with Uveitis: The Multicenter Uveitis Steroid Treatment (MUST) Trial

    PubMed Central

    Sen, H. Nida; Drye, Lea T.; Goldstein, Debra A.; Larson, Theresa A.; Merrill, Pauline T.; Pavan, Peter R.; Sheppard, John D.; Burke, Alyce; Srivastava, Sunil K.; Jabs, Douglas A.

    2013-01-01

    Purpose To assess the prevalence of hypotony in patients with severe forms of uveitis. Methods The Multicenter Uveitis Steroid Treatment (MUST) Trial, a randomized study, enrolled 255 patients. Patients with hypotony at the baseline visit were identified. Results Twenty (8.3%) of 240 patients with sufficient data had hypotony. Hypotony was more common in patients with uveitis ≥5 years duration (odds ratio [OR] = 5.0; p < .01), and in eyes with a history of ocular surgery (vitrectomy vs. none, OR = 3.1; p = .03). Hypotony was less in patients with older age of uveitis onset (>51 years vs. <51 years, OR = 0.1; p = .02), in Caucasian patients (OR = 0.1; p < .01) compared to African American patients. Hypotonous eyes were more likely to have visual impairment (OR = 22.9; p < .01). Conclusions Hypotony is an important complication of uveitis and more commonly affects African-American patients, those with uveitis onset at a younger age, and those with longer disease duration. It is associated with visual impairment. PMID:22409563

  2. Comprehensive rehabilitation with integrative medicine for subacute stroke: A multicenter randomized controlled trial.

    PubMed

    Fang, Jianqiao; Chen, Lifang; Ma, Ruijie; Keeler, Crystal Lynn; Shen, Laihua; Bao, Yehua; Xu, Shouyu

    2016-05-13

    To determine whether integrative medicine rehabilitation (IMR) that combines conventional rehabilitation (CR) with acupuncture and Chinese herbal medicine has better effects for subacute stroke than CR alone, we conducted a multicenter randomized controlled trial that involved three hospitals in China. Three hundred sixty patients with subacute stroke were randomized into IMR and CR groups. The primary outcome was the Modified Barthel Index (MBI). The secondary outcomes were the National Institutes of Health Stroke Scale (NIHSS), the Fugl-Meyer Assessment (FMA), the mini-mental state examination (MMSE), the Montreal Cognitive Assessment (MoCA), Hamilton's Depression Scale (HAMD), and the Self-Rating Depression Scale (SDS). All variables were evaluated at week 0 (baseline), week 4 (half-way of intervention), week 8 (after treatment) and week 20 (follow-up). In comparison with the CR group, the IMR group had significantly better improvements (P < 0.01 or P < 0.05) in all the primary and secondary outcomes. There were also significantly better changes from baseline in theses outcomes in the IMR group than in the CR group (P < 0.01). A low incidence of adverse events with mild symptoms was observed in the IMR group. We conclude that conventional rehabilitation combined with integrative medicine is safe and more effective for subacute stroke rehabilitation.

  3. Ocular microtremor during general anesthesia: results of a multicenter trial using automated signal analysis.

    PubMed

    Heaney, Mairead; Kevin, Leo G; Manara, Alex R; Clayton, Tracey J; Timmons, Shelly D; Angel, John J; Smith, Kenneth R; Ibata, Brent; Bolger, Ciaran; Cunningham, Anthony J

    2004-09-01

    Ocular microtremor (OMT) is a fine physiologic tremor of the eye related to neuronal activity in the reticular formation of the brainstem. The frequency of OMT is suppressed by propofol and sevoflurane and predicts the response to command at emergence from anesthesia. Previous studies have relied on post hoc computer analysis of OMT wave forms or on real-time measurements confirmed visually on an oscilloscope. Our overall aim was to evaluate an automated system of OMT signal analysis in a diverse patient population undergoing general anesthesia. In a multicenter trial involving four centers in three countries, we examined the accuracy of OMT to identify the unconscious state and to predict movement in response to airway instrumentation and surgical stimulation. We also tested the effects of neuromuscular blockade and patient position on OMT. We measured OMT continuously by using the closed-eye piezoelectric technique in 214 patients undergoing extracranial surgery with general anesthesia using a variety of anesthetics. OMT decreased at induction in all patients, increased transiently in response to surgical incision or airway instrumentation, and increased at emergence. The frequency of OMT predicted movement in response to laryngeal mask airway insertion and response to command at emergence. Neuromuscular blockade did not affect the frequency of OMT but decreased its amplitude. OMT frequency was unaffected by changes in patient position. We conclude that OMT, measured by an automated signal analysis module, accurately determines the anesthetic state in surgical patients, even during profound neuromuscular blockade and after changes in patient position.

  4. Prospective Multicenter Trial Evaluating Balloon-Catheter Partial-Breast Irradiation for Ductal Carcinoma in Situ

    SciTech Connect

    Abbott, Andrea M.; Portschy, Pamela R.; Lee, Chung; Le, Chap T.; Han, Linda K.; Washington, Tara; Kinney, Michael; Bretzke, Margit; Tuttle, Todd M.

    2013-11-01

    Purpose: To determine outcomes of accelerated partial-breast irradiation (APBI) with MammoSite in the treatment of ductal carcinoma in situ (DCIS) after breast-conserving surgery. Methods and Materials: We conducted a prospective, multicenter trial between 2003 and 2009. Inclusion criteria included age >18 years, core needle biopsy diagnosis of DCIS, and no prior breast cancer history. Patients underwent breast-conserving surgery plus MammoSite placement. Radiation was given twice daily for 5 days for a total of 34 Gy. Patients were evaluated for development of toxicities, cosmetic outcome, and ipsilateral breast tumor recurrence (IBTR). Results: A total of 41 patients (42 breasts) completed treatment in the study, with a median follow up of 5.3 years. Overall, 28 patients (68.3%) experienced an adverse event. Skin changes and pain were the most common adverse events. Cosmetic outcome at 6 months was judged excellent/good by 100% of physicians and by 96.8% of patients. At 12 months, 86.7% of physicians and 92.3% of patients rated the cosmetic outcome as excellent/good. Overall, 4 patients (9.8%) developed an IBTR (all DCIS), with a 5-year actuarial rate of 11.3%. All IBTRs were outside the treatment field. Among patients with IBTRs, the mean time to recurrence was 3.2 years. Conclusions: Accelerated partial-breast irradiation using MammoSite seems to provide a safe and cosmetically acceptable outcome; however, the 9.8% IBTR rate with median follow-up of 5.3 years is concerning. Prospective randomized trials are necessary before routine use of APBI for DCIS can be recommended.

  5. Systemic hydrocortisone to prevent bronchopulmonary dysplasia in preterm infants (the SToP-BPD study); a multicenter randomized placebo controlled trial

    PubMed Central

    2011-01-01

    Background Randomized controlled trials have shown that treatment of chronically ventilated preterm infants after the first week of life with dexamethasone reduces the incidence of the combined outcome death or bronchopulmonary dysplasia (BPD). However, there are concerns that dexamethasone may increase the risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. So far no randomized controlled trial has investigated its efficacy when administered after the first week of life to ventilated preterm infants. Methods/Design The SToP-BPD trial is a randomized double blind placebo controlled multicenter study including 400 very low birth weight infants (gestational age < 30 weeks and/or birth weight < 1250 grams), who are ventilator dependent at a postnatal age of 7 - 14 days. Hydrocortisone (cumulative dose 72.5 mg/kg) or placebo is administered during a 22 day tapering schedule. Primary outcome measure is the combined outcome mortality or BPD at 36 weeks postmenstrual age. Secondary outcomes are short term effects on the pulmonary condition, adverse effects during hospitalization, and long-term neurodevelopmental sequelae assessed at 2 years corrected gestational age. Analysis will be on an intention to treat basis. Discussion This trial will determine the efficacy and safety of postnatal hydrocortisone administration at a moderately early postnatal onset compared to placebo for the reduction of the combined outcome mortality and BPD at 36 weeks postmenstrual age in ventilator dependent preterm infants. Trial registration number Netherlands Trial Register (NTR): NTR2768 PMID:22070744

  6. HLA-DR EXPRESSION AS A BIOMARKER OF INFLAMMATION FOR MULTICENTER CLINICAL TRIALS OF OCULAR SURFACE DISEASE

    PubMed Central

    Epstein, Seth P.; Gadaria-Rathod, Neha; Wei, Yi; Maguire, Maureen G.; Asbell, Penny A.

    2014-01-01

    There are currently no validated minimally invasive objective metrics for the classification and evaluation of ocular surface diseases and/or for evaluating treatment efficacy. We thus sought to establish a standardized methodology for determining the relative amount of the inflammatory biomarker HLA-DR on the ocular surface and to evaluate the precision, reliability and repeatability of its use for large multicenter clinical trials and translational research studies of ocular surface disease. Multiple studies were conducted to establish a Standard Operating Procedure (SOP) for utilizing HLA-DR expression as a minimally invasive, objective, ocular surface inflammatory biomarker. The established SOPs provide specific guidelines for HLA-DR collection and analysis, in order to incorporate it reliably into multicenter clinical trials and/or translational research. Duplicate cell samples from impression cytology (IC) samples of both normal and dry eye individuals were collected and split to assess repeatability (between the splits and between the duplicate samples). To determine storage capability, one duplicate was stained immediately and the other after 30 days cold storage. To demonstrate the feasibility of the use of the SOP for a multicenter clinical trial, clinicians out-of-state were trained to collect IC samples, and the samples shipped to our Biomarker Laboratory, logged, processed and analyzed. Demonstration of the ability to incorporate of IC into a randomized double masked clinical trial of dry eye disease (DED) was performed. In all cases, processing and analyses were performed by a masked independent observer. The validity/viability of the SOPs was established by demonstrating that: 1) sufficient numbers of cells can be collected via IC; 2) the precision/repeatability of the relative biomarker expression quantified in samples; 3) personnel at distant sites can be taught to collect, store and ship samples successfully; 4) samples can be stored for up to 30

  7. Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis

    PubMed Central

    Christodoulou, C.; Melville, P.; Scherl, W.F.; Pai, L.-Y.; Muenz, L.R.; He, D.; Benedict, R.H.B.; Goodman, A.; Rizvi, S.; Schwid, S.R.; Weinstock-Guttman, B.; Westervelt, H.J.; Wishart, H.

    2011-01-01

    Objectives: The goal of this study was to determine if memory would be improved by donepezil as compared to placebo in a multicenter, double-blind, randomized clinical trial (RCT). Methods: Donepezil 10 mg daily was compared to placebo to treat memory impairment. Eligibility criteria included the following: age 18–59 years, clinically definite multiple sclerosis (MS), and performance ≤½ SD below published norms on the Rey Auditory Verbal Learning Test (RAVLT). Neuropsychological assessments were performed at baseline and 24 weeks. Primary outcomes were change on the Selective Reminding Test (SRT) of verbal memory and the participant's impression of memory change. Secondary outcomes included changes on other neuropsychological tests and the evaluating clinician's impression of memory change. Results: A total of 120 participants were enrolled and randomized to either donepezil or placebo. No significant treatment effects were found between groups on either primary outcome of memory or any secondary cognitive outcomes. A trend was noted for the clinician's impression of memory change in favor of donepezil (37.7%) vs placebo (23.7%) (p = 0.097). No serious or unanticipated adverse events attributed to study medication developed. Conclusions: Donepezil did not improve memory as compared to placebo on either of the primary outcomes in this study. Classification of evidence: This study provides Class I evidence which does not support the hypothesis that 10 mg of donepezil daily for 24 weeks is superior to placebo in improving cognition as measured by the SRT in people with MS whose baseline RAVLT score was 0.5 SD or more below average. PMID:21519001

  8. Written pain neuroscience education in fibromyalgia: a multicenter randomized controlled trial.

    PubMed

    van Ittersum, Miriam W; van Wilgen, C Paul; van der Schans, Cees P; Lambrecht, Luc; Groothoff, Johan W; Nijs, Jo

    2014-11-01

    Mounting evidence supports the use of face-to-face pain neuroscience education for the treatment of chronic pain patients. This study aimed at examining whether written education about pain neuroscience improves illness perceptions, catastrophizing, and health status in patients with fibromyalgia. A double-blind, multicenter randomized controlled clinical trial with 6-month follow-up was conducted. Patients with FM (n = 114) that consented to participate were randomly allocated to receive either written pain neuroscience education or written relaxation training. Written pain neuroscience education comprised of a booklet with pain neuroscience education plus a telephone call to clarify any difficulties; the relaxation group received a booklet with relaxation education and a telephone call. The revised illness perception questionnaire, Pain Catastrophizing Scale, and fibromyalgia impact questionnaire were used as outcome measures. Both patients and assessors were blinded. Repeated-measures analyses with last observation carried forward principle were performed. Cohen's d effect sizes (ES) were calculated for all within-group changes and between-group differences. The results reveal that written pain neuroscience education does not change the impact of FM on daily life, catastrophizing, or perceived symptoms of patients with FM. Compared with written relaxation training, written pain neuroscience education improved beliefs in a chronic timeline of FM (P = 0.03; ES = 0.50), but it does not impact upon other domains of illness perceptions. Compared with written relaxation training, written pain neuroscience education slightly improved illness perceptions of patients with FM, but it did not impart clinically meaningful effects on pain, catastrophizing, or the impact of FM on daily life. Face-to-face sessions of pain neuroscience education are required to change inappropriate cognitions and perceived health in patients with FM.

  9. A Multicenter, Randomized, Controlled Trial of Osteopathic Manipulative Treatment on Preterms

    PubMed Central

    Cerritelli, Francesco; Pizzolorusso, Gianfranco; Renzetti, Cinzia; Cozzolino, Vincenzo; D’Orazio, Marianna; Lupacchini, Mariacristina; Marinelli, Benedetta; Accorsi, Alessandro; Lucci, Chiara; Lancellotti, Jenny; Ballabio, Silvia; Castelli, Carola; Molteni, Daniela; Besana, Roberto; Tubaldi, Lucia; Perri, Francesco Paolo; Fusilli, Paola; D’Incecco, Carmine; Barlafante, Gina

    2015-01-01

    Background Despite some preliminary evidence, it is still largely unknown whether osteopathic manipulative treatment improves preterm clinical outcomes. Materials and Methods The present multi-center randomized single blind parallel group clinical trial enrolled newborns who met the criteria for gestational age between 29 and 37 weeks, without any congenital complication from 3 different public neonatal intensive care units. Preterm infants were randomly assigned to usual prenatal care (control group) or osteopathic manipulative treatment (study group). The primary outcome was the mean difference in length of hospital stay between groups. Results A total of 695 newborns were randomly assigned to either the study group (n= 352) or the control group (n=343). A statistical significant difference was observed between the two groups for the primary outcome (13.8 and 17.5 days for the study and control group respectively, p<0.001, effect size: 0.31). Multivariate analysis showed a reduction of the length of stay of 3.9 days (95% CI -5.5 to -2.3, p<0.001). Furthermore, there were significant reductions with treatment as compared to usual care in cost (difference between study and control group: 1,586.01€; 95% CI 1,087.18 to 6,277.28; p<0.001) but not in daily weight gain. There were no complications associated to the intervention. Conclusions Osteopathic treatment reduced significantly the number of days of hospitalization and is cost-effective on a large cohort of preterm infants. PMID:25974071

  10. Excimer laser angioplasty in acute myocardial infarction (the CARMEL multicenter trial).

    PubMed

    Topaz, On; Ebersole, Douglas; Das, Tony; Alderman, Edwin L; Madyoon, Hooman; Vora, Kishor; Baker, John D; Hilton, David; Dahm, Johannes B

    2004-03-15

    Patients with acute myocardial infarction (AMI) with thrombus-laden lesions constitute a revascularization challenge. Thrombus and atherosclerotic plaque absorb laser energy; thus, we studied the safety and efficacy of excimer laser in AMI. In a multicenter trial, 151 patients with AMI underwent excimer laser angioplasty. Baseline left ventricular ejection fraction was 44 +/- 13%, and 13% of patients were in cardiogenic shock. A saphenous vein graft was the target vessel in 21%. Quantitative coronary angiography and statistical analysis were performed by independent core laboratories. A 95% device success, 97% angiographic success, and 91% overall procedural success rate were recorded. Maximal laser gain was achieved in lesions with extensive thrombus burden (p <0.03 vs small burden). Thrombolysis In Myocardial Infarction (TIMI) trial flow increased significantly by laser: 1.2 +/- 1.1 to 2.8 +/- 0.5 (p <0.001), reaching a final 3.0 +/- 0.2 (p <0.001 vs baseline). Minimal luminal diameter increased by laser from 0.5 +/- 0.5 to 1.6 +/- 0.5 mm (mean +/- SD, p <0.001), followed by 2.7 +/- 0.6 mm after stenting (p <0.001 vs baseline and vs after laser). Laser decreased target stenosis from 83 +/- 17% to 52 +/- 15% (mean +/- SD, p <0.001 vs baseline), followed by 20 +/- 16% after stenting (p <0.001 vs baseline and vs after laser). Six patients (4%) died, each presented with cardiogenic shock. Complications included perforation (0.6%), dissection (5% major, 3% minor), acute closure (0.6%), distal embolization (2%), and bleeding (3%). In a multivariant regression model, absence of cardiogenic shock was a significant factor affecting procedural success. Thus, in the setting of AMI, gaining maximal thrombus dissolution in lesions with extensive thrombus burden, combined with a considerable increase in minimal luminal diameter and restoration of anterograde TIMI flow, support successful debulking by excimer laser. The presence of thrombus does not adversely affect procedural

  11. A multi-center randomized trial of two different intravenous fluids during labor

    PubMed Central

    DAPUZZO-ARGIRIOU, Lisa M.; SMULIAN, John C.; ROCHON, Meredith L.; GALDI, Luisa; KISSLING, Jessika M.; SCHNATZ, Peter F.; RIOS, Angel GONZALEZ; AIROLDI, James; CARRILLO, Mary Anne; MAINES, Jaimie; KUNSELMAN, Allen R.; REPKE, John; LEGRO, Richard S.

    2017-01-01

    Objective To determine if the intrapartum use of a 5% glucose-containing intravenous solution decreases the chance of a cesarean delivery for women presenting in active labor. Methods This was a multi-center, prospective, single (patient) blind, randomized study design implemented at 4 obstetric residency programs in Pennsylvania. Singleton, term, consenting women presenting in active spontaneous labor with a cervical dilation of <6cm were randomized to lactated Ringer's with or without 5% glucose (LR versus D5LR) as their maintenance intravenous fluid. The primary outcome was the cesarean birth rate. Secondary outcomes included labor characteristics, as well as maternal or neonatal complications. Results There were 309 women analyzed. Demographic variables and admitting cervical dilation were similar among study groups. There was no significant difference in the cesarean delivery rate for the D5LR group (23/153 or 15.0%) versus the LR arm (18/156 or 11.5%), [RR (95%CI) of 1.32 (0.75, 2.35), P=0.34]. There were no differences in augmentation rates or intrapartum complications. Conclusions The use of intravenous fluid containing 5% dextrose does not lower the chance of cesarean delivery for women admitted in active labor. PMID:25758624

  12. Adaptive clinical trial designs in oncology

    PubMed Central

    Zang, Yong; Lee, J. Jack

    2015-01-01

    Adaptive designs have become popular in clinical trial and drug development. Unlike traditional trial designs, adaptive designs use accumulating data to modify the ongoing trial without undermining the integrity and validity of the trial. As a result, adaptive designs provide a flexible and effective way to conduct clinical trials. The designs have potential advantages of improving the study power, reducing sample size and total cost, treating more patients with more effective treatments, identifying efficacious drugs for specific subgroups of patients based on their biomarker profiles, and shortening the time for drug development. In this article, we review adaptive designs commonly used in clinical trials and investigate several aspects of the designs, including the dose-finding scheme, interim analysis, adaptive randomization, biomarker-guided randomization, and seamless designs. For illustration, we provide examples of real trials conducted with adaptive designs. We also discuss practical issues from the perspective of using adaptive designs in oncology trials. PMID:25811018

  13. Sarcopenia: designing phase IIB trials.

    PubMed

    Chumlea, Wm C; Cesari, M; Evans, W J; Ferrucci, L; Fielding, R A; Pahor, M; Studenski, S; Vellas, B

    2011-06-01

    Sarcopenia is the age-related involuntary loss of skeletal muscle mass and functionality that can lead to the development of disability, frailty and increased health care costs. The development of interventions aimed at preventing and/or treating sarcopenia is complex, requiring the adoption of assumptions and standards that are not well established scientifically or clinically. A number of investigators and clinicians (both from academia and industry) met in Rome (Italy) in 2009 to develop a consensus definition of sarcopenia. Subsequently, in Albuquerque (New Mexico, USA) in 2010, the same group met again to consider the complex issues necessary for designing Phase II clinical trials for sarcopenia. Current clinical trial data indicate that fat-free mass (FFM) parameters are responsive to physical activity/nutritional treatment modalities over short time periods, but pharmacological trials of sarcopenia have yet to show significant efficacy. In order to conduct a clinical trial within a reasonable time frame, groups that model or display accelerated aging and loss of FFM are necessary. Few studies have used acceptable designs for testing treatment effects, sample sizes or primary outcomes that could provide interpretable findings or effects across studies. Dual energy x-ray absorptiometry (DXA) is the measure of choice for assessing FFM, but sufficient time is needed for changes to be detected accurately and reliably. A tool set that would allow clinical, basic and epidemiological research on sarcopenia to advance rapidly toward diagnosis and treatment phases should be those reflecting function and strength.

  14. Efficacy of Levofloxacin in the Treatment of BK Viremia: A Multicenter, Double-Blinded, Randomized, Placebo-Controlled Trial

    PubMed Central

    Lee, Belinda T.; Gabardi, Steven; Grafals, Monica; Hofmann, R. Michael; Akalin, Enver; Aljanabi, Aws; Mandelbrot, Didier A.; Adey, Deborah B.; Heher, Eliot; Fan, Pang-Yen; Conte, Sarah; Dyer-Ward, Christine

    2014-01-01

    Background and objectives BK virus reactivation in kidney transplant recipients can lead to progressive allograft injury. Reduction of immunosuppression remains the cornerstone of treatment for active BK infection. Fluoroquinolone antibiotics are known to have in vitro antiviral properties, but the evidence for their use in patients with BK viremia is inconclusive. The objective of the study was to determine the efficacy of levofloxacin in the treatment of BK viremia. Design, setting, participants, & measurements Enrollment in this prospective, multicenter, double-blinded, placebo-controlled trial occurred from July 2009 to March 2012. Thirty-nine kidney transplant recipients with BK viremia were randomly assigned to receive levofloxacin, 500 mg daily, or placebo for 30 days. Immunosuppression in all patients was adjusted on the basis of standard clinical practices at each institution. Plasma BK viral load and serum creatinine were measured monthly for 3 months and at 6 months. Results At the 3-month follow-up, the percentage reductions in BK viral load were 70.3% and 69.1% in the levofloxacin group and the placebo group, respectively (P=0.93). The percentage reductions in BK viral load were also equivalent at 1 month (58% versus and 67.1%; P=0.47) and 6 months (82.1% versus 90.5%; P=0.38). Linear regression analysis of serum creatinine versus time showed no difference in allograft function between the two study groups during the follow-up period. Conclusions A 30-day course of levofloxacin does not significantly improve BK viral load reduction or allograft function when used in addition to overall reduction of immunosuppression. PMID:24482066

  15. Internet-delivered cognitive-behavioral treatment for adolescents with chronic pain and their parents: a randomized controlled multicenter trial.

    PubMed

    Palermo, Tonya M; Law, Emily F; Fales, Jessica; Bromberg, Maggie H; Jessen-Fiddick, Tricia; Tai, Gabrielle

    2016-01-01

    Internet-delivered interventions are emerging as a strategy to address barriers to care for individuals with chronic pain. This is the first large multicenter randomized controlled trial of Internet-delivered cognitive-behavioral therapy (CBT) for pediatric chronic pain. Participants included were 273 adolescents (205 females and 68 males), aged 11 to 17 years with mixed chronic pain conditions and their parents, who were randomly assigned in a parallel-group design to Internet-delivered CBT (n = 138) or Internet-delivered Education (n = 135). Assessments were completed before treatment, immediately after treatment, and at 6-month follow-up. All data collection and procedures took place online. The primary analysis used linear growth models. Results demonstrated significantly greater reduction on the primary outcome of activity limitations from baseline to 6-month follow-up for Internet CBT compared with Internet education (b = -1.13, P = 0.03). On secondary outcomes, significant beneficial effects of Internet CBT were found on sleep quality (b = 0.14, P = 0.04), on reducing parent miscarried helping (b = -2.66, P = 0.007) and protective behaviors (b = -0.19, P = 0.001), and on treatment satisfaction (P values < 0.05). On exploratory outcomes, benefits of Internet CBT were found for parent-perceived impact (ie, reductions in depression, anxiety, self-blame about their adolescent's pain, and improvement in parent behavioral responses to pain). In conclusion, our Internet-delivered CBT intervention produced a number of beneficial effects on adolescent and parent outcomes, and could ultimately lead to wide dissemination of evidence-based psychological pain treatment for youth and their families.

  16. Adjustment of Open-Loop Settings to Improve Closed-Loop Results in Type 1 Diabetes: A Multicenter Randomized Trial

    PubMed Central

    Dassau, Eyal; Brown, Sue A.; Basu, Ananda; Pinsker, Jordan E.; Kudva, Yogish C.; Gondhalekar, Ravi; Patek, Steve; Lv, Dayu; Schiavon, Michele; Lee, Joon Bok; Dalla Man, Chiara; Hinshaw, Ling; Castorino, Kristin; Mallad, Ashwini; Dadlani, Vikash; McCrady-Spitzer, Shelly K.; McElwee-Malloy, Molly; Wakeman, Christian A.; Bevier, Wendy C.; Bradley, Paige K.; Kovatchev, Boris; Cobelli, Claudio; Zisser, Howard C.

    2015-01-01

    Context: Closed-loop control (CLC) relies on an individual's open-loop insulin pump settings to initialize the system. Optimizing open-loop settings before using CLC usually requires significant time and effort. Objective: The objective was to investigate the effects of a one-time algorithmic adjustment of basal rate and insulin to carbohydrate ratio open-loop settings on the performance of CLC. Design: This study reports a multicenter, outpatient, randomized, crossover clinical trial. Patients: Thirty-seven adults with type 1 diabetes were enrolled at three clinical sites. Interventions: Each subject's insulin pump settings were subject to a one-time algorithmic adjustment based on 1 week of open-loop (i.e., home care) data collection. Subjects then underwent two 27-hour periods of CLC in random order with either unchanged (control) or algorithmic adjusted basal rate and carbohydrate ratio settings (adjusted) used to initialize the zone-model predictive control artificial pancreas controller. Subject's followed their usual meal-plan and had an unannounced exercise session. Main Outcomes and Measures: Time in the glucose range was 80–140 mg/dL, compared between both arms. Results: Thirty-two subjects completed the protocol. Median time in CLC was 25.3 hours. The median time in the 80–140 mg/dl range was similar in both groups (39.7% control, 44.2% adjusted). Subjects in both arms of CLC showed minimal time spent less than 70 mg/dl (median 1.34% and 1.37%, respectively). There were no significant differences more than 140 mg/dL. Conclusions: A one-time algorithmic adjustment of open-loop settings did not alter glucose control in a relatively short duration outpatient closed-loop study. The CLC system proved very robust and adaptable, with minimal (<2%) time spent in the hypoglycemic range in either arm. PMID:26204135

  17. Melphalan, prednisone, thalidomide and defibrotide in relapsed/refractory multiple myeloma: results of a multicenter phase I/II trial

    PubMed Central

    Palumbo, Antonio; Larocca, Alessandra; Genuardi, Mariella; Kotwica, Katarzyna; Gay, Francesca; Rossi, Davide; Benevolo, Giulia; Magarotto, Valeria; Cavallo, Federica; Bringhen, Sara; Rus, Cecilia; Masini, Luciano; Iacobelli, Massimo; Gaidano, Gianluca; Mitsiades, Constantine; Anderson, Kenneth; Boccadoro, Mario; Richardson, Paul

    2010-01-01

    Background Defibrotide is a novel orally bioavailable polydisperse oligonucleotide with anti-thrombotic and anti-adhesive effects. In SCID/NOD mice, defibrotide showed activity in human myeloma xenografts. This phase I/II study was conducted to identify the most appropriate dose of defibrotide in combination with melphalan, prednisone and thalidomide in patients with relapsed and relapsed/refractory multiple myeloma, and to determine its safety and tolerability as part of this regimen. Design and Methods This was a phase I/II, multicenter, dose-escalating, non-comparative, open label study. Oral melphalan was administered at a dose of 0.25 mg/kg on days 1–4, prednisone at a dose of 1.5 mg/kg also on days 1–4 and thalidomide at a dose of 50–100 mg/day continuously. Defibrotide was administered orally at three dose-levels: 2.4, 4.8 or 7.2 g on days 1–4 and 1.6, 3.2, or 4.8 g on days 5–35. Results Twenty-four patients with relapsed/refractory multiple myeloma were enrolled. No dose-limiting toxicity was observed. In all patients, the complete response plus very good partial response rate was 9%, and the partial response rate was 43%. The 1-year progression-free survival and 1-year overall survival rates were 34% and 90%, respectively. The most frequent grade 3–4 adverse events included neutropenia, thrombocytopenia, anemia and fatigue. Deep vein thrombosis was reported in only one patient. Conclusions This combination of melphalan, prednisone and thalidomide together with defibrotide showed anti-tumor activity with a favorable tolerability. The maximum tolerated dose of defibrotide was identified as 7.2 g p.o. on days 1–4 followed by 4.8 g p.o. on days 5–35. Further trials are needed to confirm the role of this regimen and to evaluate the combination of defibrotide with new drugs (ClinicalTrials.gov Identifier: NCT00406978). PMID:20053869

  18. The Belgian trial with azithromycin for acute COPD exacerbations requiring hospitalization: an investigator-initiated study protocol for a multicenter, randomized, double-blind, placebo-controlled trial

    PubMed Central

    Vermeersch, Kristina; Gabrovska, Maria; Deslypere, Griet; Demedts, Ingel K; Slabbynck, Hans; Aumann, Joseph; Ninane, Vincent; Verleden, Geert M; Troosters, Thierry; Bogaerts, Kris; Brusselle, Guy G; Janssens, Wim

    2016-01-01

    Background Long-term use of macrolide antibiotics is effective to prevent exacerbations in chronic obstructive pulmonary disease (COPD). As risks and side effects of long-term intervention outweigh the benefits in the general COPD population, the optimal dose, duration of treatment, and target population are yet to be defined. Hospitalization for an acute exacerbation (AE) of COPD may offer a targeted risk group and an obvious risk period for studying macrolide interventions. Methods/design Patients with COPD, hospitalized for an AE, who have a smoking history of ≥10 pack-years and had ≥1 exacerbation in the previous year will be enrolled in a multicenter, randomized, double-blind, placebo-controlled trial (NCT02135354). On top of a standardized treatment of systemic corticosteroids and antibiotics, subjects will be randomized to receive either azithromycin or placebo during 3 months, at an uploading dose of 500 mg once a day for 3 days, followed by a maintenance dose of 250 mg once every 2 days. The primary endpoint is the time-to-treatment failure during the treatment phase (ie, from the moment of randomization until the end of intervention). Treatment failure is a novel composite endpoint defined as either death, the admission to intensive care or the requirement of additional systemic steroids or new antibiotics for respiratory reasons, or the diagnosis of a new AE after discharge. Discussion We investigate whether azithromycin initiated at the onset of a severe exacerbation, with a limited duration and at a low dose, might be effective and safe in the highest risk period during and immediately after the acute event. If proven effective and safe, this targeted approach may improve the treatment of severe AEs and redirect the preventive use of azithromycin in COPD to a temporary intervention in the subgroup with the highest unmet needs. PMID:27099485

  19. Rationale and design of the HepZero study: a prospective, multicenter, international, open, randomized, controlled clinical study with parallel groups comparing heparin-free dialysis with heparin-coated dialysis membrane (Evodial) versus standard care: study protocol for a randomized controlled trial

    PubMed Central

    2013-01-01

    Background Anticoagulation for chronic dialysis patients with contraindications to heparin administration is challenging. Current guidelines state that in patients with increased bleeding risks, strategies that can induce systemic anticoagulation should be avoided. Heparin-free dialysis using intermittent saline flushes is widely adopted as the method of choice for patients at risk of bleeding, although on-line blood predilution may also be used. A new dialyzer, Evodial (Gambro, Lund, Sweden), is grafted with unfractionated heparin during the manufacturing process and may allow safe and efficient heparin-free hemodialysis sessions. In the present trial, Evodial was compared to standard care with either saline flushes or blood predilution. Methods The HepZero study is the first international (seven countries), multicenter (10 centers), randomized, controlled, open-label, non-inferiority (and if applicable subsequently, superiority) trial with two parallel groups, comprising 252 end-stage renal disease patients treated by maintenance hemodialysis for at least 3 months and requiring heparin-free dialysis treatments. Patients will be treated during a maximum of three heparin-free dialysis treatments with either saline flushes or blood predilution (control group), or Evodial. The first heparin-free dialysis treatment will be considered successful when there is: no complete occlusion of air traps or dialyzer rendering dialysis impossible; no additional saline flushes to prevent clotting; no change of dialyzer or blood lines because of clotting; and no premature termination (early rinse-back) because of clotting. The primary objectives of the study are to determine the effectiveness of the Evodial dialyzer, compared with standard care in terms of successful treatments during the first heparin-free dialysis. If the non-inferiority of Evodial is demonstrated then the superiority of Evodial over standard care will be tested. The HepZero study results may have major clinical

  20. The Design of Cluster Randomized Crossover Trials

    ERIC Educational Resources Information Center

    Rietbergen, Charlotte; Moerbeek, Mirjam

    2011-01-01

    The inefficiency induced by between-cluster variation in cluster randomized (CR) trials can be reduced by implementing a crossover (CO) design. In a simple CO trial, each subject receives each treatment in random order. A powerful characteristic of this design is that each subject serves as its own control. In a CR CO trial, clusters of subjects…

  1. Disclosure of investigators' recruitment performance in multicenter clinical trials: a further step for research transparency.

    PubMed

    Dal-Ré, Rafael; Moher, David; Gluud, Christian; Treweek, Shaun; Demotes-Mainard, Jacques; Carné, Xavier

    2011-12-01

    Rafael Dal-Ré and colleagues argue that the recruitment targets and performance of all site investigators in multi-centre clinical trials should be disclosed in trial registration sites before a trial starts, and when it ends.

  2. Design, analysis, and presentation of crossover trials

    PubMed Central

    Mills, Edward J; Chan, An-Wen; Wu, Ping; Vail, Andy; Guyatt, Gordon H; Altman, Douglas G

    2009-01-01

    Objective Although crossover trials enjoy wide use, standards for analysis and reporting have not been established. We reviewed methodological aspects and quality of reporting in a representative sample of published crossover trials. Methods We searched MEDLINE for December 2000 and identified all randomized crossover trials. We abstracted data independently, in duplicate, on 14 design criteria, 13 analysis criteria, and 14 criteria assessing the data presentation. Results We identified 526 randomized controlled trials, of which 116 were crossover trials. Trials were drug efficacy (48%), pharmacokinetic (28%), and nonpharmacologic (30%). The median sample size was 15 (interquartile range 8–38). Most (72%) trials used 2 treatments and had 2 periods (64%). Few trials reported allocation concealment (17%) or sequence generation (7%). Only 20% of trials reported a sample size calculation and only 31% of these considered pairing of data in the calculation. Carry-over issues were addressed in 29% of trial's methods. Most trials reported and defended a washout period (70%). Almost all trials (93%) tested for treatment effects using paired data and also presented details on by-group results (95%). Only 29% presented CIs or SE so that data could be entered into a meta-analysis. Conclusion Reports of crossover trials frequently omit important methodological issues in design, analysis, and presentation. Guidelines for the conduct and reporting of crossover trials might improve the conduct and reporting of studies using this important trial design. PMID:19405975

  3. High-fluoride toothpaste: a multicenter randomized controlled trial in adults

    PubMed Central

    Srinivasan, Murali; Schimmel, Martin; Riesen, Martine; Ilgner, Alexander; Wicht, Michael J; Warncke, Michael; Ellwood, Roger P; Nitschke, Ina; Müller, Frauke; Noack, Michael J

    2014-01-01

    Objective The aim of this single – blind, multicenter, parallel, randomized controlled trial was to evaluate the effectiveness of the application of a high-fluoride toothpaste on root caries in adults. Methods Adult patients (n = 130, ♂ = 74, ♀ = 56; mean age ± SD: 56.9 ± 12.9) from three participating centers, diagnosed with root caries, were randomly allocated into two groups: Test (n = 64, ♂ = 37, ♀ = 27; lesions = 144; mean age: 59.0 ± 12.1; intervention: high-fluoride toothpaste with 5000 ppm F), and Control (n = 66, ♂ = 37, ♀ = 29; lesions = 160; mean age: 54.8 ± 13.5; intervention: regular-fluoride toothpaste with 1350 ppm F) groups. Clinical examinations and surface hardness scoring of the carious lesions were performed for each subject at specified time intervals (T0 – at baseline before intervention, T1 – at 3 months and T2 – at 6 months after intervention). Mean surface hardness scores (HS) were calculated for each patient. Statistical analyses comprised of two-way analysis of variance and post hoc comparisons using the Bonferroni–Dunn correction. Results At T0, there was no statistical difference between the two groups with regard to gender (P = 0.0682, unpaired t-test), or age (P = 0.9786, chi-squared test), and for the overall HS (Test group: HS = 3.4 ± 0.61; Control group: HS = 3.4 ± 0.66; P = 0.8757, unpaired t-test). The anova revealed significantly better HS for the test group than for the control groups (T1: Test group: HS = 2.9 ± 0.67; Control group: HS = 3.1 ± 0.75; T2: Test group: HS = 2.4 ± 0.81; Control group: HS = 2.8 ± 0.79; P < 0.0001). However, the interaction term time-point*group was not significant. Conclusions The application of a high-fluoride containing dentifrice (5000 ppm F) in adults, twice daily, significantly improves the surface hardness of otherwise untreated root caries lesions when compared with the use of regular fluoride

  4. Multicenter Analysis of Immune Biomarkers and Heart Transplant Outcomes: Results of the Clinical Trials in Organ Transplantation-05 Study.

    PubMed

    Starling, R C; Stehlik, J; Baran, D A; Armstrong, B; Stone, J R; Ikle, D; Morrison, Y; Bridges, N D; Putheti, P; Strom, T B; Bhasin, M; Guleria, I; Chandraker, A; Sayegh, M; Daly, K P; Briscoe, D M; Heeger, P S

    2016-01-01

    Identification of biomarkers that assess posttransplant risk is needed to improve long-term outcomes following heart transplantation. The Clinical Trials in Organ Transplantation (CTOT)-05 protocol was an observational, multicenter, cohort study of 200 heart transplant recipients followed for the first posttransplant year. The primary endpoint was a composite of death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR), and cardiac allograft vasculopathy (CAV) as defined by intravascular ultrasound (IVUS). We serially measured anti-HLA- and auto-antibodies, angiogenic proteins, peripheral blood allo-reactivity, and peripheral blood gene expression patterns. We correlated assay results and clinical characteristics with the composite endpoint and its components. The composite endpoint was associated with older donor allografts (p < 0.03) and with recipient anti-HLA antibody (p < 0.04). Recipient CMV-negativity (regardless of donor status) was associated with BPAR (p < 0.001), and increases in plasma vascular endothelial growth factor-C (OR 20; 95%CI:1.9-218) combined with decreases in endothelin-1 (OR 0.14; 95%CI:0.02-0.97) associated with CAV. The remaining biomarkers showed no relationships with the study endpoints. While suboptimal endpoint definitions and lower than anticipated event rates were identified as potential study limitations, the results of this multicenter study do not yet support routine use of the selected assays as noninvasive approaches to detect BPAR and/or CAV following heart transplantation.

  5. Effectiveness of a 16-Week Multimodal Exercise Program on Individuals With Dementia: Study Protocol for a Multicenter Randomized Controlled Trial

    PubMed Central

    Scharpf, Andrea; Barisch-Fritz, Bettina; Niermann, Christina; Woll, Alexander

    2017-01-01

    Background The increasing prevalence of dementia in the next decades is accompanied by various societal and economic problems. Previous studies have suggested that physical activity positively affects motor and cognitive skills in individuals with dementia (IWD). However, there is insufficient evidence probably related to several methodological limitations. Moreover, to date adequate physical activity interventions specifically developed for IWD are lacking. Objective This study aims to investigate the effectiveness of a multimodal exercise program (MEP) on motor and cognitive skills in IWD in a high-quality multicenter trial. Methods A multicenter randomized controlled trial with baseline and postassessments will be performed. It is planned to enroll 405 participants with dementia of mild to moderate stage, aged 65 years and older. The intervention group will participate in a 16-week ritualized MEP especially developed for IWD. The effectiveness of the MEP on the primary outcomes balance, mobility, and gait will be examined using a comprehensive test battery. Secondary outcomes are strength and function of lower limbs, activities of daily living, and cognition (overall cognition, language, processing speed, learning and memory, and visual spatial cognition). Results Enrollment for the study started in May 2015. It is planned to complete postassessments by the beginning of 2017. Results are expected to be available in the first half of 2017. Conclusions This study will contribute to enhancing evidence for the effects of physical activity on motor and cognitive skills in IWD. Compared to previous studies, this study is characterized by a dementia-specific intervention based on scientific knowledge, a combination of motor and cognitive tasks in the intervention, and high standards regarding methodology. Findings are highly relevant to influence the multiple motor and cognitive impairments of IWD who are often participating in limited physical activity. Trial

  6. Golden plaster for pain therapy in patients with knee osteoarthritis: study protocol for a multicenter randomized, double-blind, placebo-controlled trial

    PubMed Central

    2013-01-01

    Background Osteoarthritis is a relatively common musculoskeletal disorder that increases in prevalence with age. Worldwide, knee osteoarthritis is one of the leading causes of disability, particularly in the elderly. In numerous trials of agents for long-term pain therapy, no well-established and replicable results have been achieved. Complementary and alternative medical approaches have been employed for thousands of years to relieve knee osteoarthritis pain. Among herbal medicines, the golden plaster is the preferred and most commonlyused method in China to reduce pain in patients with knee osteoarthritis, as it causes few adverse effects. The purpose of this study will be to evaluate the efficacy and safety of golden plaster on pain in patients with knee osteoarthritis. Methods/Design This study will be a multicenter randomized, double-blind, placebo-controlled trial. A total of 320 participants aged 45 to 79 years with knee osteoarthritis, whose scores on a visual analog scale (VAS) are more than 20 mm,will be randomly allocated into a treatment group and a control group. A golden plaster will be administered externally to participants in the treatment group for 2 weeks, while the control group will receive a placebo plaster externally for 2 weeks. Follow-up will be at regular intervals during a 4-week period with a VAS score for pain, quality of life, and complications. Discussion This study will be a methodologically sound randomized controlled trial to assess pain relief after the intervention of golden plaster, compared to a placebo intervention in patients with knee osteoarthritis. Trial registration ClinicalTrials.gov identifier: ChiCTR-TRC-13003418 PMID:24220504

  7. The efficacy and safety of electroacupuncture for women with pure stress urinary incontinence: study protocol for a multicenter randomized controlled trial

    PubMed Central

    2013-01-01

    Background Although available evidence relating to its effectiveness is weak, acupuncture is used as an alternative therapy for stress urinary incontinence. We report a protocol of a randomized controlled trial using electroacupuncture (the passing of a weak current between inserted acupuncture needles) to treat women with pure stress urinary incontinence. Methods/Design This is a large-scale multicenter subject-blinded randomized controlled trial. A total of 500 women with pure stress urinary incontinence will be randomly assigned to two groups: a treatment group and a control group. The treatment group will receive electroacupuncture with deep needling at acupuncture points BL33 and BL35. The control group will receive sham electroacupuncture with non-penetrating needling at sham locations for the acupuncture points of BL33 and BL35. Participants will be given three sessions a week for 6 weeks. A 24-week-long follow-up will be conducted. The primary outcome will be the change in amount of urine leakage at the sixth week from a baseline measured by a 1-h pad test. The secondary outcomes include: the 72-h incontinence episode frequency based on a 72-h bladder diary; the score of International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form; the degree of urinary incontinence based on a 72-h bladder diary; self-assessment of the therapeutic effect; weekly consumption of pads; application of other treatments for stress urinary incontinence; and subgroup analysis stratified by incontinence severity. The safety of electroacupuncture will also be assessed. Discussion This trial will help to identify whether electroacupuncture is effective for stress urinary incontinence, and, if so, whether it is a therapeutic effect rather than a placebo effect. Trial Registration Clinical Trials.gov NCT01784172 PMID:24079823

  8. DESIGN OF THE SPINE PATIENT OUTCOMES RESEARCH TRIAL (SPORT)

    PubMed Central

    Birkmeyer, Nancy J. O.; Weinstein, James N.; Tosteson, Anna N. A.; Tosteson, Tor D.; Skinner, Jonathan S.; Lurie, Jon D.; Deyo, Richard; Wennberg, John E.

    2010-01-01

    Summary of Background Data The Spine Patient Outcomes Research Trial (SPORT) was designed to assess the relative efficacy and cost-effectiveness of surgical and non-surgical approaches to the treatment of common conditions associated with low back and leg pain. Objectives To describe the rationale and design of the SPORT project and discuss its strengths and limitations. Study Design Descriptive Methods First, we explain the rationale for embarking on SPORT, i.e. deficiencies in the existing scientific knowledge base for treatment of these conditions. Second, we describe the design of SPORT, including topics such as: specific aims; participating sites; study population; recruitment and enrollment; study interventions; follow-up; outcomes; statistical analysis; and study governance and organization. Finally, we discuss issues that complicate the performance of randomized trials in surgery as they relate to the design and conduct of SPORT. Results The SPORT project is being conducted at 11 clinical centers around the United States. It involves the simultaneous conduct of three multi-center, randomized, controlled clinical trials. The study includes patients with the three most common diagnoses for which spine surgery is performed: intervertebral disc herniation (IDH), spinal stenosis (SpS) and degenerative spondylolisthesis (DS), and compares the most commonly used standard surgical and non-surgical treatments for patients with these diagnoses. By the end of enrollment we anticipate a total of 500 IDH, 370 SpS, and 300 DS patients in the randomized trials. Patients who meet the eligibility criteria but decline to be randomized are invited to participate in an observational cohort study. Patients are being followed for a minimum of 24 months with visits scheduled at 6 weeks, 3, 6, 12, and 24 months. Conclusions The results of this study will provide high-quality scientific evidence to aid clinical decision making and improve treatment outcomes for these common, costly

  9. Design and methods in a multi-center case-control interview study.

    PubMed Central

    Hartge, P; Cahill, J I; West, D; Hauck, M; Austin, D; Silverman, D; Hoover, R

    1984-01-01

    We conducted a case-control study in ten areas of the United States in which a total of 2,982 bladder cancer patients and 5,782 population controls were interviewed. We employed a variety of existing and new techniques to reduce bias and to monitor the quality of data collected. We review here many of the design elements and field methods that can be generally applied in epidemiologic studies, particularly multi-center interview studies, and explain the reasons for our selection of the methods, instruments, and procedures used. PMID:6689843

  10. Effects of Shenfu Injection in the Treatment of Septic Shock Patients: A Multicenter, Controlled, Randomized, Open-Label Trial

    PubMed Central

    Zhang, Xinchao; Lin, Peihong; Wei, Jie; Cao, Yu; Pan, Shuming; Walline, Joseph; Qian, Chuanyun; Shan, Zhigang

    2016-01-01

    The effect of Shenfu on biochemical parameters and survival during resuscitation in patients with septic shock was examined. This was a multicenter, controlled, randomized, open-label trial carried out in 210 patients with septic shock from seven medical centers in China. They were randomized to Shenfu or saline. The primary outcome was lactate clearance. The secondary outcomes were shock index normalization, dose of vasopressors, ICU stay, hospital stay, and mortality. A total of 199 patients completed the trial. Blood pressure, heart rate, and other routine lab tests showed no difference between the groups. Lactate levels and lactate clearance were similar between the two groups. Hospital and ICU stay were similar between the two groups. When considering all patients, the 7- and 28-day mortality were similar between the two groups, but when considering only patients with lactate levels ≥4.5 mmol/L, the Shenfu group showed a better 7-day survival than the control group (7 days: 83.3% versus 54.5%, P = 0.034; 28 days: 72.7% versus 47.6%, P = 0.092). Shenfu may improve the 7-day survival in patients with impaired lactate clearance (≥4.5 mmol/L), but the mechanism for this effect is unclear. Additional studies are necessary to characterize the hemodynamic changes after Shenfu infusion. This trial is registered with ChiCTR-TRC-11001369. PMID:27446222

  11. [Results of Russian multicenter trial of immunogenicity, reactogenicity and safety of new combination vaccine against hepatitis A and B (Twinrix)].

    PubMed

    Tatochenko, V K; Il'ina, N I; Romanenko, V V; Alikova, O A; Fassakhov, R S; Miasnikova, T N; Patlusova, V V; Zima, Iu Iu; Reshetnikova, I D; Frolova, G S; Smolenov, I V

    2006-01-01

    Results of registration trial of combination vaccine for prevention of hepatitis A and B are presented. The trial was conducted in 5 centers of Russia in 2004-2005 with full accordance to good clinical practice requirements and standards for multicenter open randomized trials. Immunogenicity of studied combination vaccine Twinrix was evaluated in comparison with two simultaneously administered monovalent vaccines against hepatitis A and B (Havrix and Engerix-B) in 200 healthy subjects aged 18-40, which were seronegative to hepatitis A and B. Reactogenicity based on interviewed and non-interviewed symptoms ranged on intensity was assessed also. 1 month after completion of primary vaccination all subjects in both groups were seropositive to hepatitis A. Sero-protection level of antibodies to hepatitis B virus was detected in 98.9% of participants vaccinated with Twinrix and in 95.6% of participants vaccinated with Engerix-B and Havrix. Overall, reactogenicity of vaccines was minor, marked adverse events caused by vaccination were rare (approximately 1%). Study shows that combination vaccine against hepatitis A and B (Twinrix) at least non inferior in terms of immunogenicity, safety and tolerability to monovalent vaccines (Havrix and Engerix-B), were registered in Russia.

  12. Using simulation to aid trial design: Ring-vaccination trials

    PubMed Central

    Hitchings, Matt David Thomas; Grais, Rebecca Freeman

    2017-01-01

    Background The 2014–6 West African Ebola epidemic highlights the need for rigorous, rapid clinical trial methods for vaccines. A challenge for trial design is making sample size calculations based on incidence within the trial, total vaccine effect, and intracluster correlation, when these parameters are uncertain in the presence of indirect effects of vaccination. Methods and findings We present a stochastic, compartmental model for a ring vaccination trial. After identification of an index case, a ring of contacts is recruited and either vaccinated immediately or after 21 days. The primary outcome of the trial is total vaccine effect, counting cases only from a pre-specified window in which the immediate arm is assumed to be fully protected and the delayed arm is not protected. Simulation results are used to calculate necessary sample size and estimated vaccine effect. Under baseline assumptions about vaccine properties, monthly incidence in unvaccinated rings and trial design, a standard sample-size calculation neglecting dynamic effects estimated that 7,100 participants would be needed to achieve 80% power to detect a difference in attack rate between arms, while incorporating dynamic considerations in the model increased the estimate to 8,900. This approach replaces assumptions about parameters at the ring level with assumptions about disease dynamics and vaccine characteristics at the individual level, so within this framework we were able to describe the sensitivity of the trial power and estimated effect to various parameters. We found that both of these quantities are sensitive to properties of the vaccine, to setting-specific parameters over which investigators have little control, and to parameters that are determined by the study design. Conclusions Incorporating simulation into the trial design process can improve robustness of sample size calculations. For this specific trial design, vaccine effectiveness depends on properties of the ring

  13. Design, Rationale, and Initiation of the Surgical Interventions for Moderate Ischemic Mitral Regurgitation Trial: A Report from the Cardiothoracic Surgical Trials Network

    PubMed Central

    Smith, Peter K.; Michler, Robert E.; Woo, Y. Joseph; Alexander, John H.; Puskas, John D.; D’Alessandro, David A.; Hahn, Rebecca T.; Williams, Judson B.; Dent, John M.; Ferguson, T. Bruce; Moquete, Ellen; Pagé, Pierre; Jeffries, Neal O.; O’Gara, Patrick T.; Ascheim, Deborah D.

    2011-01-01

    Background Patients with moderate ischemic mitral regurgitation have demonstrably poorer outcome compared to coronary artery disease patients without mitral regurgitation. The optimal treatment of this condition has become increasingly controversial and a randomized trial evaluating current practices is warranted. Methods and Results We describe the design and initial execution of the Cardiothoracic Surgical Trials Network moderate ischemic mitral regurgitation trial. This is an ongoing prospective, multi-center, randomized, controlled clinical trial designed to test the safety and efficacy of mitral repair in addition to coronary artery bypass grafting in the treatment of moderate ischemic mitral regurgitation. Conclusion The results of the Cardiothoracic Surgical Trials Network ischemic mitral regurgitation trials will provide long-awaited information on controversial therapies for a morbid disease process. PMID:21788032

  14. Effects of the traditional Chinese medicine Yi Shen Jian Gu granules on aromatase inhibitor-associated musculoskeletal symptoms: a study protocol for a multicenter, randomized, controlled clinical trial

    PubMed Central

    2014-01-01

    Background Aromatase inhibitors (AIs) are widely used as an adjuvant endocrine treatment in postmenopausal women with early-stage breast cancer. One of the main adverse effects of AIs is musculoskeletal symptoms, which leads to a lower quality of life and poor adherence to AI treatment. To date, no effective management of aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) has been developed. Methods/design To determine whether the traditional Chinese medicine Yi Shen Jian Gu granules could effectively manage AIMSS we will conduct a multicenter, randomized, double-blind, placebo-controlled clinical trial. Patients experiencing musculoskeletal symptoms after taking AIs will be enrolled and treated with traditional Chinese medicine or placebo for 12 weeks. The primary outcome measures include Brief Pain Inventory-Short Form, Western Ontario and McMaster Universities Osteoarthritis Index, and Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands, which will be obtained at baseline and at 4, 8, 12 and 24 weeks. Discussion The results of this study will provide a new strategy to help relieve AIMSS. Trial registration ISCTN: ISRCTN06129599 (assigned 14 August 2013). PMID:24885324

  15. The Pregnancy in Polycystic Ovary Syndrome Study II: Baseline Characteristics and Effects of Obesity from a Multi-Center Randomized Clinical Trial

    PubMed Central

    Legro, Richard S.; Brzyski, Robert G.; Diamond, Michael P.; Coutifaris, Christos; Schlaff, William D.; Alvero, Ruben; Casson, Peter; Christman, Gregory M.; Huang, Hao; Yan, Qingshang; Haisenleder, Daniel J.; Barnhart, Kurt T.; Bates, G. Wright; Usadi, Rebecca; Lucidi, Richard; Baker, Valerie; Trussell, J.C.; Krawetz, Stephen A.; Snyder, Peter; Ohl, Dana; Santoro, Nanette; Eisenberg, Esther; Zhang, Heping

    2014-01-01

    Objective To summarize baseline characteristics from a large multi-center infertility clinical trial. Design Cross-sectional baseline data from a double-blind randomized trial of 2 treatment regimens (letrozole vs. clomiphene). Setting Academic Health Centers throughout the U.S. Interventions None Main Outcome Measure(s) Historical, biometric, biochemical and questionnaire parameters. Participants 750 women with PCOS and their male partners took part in the study. Results Females averaged ~30 years old and were obese (BMI 35) with ~20% from a racial/ethnic minority. Most (87%) were hirsute and nulligravid (63%). . Most of the females had an elevated antral follicle count and enlarged ovarian volume on ultrasound. Women had elevated mean circulating androgens, LH:FSH ratio (~2), and AMH levels (8.0 ng/mL). Additionally, women had evidence for metabolic dysfunction with elevated mean fasting insulin and dyslipidemia. Increasing obesity was associated with decreased LH:FSH levels, AMH levels and antral follicle counts but increasing cardiovascular risk factors, including prevalence of the metabolic syndrome. Males were obese (BMI 30) and had normal mean semen parameters. Conclusions The treatment groups were well-matched at baseline. Obesity exacerbates select female reproductive and most metabolic parameters. We have also established a database and sample repository that will eventually be accessible to investigators. PMID:24156957

  16. A prospective, randomized, placebo-controlled, double-blind, multicenter study of the effects of irbesartan on aortic dilatation in Marfan syndrome (AIMS trial): study protocol

    PubMed Central

    2013-01-01

    Background Cardiovascular complications are the leading cause of mortality and morbidity in Marfan syndrome (MFS), a dominantly inherited disorder caused by mutations in the gene that encodes fibrillin-1. There are approximately 18,000 patients in the UK with MFS. Current treatment includes careful follow-up, beta blockers, and prophylactic surgical intervention; however, there is no known treatment which effectively prevents the rate of aortic dilatation in MFS. Preclinical, neonatal, and pediatric studies have indicated that angiotensin receptor blockers (ARBs) may reduce the rate of aortic dilatation. This trial will investigate the effects of irbesartan on aortic dilatation in Marfan syndrome. Methods/Design The Aortic Irbesartan Marfan Study (AIMS) is an investigator-led, prospective, randomized, placebo-controlled, double-blind, phase III, multicenter trial. Currently, 26 centers in the UK will recruit 490 clinically confirmed MFS patients (aged ≥6 to ≤40 years) using the revised Ghent diagnostic criteria. Patients will be randomized to irbesartan or placebo. Aortic root dilatation will be measured by transthoracic echocardiography at baseline and annually thereafter. The primary outcome is the absolute change in aortic root diameter per year measured by echocardiography. The follow-up period will be a minimum of 36 months with an expected mean follow-up period of 48 months. Discussion This is the first clinical trial to evaluate the ARB irbesartan versus placebo in reducing the rate of aortic root dilatation in MFS. Not only will this provide useful information on the safety and efficacy of ARBs in MFS, it will also provide a rationale basis for potentially lifesaving therapy for MFS patients. Trial registration ISRCTN, 90011794 PMID:24289736

  17. The National Lung Screening Trial: overview and study design.

    PubMed

    Aberle, Denise R; Berg, Christine D; Black, William C; Church, Timothy R; Fagerstrom, Richard M; Galen, Barbara; Gareen, Ilana F; Gatsonis, Constantine; Goldin, Jonathan; Gohagan, John K; Hillman, Bruce; Jaffe, Carl; Kramer, Barnett S; Lynch, David; Marcus, Pamela M; Schnall, Mitchell; Sullivan, Daniel C; Sullivan, Dorothy; Zylak, Carl J

    2011-01-01

    The National Lung Screening Trial (NLST) is a randomized multicenter study comparing low-dose helical computed tomography (CT) with chest radiography in the screening of older current and former heavy smokers for early detection of lung cancer, which is the leading cause of cancer-related death in the United States. Five-year survival rates approach 70% with surgical resection of stage IA disease; however, more than 75% of individuals have incurable locally advanced or metastatic disease, the latter having a 5-year survival of less than 5%. It is plausible that treatment should be more effective and the likelihood of death decreased if asymptomatic lung cancer is detected through screening early enough in its preclinical phase. For these reasons, there is intense interest and intuitive appeal in lung cancer screening with low-dose CT. The use of survival as the determinant of screening effectiveness is, however, confounded by the well-described biases of lead time, length, and overdiagnosis. Despite previous attempts, no test has been shown to reduce lung cancer mortality, an endpoint that circumvents screening biases and provides a definitive measure of benefit when assessed in a randomized controlled trial that enables comparison of mortality rates between screened individuals and a control group that does not undergo the screening intervention of interest. The NLST is such a trial. The rationale for and design of the NLST are presented.

  18. Design of oncology clinical trials: a review.

    PubMed

    Ananthakrishnan, Revathi; Menon, Sandeep

    2013-10-01

    Cancer is a disease that occurs due to the uncontrolled multiplication of cells that invade nearby tissues and can spread to other parts of the body. An increased incidence of cancer in the world has led to an increase in oncology research and in the number of oncology trials. Well designed oncology clinical trials are a key part of developing effective anti-cancer drugs. This review focuses on statistical considerations in the design and analysis of oncology clinical trials.

  19. Trial to re-evaluate ultrasound in the treatment of tibial fractures (TRUST): a multicenter randomized pilot study

    PubMed Central

    2014-01-01

    Background The role of low-intensity pulsed ultrasound (LIPUS) in the management of fractures remains controversial. The purpose of this study was to assess the feasibility of a definitive trial to determine the effect of LIPUS on functional and clinical outcomes in tibial fractures managed operatively. Methods We conducted a multicenter, concealed, blinded randomized trial of 51 skeletally mature adults with operatively managed tibial fractures who were treated with either LIPUS or a sham device. All participating centers were located in Canada and site investigators were orthopedic surgeons specializing in trauma surgery. The goals of our pilot study were to determine recruitment rates in individual centers, investigators’ ability to adhere to study protocol and data collection procedures, our ability to achieve close to 100% follow-up rates, and the degree to which patients were compliant with treatment. Patients were followed for one year and a committee (blinded to allocation) adjudicated all outcomes. The committee adjudicators were experienced (10 or more years in practice) orthopedic surgeons with formal research training, specializing in trauma surgery. Results Our overall rate of recruitment was approximately 0.8 patients per center per month and site investigators successfully adhered to the study protocol and procedures. Our rate of follow-up at one year was 84%. Patient compliance, measured by an internal timer in the study devices, revealed that 39 (76%) of the patients were fully compliant and 12 (24%) demonstrated a greater than 50% compliance. Based on patient feedback regarding excessive questionnaire burden, we conducted an analysis using data from another tibial fracture trial that revealed the Short Musculoskeletal Function Assessment (SMFA) dysfunction index offered no important advantages over the SF-36 Physical Component Summary (PCS) score. No device-related adverse events were reported. Conclusions Our pilot study identified key issues

  20. Design, methods, and rationale in the Hypertension Prevention Trial. Hypertension Prevention Trial Research Group.

    PubMed

    Meinert, C L; Borhani, N O; Langford, H G

    1989-09-01

    The Hypertension Prevention Trial (HPT) was a randomized, controlled, multicenter (four clinics, four resource centers) trial designed to test the feasibility of achieving and sustaining dietary changes in the intake of calories, sodium, and potassium and to assess the effect of those changes on blood pressure in a normotensive population. The trial involved 841 men and women (plus a test cohort of 78) who, at the first baseline (BL) examination, were in the age range of 25-49 years and had diastolic blood pressure (DBP) greater than or equal to 76 but less than 100 mm Hg (average of two readings), and at the examination prior to randomization (BL 2) had DBP greater than or equal to 78 but less than 90 mm Hg (also averaged). Participants were randomly assigned to a control treatment group (no dietary counseling) or to one of four dietary treatment groups involving counseling designed to reduce calorie intake, reduce sodium intake, reduce sodium and calorie intake, and reduce sodium and increase potassium intake. Dietary counseling was provided primarily in group settings and was aimed at changing participants' shopping, cooking, and eating habits related to a designated treatment assignment. The effect of dietary counseling was measured through changes in urinary excretion of sodium and potassium, changes in body weight, and changes in reported food intake based on 24-hour food records. Blood pressure changes during the 3-year course of followup were based on measurements taken at 6-month intervals from enrollment using a random-zero sphygmomanometer. This chapter provides a general description of the design and methods of the HPT and the underlying rationale for decisions affecting the design.

  1. Plasma biomarkers of risk for death in a multicenter phase 3 trial with uniform transplant characteristics post–allogeneic HCT

    PubMed Central

    Abu Zaid, Mohammad; Wu, Juan; Wu, Cindy; Logan, Brent R.; Yu, Jeffrey; Cutler, Corey; Antin, Joseph H.; Paczesny, Sophie

    2017-01-01

    A phase 3 clinical trial (BMT CTN 0402) comparing tacrolimus/sirolimus (Tac/Sir) vs tacrolimus/methotrexate (Tac/Mtx) as graft-versus-host disease (GVHD) prophylaxis after matched-related allogeneic hematopoietic cell transplantation (HCT) recently showed no difference between study arms in acute GVHD-free survival. Within this setting of a prospective, multicenter study with uniform GVHD prophylaxis, conditioning regimen, and donor source, we explored the correlation of 10 previously identified biomarkers with clinical outcomes after allogeneic HCT. We measured biomarkers from plasma samples collected in 211 patients using enzyme-linked immunosorbent assay (Tac/Sir = 104, Tac/Mtx = 107). High suppression of tumorigenicity-2 (ST2) and T-cell immunoglobulin mucin-3 (TIM3) at day 28 correlated with 2-year nonrelapse mortality in multivariate analysis (P = .0050, P = .0075, respectively) and in a proportional hazards model with time-dependent covariates (adjusted hazard ratio: 2.43 [1.49–3.95], P = .0038 and 4.87 [2.53–9.34], P < .0001, respectively). High ST2 and TIM3 correlated with overall survival. Chemokine (C-X-C motif) ligand 9 (CXCL9) levels above the median were associated with chronic GVHD compared with levels below the median in a time-dependent proportional hazard analysis (P = .0069). Low L-Ficolin was associated with hepatic veno-occlusive disease (P = .0053, AUC = 0.80). We confirmed the correlation of plasma-derived proteins, previously assessed in single-center cohorts, with clinical outcomes after allogeneic HCT within this prospective, multicenter study. PMID:27827824

  2. Multicenter Safety and Immunogenicity Trial of an Attenuated Measles Vaccine for NHP.

    PubMed

    Yee, Joann L; McChesney, Michael B; Christe, Kari L

    2015-10-01

    Measles is a highly contagious viral disease in NHP. The infection can range from asymptomatic to rapidly fatal, resulting in significant morbidity and mortality in captive populations. In addition to appropriate quarantine practices, restricted access, the immunization of all personnel in contact with NHP, and the wearing of protective clothing including face masks, measles immunization further reduces the infection risk. Commercially available measles vaccines are effective for use in NHP, but interruptions in their availability have prevented the implementation of ongoing, consistent vaccination programs. This need for a readily available vaccine led us to perform a broad, multicenter safety and immunogenicity study of another candidate vaccine, MVac (Serum Institute of India), a monovalent measles vaccine derived from live Edmonston-Zagreb strain virus that had been attenuated after 22 passages on human diploid cells.

  3. Multicenter Safety and Immunogenicity Trial of an Attenuated Measles Vaccine for NHP

    PubMed Central

    Yee, JoAnn L; McChesney, Michael B; Christe, Kari L

    2015-01-01

    Measles is a highly contagious viral disease in NHP. The infection can range from asymptomatic to rapidly fatal, resulting in significant morbidity and mortality in captive populations. In addition to appropriate quarantine practices, restricted access, the immunization of all personnel in contact with NHP, and the wearing of protective clothing including face masks, measles immunization further reduces the infection risk. Commercially available measles vaccines are effective for use in NHP, but interruptions in their availability have prevented the implementation of ongoing, consistent vaccination programs. This need for a readily available vaccine led us to perform a broad, multicenter safety and immunogenicity study of another candidate vaccine, MVac (Serum Institute of India), a monovalent measles vaccine derived from live Edmonston–Zagreb strain virus that had been attenuated after 22 passages on human diploid cells. PMID:26473350

  4. A Machine Learning Approach to Identifying the Thought Markers of Suicidal Subjects: A Prospective Multicenter Trial.

    PubMed

    Pestian, John P; Sorter, Michael; Connolly, Brian; Bretonnel Cohen, Kevin; McCullumsmith, Cheryl; Gee, Jeffry T; Morency, Louis-Philippe; Scherer, Stefan; Rohlfs, Lesley

    2017-02-01

    Death by suicide demonstrates profound personal suffering and societal failure. While basic sciences provide the opportunity to understand biological markers related to suicide, computer science provides opportunities to understand suicide thought markers. In this novel prospective, multimodal, multicenter, mixed demographic study, we used machine learning to measure and fuse two classes of suicidal thought markers: verbal and nonverbal. Machine learning algorithms were used with the subjects' words and vocal characteristics to classify 379 subjects recruited from two academic medical centers and a rural community hospital into one of three groups: suicidal, mentally ill but not suicidal, or controls. By combining linguistic and acoustic characteristics, subjects could be classified into one of the three groups with up to 85% accuracy. The results provide insight into how advanced technology can be used for suicide assessment and prevention.

  5. A multi-center screening trial of rasagiline in patients with amyotrophic lateral sclerosis: Possible mitochondrial biomarker target engagement

    PubMed Central

    Macchi, Zachary; Wang, Yunxia; Moore, Dan; Katz, Jonathan; Saperstein, David; Walk, David; Simpson, Ericka; Genge, Angela; Bertorini, Tulio; Fernandes, J Americo; Swenson, Andrea; Elman, Lauren; Dimachkie, Mazen; Herbelin, Laura; Miller, Joann; Lu, Jianghua; Wilkins, Heather; Swerdlow, Russell H; Statland, Jeffrey; Barohn, Richard

    2015-01-01

    OBJECTIVE Rasagiline, a monoamine oxidase B inhibitor, slowed disease progression in the SOD1 mouse, and in a case series of patients with amyotrophic lateral sclerosis (ALS). Here we determine whether rasagiline is safe and effective in ALS compared to historical placebo controls, and whether it alters mitochondrial biomarkers. METHODS We performed a prospective open-label, multicenter screening trial of 36 ALS patients treated with 2mg oral rasagiline daily for 12 months. Outcomes included the slope of deterioration of the revised ALS Functional Rating Scale (ALSFRS-R), adverse event monitoring, time to treatment failure, and exploratory biomarkers. RESULTS Participants experienced no serious drug-related adverse events, and the most common adverse event was nausea (11.1%). Rasagiline did not improve the rate of decline in the ALSFRS-R; however, differences in symptom duration compared to historical placebo controls differentially affected ALSFRS-R slope estimates. Rasagiline changed biomarkers over 12 months, such that the mitochondrial membrane potential increased (JC-1 red/green fluorescent ratio 1.92, P=0.0001) and apoptosis markers decreased (Bcl-2/Bax ratio 0.24, P<0.0001). CONCLUSION Engagement of exploratory biomarkers and questions about comparability of baseline characteristics lead us to recommend a further placebo-controlled trial. PMID:25832828

  6. Reflections One Year into the 22 Center NIH-funded WRIST Study. A Primer on Conducting a Multicenter Clinical Trial

    PubMed Central

    2013-01-01

    The Wrist and Radius Surgery Trial (WRIST) study group is a collaboration of 22 hand surgery centers in the US, Canada, and Singapore to showcase the interest and capability of hand surgeons to conduct a multicenter clinical trial. The WRIST study group was formed in response to the seminal systematic review by Margaliot et al. and the Cochrane report that indicated marked deficiency in the quality of evidence in the distal radius fracture literature. Since the initial description of this fracture by Colles in 1814, over 2,000 studies have been published on this subject, yet high level studies based on the principles of evidence-based medicine are lacking. As we continue to embrace evidence-based medicine to raise the quality of research, the lessons learned during the organization and conduct of WRIST can serve as a template for others contemplating similar efforts. This paper will trace the course of WRIST by sharing the triumphs, and more importantly the struggles, faced in the first year of this study. PMID:23608306

  7. Intramuscular Artesunate for Severe Malaria in African Children: A Multicenter Randomized Controlled Trial

    PubMed Central

    Kremsner, Peter G.; Adegnika, Akim A.; Hounkpatin, Aurore B.; Zinsou, Jeannot F.; Taylor, Terrie E.; Chimalizeni, Yamikani; Liomba, Alice; Kombila, Maryvonne; Bouyou-Akotet, Marielle K.; Mawili Mboumba, Denise P.; Agbenyega, Tsiri; Ansong, Daniel; Sylverken, Justice; Ogutu, Bernhards R.; Otieno, Godfrey A.; Wangwe, Anne; Bojang, Kalifa A.; Okomo, Uduak; Sanya-Isijola, Frank; Newton, Charles R.; Njuguna, Patricia; Kazungu, Michael; Kerb, Reinhold; Geditz, Mirjam; Schwab, Matthias; Velavan, Thirumalaisamy P.; Nguetse, Christian; Köhler, Carsten; Issifou, Saadou; Bolte, Stefanie; Engleitner, Thomas; Mordmüller, Benjamin; Krishna, Sanjeev

    2016-01-01

    Background Current artesunate (ARS) regimens for severe malaria are complex. Once daily intramuscular (i.m.) injection for 3 d would be simpler and more appropriate for remote health facilities than the current WHO-recommended regimen of five intravenous (i.v.) or i.m. injections over 4 d. We compared both a three-dose i.m. and a three-dose i.v. parenteral ARS regimen with the standard five-dose regimen using a non-inferiority design (with non-inferiority margins of 10%). Methods and Findings This randomized controlled trial included children (0.5–10 y) with severe malaria at seven sites in five African countries to assess whether the efficacy of simplified three-dose regimens is non-inferior to a five-dose regimen. We randomly allocated 1,047 children to receive a total dose of 12 mg/kg ARS as either a control regimen of five i.m. injections of 2.4 mg/kg (at 0, 12, 24, 48, and 72 h) (n = 348) or three injections of 4 mg/kg (at 0, 24, and 48 h) either i.m. (n = 348) or i.v. (n = 351), both of which were the intervention arms. The primary endpoint was the proportion of children with ≥99% reduction in parasitemia at 24 h from admission values, measured by microscopists who were blinded to the group allocations. Primary analysis was performed on the per-protocol population, which was 96% of the intention-to-treat population. Secondary analyses included an analysis of host and parasite genotypes as risks for prolongation of parasite clearance kinetics, measured every 6 h, and a Kaplan–Meier analysis to compare parasite clearance kinetics between treatment groups. A post hoc analysis was performed for delayed anemia, defined as hemoglobin ≤ 7g/dl 7 d or more after admission. The per-protocol population was 1,002 children (five-dose i.m.: n = 331; three-dose i.m.: n = 338; three-dose i.v.: n = 333); 139 participants were lost to follow-up. In the three-dose i.m. arm, 265/338 (78%) children had a ≥99% reduction in parasitemia at 24 h compared to 263/331 (79

  8. The HALT Polycystic Kidney Disease Trials: Design and Implementation

    PubMed Central

    Torres, Vicente E.; Perrone, Ronald D.; Steinman, Theodore I.; Bae, Kyongtae T.; Miller, J. Philip; Miskulin, Dana C.; Oskoui, Frederic Rahbari; Masoumi, Amirali; Hogan, Marie C.; Winklhofer, Franz T.; Braun, William; Thompson, Paul A.; Meyers, Catherine M.; Kelleher, Cass; Schrier, Robert W.

    2010-01-01

    Background and objectives: Two HALT PKD trials will investigate interventions that potentially slow kidney disease progression in hypertensive autosomal dominant polycystic kidney disease (ADPKD) patients. Studies were designed in early and later stages of ADPKD to assess the impact of intensive blockade of the renin-angiotensin-aldosterone system and level of BP control on progressive renal disease. Design, settings, participants, and measurements: PKD-HALT trials are multicenter, randomized, double-blind, placebo-controlled trials studying 1018 hypertensive ADPKD patients enrolled over 3 yr with 4 to 8 yr of follow-up. In study A, 548 participants, estimated GFR (eGFR) of >60 ml/min per 1.73 m2 were randomized to one of four arms in a 2-by-2 design: combination angiotensin converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) therapy versus ACEi monotherapy at two levels of BP control. In study B, 470 participants, eGFR of 25 to 60 ml/min per 1.73 m2 compared ACEi/ARB therapy versus ACEi monotherapy, with BP control of 120 to 130/70 to 80 mmHg. Primary outcomes of studies A and B are MR-based percent change kidney volume and a composite endpoint of time to 50% reduction of baseline estimated eGFR, ESRD, or death, respectively. Results: This report describes design issues related to (1) novel endpoints such as kidney volume, (2) home versus office BP measures, and (3) the impact of RAAS inhibition on kidney and patient outcomes, safety, and quality of life. Conclusions: HALT PKD will evaluate potential benefits of rigorous BP control and inhibition of the renin-angiotensin-aldosterone system on kidney disease progression in ADPKD. PMID:20089507

  9. Stopping clinical trials by design.

    PubMed

    Whitehead, John

    2004-11-01

    Before any clinical trial begins, a detailed trial protocol must be prepared. The authority of the trial results will depend on the quality of this document. In many protocols, a key component is a plan for a series of interim analyses of the accumulating trial data, and a 'stopping rule' based on them. Such a rule might be intended to prevent participants from continuing to receive a drug that already seems to be unsafe, or to allow a successful drug to become generally available as soon as sufficient evidence of its advantages has been collected. There has been considerable misunderstanding of these rules, and controversies associated with them. Here, I discuss why this might be, and what can be done to promote their successful and beneficial use in the future.

  10. The effectiveness of a graphical presentation in addition to a frequency format in the context of familial breast cancer risk communication: a multicenter controlled trial

    PubMed Central

    2013-01-01

    Background Inadequate understanding of risk among counselees is a common problem in familial cancer clinics. It has been suggested that graphical displays can help counselees understand cancer risks and subsequent decision-making. We evaluated the effects of a graphical presentation in addition to a frequency format on counselees’ understanding, psychological well-being, and preventive intentions. Design: Multicenter controlled trial. Setting: Three familial cancer clinics in the Netherlands. Methods Participants: Unaffected women with a breast cancer family history (first-time attendees). Intervention: Immediately after standard genetic counseling, an additional consultation by a trained risk counselor took place where women were presented with their lifetime breast cancer risk in frequency format (X out of 100) (n = 63) or frequency format plus graphical display (10 × 10 human icons) (n = 91). Main outcome measures: understanding of risk (risk accuracy, risk perception), psychological well-being, and intentions regarding cancer prevention. Measurements were assessed using questionnaires at baseline, 2-week and 6-month follow-up. Results Baseline participant characteristics did not differ between the two groups. In both groups there was an increase in women’s risk accuracy from baseline to follow-up. No significant differences were found between women who received the frequency format and those who received an additional graphical display in terms of understanding, psychological well-being and intentions regarding cancer prevention. The groups did not differ in their evaluation of the process of counseling. Conclusion Women’s personal risk estimation accuracy was generally high at baseline and the results suggest that an additional graphical display does not lead to a significant benefit in terms of increasing understanding of risk, psychological well-being and preventive intentions. Trial registration Current Controlled Trials http://ISRCTN14566836

  11. Innovative clinical trial design for pediatric therapeutics

    PubMed Central

    Laughon, Matthew M; Benjamin, Daniel K; Capparelli, Edmund V; Kearns, Gregory L; Berezny, Katherine; Paul, Ian M; Wade, Kelly; Barrett, Jeff; Smith, Phillip Brian; Cohen-Wolkowiez, Michael

    2011-01-01

    Until approximately 15 years ago, sponsors rarely included children in the development of therapeutics. US and European legislation has resulted in an increase in the number of pediatric trials and specific label changes and dosing recommendations, although infants remain an understudied group. The lack of clinical trials in children is partly due to specific challenges in conducting trials in this patient population. Therapeutics in special populations, including premature infants, obese children and children receiving extracorporeal life support, are even less studied. National research networks in Europe and the USA are beginning to address some of the gaps in pediatric therapeutics using novel clinical trial designs. Recent innovations in pediatric clinical trial design, including sparse and scavenged sampling, population pharmacokinetic analyses and ‘opportunistic’ studies, have addressed some of the historical challenges associated with clinical trials in children. PMID:21980319

  12. Randomized multicenter trial on the effect of radiotherapy for plantar Fasciitis (painful heel spur) using very low doses – a study protocol

    PubMed Central

    Niewald, Marcus; Seegenschmiedt, M Heinrich; Micke, Oliver; Gräber, Stefan

    2008-01-01

    Background A lot of retrospective data concerning the effect of radiotherapy on the painful heel spur (plantar fasciitis) is available in the literature. Nevertheless, a randomized proof of this effect is still missing. Thus, the GCGBD (German cooperative group on radiotherapy for benign diseases) of the DEGRO (German Society for Radiation Oncology) decided to start a randomized multicenter trial in order to find out if the effect of a conventional total dose is superior compared to that of a very low dose. Methods/Design In a prospective, controlled and randomized phase III trial two radiotherapy schedules are to be compared: standard arm: total dose 6.0 Gy in single fractions of 1.0 Gy applied twice a week experimental arm: total dose 0.6 Gy in single fractions of 0.1 Gy applied twice a week (acting as a placebo) Patients aged over 40 years who have been diagnosed clinically and radiologically to be suffering from a painful heel spur for at least six months can be included. Former trauma, surgery or radiotherapy to the heel are not allowed nor are patients with a severe psychiatric disease or women during pregnancy and breastfeeding. According to the statistical power calculation 100 patients have to be enrolled into each arm. After having obtaining a written informed consent a patient is randomized by the statistician to one of the arms mentioned above. After radiotherapy, the patients are seen first every six weeks, then regularly up to 48 months after therapy, they additionally receive a questionnaire every six weeks after the follow-up examinations. The effect is measured using several target variables (scores): Calcaneodynia-score according to Rowe et al., SF-12 score, and visual analogue scale of pain. The most important endpoint is the pain relief three months after therapy. Patients with an inadequate result are offered a second radiotherapy series applying the standard dose (equally in both arms). This trial protocol has been approved by the expert panel

  13. Multicenter, open-label, exploratory clinical trial with Rhodiola rosea extract in patients suffering from burnout symptoms

    PubMed Central

    Kasper, Siegfried; Dienel, Angelika

    2017-01-01

    Purpose This study is the first clinical trial aiming to explore the clinical outcomes in burnout patients treated with Rhodiola rosea. The reported capacity of R. rosea to strengthen the organism against stress and its good tolerability offer a promising approach in the treatment of stress-related burnout. The aim of the treatment was to increase stress resistance, thus addressing the source rather than the symptoms of the syndrome and preventing subsequent diseases associated with a history of burnout. The objective of the trial was to provide the exploratory data required for planning future randomized trials in burnout patients in order to investigate the clinical outcomes of treatment with R. rosea dry extract in this target group. Methods The study was planned as an exploratory, open-label, multicenter, single-arm trial. A wide range of rating scales were assessed and evaluated in an exploratory data analysis to generate hypotheses regarding clinical courses and to provide a basis for the planning of subsequent studies. A total of 118 outpatients were enrolled. A daily dose of 400 mg R. rosea extract (WS® 1375, Rosalin) was administered over 12 weeks. Clinical outcomes were assessed by the German version of the Maslach Burnout Inventory, Burnout Screening Scales I and II, Sheehan Disability Scale, Perceived Stress Questionnaire, Number Connection Test, Multidimensional Mood State Questionnaire, Numerical Analogue Scales for different stress symptoms and impairment of sexual life, Patient Sexual Function Questionnaire, and the Clinical Global Impression Scales. Results The majority of the outcome measures showed clear improvement over time. Several parameters had already improved after 1 week of treatment and continued to improve further up to the end of the study. The incidence of adverse events was low with 0.015 events per observation day. Discussion The trial reported here was the first to investigate clinical outcomes in patients suffering from burnout

  14. ICT-based system to predict and prevent falls (iStoppFalls): study protocol for an international multicenter randomized controlled trial

    PubMed Central

    2014-01-01

    Background Falls are very common, especially in adults aged 65 years and older. Within the current international European Commission’s Seventh Framework Program (FP7) project ‘iStoppFalls’ an Information and Communication Technology (ICT) based system has been developed to regularly assess a person’s risk of falling in their own home and to deliver an individual and tailored home-based exercise and education program for fall prevention. The primary aims of iStoppFalls are to assess the feasibility and acceptability of the intervention program, and its effectiveness to improve balance, muscle strength and quality of life in older people. Methods/Design This international, multicenter study is designed as a single-blinded, two-group randomized controlled trial. A total of 160 community-dwelling older people aged 65 years and older will be recruited in Germany (n = 60), Spain (n = 40), and Australia (n = 60) between November 2013 and May 2014. Participants in the intervention group will conduct a 16-week exercise program using the iStoppFalls system through their television set at home. Participants are encouraged to exercise for a total duration of 180 minutes per week. The training program consists of a variety of balance and strength exercises in the form of video games using exergame technology. Educational material about a healthy lifestyle will be provided to each participant. Final reassessments will be conducted after 16 weeks. The assessments include physical and cognitive tests as well as questionnaires assessing health, fear of falling, quality of life and psychosocial determinants. Falls will be followed up for six months by monthly falls calendars. Discussion We hypothesize that the regular use of this newly developed ICT-based system for fall prevention at home is feasible for older people. By using the iStoppFalls sensor-based exercise program, older people are expected to improve in balance and strength outcomes. In addition, the exercise

  15. Triangular Titanium Implants for Minimally Invasive Sacroiliac Joint Fusion: 2-Year Follow-Up from a Prospective Multicenter Trial

    PubMed Central

    Bitan, Fabien; Lockstadt, Harry; Kovalsky, Don; Cher, Daniel; Hillen, Travis

    2016-01-01

    Background Sacroiliac joint (SIJ) dysfunction is an underdiagnosed condition. Several published cohorts have reported favorable mid-term outcomes after SIJ fusion using titanium implants placed across the SIJ. Herein we report long-term (24-month) results from a prospective multicenter clinical trial. Methods One hundred and seventy-two subjects at 26 US sites with SI joint dysfunction were enrolled and underwent minimally invasive SI joint fusion with triangular titanium implants. Subjects underwent structured assessments preoperatively and at 1, 3, 6, 12, 18 and 24 months postoperatively, including SIJ pain ratings (0-100 visual analog scale), Oswestry Disability Index (ODI), Short Form-36 (SF-36), EuroQOL-5D (EQ-5D), and patient satisfaction. Adverse events were collected throughout follow-up. All participating patients underwent a high-resolution pelvic CT scan at 1 year. Results Mean subject age was 50.9 years and 69.8% were women. SIJ pain was present for an average of 5.1 years prior to surgical treatment. SIJ pain decreased from 79.8 at baseline to 30.4 at 12 months and remained low at 26.0 at 24 months (p<.0001 for change from baseline). ODI decreased from 55.2 at baseline to 31.5 at 12 months and remained low at 30.9 at 24 months (p<.0001 for change from baseline). Quality of life (SF-36 and EQ-5D) improvements seen at 12 months were sustained at 24 months. The proportion of subjects taking opioids for SIJ or low back pain decreased from 76.2% at baseline to 55.0% at 24 months (p <.0001). To date, 8 subjects (4.7%) have undergone one or more revision SIJ surgeries. 7 device-related adverse events occurred. CT scan at one year showed a high rate (97%) of bone adherence to at least 2 implants on both the iliac and sacral sides with modest rates of bone growth across the SIJ. Conclusions In this study of patients with SIJ dysfunction, minimally invasive SI joint fusion using triangular titanium implants showed marked improvements in pain, disability and

  16. A primer on clinical trial design.

    PubMed

    Ellimoottil, Chad; Vijan, Sandeep; Flanigan, Robert C

    2015-03-01

    A well-designed and executed clinical trial is the gold standard of evidence-based medicine. It is important for readers to understand the rationale for the study design, identify common pitfalls, and scrutinize limitations. Herein, we present a brief overview of types of designs used for clinical trials and discuss the use of appropriate end points, the selection of study participants, randomization, sample size calculation, blinding, and analysis of data. Finally, we emphasize the importance of accurate and transparent reporting. Our goal is to provide a primer for practicing urologists to enhance their understanding of the clinical trial literature.

  17. A Multicenter, Randomized Controlled Trial of Cerebrospinal Fluid Drainage in Acute Spinal Cord Injury

    DTIC Science & Technology

    2015-10-01

    purpose of this randomized clinical trial is to evaluate the safety and efficacy of cerebrospinal fluid drainage (CSFD) and to provide a preliminary... clinical efficacy evaluation of the combination of CSFD and elevation of mean arterial pressure (MAP) in patients with acute spinal cord injury...and society that are expected to increase with better long term care technologies. The purpose of this randomized clinical trial is to evaluate the

  18. Malignant Peripheral Nerve Sheath Tumors in Neurofibromatosis Type 1: A Multicenter Project With 3 Clinical Trials

    DTIC Science & Technology

    2005-05-01

    is to optimize NF1 subject recruitment into 3 clinical trials related to MPNSTs . By developing a well- publicized network of NF1 Clinic Centers and...Sarcoma Centers, we plan to offer enrollment to all individuals in North America and Europe who have MPNST and NF1. One study is a case-control study...to identify risk factors for MPNST . Some individuals will be eligible for a clinical trial of neoadjuvant chemotherapy, and this will be offered to

  19. Convergence Insufficiency Treatment Trial – Attention and Reading Trial (CITT-ART): Design and Methods

    PubMed Central

    Scheiman, Mitchell; Mitchell, G. Lynn; Cotter, Susan A.; Kulp, Marjean; Chase, Christopher; Borsting, Eric; Arnold, Eugene; Denton, Carolyn; Hertle, Richard

    2016-01-01

    Objective To describe the design and methodology of the Convergence Insufficiency Treatment Trial: Attention and Reading Trial (CITT-ART), the first randomized clinical trial evaluating the effect of vision therapy on reading and attention in school-age children with symptomatic convergence insufficiency (CI). Methods CITT-ART is a multicenter, placebo-controlled, randomized clinical trial of 324 children ages 9 to 14 years in grades 3 to 8 with symptomatic CI. Participants are randomized to 16 weeks of office-based vergence/accommodative therapy (OBVAT) or placebo therapy (OBPT), both supplemented with home therapy. The primary outcome measure is the change in the Wechsler Individual Achievement Test-Version 3 (WIAT-III) reading comprehension subtest score. Secondary outcome measures are changes in attention as measured by the Strengths and Weaknesses of Attention (SWAN) as reported by parents and teachers, tests of binocular visual function, and other measures of reading and attention. The long-term effects of treatment are assessed 1 year after treatment completion. All analyses will test the null hypothesis of no difference in outcomes between the two treatment groups. The study is entering its second year of recruitment. The final results will contribute to a better understanding of the relationship between the treatment of symptomatic CI and its effect on reading and attention. Conclusion The study will provide an evidence base to help parents, eye professionals, educators, and other health care providers make informed decisions as they care for children with CI and reading and attention problems. Results may also generate additional hypothesis and guide the development of other scientific investigations of the relationships between visual disorders and other developmental disorders in children. PMID:26942226

  20. Nine-year change in statistical design, profile, and success rates of Phase II oncology trials.

    PubMed

    Ivanova, Anastasia; Paul, Barry; Marchenko, Olga; Song, Guochen; Patel, Neerali; Moschos, Stergios J

    2016-01-01

    We investigated nine-year trends in statistical design and other features of Phase II oncology clinical trials published in 2005, 2010, and 2014 in five leading oncology journals: Cancer, Clinical Cancer Research, Journal of Clinical Oncology, Annals of Oncology, and Lancet Oncology. The features analyzed included cancer type, multicenter vs. single-institution, statistical design, primary endpoint, number of treatment arms, number of patients per treatment arm, whether or not statistical methods were well described, whether the drug was found effective based on rigorous statistical testing of the null hypothesis, and whether the drug was recommended for future studies.

  1. Patient recruitment into a multicenter randomized clinical trial for kidney disease: report of the focal segmental glomerulosclerosis clinical trial (FSGS CT).

    PubMed

    Ferris, Maria; Norwood, Victoria; Radeva, Milena; Gassman, Jennifer J; Al-Uzri, Amira; Askenazi, David; Matoo, Tej; Pinsk, Maury; Sharma, Amita; Smoyer, William; Stults, Jenna; Vyas, Shefali; Weiss, Robert; Gipson, Debbie; Kaskel, Frederick; Friedman, Aaron; Moxey-Mims, Marva; Trachtman, Howard

    2013-02-01

    We describe the experience of the focal segmental glomerulosclerosis clinical trial (FSGS CT) in the identification and recruitment of participants into the study. This National Institutes of Health funded study, a multicenter, open-label, randomized comparison of cyclosporine versus oral dexamethasone pulses plus mycophenolate mofetil, experienced difficulty and delays meeting enrollment goals. These problems occurred despite the support of patient advocacy groups and aggressive recruitment strategies. Multiple barriers were identified including: (1) inaccurate estimates of the number of potential incident FSGS patients at participating centers; (2) delays in securing one of the test agents; (3) prolonged time between IRB approval and execution of a subcontract (mean 7.5 ± 0.8 months); (4) prolonged time between IRB approval and enrollment of the first patient at participating sites (mean 19.6 ± 1.4 months); and (5) reorganization of clinical coordinating core infrastructure to align resources with enrollment. A Web-based anonymous survey of site investigators revealed site-related barriers to patient recruitment. The value of a variety of recruitment tools was of marginal utility in facilitating patient enrollment. We conclude that improvements in the logistics of study approval and regulatory start-up and testing of promising novel agents are important factors in promoting enrollment into randomized clinical trials in nephrology.

  2. Patient Recruitment into a Multicenter Randomized Clinical Trial for Kidney Disease: Report of the Focal Segmental Glomerulosclerosis Clinical Trial (FSGS CT)

    PubMed Central

    Ferris, Maria; Norwood, Victoria; Radeva, Milena; Al-Uzri, Amira; Askenazi, David; Matoo, Tej; Pinsk, Maury; Sharma, Amita; Smoyer, William; Stults, Jenna; Vyas, Shefali; Weiss, Robert; Gipson, Debbie; Kaskel, Frederick; Friedman, Aaron; Moxey-Mims, Marva; Trachtman, Howard

    2015-01-01

    We describe the experience of the focal segmental glomerulosclerosis clinical trial (FSGS CT) in the identification and recruitment of participants into the study. This National Institutes of Health funded study, a multicenter open-label, randomized comparison of cyclosporine versus oral dexamethasone pulses plus mycophenolate mofetil, experienced difficulty and delays meeting enrollment goals. These problems occurred despite the support of patient advocacy groups and aggressive recruitment strategies. Multiple barriers were identified including: (1) inaccurate estimates of the number of potential incident FSGS patients at participating centers; (2) delays in securing one of the test agents; (3) prolonged time between IRB approval and execution of a subcontract (mean 7.5 ± 0.8 months); (4) prolonged time between IRB approval and enrollment of the first patient at participating sites (mean 19.6 ± 1.4 months); and (5) reorganization of clinical coordinating core infrastructure to align resources with enrollment. A web-based anonymous survey of site investigators revealed site-related barriers to patient recruitment. The value of a variety of recruitment tools was of marginal utility in facilitating patient enrollment. We conclude that improvements in the logistics of study approval and regulatory start-up and testing promising novel agents are important factors in promoting enrollment into randomized clinical trials in nephrology. PMID:23399084

  3. Biomarker-driven trial in metastatic pancreas cancer: feasibility in a multicenter study of saracatinib, an oral Src inhibitor, in previously treated pancreatic cancer.

    PubMed

    Arcaroli, John; Quackenbush, Kevin; Dasari, Arvind; Powell, Rebecca; McManus, Martine; Tan, Aik-Choon; Foster, Nathan R; Picus, Joel; Wright, John; Nallapareddy, Sujatha; Erlichman, Charles; Hidalgo, Manuel; Messersmith, Wells A

    2012-10-01

    Src tyrosine kinases are overexpressed in pancreatic cancers, and the oral Src inhibitor saracatinib has shown antitumor activity in preclinical models of pancreas cancer. We performed a CTEP-sponsored Phase II clinical trial of saracatinib in previously treated pancreas cancer patients, with a primary endpoint of 6-month survival. A Simon MinMax two-stage phase II design was used. Saracatinib (175 mg/day) was administered orally continuously in 28-day cycles. In the unselected portion of the study, 18 patients were evaluable. Only two (11%) patients survived for at least 6 months, and three 6-month survivors were required to move to second stage of study as originally designed. The study was amended as a biomarker-driven trial (leucine rich repeat containing protein 19 [LRRC19] > insulin-like growth factor-binding protein 2 [IGFBP2] "top scoring pairs" polymerase chain reaction [PCR] assay, and PIK3CA mutant) based on preclinical data in a human pancreas tumor explant model. In the biomarker study, archival tumor tissue or fresh tumor biopsies were tested. Biomarker-positive patients were eligible for the study. Only one patient was PIK3CA mutant in a 3' untranslated region (UTR) portion of the gene. This patient was enrolled in the study and failed to meet the 6-month survival endpoint. As the frequency of biomarker-positive patients was very low (<3%), the study was closed. Although we were unable to conclude whether enriching for a subset of second/third line pancreatic cancer patients treated with a Src inhibitor based on a biomarker would improve 6-month survival, we demonstrate that testing pancreatic tumor samples for a biomarker-driven, multicenter study in metastatic pancreas cancer is feasible.

  4. Design of the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST)

    PubMed Central

    Sheffet, Alice J.; Roubin, Gary; Howard, George; Howard, Virginia; Moore, Wesley; Meschia, James F.; Hobson, Robert W.; Brott, Thomas G.

    2009-01-01

    Rationale Carotid endarterectomy (CEA) and medical therapy were shown superior to medical therapy alone for symptomatic (≥50%) and asymptomatic (≥60%) stenosis. Carotid angioplasty stenting (CAS) offers a less invasive alternative. Establishing safety, efficacy, and durability of CAS requires rigorous comparison with CEA in symptomatic and asymptomatic patients. Aims The objective is to compare the efficacy of CAS versus CEA in patients with symptomatic (≥50%) or asymptomatic (≥60%) extracranial carotid stenosis. Design The Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) is a prospective, randomized, parallel, two-arm, multi-center trial with blinded endpoint adjudication. Primary endpoints are analyzed using standard time-to-event statistical modeling with adjustment for major baseline covariates. Primary analysis is on an intent-to-treat basis. Study Outcomes The primary outcome is the occurrence of any stroke, myocardial infarction, or death during a 30-day peri-procedural period, and ipsilateral stroke during follow-up of up to four years. Secondary outcomes include restenosis and health-related quality of life. PMID:20088993

  5. Effects on Balance and Walking with the CoDuSe Balance Exercise Program in People with Multiple Sclerosis: A Multicenter Randomized Controlled Trial

    PubMed Central

    von Koch, Lena

    2016-01-01

    Background. Balance and walking impairments are frequent in people with multiple sclerosis (MS). Objective. The aim was to investigate the effects of a group-based balance exercise program targeting core stability, dual tasking, and sensory strategies (CoDuSe) on balance, postural sway, walking, perceived walking limitations, and balance confidence. Design. A single-blinded randomized multicenter trial. No intervention was given to controls. Participants. People with MS able to walk 100 meters but unable to maintain tandem stance ≥30 seconds. Eighty-seven participants were randomized to intervention or control. Intervention. The 60-minute CoDuSe group program, twice weekly for seven weeks, supervised by physical therapists. Measurements. Primary outcome was dynamic balance (Berg Balance Scale (BBS)). Secondary outcomes were postural sway, walking (Timed-Up and Go test; Functional Gait Assessment (FGA)), MS Walking Scale, and Activities-specific Balance Confidence (ABC) Scale. Assessments were performed before and after (week 8) the intervention. Results. 73 participants fulfilled the study. There were significant differences between the intervention and the control groups in change in the BBS and in the secondary measures: postural sway with eyes open, FGA, MS Walking Scale, and ABC scale in favor of the intervention. Conclusions. The seven-week CoDuSe program improved dynamic balance more than no intervention. PMID:28042485

  6. Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplant to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50-75 with Intermediate-2 and High Risk Myelodysplastic Syndrome Blood and Marrow Transplant Clinical Trials Network #1102 Study Rationale, Design and Methods

    PubMed Central

    Saber, Wael; Le Rademacher, Jennifer; Sekeres, Mikkael; Logan, Brent; Lewis, Moira; Mendizabal, Adam; Leifer, Eric; Appelbaum, Frederick R.; Horowitz, Mary M; Nakamura, Ryotaro; Cutler, Corey S.

    2014-01-01

    The introduction of reduced intensity conditioning regimens (RIC) made it possible to offer allogeneic hematopoietic cell transplantation (alloHCT) to older patients with myelodysplastic syndromes (MDS). However, the relative risks and benefits of alloHCT compared to novel non-transplant therapies continue to be the source of considerable uncertainty. We will perform a prospective biologic assignment trial to compare RIC alloHCT to non-transplant therapies based on donor availability. Primary outcome is 3-year overall survival. Secondary outcomes include leukemia-free survival, quality of life, and cost-effectiveness. Four hundred patients will be enrolled over roughly 3 years. Planned subgroup analyses will evaluate key biologic questions, such as the impact of age & response to hypomethylating agents on treatment effects. Findings from this study potentially may set a new standard of care for older MDS patients who are considered candidates for alloHCT. PMID:24972249

  7. Postoperative radiation therapy for rectal cancer. An interim analysis of a prospective, randomized multicenter trial in The Netherlands

    SciTech Connect

    Treurniet-Donker, A.D.; van Putten, W.L.; Wereldsma, J.C.; Bruggink, E.D.; Hoogenraad, W.J.; Roukema, J.A.; Snijders-Keilholz, A.; Meijer, W.S.; Meerwaldt, J.H.; Wijnmaalen, A.J. )

    1991-04-15

    The authors assessed the potential benefit of postoperative radiation therapy for rectal cancer in a two-arm, prospective multicenter trial. One hundred seventy-two patients who had undergone surgical resection for rectal adenocarcinoma were randomly assigned to either treatment consisting of external irradiation to a dose of 5000 cGy in 5 weeks or a control group (no adjuvant therapy). It was assumed that the number of cells remaining after radical surgery would be low and that the dose of 5000 cGy would be adequate in eradicating the majority of those cells. The number of local recurrences was lower in the treated group of patients, but the difference was not statistically significant. It was assumed that if a significant reduction in the number of local recurrences could be obtained, improved (disease-free) survival would result. No influence on disease-free or overall survival could be detected. These results were in agreement with those reported in Europe and the US, and it was concluded that postoperative radiation therapy alone cannot be justified as a routine procedure in the primary management of resectable rectal cancer.

  8. Postoperative radiation therapy for rectal cancer. An interim analysis of a prospective, randomized multicenter trial in The Netherlands.

    PubMed

    Treurniet-Donker, A D; van Putten, W L; Wereldsma, J C; Bruggink, E D; Hoogenraad, W J; Roukema, J A; Snijders-Keilholz, A; Meijer, W S; Meerwaldt, J H; Wijnmaalen, A J

    1991-04-15

    The authors assessed the potential benefit of postoperative radiation therapy for rectal cancer in a two-arm, prospective multicenter trial. One hundred seventy-two patients who had undergone surgical resection for rectal adenocarcinoma were randomly assigned to either treatment consisting of external irradiation to a dose of 5000 cGy in 5 weeks or a control group (no adjuvant therapy). It was assumed that the number of cells remaining after radical surgery would be low and that the dose of 5000 cGy would be adequate in eradicating the majority of those cells. The number of local recurrences was lower in the treated group of patients, but the difference was not statistically significant. It was assumed that if a significant reduction in the number of local recurrences could be obtained, improved (disease-free) survival would result. No influence on disease-free or overall survival could be detected. These results were in agreement with those reported in Europe and the US, and it was concluded that postoperative radiation therapy alone cannot be justified as a routine procedure in the primary management of resectable rectal cancer.

  9. A randomized, double-blind, multicenter clinical trial on the efficacy of ivermectin against intestinal nematode infections in China.

    PubMed

    Wen, Li-Yong; Yan, Xiao-Lan; Sun, Feng-Hua; Fang, Yue-Yi; Yang, Ming-Jin; Lou, Lei-Jun

    2008-06-01

    To assess the efficacy of ivermectin against intestinal nematode infections, a randomized, double-blind, multicenter clinical trial was carried out in a total of 816 human individuals infected with different nematodes from three counties in China. The subjects were randomly assigned into experimental and control groups and orally given a single dose of 0.1, 0.2, 0.2 and 0.2mg/kg ivermectin against Ascaris lumbricoides, hookworm, Trichuris trichiura and Enterobius vermicularis, respectively. Parallel control groups to each of the ivermectin groups were given a single oral dose of 6.7 mg/kg albendazole. The cure rates with ivermectin and albendazole were 100% (102/102) and 99.0% (101/102) for Ascaris, and 66.7% (68/102) and 67.7% (69/102) for Trichuris, respectively, with no significant difference (P>0.05) between the two treatments. The parasitological cure rates of albendazole were 69.6% (71/102) for hookworm and 94.1% (96/102) for Enterobius, which were significantly higher than ivermectin (33.3% and 52.9%, respectively, P<0.0001). The expulsion of worm in the feces reached its peak 1-2 days after ivermectin treatment. The study showed that ivermectin, with few side effects, could be used as an additional treatment tool for intestinal nematodes, especially for the treatment of Ascaris and Trichuris infections in China.

  10. A prospective randomized multicenter trial shows improvement of sternum related complications in cardiac surgery with the Posthorax support vest.

    PubMed

    Gorlitzer, Michael; Wagner, Florian; Pfeiffer, Steffen; Folkmann, Sandra; Meinhart, Johann; Fischlein, Theodor; Reichenspurner, Hermann; Grabenwöger, Martin

    2010-05-01

    Sternal instability, dehiscence and mediastinitis are major causes of morbidity and mortality in cardiac surgery. The aim of this analysis is to determine the effect of a Posthorax support vest (Epple Inc, Vienna, Austria) after median sternotomy. One thousand five hundred and sixty cases were included in a prospective randomized multicenter trial. Patients were randomized as follows: 905 received a flexible dressing postoperatively (group A) and 655 patients were given a Posthorax support vest (group B). Patients in groups A and B were well matched. Their mean age was 68 years (range: 34-87 years). The patient characteristics and operative data were equally distributed in both groups. The mean total hospital stay was significantly shorter in group B than in group A (A: 17.33+/-17.5; B: 14.76+/-7.7; P=0.04). Sternal wound complications necessitating reoperation during the 90 days follow-up period were observed in 4.5%. Reoperation rates were as follows: 3.9% in group A and 0.6% in group B (P<0.05). The use of the Posthorax sternum support vest is a valuable adjunct to prevent sternum-related complications after cardiac surgery. In the 90 days follow-up period, additional surgical procedures were significantly reduced by the use of the support vest.

  11. Change in clinical indices following laser or scalpel treatment for periodontitis: A split-mouth, randomized, multi-center trial

    NASA Astrophysics Data System (ADS)

    Harris, David M.; Nicholson, Dawn M.; McCarthy, Delwin; Yukna, Raymond A.; Reynolds, Mark A.; Greenwell, Henry; Finley, James; McCawley, Thomas K.; Xenoudi, Pinelopi; Gregg, Robert H.

    2014-02-01

    Data are presented from a multi-center, prospective, longitudinal, clinical trial comparing four different treatments for periodontitis, (1) the LANAPTM protocol utilizing a FR pulsed-Nd:YAG laser; (2) flap surgery using the Modified Widman technique (MWF); (3) traditional scaling and root planing (SRP); and (4) coronal debridement (CD). Each treatment was randomized to a different quadrant. Fifty-one (54) subjects were recruited at five centers that included both private practice and university-based investigators. At 6-months and 12 months post-treatment the LANAPTM protocol and MWF yielded equivalent results based on changes in probing depths. The major difference observed between the two procedures was that patients reported significantly greater comfort following the LANAP™ procedure than following the MWF (P<0.001). There was greater reduction in bleeding in the LANAPTM quadrant than in the other three at both 6 and 12 months. Improvements following SRP were better than expected at 6 months and continued to improve, providing outcomes that were equivalent to both LANAPTM and MWF at 12 months. The improvement in the SRP quadrants suggests the hypothesis that an aspect of the LANAPTM protocol generated a significant, positive and unanticipated systemic (or trans-oral) effect on sub-gingival wound healing.

  12. Voriconazole therapeutic drug monitoring: results of a prematurely discontinued randomized multicenter trial

    PubMed Central

    Neofytos, D.; Ostrander, D.; Shoham, S.; Laverdiere, M.; Hiemenz, J.; Nguyen, H.; Clark, W.; Brass, L.; Lu, N.; Marr, K.A.

    2015-01-01

    Background Voriconazole (VOR) levels are highly variable, with potential implications to both efficacy and safety. We hypothesized that VOR therapeutic drug monitoring (TDM) will decrease the incidence of treatment failures and adverse events (AEs). Methods We initiated a prospective, randomized, non-blinded multicenter study to compare clinical outcomes in adult patients randomized to standard dosing (clinician-driven) vs. TDM (doses adjusted based on levels). VOR trough levels were obtained on day 5, 14, 28, and 42 (or at completion of drug; ± 3 days). Real-time dose adjustments were made to maintain a range between 1–5 μg/mL on the TDM-arm, while levels were assessed retrospectively in the standard arm. Patient questionnaires were administered to assess subjective AEs. Results The study was discontinued prematurely, after 29 patients were enrolled. Seventeen (58.6%) patients experienced 38 AEs: visual changes (22/38, 57.9%), neurological symptoms (13/38, 34.2%), and liver abnormalities (3/38, 7.9%). VOR was discontinued in 7 (25%) patients because of an AE (4 standard-arm, 3 TDM-arm). VOR levels were frequently out of range in the standard-arm (8 tests >5 μg/mL; 9 tests < 1 μg/mL). Three dose changes occurred in the TDM-arm for VOR levels <1 μg/mL. Levels decreased over time in the standard-arm, with mean VOR levels lower at end of therapy compared to TDM (1.3 vs. 4.6 μg/mL, P = 0.008). Conclusions VOR TDM has become widespread clinical practice, based on known variability in drug levels, which impaired accrual in this study. Although comparative conclusions are limited, observations of variability and waning levels over time support TDM. PMID:26346408

  13. Multicenter, Phase 3 Trial Comparing Selenium Supplementation With Observation in Gynecologic Radiation Oncology

    SciTech Connect

    Muecke, Ralph; Schomburg, Lutz; Glatzel, Michael; Berndt-Skorka, Regina; Baaske, Dieter; Reichl, Berthold; Buentzel, Jens; Kundt, Guenter; Prott, Franz J.; Vries, Alexander de; Stoll, Guenther; Kisters, Klaus; Bruns, Frank; Schaefer, Ulrich; Willich, Norman; Micke, Oliver

    2010-11-01

    Purpose: We assessed whether adjuvant supplementation with selenium improves the selenium status and reduces side effects of patients treated by radiotherapy (RT) for cervical and uterine cancer. Methods and Materials: Whole-blood selenium concentrations were measured in patients with cervical cancer (n = 11) and uterine cancer (n = 70) after surgical treatment, during RT, at the end of RT, and 6 weeks after RT. Patients with initial selenium concentrations of less than 84{mu}g/L were randomized before RT either to receive 500 {mu}g of selenium (in the form of sodium selenite [selenase (registered) , biosyn Arzneimittel GmbH, Fellbach, Germany]) by mouth on the days of RT and 300 {mu}g of selenium on the days without RT or to receive no supplement during RT. The primary endpoint of this multicenter Phase 3 study was to assess the efficiency of selenium supplementation during RT; the secondary endpoint was to decrease radiation-induced diarrhea and other RT-dependent side effects. Results: A total of 81 patients were randomized. We enrolled 39 in the selenium group (SG) and 42 in the control group (CG). Selenium levels did not differ between the SG and CG upon study initiation but were significantly higher in the SG at the end of RT. The actuarial incidence of diarrhea of Grade 2 or higher according to Common Toxicity Criteria (version 2) in the SG was 20.5% compared with 44.5% in the CG (p = 0.04). Other blood parameters, Eastern Cooperative Oncology Group performance status, and self-reported quality of life were not different between the groups. Conclusions: Selenium supplementation during RT is effective in improving blood selenium status in selenium-deficient cervical and uterine cancer patients and reduces the number of episodes and severity of RT-induced diarrhea.

  14. A multicenter prospective trial evaluating fetal bovine dermal graft (Xenform® Matrix) for pelvic reconstructive surgery

    PubMed Central

    2010-01-01

    Background A prospective multicenter clinical study was performed to evaluate the safety and efficacy of a bovine dermal graft (Xenform® Matrix, Boston Scientific, Natick, MA, USA) during vaginal reconstructive surgery. Methods Forty-five women with ICS stage 2 or higher pelvic organ prolapse (POP) were enrolled at 4 centers. POP-Q, pelvic floor function (PFDI-20), sexual function (PISQ-12), and patient satisfaction tools were used to assess subjects at baseline, and at 2 and 6 weeks, and 3, 6 and 12 months post surgery. The significance of symptom score changes at 6 months and 1 year were determined by the t-test for paired data. Forty-three of the 45 patients completed the 12 month study. Results The majority of the subjects had cystocele (98%) and/or rectocele (84%) defects at study entry. At 12 months, 74% of the defects had improved to a stage 0 or 1. Mean PFDI-20 scores improved by 72% (p < 0.001) at 12 months, and PISQ-12 scores were maintained during the follow-up period indicating no decline in sexual function. Three subjects experienced one serious adverse event each; one of the adverse events (constipation) was deemed by the study physician to be unrelated to Xenform®. One subject had severe pyelonephritis resulting in dialysis. This subject had a previous history of pyelonephritis, sepsis and acute renal failure. The third subject had a reported recurrent cystocele of moderate severity, possibly related to the device. No graft related erosions or pain lasting more than 30 days were reported. No subjects withdrew due to an adverse event. Conclusion This study is the first to investigate the use of Xenform® Matrix in vaginal reconstructive surgery among patients with POP. Significant improvement was maintained at 12 months utilizing both objective and subjective assessment tools, confirming the safety and efficacy of this material in vaginal surgery. Trial Registration ClinicalTrials.gov NCT01244165 PMID:21144043

  15. Triiodothyronine Supplementation in Infants and Children Undergoing Cardiopulmonary Bypass (TRICC) A Multicenter Placebo-Controlled Randomized Trial: Age Analysis

    PubMed Central

    Portman, Michael A.; Slee, April; Olson, Aaron K.; Cohen, Gordon; Karl, Tom; Tong, Elizabeth; Hastings, Laura; Patel, Hitendra; Reinhartz, Olaf; Mott, Antonio R.; Mainwaring, Richard; Linam, Justin; Danzi, Sara

    2011-01-01

    Background Triiodothyronine levels decrease in infants and children after cardiopulmonary bypass. We tested the primary hypothesis that triiodothyronine (T3) repletion is safe in this population and produces improvements in postoperative clinical outcome. Methods and Results The TRICC study was a prospective, multicenter, double-blind, randomized, placebo-controlled trial in children younger than 2 years old undergoing heart surgery with cardiopulmonary bypass. Enrollment was stratified by surgical diagnosis. Time to extubation (TTE) was the primary outcome. Patients received intravenous T3 as Triostat (n=98) or placebo (n=95), and data were analyzed using Cox proportional hazards. Overall, TTE was similar between groups. There were no differences in adverse event rates, including arrhythmia. Prespecified analyses showed a significant interaction between age and treatment (P=0.0012). For patients younger than 5 months, the hazard ratio (chance of extubation) for Triostat was 1.72. (P=0.0216). Placebo median TTE was 98 hours with 95% confidence interval (CI) of 71 to 142 compared to Triostat TTE at 55 hours with CI of 44 to 92. TTE shortening corresponded to a reduction in inotropic agent use and improvement in cardiac function. For children 5 months of age, or older, Triostat produced a significant delay in median TTE: 16 hours (CI, 7–22) for placebo and 20 hours (CI, 16–45) for Triostat and (hazard ratio, 0.60; P=0.0220). Conclusions T3 supplementation is safe. Analyses using age stratification indicate that T3 supplementation provides clinical advantages in patients younger than 5 months and no benefit for those older than 5 months. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00027417. PMID:20837917

  16. QIN DAWG Validation of Gradient Nonlinearity Bias Correction Workflow for Quantitative Diffusion-Weighted Imaging in Multicenter Trials

    PubMed Central

    Malyarenko, Dariya I.; Wilmes, Lisa J.; Arlinghaus, Lori R.; Jacobs, Michael A.; Huang, Wei; Helmer, Karl G.; Taouli, Bachir; Yankeelov, Thomas E.; Newitt, David; Chenevert, Thomas L.

    2017-01-01

    Previous research has shown that system-dependent gradient nonlinearity (GNL) introduces a significant spatial bias (nonuniformity) in apparent diffusion coefficient (ADC) maps. Here, the feasibility of centralized retrospective system-specific correction of GNL bias for quantitative diffusion-weighted imaging (DWI) in multisite clinical trials is demonstrated across diverse scanners independent of the scanned object. Using corrector maps generated from system characterization by ice-water phantom measurement completed in the previous project phase, GNL bias correction was performed for test ADC measurements from an independent DWI phantom (room temperature agar) at two offset locations in the bore. The precomputed three-dimensional GNL correctors were retrospectively applied to test DWI scans by the central analysis site. The correction was blinded to reference DWI of the agar phantom at magnet isocenter where the GNL bias is negligible. The performance was evaluated from changes in ADC region of interest histogram statistics before and after correction with respect to the unbiased reference ADC values provided by sites. Both absolute error and nonuniformity of the ADC map induced by GNL (median, 12%; range, −35% to +10%) were substantially reduced by correction (7-fold in median and 3-fold in range). The residual ADC nonuniformity errors were attributed to measurement noise and other non-GNL sources. Correction of systematic GNL bias resulted in a 2-fold decrease in technical variability across scanners (down to site temperature range). The described validation of GNL bias correction marks progress toward implementation of this technology in multicenter trials that utilize quantitative DWI. PMID:28105469

  17. Effects of exercise dose and type on sleep quality in breast cancer patients receiving chemotherapy: a multicenter randomized trial.

    PubMed

    Courneya, Kerry S; Segal, Roanne J; Mackey, John R; Gelmon, Karen; Friedenreich, Christine M; Yasui, Yutaka; Reid, Robert D; Jespersen, Diana; Cook, Diane; Proulx, Carolyn; Trinh, Linda; Dolan, Lianne B; Wooding, Evyanne; Forbes, Cynthia C; McKenzie, Donald C

    2014-04-01

    To examine the effects of different doses and types of exercise on sleep quality in breast cancer patients receiving chemotherapy. A multicenter trial in Canada randomized 301 breast cancer patients between 2008 and 2011 to thrice weekly, supervised exercise during chemotherapy consisting of either a standard dose of 25-30 min of aerobic exercise (STAN; n = 96), a higher dose of 50-60 min of aerobic exercise (HIGH; n = 101), or a combined dose of 50-60 min of aerobic and resistance exercise (COMB; n = 104). The secondary sleep outcomes in the trial were assessed by the Pittsburgh Sleep Quality Index (PSQI) at baseline, twice during chemotherapy, and postchemotherapy. We analyzed the global PSQI and the component scores. Repeated measures analyses of variance indicated that the HIGH group was statistically superior to the STAN group for global sleep quality (mean group difference = -0.90; 95 % CI -0.05 to -1.76; p = 0.039) as well as subjective sleep quality (p = 0.028) and sleep latency (p = 0.049). The COMB group was borderline statistically superior to the STAN group for global sleep quality (mean group difference = -0.76; 95 % CI +0.11 to -1.62; p = 0.085) as well as sleep duration (p = 0.051); and statistically superior for sleep efficiency (p = 0.040), and percentage of poor sleepers (p = 0.045). Compared to a standard volume of aerobic exercise, higher volumes of both aerobic and combined exercise improved some aspects of sleep quality during breast cancer chemotherapy. Exercise may be an attractive option to manage sleep dysfunction in cancer patients during chemotherapy.

  18. Design and rationale of the PRAGUE-12 trial: a large, prospective, randomized, multicenter trial that compares cardiac surgery with left atrial surgical ablation with cardiac surgery without ablation in patients with coronary and/or valvular heart disease plus atrial fibrillation.

    PubMed

    Straka, Zbyněk; Budera, Petr; Osmančík, Pavel; Vaněk, Tomáš; Hulman, Michal; Smíd, Michal; Malý, Marek; Widimský, Petr

    2013-01-01

    Surgical ablation procedure can restore sinus rhythm (SR) in patients with atrial fibrillation (AF) undergoing cardiac surgery. However, it is not known whether it has any impact on clinical outcomes. There is a need for a randomized trial with long-term follow-up to study the outcome of surgical ablation in patients with coronary and/or valve disease and AF. Patients are prospectively enrolled and randomized either to group A (cardiac surgery with left atrial ablation) or group B (cardiac surgery alone). The primary efficacy outcome is the SR presence (without any AF episode) during a 24-hour electrocardiogram after 1 year. The primary safety outcome is the combined end point of death, myocardial infarction, stroke, and renal failure at 30 days. Long-term outcomes are a composite of total mortality, stroke, bleeding, and heart failure at 1 and 5 years. We finished the enrollment with a total of 224 patients from 3 centers in 2 countries in December 2011. Currently, the incomplete 1-year data are available, and the patients who enrolled first will have their 5-year visits shortly. PRAGUE-12 is the largest study to be conducted so far comparing cardiac surgery with surgical ablation of AF to cardiac surgery without ablation in an unselected population of patients who are operated on for coronary and/or valve disease. Its long-term results will lead to a better recognition of ablation's potential clinical benefits.

  19. Clinical Trial Design in Neuroendocrine Tumors.

    PubMed

    Halperin, Daniel M; Yao, James C

    2016-02-01

    Neuroendocrine tumors (NETs) present tremendous opportunities for productive clinical investigation, but substantial challenges as well. Investigators must be aware of common pitfalls in study design, informed by an understanding of the history of trials in the field, to make the best use of available data and our patient volunteers. We believe the salient issues in clinical trial design and interpretation in the NET field are patient homogeneity, standardized response assessment, and rigorous design and execution. Whether designing or interpreting a study in patients with NET, these principles should drive assessment.

  20. BST-CarGel® Treatment Maintains Cartilage Repair Superiority over Microfracture at 5 Years in a Multicenter Randomized Controlled Trial

    PubMed Central

    Stanish, William D.; McCormack, Robert; Forriol, Francisco; Mohtadi, Nicholas; Pelet, Stéphane; Desnoyers, Jacques; Méthot, Stéphane; Vehik, Kendra; Restrepo, Alberto

    2015-01-01

    Objective The efficacy and safety of BST-CarGel®, a chitosan scaffold for cartilage repair was compared with microfracture alone at 1 year during a multicenter randomized controlled trial in the knee. This report was undertaken to investigate 5-year structural and clinical outcomes. Design The international randomized controlled trial enrolled 80 patients, aged 18 to 55 years, with grade III or IV focal lesions on the femoral condyles. Patients were randomized to receive BST-CarGel® treatment or microfracture alone, and followed standardized 12-week rehabilitation. Co-primary endpoints of repair tissue quantity and quality were evaluated by 3-dimensional MRI quantification of the degree of lesion filling (%) and T2 relaxation times. Secondary endpoints were clinical benefit measured with WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) questionnaires and safety. General estimating equations were used for longitudinal statistical analysis of repeated measures. Results Blinded MRI analysis demonstrated that BST-CarGel®-treated patients showed a significantly greater treatment effect for lesion filling (P = 0.017) over 5 years compared with microfracture alone. A significantly greater treatment effect for BST-CarGel® was also found for repair tissue T2 relaxation times (P = 0.026), which were closer to native cartilage compared to the microfracture group. BST-CarGel® and microfracture groups showed highly significant improvement at 5 years from pretreatment baseline for each WOMAC subscale (P < 0.0001), and there were no differences between the treatment groups. Safety was comparable for both groups. Conclusions BST-CarGel® was shown to be an effective mid-term cartilage repair treatment. At 5 years, BST-CarGel® treatment resulted in sustained and significantly superior repair tissue quantity and quality over microfracture alone. Clinical benefit following BST-CarGel® and microfracture treatment were highly significant over baseline

  1. A single-arm phase II Austrian/German multicenter trial on continuous daily sunitinib in primary glioblastoma at first recurrence (SURGE 01-07)

    PubMed Central

    Hutterer, Markus; Nowosielski, Martha; Haybaeck, Johannes; Embacher, Sabine; Stockhammer, Florian; Gotwald, Thaddäus; Holzner, Bernhard; Capper, David; Preusser, Matthias; Marosi, Christine; Oberndorfer, Stefan; Moik, Martin; Buchroithner, Johanna; Seiz, Marcel; Tuettenberg, Jochen; Herrlinger, Ulrich; Wick, Antje; Vajkoczy, Peter; Stockhammer, Günther

    2014-01-01

    Background Due to the redundancy of molecular pathways simultaneously involved in glioblastoma growth and angiogenesis, therapeutic approaches intervening at multiple levels seem particularly appealing. Methods This prospective, multicenter, single-arm phase II trial was designed to evaluate the antitumor activity of sunitinib, an oral small-molecule inhibitor of several receptor tyrosine kinases, in patients with first recurrence of primary glioblastoma using a continuous once-daily dosing regimen. Patients received a starting dose of sunitinib 37.5 mg, followed by a maintenance dose between 12.5 mg and 50 mg depending on drug tolerability. The primary endpoint was a 6-month progression-free survival (PFS) rate. Secondary endpoints included median PFS, overall survival (OS), safety/toxicity, quality of life, and translational studies on the expression of sunitinib target molecules. Results Forty participants were included in this study, and no objective responses were detected. PFS6 was 12.5%, median PFS 2.2 months, and median OS 9.2 months. Five participants (12.5%) showed prolonged stable disease ≥6 months with a median PFS of 16.0 months (range, 6.4–41.4 mo) and a median OS of 46.9 months (range, 21.2–49.2 mo) for this subgroup. c-KIT expression in vascular endothelial cells (n = 14 participants) was associated with improved PFS. The most common toxicities were fatigue/asthenia, mucositis/dermatitis, dysesthesias, gastrointestinal symptoms, cognitive impairment, leukoctopenia, and thrombocytopenia. Two participants (5%) terminated treatment due to toxicity. Conclusion Continuous daily sunitinib showed minimal antiglioblastoma activity and substantial toxicity when given at higher doses. High endothelial c-KIT expression may define a subgroup of patients who will benefit from sunitinib treatment by achieving prolonged PFS. ClinicalTrials.gov Identifier: NCT00535379. PMID:24311637

  2. Comparison of academic and nonacademic sites in multi-center clinical trials.

    PubMed

    Dording, Christina M; Dalton, Elizabeth D; Pencina, Michael J; Fava, Maurizio; Mischoulon, David

    2012-02-01

    The selection of appropriate subjects is a critical element of successful clinical trials. Failure to properly identify, select, and retain subjects in clinical trials of antidepressant medications may affect the ability to show separation from placebo. Little is known about which type of site, academic or nonacademic, is superior in selecting and retaining appropriate subjects. In the present investigation, the authors conducted a retrospective analysis comparing the performance of academic and nonacademic sites in selecting and retaining appropriate subjects in a recently completed multi-site clinical study of aripiprazole augmentation. The authors used a set of operationalized criteria called the SAFER to identify appropriate study subjects. No significant differences were found in rates of SAFER interview passing, study completion, and clinical outcomes between academic and nonacademic sites. Our findings suggest that academic and nonacademic sites are equally effective in their ability to identify and retain appropriate study participants.

  3. Build Better Bones With Exercise: Protocol for a Feasibility Study of a Multicenter Randomized Controlled Trial of 12 Months of Home Exercise in Women With a Vertebral Fracture

    PubMed Central

    Thabane, Lehana; Adachi, Jonathan D.; Ashe, Maureen C.; Bleakney, Robert R.; Braun, E. Anne; Cheung, Angela M.; Fraser, Lisa-Ann; Gibbs, Jenna C.; Hill, Keith D.; Hodsman, Anthony B.; Kendler, David L.; Mittmann, Nicole; Prasad, Sadhana; Scherer, Samuel C.; Wark, John D.; Papaioannou, Alexandra

    2014-01-01

    Background Our goal is to conduct a multicenter randomized controlled trial (RCT) to investigate whether exercise can reduce incident fractures compared with no intervention among women aged ≥65 years with a vertebral fracture. Objectives This pilot study will determine the feasibility of recruitment, retention, and adherence for the proposed trial. Design The proposed RCT will be a pilot feasibility study with 1:1 randomization to exercise or attentional control groups. Setting Five Canadian sites (1 community hospital partnered with an academic center and 4 academic hospitals or centers affiliated with an academic center) and 2 Australian centers (1 academic hospital and 1 center for community primary care, geriatric, and rehabilitation services). Participants One hundred sixty women aged ≥65 years with vertebral fracture at 5 Canadian and 2 Australian centers will be recruited. Intervention The Build Better Bones With Exercise (B3E) intervention includes exercise and behavioral counseling, delivered by a physical therapist in 6 home visits over 8 months, and monthly calls; participants are to exercise ≥3 times weekly. Controls will receive equal attention. Measurements Primary outcomes will include recruitment, retention, and adherence. Adherence to exercise will be assessed via calendar diary. Secondary outcomes will include physical function (lower extremity strength, mobility, and balance), posture, and falls. Additional secondary outcomes will include quality of life, pain, fall self-efficacy, behavior change variables, intervention cost, fractures, and adverse events. Analyses of feasibility objectives will be descriptive or based on estimates with 95% confidence intervals, where feasibility will be assessed relative to a priori criteria. Differences in secondary outcomes will be evaluated in intention-to-treat analyses via independent Student t tests, chi-square tests, or logistic regression. The Bonferroni method will be used to adjust the level of

  4. Reasons for non-participation in an international multicenter trial of a new drug for tuberculosis treatment

    PubMed Central

    Lamunu, D.; Chapman, K. N.; Nsubuga, P.; Muzanyi, G.; Mulumba, Y.; Mugerwa, M. A.; Goldberg, S.; Bozeman, L.; Engle, M.; Saukkonen, J.; Mastranunzio, S.; Mayanja-Kizza, H.; Johnson, J. L.

    2016-01-01

    SUMMARY SETTING Clinical trials can provide a high standard of patient care and contribute to scientific knowledge; however, only a fraction of the patients screened participate and receive treatment as part of a trial. OBJECTIVE To explore reasons why patients were not enrolled in an international tuberculosis (TB) treatment trial and to compare experiences among study sites. DESIGN An analysis of reasons why patients were not enrolled was conducted among patients screened for a TB clinical trial at 26 sites in North and South America, Africa, and Europe. RESULTS Staff at study sites screened 1119 potential candidates for the trial: 61% (n = 686) were not enrolled due to 1) failure to meet eligibility criteria (n = 405, 59%), 2) site’s decision (n = 168, 24%), or 3) candidate’s choice (n = 113, 16%). Study staff recorded a total of 144 reasons for why they believed patients chose not to participate, including concerns over research (28%), conflicts with work or school (21%), and lifestyle and family issues (20%). Socio-demographic and geographic factors also influenced participation. CONCLUSION Increased evaluation of screening outcomes and of specific interventions, such as improved education and communication about trial procedures, may increase the efficiency of screening and enrollment in clinical trials. PMID:22640513

  5. Treatment of Acute Coronary Syndrome by Telemedically Supported Paramedics Compared With Physician-Based Treatment: A Prospective, Interventional, Multicenter Trial

    PubMed Central

    Brokmann, Jörg C; Conrad, Clemens; Rossaint, Rolf; Bergrath, Sebastian; Beckers, Stefan K; Tamm, Miriam; Czaplik, Michael

    2016-01-01

    Background Prehospital treatment of acute coronary syndrome (ACS) in German emergency medical services (EMSs) is reserved for EMS physicians due to legal issues. Objective The objective of this prospective, interventional, multicenter trial was to evaluate the quality of telemedically-delegated therapy and the possible complications in patients with ACS. Methods After approval by the ethics committee and trial registration, a one-year study phase was started in August 2012 with 5 ambulances, telemedically equipped and staffed with paramedics, in 4 German EMS districts. The paramedics could contact an EMS-physician–staffed telemedicine center. After initiation of an audio connection, real-time data transmission was automatically established. If required, 12-lead electrocardiogram (ECG) and still pictures could be sent. Video was streamed from inside each ambulance. All drugs, including opioids, were delegated to the paramedics based on standardized, predefined algorithms. To compare telemedically-delegated medication and treatment in ACS cases with regular EMS missions, a matched pair analysis with historical controls was performed. Results Teleconsultation was performed on 150 patients having a cardiovascular emergency. In 39 cases, teleconsultation was started due to suspected ACS. No case had a medical complication. Correct handling of 12-lead ECG was performed equally between the groups (study group, n=38 vs control group, n=39, P>.99). There were no differences in correct handling of intravenous administration of acetylsalicylic acid, heparin, or morphine between both the groups (study group vs control group): acetylsalicylic acid, n=31 vs n=33, P=.73; unfractionated heparin, n=34 vs n=33, P>.99; morphine, n=29 vs n=27, P=.50. The correct handling of oxygen administration was significantly higher in the study group (n=29 vs n=18, P=.007). Conclusions Telemedical delegation of guideline conform medication and therapy by paramedics in patients with ACS and was

  6. Electronic data capture and DICOM data management in multi-center clinical trials

    NASA Astrophysics Data System (ADS)

    Haak, Daniel; Page, Charles-E.; Deserno, Thomas M.

    2016-03-01

    Providing eligibility, efficacy and security evaluation by quantitative and qualitative disease findings, medical imaging has become increasingly important in clinical trials. Here, subject's data is today captured in electronic case reports forms (eCRFs), which are offered by electronic data capture (EDC) systems. However, integration of subject's medical image data into eCRFs is insufficiently supported. Neither integration of subject's digital imaging and communications in medicine (DICOM) data, nor communication with picture archiving and communication systems (PACS), is possible. This aggravates the workflow of the study personnel, in special regarding studies with distributed data capture in multiple sites. Hence, in this work, a system architecture is presented, which connects an EDC system, a PACS and a DICOM viewer via the web access to DICOM objects (WADO) protocol. The architecture is implemented using the open source tools OpenClinica, DCM4CHEE and Weasis. The eCRF forms the primary endpoint for the study personnel, where subject's image data is stored and retrieved. Background communication with the PACS is completely hidden for the users. Data privacy and consistency is ensured by automatic de-identification and re-labelling of DICOM data with context information (e.g. study and subject identifiers), respectively. The system is exemplarily demonstrated in a clinical trial, where computer tomography (CT) data is de-centrally captured from the subjects and centrally read by a chief radiologists to decide on inclusion of the subjects in the trial. Errors, latency and costs in the EDC workflow are reduced, while, a research database is implicitly built up in the background.

  7. Spinal cord stimulation for predominant low back pain in failed back surgery syndrome: study protocol for an international multicenter randomized controlled trial (PROMISE study)

    PubMed Central

    2013-01-01

    Background Although results of case series support the use of spinal cord stimulation in failed back surgery syndrome patients with predominant low back pain, no confirmatory randomized controlled trial has been undertaken in this patient group to date. PROMISE is a multicenter, prospective, randomized, open-label, parallel-group study designed to compare the clinical effectiveness of spinal cord stimulation plus optimal medical management with optimal medical management alone in patients with failed back surgery syndrome and predominant low back pain. Method/Design Patients will be recruited in approximately 30 centers across Canada, Europe, and the United States. Eligible patients with low back pain exceeding leg pain and an average Numeric Pain Rating Scale score ≥5 for low back pain will be randomized 1:1 to spinal cord stimulation plus optimal medical management or to optimal medical management alone. The investigators will tailor individual optimal medical management treatment plans to their patients. Excluded from study treatments are intrathecal drug delivery, peripheral nerve stimulation, back surgery related to the original back pain complaint, and experimental therapies. Patients randomized to the spinal cord stimulation group will undergo trial stimulation, and if they achieve adequate low back pain relief a neurostimulation system using the Specify® 5-6-5 multi-column lead (Medtronic Inc., Minneapolis, MN, USA) will be implanted to capture low back pain preferentially in these patients. Outcome assessment will occur at baseline (pre-randomization) and at 1, 3, 6, 9, 12, 18, and 24 months post randomization. After the 6-month visit, patients can change treatment to that received by the other randomized group. The primary outcome is the proportion of patients with ≥50% reduction in low back pain at the 6-month visit. Additional outcomes include changes in low back and leg pain, functional disability, health-related quality of life, return to work

  8. Randomized controlled trials - a matter of design.

    PubMed

    Spieth, Peter Markus; Kubasch, Anne Sophie; Penzlin, Ana Isabel; Illigens, Ben Min-Woo; Barlinn, Kristian; Siepmann, Timo

    2016-01-01

    Randomized controlled trials (RCTs) are the hallmark of evidence-based medicine and form the basis for translating research data into clinical practice. This review summarizes commonly applied designs and quality indicators of RCTs to provide guidance in interpreting and critically evaluating clinical research data. It further reflects on the principle of equipoise and its practical applicability to clinical science with an emphasis on critical care and neurological research. We performed a review of educational material, review articles, methodological studies, and published clinical trials using the databases MEDLINE, PubMed, and ClinicalTrials.gov. The most relevant recommendations regarding design, conduction, and reporting of RCTs may include the following: 1) clinically relevant end points should be defined a priori, and an unbiased analysis and report of the study results should be warranted, 2) both significant and nonsignificant results should be objectively reported and published, 3) structured study design and performance as indicated in the Consolidated Standards of Reporting Trials statement should be employed as well as registration in a public trial database, 4) potential conflicts of interest and funding sources should be disclaimed in study report or publication, and 5) in the comparison of experimental treatment with standard care, preplanned interim analyses during an ongoing RCT can aid in maintaining clinical equipoise by assessing benefit, harm, or futility, thus allowing decision on continuation or termination of the trial.

  9. Morphologic assessment for glaucoma in the Multicenter Uveitis Steroid Treatment (MUST) Trial

    PubMed Central

    Gangaputra, Sapna; Altaweel, Michael M.; Peng, Qian; Friedman, David S.; Rao, P. Kumar; Foster, C. Stephen; Kim, Rosa Y.; Reed, Susan B.; Srivastava, Sunil K.; Wong, Ira G.; Kempen, John H.

    2013-01-01

    Purpose To compare Reading Center (RC) cup-to-disc ratio (CDR) assessment from stereoscopic photographs with clinician estimation in a uveitis clinical trial. Methods Clinical estimation of CDR was performed by ophthalmologists via dilated biomicroscopy. Photographic evaluation was performed at an independent RC by masked, certified evaluators. Quality control was performed by repeat grading of 77 randomly selected images. Results Among 481 eyes with uveitis, 353 eyes had clinical and photographic grades for CDR. Agreement between clinical and RC grading was fair, with exact agreement in 29%. Agreement within 0.1 and 0.2 CDR were 70% and 93%, respectively (wkappa=0.34). Inter-grader reproducibility at the RC was better (wkappa=0.59, ICC 0.74). Conclusion Morphologic assessment of cup to disc ratio is an important outcome and safety measure for determining glaucomatous damage in clinical trials. Masked RC measurements are more likely to be accurate than biomicroscopic grading in identifying meaningful anatomical change associated with glaucoma. PMID:21770805

  10. Costs of Home Versus Inpatient Treatment for Fever and Neutropenia: Analysis of a Multicenter Randomized Trial

    PubMed Central

    Hendricks, Ann M.; Loggers, Elizabeth Trice; Talcott, James A.

    2011-01-01

    Purpose For patients with cancer who have febrile neutropenia, relative costs of home versus hospital treatment, including unreimbursed costs borne by patients and families, are poorly characterized. We estimated costs from a randomized trial of patients with low-risk febrile neutropenia for whom outpatient care was feasible, comparing inpatient treatment with discharge to home care after inpatient observation. Methods We collected direct medical and self-reported indirect costs for 57 inpatient and 35 outpatient treatment episodes of patients enrolled in a randomized trial from 1996 through 2000. Charges from hospital bills were converted to costs using Medicare cost-to-charge ratios. Patients kept daily logs of out-of-pocket payments and time spent by informal caregivers providing care. Dollar amounts were standardized to June 2008. Results Mean total charges for the hospital arm were 49% higher than for the home treatment arm ($16,341 v $10,977; P < .01). Mean estimated total costs for the hospital arm were 30% higher ($10,143 v $7,830; P < .01). Inspection of sparse available data suggests that payments made were similar by treatment arm. Inpatients and their caregivers spent more out of pocket than their outpatient counterparts (mean, $201 v $74; P < .01). Informal caregivers for both treatment arms reported similar time caring and lost from work. Conclusion Home intravenous antibiotic treatment was less costly than continued inpatient care for carefully selected patients with cancer having febrile neutropenia without significantly increased indirect costs or caregiver burden. PMID:21931037

  11. Results from a multicenter prostate IMRT dosimetry intercomparison for an OCOG-TROG clinical trial

    SciTech Connect

    Healy, B.; Frantzis, J.; Murry, R.; Martin, J.; Plank, A.; Middleton, M.; Catton, C.; Kron, T.

    2013-07-15

    Purpose: A multi-institution dosimetry intercomparison has been undertaken of prostate intensity modulated radiation therapy (IMRT) delivery. The dosimetry intercomparison was incorporated into the quality assurance for site credentialing for the Trans-Tasman Radiation Oncology Group Prostate Fractionated Irradiation Trial 08.01 clinical trial.Methods: An anthropomorphic pelvic phantom with realistic anatomy was used along with multiplanar dosimetry tools for the assessment. Nineteen centers across Australia and New Zealand participated in the study.Results: In comparing planned versus measured dose to the target at the isocenter within the phantom, all centers were able to achieve a total delivered dose within 3% of planned dose. In multiplanar analysis with radiochromic film using the gamma analysis method to compare delivered and planned dose, pass rates for a 5%/3 mm criterion were better than 90% for a coronal slice through the isocenter. Pass rates for an off-axis coronal slice were also better than 90% except for one instance with 84% pass rate.Conclusions: Strengths of the dosimetry assessment procedure included the true anthropomorphic nature of the phantom used, the involvement of an expert from the reference center in carrying out the assessment at every site, and the ability of the assessment to detect and resolve dosimetry discrepancies.

  12. Optical Coherence Tomography Evaluation in the Multicenter Uveitis Steroid Treatment (MUST) Trial

    PubMed Central

    Domalpally, Amitha; Altaweel, Michael M.; Kempen, John H.; Myers, Dawn; Davis, Janet L; Foster, C Stephen; Latkany, Paul; Srivastava, Sunil K.; Stawell, Richard J.; Holbrook, Janet T.

    2013-01-01

    Purpose To describe the evaluation of optical coherence tomography (OCT) scans in the Muliticenter Uveitis Steroid Treatment (MUST) trial and report baseline OCT features of enrolled participants. Methods Time domain OCTs acquired by certified photographers using a standardized scan protocol were evaluated at a Reading Center. Accuracy of retinal thickness data was confirmed with quality evaluation and caliper measurement of centerpoint thickness (CPT) was performed when unreliable. Morphological evaluation included cysts, subretinal fluid,epiretinal membranes (ERMs),and vitreomacular traction. Results Of the 453 OCTs evaluated, automated retinal thickness was accurate in 69.5% of scans, caliper measurement was performed in 26%,and 4% were ungradable. Intraclass correlation was 0.98 for reproducibility of caliper measurement. Macular edema (centerpoint thickness ≥ 240um) was present in 36%. Cysts were present in 36.6% of scans and ERMs in 27.8%, predominantly central. Intergrader agreement ranged from 78 − 82% for morphological features. Conclusion Retinal thickness data can be retrieved in a majority of OCT scans in clinical trial submissions for uveitis studies. Small cysts and ERMs involving the center are common in intermediate and posterior/panuveitis requiring systemic corticosteroid therapy. PMID:23163490

  13. Irreversible Electroporation (IRE) Fails to Demonstrate Efficacy in a Prospective Multicenter Phase II Trial on Lung Malignancies: The ALICE Trial

    SciTech Connect

    Ricke, Jens Jürgens, Julian H. W.; Deschamps, Frederic; Tselikas, Lambros; Uhde, Katja; Kosiek, Ortrud; Baere, Thierry De

    2015-04-15

    PurposeTo assess safety and efficacy of irreversible electroporation (IRE) of lung malignancies.Materials and MethodsPatients with primary and secondary lung malignancies and preserved lung function were included in this prospective single arm trial. Primary and secondary endpoints were safety and efficacy. Recruitment goal was 36 subjects in 2 centers. Patients underwent IRE under general anesthesia with probe placement performed in Fluoroscopy-CT. The IRE system employed was NanoKnife{sup ®} (Angiodynamics). System settings for the ablation procedure followed the manufacturer’s recommendations. The Mann–Whitney U test was used to evaluate the correlation of nine technical parameters with local tumor control. Median follow up was 12 months.ResultsThe expected efficacy was not met at interim analysis and the trial was stopped prematurely after inclusion of 23 patients (13/10 between both centers). The dominant tumor entity was colorectal (n = 13). The median tumor diameter was 16 mm (8–27 mm). Pneumothoraces were observed in 11 of 23 patients with chest tubes required in 8 (35 %). Frequently observed alveolar hemorrhage never led to significant hemoptysis. 14/23 showed progressive disease (61 %). Stable disease was found in 1 (4 %), partial remission in 1 (4 %) and complete remission in 7 (30 %) patients. The relative increase of the current during ablation was significantly higher in the group treated successfully as compared to the group presenting local recurrence (p < 0.05). Needle tract seeding was found in three cases (13 %).ConclusionsIRE is not effective for the treatment of lung malignancies. We hypothesize that the energy deposition with current IRE probes is highly sensitive to air exposure.

  14. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial.

    PubMed

    Fermand, J P; Ravaud, P; Chevret, S; Divine, M; Leblond, V; Belanger, C; Macro, M; Pertuiset, E; Dreyfus, F; Mariette, X; Boccacio, C; Brouet, J C

    1998-11-01

    Results to date indicate that high-dose therapy (HDT) with autologous stem cell support improves survival of patients with symptomatic multiple myeloma (MM). We performed a multicenter, sequential, randomized trial designed to assess the optimal timing of HDT and autotransplantation. Among 202 enrolled patients who were up to 56 years old, 185 were randomly assigned to receive HDT and peripheral blood stem cell (PBSC) autotransplantation (early HDT group, n = 91) or a conventional-dose chemotherapy (CCT) regimen (late HDT group, n = 94). In the late HDT group, HDT and transplantation were performed as rescue treament, in case of primary resistance to CCT or at relapse in responders. PBSC were collected before randomization, after mobilization by chemotherapy, and, in the two groups, HDT was preceded by three or four treatments with vincristine, doxorubicin, and methylprednisolone. Data were analyzed on an intent-to-treat basis using a sequential design. Within a median follow-up of 58 months, estimated median overall survival (OS) was 64.6 months in the early HDT group and 64 months in the late group. Survival curves were not different (P = .92, log-rank test). Median event-free survival (EFS) was 39 months in the early HDT group whereas median time between randomization and CCT failure was 13 months in the late group. Average time without symptoms, treatment, and treatment toxicity (TWiSTT) were 27.8 months (95% confidence interval [CI]; range, 23.8 to 31.8) and 22.3 months (range, 16.0 to 28.6) in the two groups, respectively. HDT with PBSC transplantation obtained a median OS exceeding 5 years in young patients with symptomatic MM, whether performed early, as first-line therapy, or late, as rescue treatment. Early HDT may be preferred because it is associated with a shorter period of chemotherapy.

  15. Multicenter Randomized Controlled Trial on Duration of Therapy for Thrombosis in Children and Young Adults (Kids-DOTT): Pilot/Feasibility Phase Findings

    PubMed Central

    Goldenberg, N.A.; Abshire, T.; Blatchford, P.J.; Fenton, L.Z.; Halperin, J.L.; Hiatt, W.R.; Kessler, C.M.; Kittelson, J.M.; Manco-Johnson, M.J.; Spyropoulos, A.C.; Steg, P.G.; Stence, N.V.; Turpie, A.G.G.; Schulman, S.

    2015-01-01

    BACKGROUND Randomized controlled trials (RCTs) in pediatric venous thromboembolism (VTE) treatment have been challenged by unsubstantiated design assumptions and/or poor accrual. Pilot/feasibility (P/F) studies are critical to future RCT success. METHODS Kids-DOTT is a multicenter RCT investigating non-inferiority of a 6-week (shortened) vs. 3-month (conventional) duration of anticoagulation in patients <21 years old with provoked venous thrombosis. Primary efficacy and safety endpoints are symptomatic recurrent VTE at 1 year and anticoagulant-related, clinically-relevant bleeding. In the P/F phase, 100 participants were enrolled in an open, blinded endpoint, parallel-cohort RCT design. RESULTS No eligibility violations or randomization errors occurred. Of enrolled patients, 69% were randomized, 3% missed the randomization window, and 28% were followed in pre-specified observational cohorts for completely occlusive thrombosis or persistent antiphospholipid antibodies. Retention at 1 year was 82%. Inter-observer agreement between local vs. blinded central determination of venous occlusion by imaging at 6 weeks post-diagnosis was strong (κ-statistic=0.75; 95% confidence interval [CI] 0.48–1.0). Primary efficacy and safety event rates were 3.3% (95% CI 0.3–11.5%) and 1.4% (0.03–7.4%). CONCLUSIONS The P/F phase of Kids-DOTT has demonstrated validity of vascular imaging findings of occlusion as a randomization criterion, and defined randomization, retention, and endpoint rates to inform the fully-powered RCT. PMID:26118944

  16. Prevention of Recurrent Foot Ulcers With Plantar Pressure–Based In-Shoe Orthoses: The CareFUL Prevention Multicenter Randomized Controlled Trial

    PubMed Central

    Ulbrecht, Jan S.; Hurley, Timothy; Mauger, David T.

    2014-01-01

    OBJECTIVE To assess the efficacy of in-shoe orthoses that were designed based on shape and barefoot plantar pressure in reducing the incidence of submetatarsal head plantar ulcers in people with diabetes, peripheral neuropathy, and a history of similar prior ulceration. RESEARCH DESIGN AND METHODS Single-blinded multicenter randomized controlled trial with subjects randomized to wear shape- and pressure-based orthoses (experimental, n = 66) or standard-of-care A5513 orthoses (control, n = 64). Patients were followed for 15 months, until a study end point (forefoot plantar ulcer or nonulcerative plantar forefoot lesion) or to study termination. Proportional hazards regression was used for analysis. RESULTS There was a trend in the composite primary end point (both ulcers and nonulcerative lesions) across the full follow-up period (P = 0.13) in favor of the experimental orthoses. This trend was due to a marked difference in ulcer occurrence (P = 0.007) but no difference in the rate of nonulcerative lesions (P = 0.76). At 180 days, the ulcer prevention effect of the experimental orthoses was already significant (P = 0.003) when compared with control, and the benefit of the experimental orthoses with respect to the composite end point was also significant (P = 0.042). The hazard ratio was 3.4 (95% CI 1.3–8.7) for the occurrence of a submetatarsal head plantar ulcer in the control compared with experimental arm over the duration of the study. CONCLUSIONS We conclude that shape- and barefoot plantar pressure–based orthoses were more effective in reducing submetatarsal head plantar ulcer recurrence than current standard-of-care orthoses, but they did not significantly reduce nonulcerative lesions. PMID:24760263

  17. Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial

    PubMed Central

    Levkovitz, Yechiel; Isserles, Moshe; Padberg, Frank; Lisanby, Sarah H; Bystritsky, Alexander; Xia, Guohua; Tendler, Aron; Daskalakis, Zafiris J; Winston, Jaron L; Dannon, Pinhas; Hafez, Hisham M; Reti, Irving M; Morales, Oscar G; Schlaepfer, Thomas E; Hollander, Eric; Berman, Joshua A; Husain, Mustafa M; Sofer, Uzi; Stein, Ahava; Adler, Shmulik; Deutsch, Lisa; Deutsch, Frederic; Roth, Yiftach; George, Mark S; Zangen, Abraham

    2015-01-01

    Major depressive disorder (MDD) is a prevalent and disabling condition, and many patients do not respond to available treatments. Deep transcranial magnetic stimulation (dTMS) is a new technology allowing non-surgical stimulation of relatively deep brain areas. This is the first double-blind randomized controlled multicenter study evaluating the efficacy and safety of dTMS in MDD. We recruited 212 MDD outpatients, aged 22–68 years, who had either failed one to four antidepressant trials or not tolerated at least two antidepressant treatments during the current episode. They were randomly assigned to monotherapy with active or sham dTMS. Twenty sessions of dTMS (18 Hz over the prefrontal cortex) were applied during 4 weeks acutely, and then biweekly for 12 weeks. Primary and secondary efficacy endpoints were the change in the Hamilton Depression Rating Scale (HDRS-21) score and response/remission rates at week 5, respectively. dTMS induced a 6.39 point improvement in HDRS-21 scores, while a 3.28 point improvement was observed in the sham group (p+0.008), resulting in a 0.76 effect size. Response and remission rates were higher in the dTMS than in the sham group (response: 38.4 vs. 21.4%, p+0.013; remission: 32.6 vs. 14.6%, p+0.005). These differences between active and sham treatment were stable during the 12-week maintenance phase. dTMS was associated with few and minor side effects apart from one seizure in a patient where a protocol violation occurred. These results suggest that dTMS constitutes a novel intervention in MDD, which is efficacious and safe in patients not responding to antidepressant medications, and whose effect remains stable over 3 months of maintenance treatment. PMID:25655160

  18. A randomized, controlled, multicenter contraceptive efficacy clinical trial of the intravas device, a nonocclusive surgical male sterilization

    PubMed Central

    Lu, Wen-Hong; Liang, Xiao-Wei; Gu, Yi-Qun; Wu, Wei-Xiong; Bo, Li-Wei; Zheng, Tian-Gui; Chen, Zhen-Wen

    2014-01-01

    Because of unavoidable complications of vasectomy, this study was undertaken to assess the efficacy and safety of male sterilization with a nonobstructive intravas device (IVD) implanted into the vas lumen by a mini-surgical method compared with no-scalpel vasectomy (NSV). IVDs were categorized into two types: IVD-B has a tail used for fixing to the vas deferens (fixed wing) whereas IVD-A does not. A multicenter prospective randomized controlled clinical trial was conducted in China. The study was comprised of 1459 male volunteers seeking vasectomy who were randomly assigned to the IVD-A (n = 487), IVD-B (n = 485) or NSV (n = 487) groups and underwent operation. Follow-up included visits at the 3rd–6th and 12th postoperative months. The assessments of the subjects involved regular physical examinations (including general and andrological examinations) and semen analysis. The subjects’ partners also underwent monitoring for pregnancy by monthly interviews regarding menstruation and if necessary, urine tests. There were no significant differences in pregnancy rates (0.65% for IVD-A, 0 for IVD-B and 0.21% for NSV) among the three groups (P > 0.05). The cumulative rates of complications at the 12th postoperative month were zero, 0.9% and 1.7% in the three groups, respectively. In conclusion, IVD male sterilization exhibits a low risk of long-term adverse events and was found to be effective as a male sterilization method, similar to the NSV technique. IVD male sterilization is expected to be a novel contraceptive method. PMID:24589454

  19. A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children.

    PubMed

    Brousseau, David C; Scott, J Paul; Badaki-Makun, Oluwakemi; Darbari, Deepika S; Chumpitazi, Corrie E; Airewele, Gladstone E; Ellison, Angela M; Smith-Whitley, Kim; Mahajan, Prashant; Sarnaik, Sharada A; Casper, T Charles; Cook, Lawrence J; Dean, J Michael; Leonard, Julie; Hulbert, Monica L; Powell, Elizabeth C; Liem, Robert I; Hickey, Robert; Krishnamurti, Lakshmanan; Hillery, Cheryl A; Nimmer, Mark; Panepinto, Julie A

    2015-10-01

    Magnesium, a vasodilator, anti-inflammatory, and pain reliever, could alter the pathophysiology of sickle cell pain crises. We hypothesized that intravenous magnesium would shorten length of stay, decrease opioid use, and improve health-related quality of life (HRQL) for pediatric patients hospitalized with sickle cell pain crises. The Magnesium for Children in Crisis (MAGiC) study was a randomized, double-blind, placebo-controlled trial of intravenous magnesium vs normal saline placebo conducted at 8 sites within the Pediatric Emergency Care Applied Research Network (PECARN). Children 4 to 21 years old with hemoglobin SS or Sβ(0) thalassemia requiring hospitalization for pain were eligible. Children received 40 mg/kg of magnesium or placebo every 8 hours for up to 6 doses plus standard therapy. The primary outcome was length of stay in hours from the time of first study drug infusion, compared using a Van Elteren test. Secondary outcomes included opioid use and HRQL. Of 208 children enrolled, 204 received the study drug (101 magnesium, 103 placebo). Between-group demographics and prerandomization treatment were similar. The median interquartile range (IQR) length of stay was 56.0 (27.0-109.0) hours for magnesium vs 47.0 (24.0-99.0) hours for placebo (P = .24). Magnesium patients received 1.46 mg/kg morphine equivalents vs 1.28 mg/kg for placebo (P = .12). Changes in HRQL before discharge and 1 week after discharge were similar (P > .05 for all comparisons). The addition of intravenous magnesium did not shorten length of stay, reduce opioid use, or improve quality of life in children hospitalized for sickle cell pain crisis. This trial was registered at www.clinicaltrials.gov as #NCT01197417.

  20. Rationale and design of the Multicenter Medication Reconciliation Quality Improvement Study (MARQUIS)

    PubMed Central

    2013-01-01

    Background Unresolved medication discrepancies during hospitalization can contribute to adverse drug events, resulting in patient harm. Discrepancies can be reduced by performing medication reconciliation; however, effective implementation of medication reconciliation has proven to be challenging. The goals of the Multi-Center Medication Reconciliation Quality Improvement Study (MARQUIS) are to operationalize best practices for inpatient medication reconciliation, test their effect on potentially harmful unintentional medication discrepancies, and understand barriers and facilitators of successful implementation. Methods Six U.S. hospitals are participating in this quality improvement mentored implementation study. Each hospital has collected baseline data on the primary outcome: the number of potentially harmful unintentional medication discrepancies per patient, as determined by a trained on-site pharmacist taking a “gold standard” medication history. With the guidance of their mentors, each site has also begun to implement one or more of 11 best practices to improve medication reconciliation. To understand the effect of the implemented interventions on hospital staff and culture, we are performing mixed methods program evaluation including surveys, interviews, and focus groups of front line staff and hospital leaders. Discussion At baseline the number of unintentional medication discrepancies in admission and discharge orders per patient varies by site from 2.35 to 4.67 (mean=3.35). Most discrepancies are due to history errors (mean 2.12 per patient) as opposed to reconciliation errors (mean 1.23 per patient). Potentially harmful medication discrepancies averages 0.45 per patient and varies by site from 0.13 to 0.82 per patient. We discuss several barriers to implementation encountered thus far. In the end, we anticipate that MARQUIS tools and lessons learned have the potential to decrease medication discrepancies and improve patient outcomes. Trial

  1. Davunetide for Progressive Supranuclear Palsy: a multicenter, randomized, double-blind, placebo controlled trial

    PubMed Central

    Boxer, Adam L.; Lang, Anthony E.; Grossman, Murray; Knopman, David S.; Miller, Bruce L.; Schneider, Lon S.; Doody, Rachelle S.; Lees, Andrew; Golbe, Lawrence I.; Williams, David R.; Corvol, Jean-Cristophe; Ludolph, Albert; Burn, David; Lorenzl, Stefan; Litvan, Irene; Roberson, Erik D.; Höglinger, Günter U.; Koestler, Mary; Jack, Clifford R.; Van Deerlin, Viviana; Randolph, Christopher; Lobach, Iryna V.; Heuer, Hilary W.; Gozes, Illana; Parker, Lesley; Whitaker, Steve; Hirman, Joe; Stewart, Alistair J.; Gold, Michael; Morimoto, Bruce H.

    2014-01-01

    Summary Background Davunetide (AL-108, NAP) is an eightamino acid peptide that promotes microtubule stability and decreases tau phosphorylation in pre-clinical studies. Since PSP is tightly linked to tau pathology, davunetide could be an effective treatment for PSP.The goals of this study were to evaluate the efficacy and safety of davunetide in PSP. Methods A phase 2/3 double-blind, parallel group, clinical trial of davunetide 30 mg or placebo (randomized 1:1) administered intranasally twice daily for 52 weeks was conducted at 48centers. Participants met modifiedNNIPPS criteria for possible or probable PSP. Co-primary endpointswere the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England ADL(SEADL) scale at up to 52 weeks. Data from all individuals who received at least one dose of medication and had a post-baseline efficacy assessment were compared using a rank-based method.Secondary outcomes included the Clinical Global Impression of Change (CGIC) and the change in regional brain volumeon MRI. Clinicaltrials.gov identifier: NCT01110720. Findings 360 participants were screened, 313 were randomized and 243 (77.6%) completed the study. There were no group differences in PSPRS (mean difference: 0.49 [95% CI: −1.5, 2.5], p = 0.72) or SEADL (1% [−2, 4%], p = 0.76) change from baseline (CFB) and mean 52 week CFB PSPRS scores were similar between the davunetide (11.3 [9.8,12.8]) and placebo groups (10.9 [9.1, 13.0]). There wereno differences in any of the secondary or exploratory endpoints. There were 11deaths in the davunetide group and tenin the placebo group. There were more nasal adverse events in the davunetide group. Interpretation Davunetide is well tolerated but is not an effective treatment for PSP. Clinical trials of disease modifying therapy are feasible in PSP and should be pursued with other promising tau-directed therapies. Funding Allon Therapeutics PMID:24873720

  2. Cervicothoracic Manual Therapy Plus Exercise Therapy Versus Exercise Therapy Alone in the Management of Individuals With Shoulder Pain: A Multicenter Randomized Controlled Trial.

    PubMed

    Mintken, Paul E; McDevitt, Amy W; Cleland, Joshua A; Boyles, Robert E; Beardslee, Amber R; Burns, Scott A; Haberl, Matthew D; Hinrichs, Lauren A; Michener, Lori A

    2016-08-01

    Study Design Multicenter randomized controlled trial. Background Cervicothoracic manual therapy has been shown to improve pain and disability in individuals with shoulder pain, but the incremental effects of manual therapy in addition to exercise therapy have not been investigated in a randomized controlled trial. Objectives To compare the effects of cervicothoracic manual therapy and exercise therapy to those of exercise therapy alone in individuals with shoulder pain. Methods Individuals (n = 140) with shoulder pain were randomly assigned to receive 2 sessions of cervicothoracic range-of-motion exercises plus 6 sessions of exercise therapy, or 2 sessions of high-dose cervicothoracic manual therapy and range-of-motion exercises plus 6 sessions of exercise therapy (manual therapy plus exercise). Pain and disability were assessed at baseline, 1 week, 4 weeks, and 6 months. The primary aim (treatment group by time) was examined using linear mixed-model analyses and the repeated measure of time for the Shoulder Pain and Disability Index (SPADI), the numeric pain-rating scale, and the shortened version of the Disabilities of the Arm, Shoulder and Hand questionnaire (QuickDASH). Patient-perceived success was assessed and analyzed using the global rating of change (GROC) and the Patient Acceptable Symptom State (PASS), using chi-square tests of independence. Results There were no significant 2-way interactions of group by time or main effects by group for pain or disability. Both groups improved significantly on the SPADI, numeric pain-rating scale, and QuickDASH. Secondary outcomes of success on the GROC and PASS significantly favored the manual therapy-plus-exercise group at 4 weeks (P = .03 and P<.01, respectively) and on the GROC at 6 months (P = .04). Conclusion Adding 2 sessions of high-dose cervicothoracic manual therapy to an exercise program did not improve pain or disability in patients with shoulder pain, but did improve patient-perceived success at 4 weeks

  3. Fluoxetine for motor recovery after acute intracerebral hemorrhage (FMRICH): study protocol for a randomized, double-blind, placebo-controlled, multicenter trial

    PubMed Central

    2013-01-01

    Background Spontaneous, nontraumatic intracerebral hemorrhage (ICH) is a subtype of stroke that causes a great amount of disability and economic and social burden. This is particularly true in developing countries where it accounts for between 20% and 50% of all strokes. Pharmacological and surgical interventions have been attempted to reduce the mortality and disability caused by ICH, with unsuccessful results. Recently, the use of fluoxetine in addition to physical rehabilitation has been proven useful to improve motor recovery following cerebral infarct. The purpose of this study is to test whether a 3-month treatment with fluoxetine enhances motor recovery in nondepressed patients with acute intracerebral hemorrhage. Methods/design Our study is a randomized, double-blind, placebo-controlled, multicenter clinical trial. We will recruit 86 patients with intracerebral hemorrhage of both sexes, aged >18 years, from four Mexican hospitals. The patients will receive either 20 mg of fluoxetine or a placebo once daily for 90 days. The primary outcome is the mean change in the Fugl-Meyer Motor Scale score between inclusion (day 0) and day 90. The secondary outcomes will be changes in the Barthel Index, the Modified Rankin scale and the National Institutes of Health stroke scale. The outcomes will be measured at day 42 ± 7days and at day 90, for a total of four visits with each subject (at screening and at 0, 42 and 90 days). Discussion Current guidelines recommend early supported hospital discharge and home-based rehabilitation programs as the only cost-effective intervention to aid the recovery of patients with intracerebral hemorrhage. Nevertheless, such interventions are dependent on available resources and funding, which make them very difficult to implement in developing countries. We believe that the identification of a helpful pharmacological intervention to aid the motor recovery of these patients will constitute a breakthrough that will have a major impact in

  4. Bayesian methods to determine performance differences and to quantify variability among centers in multi-center trials: the IHAST trial

    PubMed Central

    2013-01-01

    Background To quantify the variability among centers and to identify centers whose performance are potentially outside of normal variability in the primary outcome and to propose a guideline that they are outliers. Methods Novel statistical methodology using a Bayesian hierarchical model is used. Bayesian methods for estimation and outlier detection are applied assuming an additive random center effect on the log odds of response: centers are similar but different (exchangeable). The Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) is used as an example. Analyses were adjusted for treatment, age, gender, aneurysm location, World Federation of Neurological Surgeons scale, Fisher score and baseline NIH stroke scale scores. Adjustments for differences in center characteristics were also examined. Graphical and numerical summaries of the between-center standard deviation (sd) and variability, as well as the identification of potential outliers are implemented. Results In the IHAST, the center-to-center variation in the log odds of favorable outcome at each center is consistent with a normal distribution with posterior sd of 0.538 (95% credible interval: 0.397 to 0.726) after adjusting for the effects of important covariates. Outcome differences among centers show no outlying centers. Four potential outlying centers were identified but did not meet the proposed guideline for declaring them as outlying. Center characteristics (number of subjects enrolled from the center, geographical location, learning over time, nitrous oxide, and temporary clipping use) did not predict outcome, but subject and disease characteristics did. Conclusions Bayesian hierarchical methods allow for determination of whether outcomes from a specific center differ from others and whether specific clinical practices predict outcome, even when some centers/subgroups have relatively small sample sizes. In the IHAST no outlying centers were found. The estimated variability between centers

  5. Update of Dutch Multicenter Dose-Escalation Trial of Radiotherapy for Localized Prostate Cancer

    SciTech Connect

    Al-Mamgani, Abrahim Putten, Wim L.J. van; Heemsbergen, Wilma D.; Leenders, Geert J.L.H. van; Slot, Annerie; Dielwart, Michel F.H.; Incrocci, Luca; Lebesque, Joos V.

    2008-11-15

    Purpose: To update the analysis of the Dutch dose-escalation trial of radiotherapy for prostate cancer. Patients and Methods: A total of 669 patients with localized prostate cancer were randomly assigned to receive 68 or 78 Gy. The patients were stratified by age, institution, use of neoadjuvant or adjuvant hormonal therapy, and treatment group. The primary endpoint was freedom from failure (FFF), with failure defined as clinical or biochemical failure. Two definitions of biochemical failure were used: the American Society for Therapeutic Radiology and Oncology definition (three consecutive increases in prostate-specific antigen level) and the Phoenix definition (nadir plus 2 {mu}g/L). The secondary endpoints were freedom from clinical failure, overall survival, and genitourinary and gastrointestinal toxicity. Results: After a median follow-up of 70 months, the FFF using the American Society for Therapeutic Radiology and Oncology definition was significantly better in the 78-Gy arm than in the 68-Gy arm (7-year FFF rate, 54% vs. 47%, respectively; p = 0.04). The FFF using the Phoenix definition was also significantly better in the 78-Gy arm than in the 68-Gy arm (7-year FFF rate, 56% vs. 45%, respectively; p = 0.03). However, no differences in freedom from clinical failure or overall survival were observed. The incidence of late Grade 2 or greater genitourinary toxicity was similar in both arms (40% and 41% at 7 years; p = 0.6). However, the cumulative incidence of late Grade 2 or greater gastrointestinal toxicity was increased in the 78-Gy arm compared with the 68-Gy arm (35% vs. 25% at 7 years; p = 0.04). Conclusion: The results of our study have shown a statistically significant improvement in FFF in prostate cancer patients treated with 78 Gy but with a greater rate of late gastrointestinal toxicity.

  6. Enhanced weight loss following coadministration of pramlintide with sibutramine or phentermine in a multicenter trial.

    PubMed

    Aronne, Louis J; Halseth, Amy E; Burns, Colleen M; Miller, Stephan; Shen, Larry Z

    2010-09-01

    Preclinical evidence suggests that pharmacotherapy for obesity using combinations of agents targeted at distinct regulatory pathways may produce robust additive or synergistic effects on weight loss. This randomized placebo-controlled trial examined the safety and efficacy of the amylin analogue pramlintide alone or in combination with either phentermine or sibutramine. All patients also received lifestyle intervention. Following a 1-week placebo lead-in, 244 obese or overweight, nondiabetic subjects (88% female; 41 +/- 11 years; BMI 37.7 +/- 5.4 kg/m(2); weight 103 +/- 19 kg; mean +/- s.d.) received placebo subcutaneously (sc) t.i.d., pramlintide sc (120 microg t.i.d.), pramlintide sc (120 microg t.i.d.) + oral sibutramine (10 mg q.a.m.), or pramlintide sc (120 microg t.i.d.) + oral phentermine (37.5 mg q.a.m.) for 24 weeks. Treatment was single-blind for subjects receiving subcutaneous medication only and open-label for subjects in the combination arms. Weight loss achieved at week 24 with either combination treatment was greater than with pramlintide alone or placebo (P < 0.001; 11.1 +/- 1.1% with pramlintide + sibutramine, 11.3 +/- 0.9% with pramlintide + phentermine, -3.7 +/- 0.7% with pramlintide; -2.2 +/- 0.7% with placebo; mean +/- s.e.). Elevations from baseline in heart rate and diastolic blood pressure were demonstrated with both pramlintide + sibutramine (3.1 +/- 1.2 beats/min, P < 0.05; 2.7 +/- 0.9 mm Hg, P < 0.01) and pramlintide + phentermine (4.5 +/- 1.3 beats/min, P < 0.01; 3.5 +/- 1.2 mm Hg, P < 0.001) using 24-h ambulatory monitoring. However, the majority of subjects receiving these treatments remained within normal blood pressure ranges. These results support the potential of pramlintide-containing combination treatments for obesity.

  7. Evaluation of the FilmArray Blood Culture Identification Panel: Results of a Multicenter Controlled Trial

    PubMed Central

    Salimnia, Hossein; Lephart, Paul R.; Schreckenberger, Paul; DesJarlais, Sharon M.; Johnson, J. Kristie; Robinson, Gwen; Carroll, Karen C.; Greer, Amy; Morgan, Margie; Chan, Raymond; Loeffelholz, Michael; Valencia-Shelton, Frances; Jenkins, Stephen; Schuetz, Audrey N.; Daly, Judy A.; Barney, Trenda; Hemmert, Andrew; Kanack, Kristen J.

    2016-01-01

    Sepsis is a major cause of morbidity, mortality, and increased medical expense. Rapid diagnosis improves outcomes and reduces costs. The FilmArray blood culture identification panel (BioFire Diagnostics LLC, Salt Lake City, UT), a highly multiplexed PCR assay, can identify 24 etiologic agents of sepsis (8 Gram-positive, 11 Gram-negative, and 5 yeast species) and three antimicrobial resistance genes (mecA, vanA/B, and blaKPC) from positive blood culture bottles. It provides results in about 1 h with 2 min for assay setup. We present the results of an eight-center trial comparing the sensitivity and specificity of the panel with those of the laboratories' standard phenotypic identification techniques, as well as with molecular methods used to distinguish Acinetobacter baumannii from other members of the A. calcoaceticus-A. baumannii complex and to detect antimicrobial resistance genes. Testing included 2,207 positive aerobic blood culture samples, 1,568 clinical and 639 seeded. Samples were tested fresh or were frozen for later testing within 8 h after the bottles were flagged as positive by an automated blood culture system. At least one organism was detected by the panel in 1,382 (88.1%) of the positive clinical specimens. The others contained primarily off-panel organisms. The panel reported multiple organisms in 81 (5.86%) positive clinical specimens. The unresolved blood culture identification sensitivity for all target detections exceeded 96%, except for Klebsiella oxytoca (92.2%), which achieved 98.3% sensitivity after resolution of an unavoidable phenotypic error. The sensitivity and specificity for vanA/B and blaKPC were 100%; those for mecA were 98.4 and 98.3%, respectively. PMID:26739158

  8. Antiproteinuric effect of cilnidipine in hypertensive Japanese treated with renin-angiotensin-system inhibitors - a multicenter, open, randomized trial using 24-hour urine collection.

    PubMed

    Miwa, Yoshikazu; Tsuchihashi, Takuya; Ohta, Yuko; Tominaga, Mitsuhiro; Kawano, Yuhei; Sasaguri, Toshiyuki; Ueno, Michio; Matsuoka, Hiroaki

    2010-01-01

    Sustained proteinuria is an important risk factor for not only renal but also cardiovascular morbidity and mortality. Although inhibitors of the renin-angiotensin system (RAS) have been shown to reduce proteinuria. Monotherapy with those drugs is often insufficient for optimal blood pressure (BP)-lowering and therefore, combined therapy is needed. Recent reports suggested that cilnidipine, a dual L-/N-type calcium channel blocker, has renoprotective effect by dilating both efferent and afferent arterioles. In this study, a multicenter, open, randomized trial was designed to compare the antiproteinuric effect between cilnidipine and amlodipine when coupled with RAS inhibitors in hypertensive patients with significant proteinuria. Proteinuria was evaluated by 24-h home urine collection for all patients. A total of 35 proteinuric (>0.1 g/day) patients with uncontrolled BP (>135/85 mmHg) were randomized to receive either cilnidipine (n = 18) or amlodipine (n = 17) after a 6-month treatment with RAS inhibitors and were followed for 48 weeks. At baseline, the cilnidipine group was older and had lower body mass index (BMI) compared to the amlodipine group. After 32 weeks of treatment, diastolic blood pressure (DBP) was slightly, but significantly reduced, in the cilnidipine group, although systolic blood pressure (SBP) and mean BP did not differ. The urinary protein did not differ at baseline (cilnidipine group 0.48 g/day, amlodipine group 0.52 g/day); however, it significantly decreased in the cilnidipine group (0.22 g/day) compared to the amlodipine group (0.50 g/day) after 48 weeks of treatment. Our findings suggest that cilnidipine is superior to amlodipine in preventing the progression of proteinuria in hypertensive patients even undergoing treatment with RAS inhibitors.

  9. Multicenter phase II trial of Genexol-PM, a Cremophor-free, polymeric micelle formulation of paclitaxel, in patients with metastatic breast cancer.

    PubMed

    Lee, Keun Seok; Chung, Hyun Cheol; Im, Seock Ah; Park, Yeon Hee; Kim, Chul Soo; Kim, Sung-Bae; Rha, Sun Young; Lee, Min Young; Ro, Jungsil

    2008-03-01

    Genexol-PM is a novel Cremophor EL-free polymeric micelle formulation of paclitaxel. This single arm, multicenter phase II study was designed to evaluate the efficacy and safety of Genexol-PM in patients with histologically confirmed metastatic breast cancer (MBC). Forty-one women received Genexol-PM by intravenous infusion at 300 mg/m2 over 3 h every 3 weeks without premedication until disease progression or intolerability. A total of 331 chemotherapy cycles were administered, with a median of 8 cycles per patient (range, 1-16). Overall response rate was 58.5% (95% CI: 43.5-72.3) with 5 complete responses and 19 partial responses. Thirty-seven patients who received Genexol-PM as a first-line therapy for their metastatic disease showed a response rate of 59.5% (95% CI: 43.5-73.7), and two responses were reported in four patients treated in the second-line setting for their metastatic disease. The median time to progression (TTP) for all patients was 9.0 months (range, 1.0-17.0+ months). Grade 3 non-hematologic toxicities included sensory peripheral neuropathy (51.2%), and myalgia (2.4%). Eight patients (19.5%) experienced hypersensitivity reactions, with grade 3 in two patients. Hematologic toxicities were grade 3 and 4 neutropenia (51.2 and 17.1%, respectively), and grade 1 and 2 thrombocytopenia (22.0%). Notably, no febrile neutropenia was observed. Genexol-PM appears a promising new paclitaxel in view of significant efficacies. Further trials with different dosing schedules, durations of delivery, or in combination with other drugs are warranted.

  10. Sequential alternating deferiprone and deferoxamine treatment compared to deferiprone monotherapy: main findings and clinical follow-up of a large multicenter randomized clinical trial in -thalassemia major patients.

    PubMed

    Pantalone, Gaetano Restivo; Maggio, Aurelio; Vitrano, Angela; Capra, Marcello; Cuccia, Liana; Gagliardotto, Francesco; Filosa, Aldo; Romeo, Maria Antonietta; Magnano, Carmelo; Caruso, Vincenzo; Argento, Crocetta; Gerardi, Calogera; Campisi, Saveria; Violi, Pietro; Malizia, Roberto; Cianciulli, Paolo; Rizzo, Michele; D'Ascola, Domenico Giuseppe; Quota, Alessandra; Prossomariti, Luciano; Fidone, Carmelo; Rigano, Paolo; Pepe, Alessia; D'Amico, Gennaro; Morabito, Alberto; Gluud, Christian

    2011-01-01

    In β-thalassemia major (β-TM) patients, iron chelation therapy is mandatory to reduce iron overload secondary to transfusions. Recommended first line treatment is deferoxamine (DFO) from the age of 2 and second line treatment after the age of 6 is deferiprone (L1). A multicenter randomized open-label trial was designed to assess the effectiveness of long-term alternating sequential L1-DFO vs. L1 alone iron chelation therapy in β-TM patients. Deferiprone 75 mg/kg 4 days/week and DFO 50 mg/kg/day for 3 days/week was compared with L1 alone 75 mg/kg 7 days/week during a 5-year follow-up. A total of 213 thalassemia patients were randomized and underwent intention-to-treat analysis. Statistically, a decrease of serum ferritin level was significantly higher in alternating sequential L1-DFO patients compared with L1 alone patients (p = 0.005). Kaplan-Meier survival analysis for the two chelation treatments did not show statistically significant differences (log-rank test, p = 0.3145). Adverse events and costs were comparable between the groups. Alternating sequential L1-DFO treatment decreased serum ferritin concentration during a 5-year treatment by comparison to L1 alone, without significant differences of survival, adverse events or costs. These findings were confirmed in a further 21-month follow-up. These data suggest that alternating sequential L1-DFO treatment may be useful for some β-TM patients who may not be able to receive other forms of chelation treatment.

  11. Randomized Multicenter Trial of the Effects of Melanoma-Associated Helper Peptides and Cyclophosphamide on the Immunogenicity of a Multipeptide Melanoma Vaccine

    PubMed Central

    Slingluff, Craig L.; Petroni, Gina R.; Chianese-Bullock, Kimberly A.; Smolkin, Mark E.; Ross, Merrick I.; Haas, Naomi B.; von Mehren, Margaret; Grosh, William W.

    2011-01-01

    Purpose This multicenter randomized trial was designed to test whether melanoma-associated helper peptides augment CD8+ T-cell responses to a melanoma vaccine and whether cyclophosphamide (CY) pretreatment augments CD4+ or CD8+ T-cell responses to that vaccine. Patients and Methods In all, 167 eligible patients with resected stage IIB to IV melanoma were randomly assigned to four vaccination study arms. Patients were vaccinated with 12 class I major histocompatibility complex–restricted melanoma peptides (12MP) to stimulate CD8+ T cells and were randomly assigned to receive a tetanus helper peptide or a mixture of six melanoma-associated helper peptides (6MHP) to stimulate CD4+ T cells. Before vaccination, patients were also randomly assigned to receive CY pretreatment or not. T-cell responses were assessed by an ex vivo interferon gamma ELISpot assay. Clinical outcomes and toxicities were recorded. Results Vaccination with 12MP plus tetanus induced CD8+ T-cell responses in 78% of patients and CD4+ T-cell responses to tetanus peptide in 93% of patients. Vaccination with 12MP plus 6MHP induced CD8+ responses in 19% of patients and CD4+ responses to 6MHP in 48% of patients. CY had no significant effect on T-cell responses. Overall 3-year survival was 79% (95% CI, 71% to 86%), with no significant differences (at this point) by study arm. Conclusion Melanoma-associated helper peptides paradoxically decreased CD8+ T-cell responses to a melanoma vaccine (P < .001), and CY pretreatment had no immunologic or clinical effect. Prior work showed immunologic and clinical activity of 6MHP alone. Possible explanations for negative effects on CD8 responses include modulation of homing receptor expression or induction of antigen-specific regulatory T cells. PMID:21690475

  12. Clinical trial designs for therapeutic cancer vaccines.

    PubMed

    Simon, Richard

    2005-01-01

    Therapeutic cancer vaccines have characteristics that require a new paradigm for phase I and phase II clinical development. Effective development plans may take advantage of some of the following observations: Dose ranging safety trials are not appropriate for many cancer vaccines. Dose ranging trials to establish an optimal biologic dose are often not practical. We have presented an efficient design of Korn et al. (4) to identify an immunogenic dose. Vaccine efficacy can be efficiently evaluated with tumor response as endpoint utilizing a two stage design with only 9 patients in the first stage. If no partial or complete responses are observed in the initial 9 patients, accrual to the trial is terminated. Optimization of vaccine delivery by comparing results of single arm phase II studies using immunological response as endpoint is problematic because of assay variation and potential non-comparability of patients in different studies. Randomized screening studies can be used to efficiently optimize vaccine immunogenicity. Efficiency in use of patients depends on having assay variation and inter-patient variability small relative to the difference in immunogenicity to be detected. Phase II studies using time to progression as endpoint are most interpretable if they employ randomized designs with a no-vaccine control group. Such designs may use an inflated type 1 error rate, and need not be prohibitively large if patients with rapidly progressive disease are studied. Interim monitoring plans may effectively limit the size of the trials by terminating accrual early when results are not consistent with the targeted improvement.

  13. Veterinary oncology clinical trials: design and implementation.

    PubMed

    Thamm, Douglas H; Vail, David M

    2015-08-01

    There has been a recent increase in interest among veterinarians and the larger biomedical community in the evaluation of novel cancer therapies in client-owned (pet) animals with spontaneous cancer. This includes novel drugs designed to be veterinary therapeutics, as well as agents for which data generated in animals with tumors may inform human clinical trial design and implementation. An understanding of the process involved in moving a therapeutic agent through the stages of clinical evaluation is critical to the successful implementation of clinical investigations, as well as interpretation of the veterinary oncology literature. This review outlines considerations in the design and conduct of the various phases of oncology clinical trials, along with recent adaptations/modifications of these basic designs that can enhance the generation of timely and meaningful clinical data.

  14. Challenges of Conducting Multi-Center, Multi-Disciplinary Urinary Incontinence Clinical Trials: Experience of the Urinary Incontinence Treatment Network

    PubMed Central

    Steers, William; Richter, Holly; Nyberg, Leroy; Kusek, John; Kraus, Stephen; Dandrea, Kimberly; Chai, Toby; Brubaker, Linda

    2009-01-01

    Aims The Urinary Incontinence Treatment Network (UITN) was established in 2000 as a multi-disciplinary, multi-institutional network by the National Institute for Diabetes, Digestive, and Kidney Diseases (NIDDK) to investigate treatments for urinary incontinence in women. Methods Over 8 years this network composed of urologists, urogynecologists, geriatricians, behavioral psychologists, physical therapists, nurses, epidemiologists, social scientists and statisticians from nine academic sites and a Data Coordinating Center has been effective in designing and completing prospective randomized clinical trials for treatments of urinary incontinence in women. Results Two major clinical trials have been completed and a third has completed recruitment. The focus of the completed trials was a comparison of surgical methods to treat stress urinary incontinence whereas the third examined the potential benefit of combined behavioral intervention and antimuscarinic drug therapy to eliminate the need for long-term use of drug therapy alone to manage urge urinary incontinence. The scientific output of the network measured by abstracts, original papers and presentations demonstrates the productivity of the network. Conclusions Many unique challenges are posed by a multi-disciplinary team located at sites across the United States undertaking several clinical trials. This review presents some of the logistics, barriers, tactics, and strategies used to create this successful clinical trials network focused on urinary incontinence. PMID:19030190

  15. Optimizing Trial Designs for Targeted Therapies

    PubMed Central

    Beckman, Robert A.; Burman, Carl-Fredrik; König, Franz; Stallard, Nigel; Posch, Martin

    2016-01-01

    An important objective in the development of targeted therapies is to identify the populations where the treatment under consideration has positive benefit risk balance. We consider pivotal clinical trials, where the efficacy of a treatment is tested in an overall population and/or in a pre-specified subpopulation. Based on a decision theoretic framework we derive optimized trial designs by maximizing utility functions. Features to be optimized include the sample size and the population in which the trial is performed (the full population or the targeted subgroup only) as well as the underlying multiple test procedure. The approach accounts for prior knowledge of the efficacy of the drug in the considered populations using a two dimensional prior distribution. The considered utility functions account for the costs of the clinical trial as well as the expected benefit when demonstrating efficacy in the different subpopulations. We model utility functions from a sponsor’s as well as from a public health perspective, reflecting actual civil interests. Examples of optimized trial designs obtained by numerical optimization are presented for both perspectives. PMID:27684573

  16. Randomized controlled trials and neuro-oncology: should alternative designs be considered?

    PubMed

    Mansouri, Alireza; Shin, Samuel; Cooper, Benjamin; Srivastava, Archita; Bhandari, Mohit; Kondziolka, Douglas

    2015-09-01

    Deficiencies in design and reporting of randomized controlled trials (RCTs) hinders interpretability and critical appraisal. The reporting quality of recent RCTs in neuro-oncology was analyzed to assess adequacy of design and reporting. The MEDLINE and EMBASE databases were searched to identify non-surgical RCTs (years 2005-2014, inclusive). The CONSORT and Jadad scales were used to assess the quality of design/reporting. Studies published in 2005-2010 were compared as a cohort against studies published in 2011-2014, in terms of general characteristics and reporting quality. A PRECIS-based scale was used to designate studies on the pragmatic-explanatory continuum. Spearman's test was used to assess correlations. Regression analysis was used to assess associations. Overall 68 RCTs were identified. Studies were often chemotherapy-based (n = 41 studies) focusing upon high grade gliomas (46 %) and metastases (41 %) as the top pathologies. Multi-center trials (71 %) were frequent. The overall median CONSORT and Jadad scores were 34.5 (maximum 44) and 2 (maximum 5), respectively; these scores were similar in radiation and chemotherapy-based trials. Major areas of deficiency pertained to allocation concealment, implementation of methods, and blinding whereby less than 20 % of articles fulfilled all criteria. Description of intervention, random sequence generation, and the details regarding recruitment were also deficient; less than 50 % of studies fulfilled all criteria. Description of sample size calculations and blinding improved in later published cohorts. Journal impact factor was significantly associated with higher quality (p = 0.04). Large academic consortia, multi-center designs, ITT analysis, collaboration with biostatisticians, larger sample sizes, and studies with pragmatic objectives were more likely to achieve positive primary outcomes on univariate analysis; none of these variables were significant on multivariate analysis. Deficiencies in the

  17. United States multicenter clinical trial of the cochlear nucleus hybrid implant system

    PubMed Central

    Gantz, Bruce J.; Waltzman, Susan B.; Parkinson, Aaron J.

    2015-01-01

    Objectives/Hypothesis To evaluate the safety and efficacy of acoustic and electric sound processing for individuals with significant residual low‐frequency hearing and severe‐to‐profound high‐frequency sensorineural hearing loss. Study Design Prospective, single‐arm repeated measures, single‐subject design. Methods Fifty individuals, ≥ 18 years old, with low‐frequency hearing and severe high‐frequency loss were implanted with the Cochlear Nucleus Hybrid L24 implant at 10 investigational sites. Preoperatively, subjects demonstrated consonant‐nucleus‐consonant word scores of 10% through 60% in the ear to be implanted. Subjects were assessed prospectively, preoperatively, and postoperatively on coprimary endpoints of consonant‐nucleus‐consonant words, AzBio sentences in noise, and self‐assessment measures. Results Significant mean improvements were observed for coprimary endpoints: consonant‐nucleus‐consonant words (35.8 percentage points) and AzBio sentences in noise (32.0 percentage points), both at P < 0.001. Ninety‐six percent of subjects performed equal or better on speech in quiet and 90% in noise. Eighty‐two percent of subjects showed improved performance on speech in quiet and 74% in noise. Self‐assessments were positive, corroborating speech perception results. Conclusion The Nucleus Hybrid System provides significant improvements in speech intelligibility in quiet and noise for individuals with severe high‐frequency loss and some low‐frequency hearing. This device expands indications to hearing‐impaired individuals who perform poorly with amplification due to bilateral high‐frequency hearing loss and who previously were not implant candidates. Level of Evidence 2b. Laryngoscope, 126:175–181, 2016 PMID:26152811

  18. [Evaluation of the Effectiveness and Safety in a Multi-center Clinical Trial of VIBRANT SOUNDBRIDGE in Japan].

    PubMed

    Doi, Katsumi; Kanzaki, Sho; Kumakawa, Kozo; Usami, Shin-ichi; Iwasaki, Satoshi; Yamanaka, Noboru; Naito, Yasushi; Gyo, Kiyofumi; Tono, Tetsuya; Takahashi, Haruo; Kanda, Yukihiko

    2015-12-01

    Middle ear implants (MEIs) such as the Vibrant Soundbridge (VSB) are attractive and alternative treatments for patients with conductive, sensorineural, and mixed hearing loss who do not benefit from, or who choose not to wear, conventional hearing aids (HAs). Recent studies suggest that MEIs can provide better improvements in functional gain, speech perception, and quality of life than HAs, although there are certain risks associated with the surgery which should be taken into consideration, including facial nerve or chorda tympanic nerve damage, dysfunctions of the middle and inner ears, and future device failure/explantation. In Japan, a multi-center clinical trial of VSB was conducted between 2011-2014. A round window vibroplasty via the transmastoid approach was adopted in the protocol. The bony lip overhanging the round window membrane (RWM) was extensively but very carefully drilled to introduce the Floating Mass Transducer (FMT). Perichondrium sheets were used to stabilize the FMT onto the RWM. According to the audiological criteria, the upper limit of bone conduction should be 45 dB, 50 dB, and 65 dB from 500 Hz to 4, 000 Hz. Twenty-five patients underwent the surgery so far at 13 different medical centers. The age at the surgery was between 26-79 years old, and there were 15 males and 10 females. The cause of conductive or mixed hearing loss was middle ear diseases in 23 cases and congenital aural atresia in two cases. The data concerning on the effectiveness and safety of VSB was collected before the surgery and 20 weeks after the surgery. Significant improvements of free-field Pure Tone Audiogram (PTA) from 250 Hz to 8, 000 Hz were confirmed (p < 0.001). Hearing gain up to 40 dB was achieved in the 1, 000 Hz to 4, 000 Hz range. No deterioration in either air conduction or bone conduction at PTA was noted at 20 weeks after the surgery. Monosyllable speech perception in both quiet and noisy conditions improved significantly (p < 0.001). The speech

  19. Comparison of novel lipid-based eye drops with aqueous eye drops for dry eye: a multicenter, randomized controlled trial

    PubMed Central

    Simmons, Peter A; Carlisle-Wilcox, Cindy; Vehige, Joseph G

    2015-01-01

    Background Dry eye may be caused or exacerbated by deficient lipid secretion. Recently, lipid-containing artificial tears have been developed to alleviate this deficiency. Our study compared the efficacy, safety, and acceptability of lipid-containing eye drops with that of aqueous eye drops. Methods A non-inferiority, randomized, parallel-group, investigator-masked multicenter trial was conducted. Subjects with signs and symptoms of dry eye were randomized to use one of two lipid-containing artificial tears, or one of two aqueous artificial tears. Subjects instilled assigned drops in each eye at least twice daily for 30 days. The primary efficacy analysis tested non-inferiority of a preservative-free lipid tear formulation (LT UD) to a preservative-free aqueous tear formulation (AqT UD) for change in Ocular Surface Disease Index (OSDI) score from baseline at day 30. Secondary measures included OSDI at day 7, tear break-up time (TBUT), corneal and conjunctival staining, Schirmer’s test, acceptability and usage questionnaires, and safety assessments. Results A total of 315 subjects were randomized and included in the analyses. Subjects reported instilling a median of three doses of study eye drops per day in all groups. At days 7 and 30, all groups showed statistically significant improvements from baseline in OSDI (P<0.001) and TBUT (P≤0.005). LT UD was non-inferior to AqT UD for mean change from baseline in OSDI score at day 30. No consistent or clinically relevant differences for the other efficacy variables were observed. Acceptability was generally similar across the groups and there was a low incidence of adverse events. Conclusion In this heterogeneous population of dry eye subjects, there were no clinically significant differences in safety, effectiveness, and acceptability between lipid-containing artificial tears and aqueous eye drops. The results suggest that lipid-containing artificial tears can be used to counteract lipid deficiency that is common in

  20. A matched crossover design for clinical trials.

    PubMed

    Simon, Laura J; Chinchilli, Vernon M

    2007-09-01

    Two design principles are used frequently in clinical trials: 1) A subject is "matched" or "paired" with a similar subject to reduce the chance that other variables obscure the primary comparison of interest. 2) A subject serves as his/her own control by "crossing over" from one treatment to another during the course of an experiment. There are situations in which it may be advantageous to use the two design principles - crossing over and matching - simultaneously. That is, it may be advantageous to conduct a "paired crossover design," in which each subject, while paired with a similar subject, crosses over and receives each experimental treatment. In this paper, we describe two clinical trials conducted by the National Heart, Lung and Blood Institute's Asthma Clinical Research Network that used a paired 2x2 crossover design. The Beta Adrenergic Response by GEnotype (BARGE) Study compared the effects of regular use of inhaled albuterol on mildly asthmatic patients with different genotypes at the 16th position of the beta-agonist receptor gene. The Smoking Modulates Outcomes of Glucocorticoid (SMOG) Therapy in Asthma Study evaluated the hypothesis that smoking reduces the response to inhaled corticosteroids. For such paired crossover designs, the primary parameter of interest is typically the treatment-by-pairing interaction term. In evaluating the relative efficiency of the paired 2x2 crossover design to two independent crossover designs with respect to this interaction term, we show that the paired 2x2 crossover design is more efficient if the correlations between the paired members on the same treatments are greater than their correlations on different treatments. This condition should hold in most circumstances, and therefore the paired crossover design deserves serious consideration for any clinical trial in which the crossing over and matching of subjects is deemed simultaneously beneficial.

  1. THE ASSOCIATION BETWEEN PHYSIOLOGIC DEAD-SPACE FRACTION AND MORTALITY IN PATIENTS WITH THE ACUTE RESPIRATORY DISTRESS SYNDROME ENROLLED INTO A PROSPECTIVE MULTI-CENTERED CLINICAL TRIAL

    PubMed Central

    Kallet, Richard H; Zhuo, Hanjing; Liu, Kathleen D.; Calfee, Carolyn S.; Matthay, Michael A

    2014-01-01

    Objective To test the association between pulmonary dead-space fraction (VD/VT) and mortality in patients with ARDS (Berlin Definition, PaO2/FiO2 ≤ 300 mm Hg; PEEP ≥ 5 cm H2O) enrolled into a clinical trial incorporating lung-protective ventilation. Design Prospective, multi-center study. Setting Medical-surgical intensive care units in the United States. Subjects 126 ALI patients enrolled into a phase III randomized, placebo-controlled study of aerosolized albuterol. Interventions None Measurements and Main Results VD/VT and pulmonary mechanics were measured within 4 hours of enrollment and repeated daily on study days 1 and 2 in subjects requiring arterial blood gases for clinical management. At baseline, non-survivors had a trend towards higher VD/VT compared to survivors (0.62 ± 0.11 vs. 0.56 ± 0.11 respectively, p = 0.08). Differences in VD/VT between non-survivors and survivors became significant on study days 1 (0.64 ± 0.12 vs. 0.55 ± 0.11 respectively, p = 0.01) and 2 (0.67 ± 0.12 vs. 0.56 ± 0.11 respectively, p=0.004). Likewise, the association between VD/VT and mortality was significant on study day 1 (odds ratio per 0.10 change in VD/VT [95% confidence interval]: 6.84 [1.62–28.84] p = 0.01; and study day 2: 4.90 [1.28–18.73] p = 0.02) after adjusting for VD/VT, PaO2/FiO2, oxygenation index, vasopressor use and the primary risk for ARDS. Using a Cox proportional hazard model, VD/VT was associated with a trend towards higher mortality (HR = 4.37 [CI: 0.99 – 19.32]; p = 0.052) that became significant when the analysis was adjusted for daily oxygenation index (HR = 1.74 [95% CI: 1.12 – 3.35] p = 0.04). Conclusions Markedly elevated VD/VT (≥ 0.60) in early ARDS is associated with higher mortality. Measuring VD/VT may be useful in identifying ARDS patients at increased risk of death who are enrolled into a therapeutic trial. PMID:24381187

  2. A prospective randomized multicenter trial of amnioreduction versus selective fetoscopic laser photocoagulation for the treatment of severe twin–twin transfusion syndrome

    PubMed Central

    Crombleholme, Timothy M.; Shera, David; Lee, Hanmin; Johnson, Mark; D’Alton, Mary; Porter, Flint; Chyu, Jacquelyn; Silver, Richard; Abuhamad, Alfred; Saade, George; Shields, Laurence; Kauffman, David; Stone, Joanne; Albanese, Craig T.; Bahado-Singh, Ray; Ball, Robert H.; Bilaniuk, Larissa; Coleman, Beverly; Farmer, Diana; Feldstein, Vickie; Harrison, Michael R.; Hedrick, Holly; Livingston, Jeffrey; Lorenz, Robert P.; Miller, David A.; Norton, Mary E.; Polzin, William J.; Robinson, Julian N.; Rychik, Jack; Sandberg, Per L.; Seri, Istvan; Simon, Erin; Simpson, Lynn L.; Yedigarova, Larisa; Wilson, R. Douglas; Young, Bruce

    2009-01-01

    Objective To examine the effect of selective fetoscopic laser photocoagulation (SFLP) versus serial amnioreduction (AR) on perinatal mortality in severe twin-twin transfusion syndrome (TTTS). Study Design 5-year multicenter prospective randomized controlled trial. The primary outcome variable was 30-day postnatal survival of donors and recipients. Results There is no statistically significant difference in 30-day postnatal survival between SFLP or AR treatment for donors at 55% (11/20) vs 55% (11/20) (p=1, OR=1, 95%CI=0.242 to 4.14) or recipients at 30% (6/20) vs 45% (9/20) (p=0.51, OR=1.88, 95%CI=0.44 to 8.64). There is no difference in 30-day survival of one or both twins on a per pregnancy basis between AR at 75% (15/20) and SFLP at 65% (13/20) (p=0.73, OR=1.62, 95%CI=0.34 to 8.09). Overall survival (newborns divided by the number of fetuses treated) is not statistically significant for AR at 60% (24/40) vs SFLP 45% (18/40) (p=0.18, OR=2.01, 95%CI=0.76 to 5.44). There is a statistically significant increase in fetal recipient mortality in the SFLP arm at 70% (14/20) versus the AR arm at 35% (7/20) (p=0.25, OR=5.31, 95%CI=1.19 to 27.6). This is offset by increased recipient neonatal mortality of 30% (6/20) in the AR arm. Echocardiographic abnormality in recipient twin Cardiovascular Profile Score is the most significant predictor of recipient mortality (p=0.055, OR=3.025/point) by logistic regression analysis. Conclusions The outcome of the trial does not conclusively determine whether AR or SFLP is a superior treatment modality. TTTS cardiomyopathy appears to be an important factor in recipient survival in TTTS. PMID:17904975

  3. The NEtherlands Cervical Kinematics (NECK) Trial. Cost-effectiveness of anterior cervical discectomy with or without interbody fusion and arthroplasty in the treatment of cervical disc herniation; a double-blind randomised multicenter study

    PubMed Central

    2010-01-01

    Background Patients with cervical radicular syndrome due to disc herniation refractory to conservative treatment are offered surgical treatment. Anterior cervical discectomy is the standard procedure, often in combination with interbody fusion. Accelerated adjacent disc degeneration is a known entity on the long term. Recently, cervical disc prostheses are developed to maintain motion and possibly reduce the incidence of adjacent disc degeneration. A comparative cost-effectiveness study focused on adjacent segment degeneration and functional outcome has not been performed yet. We present the design of the NECK trial, a randomised study on cost-effectiveness of anterior cervical discectomy with or without interbody fusion and arthroplasty in patients with cervical disc herniation. Methods/Design Patients (age 18-65 years) presenting with radicular signs due to single level cervical disc herniation lasting more than 8 weeks are included. Patients will be randomised into 3 groups: anterior discectomy only, anterior discectomy with interbody fusion, and anterior discectomy with disc prosthesis. The primary outcome measure is symptomatic adjacent disc degeneration at 2 and 5 years after surgery. Other outcome parameters will be the Neck Disability Index, perceived recovery, arm and neck pain, complications, re-operations, quality of life, job satisfaction, anxiety and depression assessment, medical consumption, absenteeism, and costs. The study is a randomised prospective multicenter trial, in which 3 surgical techniques are compared in a parallel group design. Patients and research nurses will be kept blinded of the allocated treatment for 2 years. The follow-up period is 5 years. Discussion Currently, anterior cervical discectomy with fusion is the golden standard in the surgical treatment of cervical disc herniation. Whether additional interbody fusion or disc prothesis is necessary and cost-effective will be determined by this trial. Trial Registration Netherlands

  4. Adaptive enrichment designs for clinical trials.

    PubMed

    Simon, Noah; Simon, Richard

    2013-09-01

    Modern medicine has graduated from broad spectrum treatments to targeted therapeutics. New drugs recognize the recently discovered heterogeneity of many diseases previously considered to be fairly homogeneous. These treatments attack specific genetic pathways which are only dysregulated in some smaller subset of patients with the disease. Often this subset is only rudimentarily understood until well into large-scale clinical trials. As such, standard practice has been to enroll a broad range of patients and run post hoc subset analysis to determine those who may particularly benefit. This unnecessarily exposes many patients to hazardous side effects, and may vastly decrease the efficiency of the trial (especially if only a small subset of patients benefit). In this manuscript, we propose a class of adaptive enrichment designs that allow the eligibility criteria of a trial to be adaptively updated during the trial, restricting entry to patients likely to benefit from the new treatment. We show that our designs both preserve the type 1 error, and in a variety of cases provide a substantial increase in power.

  5. A multicenter randomized controlled trial for bright light therapy in adults with intellectual disabilities and depression: Study protocol and obstacle management.

    PubMed

    Hamers, Pauline C M; Evenhuis, Heleen M; Hermans, Heidi

    2017-01-01

    Due to the limited cognitive and communicative abilities of adults with intellectual disabilities (ID), current treatment options for depression are often limited to lifestyle changes and pharmacological treatment. Bright light therapy (BLT) is an effective intervention for both seasonal and non-seasonal depression in the general population. BLT is an inexpensive, easy to carry out intervention with minimal side effects. However, knowledge on its anti-depressant effect in adults with ID is lacking. Obstacles in realizing a controlled intervention study in this particular study population may have contributed to this lack. To study the effect of BLT on depression in this population, it is necessary to successfully execute a multicenter randomized controlled trial (RCT). Therefore, the study protocol and the management of anticipated obstacles regarding this trial are presented.

  6. Innovative trends in the design of therapeutic trials in psychopharmacology and psychotherapy.

    PubMed

    Fava, Giovanni A; Tomba, Elena; Tossani, Eliana

    2013-01-10

    The standard randomized controlled trial design is still based on the acute disease model. This is in sharp contrast with the fact that the patient is likely to have experienced other treatments before, that may actually modify clinical course and responsiveness. The current standard of therapeutic trial in psychiatry is represented by the large, multi-center, controlled randomized trial with broad inclusion criteria, and little attention to other factors such as the clinical history of patients and comorbidity. The heterogeneous features of these patients would then affect the outcome of the trial. Conflicting results among randomized controlled trials can represent a spectrum of outcomes, based on different patient groups, more than bias or random variability. If a treatment is tested by a series of small trials with inclusion criteria for specific characteristics (including treatment history, subgroups and comorbidity), we may have a better knowledge of its indications and contraindications. Further, there is increasing need of expanding the content of customary clinical information, by including evaluation of variables such as stress, lifestyle, well-being, illness behavior and psychological symptoms. These joint strategies would actually constitute a paradigm shift in psychopharmacology and psychotherapy research.

  7. Population screening for colorectal cancer by flexible sigmoidoscopy or CT colonography: study protocol for a multicenter randomized trial

    PubMed Central

    2014-01-01

    Background Colorectal cancer (CRC) is the second most prevalent type of cancer in Europe. A single flexible sigmoidoscopy (FS) screening at around the age of 60 years prevents about one-third of CRC cases. However, FS screens only the distal colon, and thus mortality from proximal CRC is unaffected. Computed tomography colonography (CTC) is a highly accurate examination that allows assessment of the entire colon. However, the benefit of CTC testing as a CRC screening test is uncertain. We designed a randomized trial to compare participation rate, detection rates, and costs between CTC (with computer-aided detection) and FS as primary tests for population-based screening. Methods/Design An invitation letter to participate in a randomized screening trial comparing CTC versus FS will be mailed to a sample of 20,000 people aged 58 or 60 years, living in the Piedmont region and the Verona district of Italy. Individuals with a history of CRC, adenomas, inflammatory bowel disease, or recent colonoscopy, or with two first-degree relatives with CRC will be excluded from the study by their general practitioners. Individuals responding positively to the invitation letter will be then randomized to the intervention group (CTC) or control group (FS), and scheduled for the screening procedure. The primary outcome parameter of this part of the trial is the difference in advanced neoplasia detection between the two screening tests. Secondary outcomes are cost-effectiveness analysis, referral rates for colonoscopy induced by CTC versus FS, and the expected and perceived burden of the procedures. To compare participation rates for CTC versus FS, 2,000 additional eligible subjects will be randomly assigned to receive an invitation for screening with CTC or FS. In the CTC arm, non-responders will be offered fecal occult blood test (FOBT) as alternative screening test, while in the FS arm, non-responders will receive an invitation letter to undergo screening with either FOBT or CTC

  8. Patient-centeredness in the design of clinical trials.

    PubMed

    Mullins, C Daniel; Vandigo, Joseph; Zheng, Zhiyuan; Wicks, Paul

    2014-06-01

    Evidence from clinical trials should contribute to informed decision making and a learning health care system. People frequently, however, find participating in clinical trials meaningless or disempowering. Moreover, people often do not incorporate trial results directly into their decision making. The lack of patient centeredness in clinical trials may be partially addressed through trial design. For example, Bayesian adaptive trials designed to adjust in a prespecified manner to changes in clinical practice could motivate people and their health care providers to view clinical trials as more applicable to real-world clinical decisions. The way in which clinical trials are designed can transform the evidence generation process to be more patient centered, providing people with an incentive to participate or continue participating in clinical trials. To achieve the transformation to patient-centeredness in clinical trial decisions, however, there is a need for transparent and reliable methods and education of trial investigators and site personnel.

  9. Challenges in the design of antibiotic equivalency studies: the multicenter equivalency study of oral amoxicillin versus injectable penicillin in children aged 3-59 months with severe pneumonia.

    PubMed

    Hibberd, Patricia L; Patel, Archana

    2004-08-15

    The World Health Organization (WHO) recommends that children with severe pneumonia (characterized by cough or difficult breathing, as well as lower chest wall indrawing) be hospitalized and treated with parenteral penicillin. Oral amoxicillin, if equally effective for treating severe pneumonia, would address challenges associated with providing parenteral therapy, including risk of transmission of bloodborne pathogens from contaminated needles, exposure to nosocomial pathogens during hospitalization, inadequate access to health care facilities, and cost. The recently completed multicenter international trial of oral amoxicillin versus parenteral penicillin for treatment of severe pneumonia demonstrated the equivalency of these agents in children with severe pneumonia. This article focuses on the challenges of designing an equivalence study and the threats to the validity of the trial results, particularly the implications of the bias toward finding equivalence when subjects are unlikely to respond to either study therapy. These considerations have implications for use of the Amoxicillin Penicillin Pneumonia International Study (APPIS) results in clinical practice and for potential modification of WHO treatment guidelines.

  10. INTERBED: internet-based guided self-help for overweight and obese patients with full or subsyndromal binge eating disorder. A multicenter randomized controlled trial

    PubMed Central

    2012-01-01

    Background Binge eating disorder (BED) is a prevalent clinical eating disorder associated with increased psychopathology, psychiatric comorbidity, overweight and obesity, and increased health care costs. Since its inclusion in the DSM-IV, a few randomized controlled trials (RCTs) have suggested efficacy of book-based self-help interventions in the treatment of this disorder. However, evidence from larger RCTs is needed. Delivery of self-help through new technologies such as the internet should be investigated in particular, as these approaches have the potential to be more interactive and thus more attractive to patients than book-based approaches. This study will evaluate the efficacy of an internet-based guided self-help program (GSH-I) and cognitive-behavioral therapy (CBT), which has been proven in several studies to be the gold standard treatment for BED, in a prospective multicenter randomized trial. Methods The study assumes the noninferiority of GSH-I compared to CBT. Both treatments lasted 4 months, and maintenance of outcome will be assessed 6 and 18 months after the end of treatment. A total of 175 patients with BED and a body mass index between 27 and 40 kg/m2 were randomized at 7 centers in Germany and Switzerland. A 20% attrition rate was assumed. As in most BED treatment trials, the difference in the number of binge eating days over the past 28 days is the primary outcome variable. Secondary outcome measures include the specific eating disorder psychopathology, general psychopathology, body weight, quality of life, and self-esteem. Predictors and moderators of treatment outcome will be determined, and the cost-effectiveness of both treatment conditions will be evaluated. Results The methodology for the INTERBED study has been detailed. Conclusions Although there is evidence that CBT is the first-line treatment for BED, it is not widely available. As BED is still a recent diagnostic category, many cases likely remain undiagnosed, and a large number of

  11. Cognitive Effects of High-Frequency rTMS in Schizophrenia Patients With Predominant Negative Symptoms: Results From a Multicenter Randomized Sham-Controlled Trial.

    PubMed

    Hasan, Alkomiet; Guse, Birgit; Cordes, Joachim; Wölwer, Wolfgang; Winterer, Georg; Gaebel, Wolfgang; Langguth, Berthold; Landgrebe, Michael; Eichhammer, Peter; Frank, Elmar; Hajak, Göran; Ohmann, Christian; Verde, Pablo E; Rietschel, Marcella; Ahmed, Raees; Honer, William G; Malchow, Berend; Karch, Susanne; Schneider-Axmann, Thomas; Falkai, Peter; Wobrock, Thomas

    2016-05-01

    Cognitive impairments are one of the main contributors to disability and poor long-term outcome in schizophrenia. Proof-of-concept trials indicate that repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (DLPFC) has the potential to improve cognitive functioning. We analyzed the effects of 10-Hz rTMS to the left DLPFC on cognitive deficits in schizophrenia in a large-scale and multicenter, sham-controlled study. A total of 156 schizophrenia patients with predominant negative symptoms were randomly assigned to a 3-week intervention (10-Hz rTMS, 15 sessions, 1000 stimuli per session) with either active or sham rTMS. The Rey Auditory Verbal Learning Test, Trail Making Test A and B, Wisconsin Card Sorting Test, Digit Span Test, and the Regensburg Word Fluency Test were administered before intervention and at day 21, 45, and 105 follow-up. From the test results, a neuropsychological composite score was computed. Both groups showed no differences in any of the outcome variables before and after intervention. Both groups improved markedly over time, but effect sizes indicate a numeric, but nonsignificant superiority of active rTMS in certain cognitive tests. Active 10-Hz rTMS applied to the left DLPFC for 3 weeks was not superior to sham rTMS in the improvement of various cognitive domains in schizophrenia patients with predominant negative symptoms. This is in contrast to previous preliminary proof-of-concept trials, but highlights the need for more multicenter randomized controlled trials in the field of noninvasive brain stimulation.

  12. A Multicenter, Open-Label Trial to Evaluate the Quality of Life in Adults with ADHD Treated with Long-Acting Methylphenidate (OROS MPH): Concerta Quality of Life (CONQoL) Study

    ERIC Educational Resources Information Center

    Mattos, Paulo; Rodrigues Louza, Mario; Fernandes Palmini, Andre Luis; de Oliveira, Irismar Reis; Lopes Rocha, Fabio

    2013-01-01

    The available literature provides few studies on the effectiveness of methylphenidate in improving quality of life in individuals with ADHD. Objective: To assess the effectiveness of Methyphenidate OROS formulation (OROS MPH) through QoL in adults with ADHD. Method: A 12-week, multicenter, open-label trial involving 60 patients was used. The…

  13. HIV-1 vaccines and adaptive trial designs.

    PubMed

    Corey, Lawrence; Nabel, Gary J; Dieffenbach, Carl; Gilbert, Peter; Haynes, Barton F; Johnston, Margaret; Kublin, James; Lane, H Clifford; Pantaleo, Giuseppe; Picker, Louis J; Fauci, Anthony S

    2011-04-20

    Developing a vaccine against the human immunodeficiency virus (HIV) poses an exceptional challenge. There are no documented cases of immune-mediated clearance of HIV from an infected individual, and no known correlates of immune protection. Although nonhuman primate models of lentivirus infection have provided valuable data about HIV pathogenesis, such models do not predict HIV vaccine efficacy in humans. The combined lack of a predictive animal model and undefined biomarkers of immune protection against HIV necessitate that vaccines to this pathogen be tested directly in clinical trials. Adaptive clinical trial designs can accelerate vaccine development by rapidly screening out poor vaccines while extending the evaluation of efficacious ones, improving the characterization of promising vaccine candidates and the identification of correlates of immune protection.

  14. Clinical designs of recent robot rehabilitation trials.

    PubMed

    Lo, Albert C

    2012-11-01

    Rehabilitation robots are increasingly being tested and promoted for clinical neurorehabilitation. Compared with conventional and manual methods, robots allow for a variety of advantages, particularly in the areas of interventional control and the ability to provide a high volume of facilitated movement. Since 1997, there have been more than 60 clinical trials reporting the use of two dozen different robots for neurorehabilitation. Although there are a number of smaller pilot studies, there are only few larger clinical trials. There may be a number of reasons why pilot robot studies do not materialize into larger studies. Beyond devices that failed to perform as intended, what are the clinical design issues that have limited these studies? Some basic considerations include randomization, inclusion of a control group, power calculation based on a clinically meaningful outcome, and finally, reproducible descriptions of the intervention being tested. Although many of these issues are general challenges presented for all rehabilitation studies, there are clinical design features that would likely greatly improve interpretation of results and better position robot devices toward the next clinical trial step. On the other hand, the absence of these elements, even in the setting of a pilot study, may significantly hamper the interpretation of results and not yield sufficient information on treatment effects, adverse event rates, dropout rate, and so on, to allow further testing to proceed to follow-up Food and Drug Administration phase II and III studies. Development of rehabilitation robots for clinical use needs to occur hand in hand with well-conducted clinical trials to provide evidence of efficacy while also taking into account costs.

  15. The Sleep Apnea cardioVascular Endpoints (SAVE) Trial: Rationale, Ethics, Design, and Progress

    PubMed Central

    Antic, Nick A.; Heeley, Emma; Anderson, Craig S.; Luo, Yuanming; Wang, Jiguang; Neal, Bruce; Grunstein, Ron; Barbe, Ferran; Lorenzi-Filho, Geraldo; Huang, Shaoguang; Redline, Susan; Zhong, Nanshan; McEvoy, R. Doug

    2015-01-01

    The Sleep Apnea cardioVascular Endpoints (SAVE) study is an ongoing investigator-initiated and conducted, international, multicenter, open, blinded endpoint, randomized controlled trial that was designed to determine whether treatment of obstructive sleep apnea (OSA) with continuous positive airways pressure (CPAP) can reduce the risk of serious cardiovascular (CV) events in patients with established CV disease (clinical trial registration NCT00738179). The results of this study will have important implications for the provision of health care to patients with sleep apnea around the world. The SAVE study has brought together respiratory, sleep, CV and stroke clinicians-scientists in an interdisciplinary collaboration with industry and government sponsorship to conduct an ambitious clinical trial. Following its launch in Australia and China in late 2008, the recruitment network expanded across 89 sites that included New Zealand, India, Spain, USA, and Brazil for a total of 2,717 patients randomized by December 2013. These patients are being followed until December 2015 so that the average length of follow-up of the cohort will be over 4 y. This article describes the rationale for the SAVE study, considerations given to the design including how various cultural and ethical challenges were addressed, and progress in establishing and maintaining the recruitment network, patient follow-up, and adherence to CPAP and procedures. The assumptions underlying the original trial sample size calculation and why this was revised downward in 2012 are also discussed. Clinical Trials Registration Number: NCT00738179. Australia New Zealand Clinical Trials Registry Number: ACTRN12608000409370. Citation: Antic NA, Heeley E, Anderson CS, Luo Y, Wang J, Neal B, Grunstein R, Barbe F, Lorenzi-Filho G, Huang S, Redline S, Zhong N, McEvoy RD. The sleep apnea cardiovascular endpoints (SAVE) trial: rationale, ethics, design, and progress. SLEEP 2015;38(8):1247–1257. PMID:25669180

  16. Globally optimal trial design for local decision making.

    PubMed

    Eckermann, Simon; Willan, Andrew R

    2009-02-01

    Value of information methods allows decision makers to identify efficient trial design following a principle of maximizing the expected value to decision makers of information from potential trial designs relative to their expected cost. However, in health technology assessment (HTA) the restrictive assumption has been made that, prospectively, there is only expected value of sample information from research commissioned within jurisdiction. This paper extends the framework for optimal trial design and decision making within jurisdiction to allow for optimal trial design across jurisdictions. This is illustrated in identifying an optimal trial design for decision making across the US, the UK and Australia for early versus late external cephalic version for pregnant women presenting in the breech position. The expected net gain from locally optimal trial designs of US$0.72M is shown to increase to US$1.14M with a globally optimal trial design. In general, the proposed method of globally optimal trial design improves on optimal trial design within jurisdictions by: (i) reflecting the global value of non-rival information; (ii) allowing optimal allocation of trial sample across jurisdictions; (iii) avoiding market failure associated with free-rider effects, sub-optimal spreading of fixed costs and heterogeneity of trial information with multiple trials.

  17. A multicenter, double-blind, placebo-controlled trial comparing piperacillin-tazobactam with and without amikacin as empiric therapy for febrile neutropenia.

    PubMed

    Del Favero, A; Menichetti, F; Martino, P; Bucaneve, G; Micozzi, A; Gentile, G; Furno, P; Russo, D; D'Antonio, D; Ricci, P; Martino, B; Mandelli, F

    2001-10-15

    In a prospective, multicenter, double-blind, randomized clinical trial, we compared the efficacy of piperacillin-tazobactam (4.5 g 3 times daily intravenously) plus placebo versus piperacillin-tazobactam plus amikacin (7.5 mg/kg twice daily intravenously) for the treatment of 760 febrile, adult patients with cancer with chemotherapy-induced profound (<500 neutrophils/mm3) and prolonged (>10 days) neutropenia. A total of 733 patients were assessable for efficacy of the drug regimens, and an overall successful outcome was reported in 49% (179 of 364) of the patients who received monotherapy, compared with 53% (196 of 369) of patients who received combination therapy (P=.2). Response rates were similar with both regimens, as were incidences of bacteremia and clinically documented and possible infections. In our epidemiological setting, the initial empiric combination therapy was not associated with improved outcomes when compared with initial monotherapy.

  18. Diagnostic performance of combined noninvasive coronary angiography and myocardial perfusion imaging using 320 row detector computed tomography: design and implementation of the CORE320 multicenter, multinational diagnostic study.

    PubMed

    Vavere, Andrea L; Simon, Gregory G; George, Richard T; Rochitte, Carlos E; Arai, Andrew E; Miller, Julie M; Di Carli, Marcello; Arbab-Zadeh, Armin; Zadeh, Armin A; Dewey, Marc; Niinuma, Hiroyuki; Laham, Roger; Rybicki, Frank J; Schuijf, Joanne D; Paul, Narinder; Hoe, John; Kuribyashi, Sachio; Sakuma, Hajime; Nomura, Cesar; Yaw, Tan Swee; Kofoed, Klaus F; Yoshioka, Kunihiro; Clouse, Melvin E; Brinker, Jeffrey; Cox, Christopher; Lima, Joao A C

    2011-01-01

    Multidetector coronary computed tomography angiography (CTA) is a promising modality for widespread clinical application because of its noninvasive nature and high diagnostic accuracy as found in previous studies using 64 to 320 simultaneous detector rows. It is, however, limited in its ability to detect myocardial ischemia. In this article, we describe the design of the CORE320 study ("Combined coronary atherosclerosis and myocardial perfusion evaluation using 320 detector row computed tomography"). This prospective, multicenter, multinational study is unique in that it is designed to assess the diagnostic performance of combined 320-row CTA and myocardial CT perfusion imaging (CTP) in comparison with the combination of invasive coronary angiography and single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI). The trial is being performed at 16 medical centers located in 8 countries worldwide. CT has the potential to assess both anatomy and physiology in a single imaging session. The co-primary aim of the CORE320 study is to define the per-patient diagnostic accuracy of the combination of coronary CTA and myocardial CTP to detect physiologically significant coronary artery disease compared with (1) the combination of conventional coronary angiography and SPECT-MPI and (2) conventional coronary angiography alone. If successful, the technology could revolutionize the management of patients with symptomatic CAD.

  19. The EVIDENT-trial: protocol and rationale of a multicenter randomized controlled trial testing the effectiveness of an online-based psychological intervention

    PubMed Central

    2013-01-01

    Background Depressive disorders are among the leading causes of worldwide disability with mild to moderate forms of depression being particularly common. Low-intensity treatments such as online psychological treatments may be an effective way to treat mild to moderate depressive symptoms and prevent the emergence or relapse of major depression. Methods/Design This study is a currently recruiting multicentre parallel-groups pragmatic randomized-controlled single-blind trial. A total of 1000 participants with mild to moderate symptoms of depression from various settings including in- and outpatient services will be randomized to an online psychological treatment or care as usual (CAU). We hypothesize that the intervention will be superior to CAU in reducing depressive symptoms assessed with the Personal Health Questionnaire (PHQ-9, primary outcome measure) following the intervention (12 wks) and at follow-up (24 and 48 wks). Further outcome parameters include quality of life, use of health care resources and attitude towards online psychological treatments. Discussion The study will yield meaningful answers to the question of whether online psychological treatment can contribute to the effective and efficient prevention and treatment of mild to moderate depression on a population level with a low barrier to entry. Trial registration Trial Registration Number: NCT01636752 PMID:24074299

  20. German Cancer Society Neuro-Oncology Working Group NOA-03 multicenter trial of single-agent high-dose methotrexate for primary central nervous system lymphoma.

    PubMed

    Herrlinger, Ulrich; Schabet, Martin; Brugger, Wolfram; Kortmann, Rolf-Dieter; Küker, Wilhelm; Deckert, Martina; Engel, Corinna; Schmeck-Lindenau, Hans-Jürgen; Mergenthaler, Hans-Günther; Krauseneck, Peter; Benöhr, Christian; Meisner, Christoph; Wiestler, Otmar D; Dichgans, Johannes; Kanz, Lothar; Bamberg, Michael; Weller, Michael

    2002-02-01

    The prospective multicenter NOA-03 trial, conducted by the Neuro-Oncology Working Group (NOA) of the German Cancer Society, was initiated to define the feasibility and efficacy of single-agent high-dose methotrexate therapy without concomitant radiotherapy in immunocompetent patients with primary central nervous system lymphoma. Thirty-seven patients (median age, 60 years) received 179 biweekly courses of 8 g/m2 methotrexate. Response was assessed after 3 and 6 courses. We had planned to enter 105 patients into the trial. Since fewer than the projected 18 of 37 patients achieved a complete response after an intermediate analysis, the trial was closed. In intention-to-treat analysis, 11 of 37 patients (29.7%) achieved complete response, whereas 14 of 37 patients (37.8%) were found to have progressive disease. The median relapse-free survival among complete response patients was 13.7 months. Multivariate logistic regression analysis revealed that corticosteroid application during the first methotrexate course was associated with complete response. The regimen was well tolerated, but, unlike previously reported results, the activity of high-dose methotrexate was only moderate.

  1. Dual sensory loss: development of a dual sensory loss protocol and design of a randomized controlled trial

    PubMed Central

    2013-01-01

    Background Dual sensory loss (DSL) has a negative impact on health and wellbeing and its prevalence is expected to increase due to demographic aging. However, specialized care or rehabilitation programs for DSL are scarce. Until now, low vision rehabilitation does not sufficiently target concurrent impairments in vision and hearing. This study aims to 1) develop a DSL protocol (for occupational therapists working in low vision rehabilitation) which focuses on optimal use of the senses and teaches DSL patients and their communication partners to use effective communication strategies, and 2) describe the multicenter parallel randomized controlled trial (RCT) designed to test the effectiveness and cost-effectiveness of the DSL protocol. Methods/design To develop a DSL protocol, literature was reviewed and content was discussed with professionals in eye/ear care (interviews/focus groups) and DSL patients (interviews). A pilot study was conducted to test and confirm the DSL protocol. In addition, a two-armed international multi-center RCT will evaluate the effectiveness and cost-effectiveness of the DSL protocol compared to waiting list controls, in 124 patients in low vision rehabilitation centers in the Netherlands and Belgium. Discussion This study provides a treatment protocol for rehabilitation of DSL within low vision rehabilitation, which aims to be a valuable addition to the general low vision rehabilitation care. Trial registration Netherlands Trial Register (NTR) identifier: NTR2843 PMID:23941667

  2. Tetrodotoxin for moderate to severe cancer pain: a randomized, double blind, parallel design multicenter study.

    PubMed

    Hagen, Neil A; du Souich, Patrick; Lapointe, Bernard; Ong-Lam, May; Dubuc, Benoit; Walde, David; Love, Robin; Ngoc, Anh Ho

    2008-04-01

    Cancer pain is a serious public health issue and more effective treatments are needed. This study evaluates the analgesic activity of tetrodotoxin, a highly selective sodium channel blocker. This randomized, placebo-controlled, parallel design study of subcutaneous tetrodotoxin, in patients with moderate or severe unrelieved cancer pain persisting despite best available treatment, involved 22 centers across Canada. The design called for tetrodotoxin administered subcutaneously over Days 1-4 with a period of observation to Day 15 or longer. All patients could enroll into an open-label extension efficacy and safety trial. The primary endpoint was the proportion of analgesic responders in each treatment arm. Eighty-two patients were randomized, and results on 77 were available for analysis. There was a nonstatistically significant trend toward more responders in the active treatment arm based on the primary endpoint (pain intensity difference). However, analysis of secondary endpoints, and an exploratory post hoc analysis, suggested there may be a robust analgesic effect if a composite endpoint is used, including either fall in pain level, or fall in opioid dose, plus improvement in quality of life. Most patients described transient perioral tingling or other mild sensory phenomena within about an hour of each treatment. Nausea and other toxicities were generally mild, but one patient experienced a serious, adverse event, truncal and gait ataxia. This trial suggests tetrodotoxin may potentially relieve moderate to severe, treatment-resistant cancer pain in a large proportion of patients, and often for prolonged periods following treatment, but further study is warranted using a composite primary endpoint.

  3. Efficacy of a dilemma-focused intervention for unipolar depression: study protocol for a multicenter randomized controlled trial

    PubMed Central

    2013-01-01

    Background Depression is one of the more severe and serious health problems because of its morbidity, disabling effects and for its societal and economic burden. Despite the variety of existing pharmacological and psychological treatments, most of the cases evolve with only partial remission, relapse and recurrence. Cognitive models have contributed significantly to the understanding of unipolar depression and its psychological treatment. However, success is only partial and many authors affirm the need to improve those models and also the treatment programs derived from them. One of the issues that requires further elaboration is the difficulty these patients experience in responding to treatment and in maintaining therapeutic gains across time without relapse or recurrence. Our research group has been working on the notion of cognitive conflict viewed as personal dilemmas according to personal construct theory. We use a novel method for identifying those conflicts using the repertory grid technique (RGT). Preliminary results with depressive patients show that about 90% of them have one or more of those conflicts. This fact might explain the blockage and the difficult progress of these patients, especially the more severe and/or chronic. These results justify the need for specific interventions focused on the resolution of these internal conflicts. This study aims to empirically test the hypothesis that an intervention focused on the dilemma(s) specifically detected for each patient will enhance the efficacy of cognitive behavioral therapy (CBT) for depression. Design A therapy manual for a dilemma-focused intervention will be tested using a randomized clinical trial by comparing the outcome of two treatment conditions: combined group CBT (eight, 2-hour weekly sessions) plus individual dilemma-focused therapy (eight, 1-hour weekly sessions) and CBT alone (eight, 2-hour group weekly sessions plus eight, 1-hour individual weekly sessions). Method Participants are

  4. Strengthening of the Hip and Core Versus Knee Muscles for the Treatment of Patellofemoral Pain: A Multicenter Randomized Controlled Trial

    PubMed Central

    Ferber, Reed; Bolgla, Lori; Earl-Boehm, Jennifer E.; Emery, Carolyn; Hamstra-Wright, Karrie

    2015-01-01

    Context: Patellofemoral pain (PFP) is the most common injury in running and jumping athletes. Randomized controlled trials suggest that incorporating hip and core strengthening (HIP) with knee-focused rehabilitation (KNEE) improves PFP outcomes. However, no randomized controlled trials have, to our knowledge, directly compared HIP and KNEE programs. Objective: To compare PFP pain, function, hip- and knee-muscle strength, and core endurance between KNEE and HIP protocols after 6 weeks of rehabilitation. We hypothesized greater improvements in (1) pain and function, (2) hip strength and core endurance for patients with PFP involved in the HIP protocol, and (3) knee strength for patients involved in the KNEE protocol. Design: Randomized controlled clinical trial. Setting: Four clinical research laboratories in Calgary, Alberta; Chicago, Illinois; Milwaukee, Wisconsin; and Augusta, Georgia. Patients or Other Participants: Of 721 patients with PFP screened, 199 (27.6%) met the inclusion criteria (66 men [31.2%], 133 women [66.8%], age = 29.0 ± 7.1 years, height = 170.4 ± 9.4 cm, weight = 67.6 ± 13.5 kg). Intervention(s): Patients with PFP were randomly assigned to a 6-week KNEE or HIP protocol. Main Outcome Measure(s): Primary variables were self-reported visual analog scale and Anterior Knee Pain Scale measures, which were conducted weekly. Secondary variables were muscle strength and core endurance measured at baseline and at 6 weeks. Results: Compared with baseline, both the visual analog scale and the Anterior Knee Pain Scale improved for patients with PFP in both the HIP and KNEE protocols (P < .001), but the visual analog scale scores for those in the HIP protocol were reduced 1 week earlier than in the KNEE group. Both groups increased in strength (P < .001), but those in the HIP protocol gained more in hip-abductor (P = .01) and -extensor (P = .01) strength and posterior core endurance (P = .05) compared with the KNEE group. Conclusions: Both the HIP and KNEE

  5. Designing Drug Trials: Considerations for Pregnant Women

    PubMed Central

    Sheffield, Jeanne S.; Siegel, David; Mirochnick, Mark; Heine, R. Phillips; Nguyen, Christine; Bergman, Kimberly L.; Savic, Rada M.; Long, Jill; Dooley, Kelly E.; Nesin, Mirjana

    2014-01-01

    Clinical pharmacology studies that describe the pharmacokinetics and pharmacodynamics of drugs in pregnant women are critical for informing on the safe and effective use of drugs during pregnancy. That being said, multiple factors have hindered the ability to study drugs in pregnant patients. These include concerns for maternal and fetal safety, ethical considerations, the difficulty in designing appropriate trials to assess the study objectives, and funding limitations. This document summarizes the recommendations of a panel of experts convened by the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. These experts were charged with reviewing the issues related to the development of preclinical and clinical drug studies in pregnant women and to develop strategies for addressing these issues. These findings may also be utilized in the development of future drug studies involving pregnant women and their fetus/neonate. PMID:25425722

  6. The Effectiveness of Parent Training as a Treatment for Preschool Attention-Deficit/Hyperactivity Disorder: Study Protocol for a Randomized Controlled, Multicenter Trial of the New Forest Parenting Program in Everyday Clinical Practice

    PubMed Central

    Daley, David; Frydenberg, Morten; Rask, Charlotte U; Sonuga-Barke, Edmund; Thomsen, Per H

    2016-01-01

    Background Parent training is recommended as the first-line treatment for attention-deficit/hyperactivity disorder (ADHD) in preschool children. The New Forest Parenting Programme (NFPP) is an evidence-based parenting program developed specifically to target preschool ADHD. Objective The objective of this trial is to investigate whether the NFPP can be effectively delivered for children referred through official community pathways in everyday clinical practice. Methods A multicenter randomized controlled parallel arm trial design is employed. There are two treatment arms, NFPP and treatment as usual. NFPP consists of eight individually delivered parenting sessions, where the child attends during three of the sessions. Outcomes are examined at three time points (T1, T2, T3): T1 (baseline), T2 (week 12, post intervention), and T3 (6 month follow/up). 140 children between the ages of 3-7, with a clinical diagnosis of ADHD, informed by the Development and Well Being Assessment, and recruited from three child and adolescent psychiatry departments in Denmark will take part. Randomization is on a 1:1 basis, stratified for age and gender. Results The primary endpoint is change in ADHD symptoms as measured by the Preschool ADHD-Rating Scale (ADHD-RS) by T2. Secondary outcome measures include: effects on this measure at T3 and T2 and T3 measures of teacher reported Preschool ADHD-RS scores, parent and teacher rated scores on the Strength & Difficulties Questionnaire, direct observation of ADHD behaviors during Child’s Solo Play, observation of parent-child interaction, parent sense of competence, and family stress. Results will be reported using the standards set out in the Consolidated Standards of Reporting Trials Statement for Randomized Controlled Trials of nonpharmacological treatments. Conclusions The trial will provide evidence as to whether NFPP is a more effective treatment for preschool ADHD than the treatment usually offered in everyday clinical practice. Trial

  7. Challenging Issues in Clinical Trial Design: Part 4 of a 4-Part Series on Statistics for Clinical Trials.

    PubMed

    Pocock, Stuart J; Clayton, Tim C; Stone, Gregg W

    2015-12-29

    As a sequel to last week's paper on the fundamentals of clinical trial design, this paper tackles related controversial issues: noninferiority trials, the value of factorial designs, the importance and challenges of strategy trials, Data Monitoring Committees (including when to stop a trial early), and the role of adaptive designs. All topics are illustrated by relevant examples from cardiology trials.

  8. The Efficacy and Safety of Miconazole Nitrate Mucoadhesive Tablets versus Itraconazole Capsules in the Treatment of Oral Candidiasis: An Open-Label, Randomized, Multicenter Trial

    PubMed Central

    Liu, Yang; Han, Ying; Lin, Mei; Wang, Wenmei; Guan, Xiaobing; Zhu, Shengrong; Zhang, Handong; Wang, Qintao; Chou, Lihong; Zhu, Xinghao; Hua, Hong

    2016-01-01

    Background Oral candidiasis (OC) is a common oral fungal infection. Recently, miconazole mucoadhesive tablets have been gaining attention for OC treatment. Despite trials in patients with human immunodeficiency virus and cancer, evidence of its application in the large-scale, general population with OC is lacking. This study aimed to evaluate the efficacy and safety of miconazole nitrate mucoadhesive tablets in comparison with itraconazole capsules for OC treatment. Methods The study was a randomized, open-label, parallel-armed, multicenter clinical trial. Totally, 343 patients diagnosed with OC, who met the inclusion criteria, were randomly assigned to either a treatment group that received miconazole nitrate mucoadhesive tablets (10 mg) once daily or a control group that received itraconazole capsules (100 mg QD) for 2 weeks, and were followed up for 2 weeks. The clinical cure, improvement of clinical symptoms/signs, mycologic cure, and safety were evaluated. Results The mucoadhesive tablets (n = 171) did not show inferiority to itraconazole (n = 172) in the treatment of OC. At the end of the 14-day treatment, the clinical cure rates were 45.29% and 41.76% in the miconazole and itraconazole groups, respectively (P = 0.3472). At the end of the 14-day follow-up, the clinical cure rates were 51.18% and 41.76% in the miconazole and itraconazole groups, respectively (P = 0.0329). Adverse events occurred in 53 subjects (33 in the miconazole group and 20 in the itraconazole group). There was no statistical difference in the safety profile between miconazole and itraconazole (P = 0.0533). Thrombocytopenic purpura, although rare, occurred in one patient in the miconazole group and was considered a drug-related, severe adverse event. Conclusion Miconazole nitrate mucoadhesive tablets may be as effective as systemic itraconazole capsule for OC treatment. Physicians should be cautious about thrombocytopenic purpura occurring as a rare and serious adverse event of miconazole

  9. Improving survival with deferiprone treatment in patients with thalassemia major: a prospective multicenter randomised clinical trial under the auspices of the Italian Society for Thalassemia and Hemoglobinopathies.

    PubMed

    Maggio, Aurelio; Vitrano, Angela; Capra, Marcello; Cuccia, Liana; Gagliardotto, Francesco; Filosa, Aldo; Magnano, Carmelo; Rizzo, Michele; Caruso, Vincenzo; Gerardi, Calogera; Argento, Crocetta; Campisi, Saveria; Cantella, Francesco; Commendatore, Francesca; D'Ascola, Domenico Giuseppe; Fidone, Carmelo; Ciancio, Angela; Galati, Maria Concetta; Giuffrida, Gaetano; Cingari, Rocca; Giugno, Giovanni; Lombardo, Turi; Prossomariti, Luciano; Malizia, Roberto; Meo, Anna; Roccamo, Gaetano; Romeo, Maria Antonietta; Violi, Pietro; Cianciulli, Paolo; Rigano, Paolo

    2009-01-01

    The prognosis for thalassemia major has dramatically improved in the last two decades. However, many transfusion-dependent patients continue to develop progressive accumulation of iron. This can lead to tissue damage and eventually death, particularly from cardiac disease. Previous studies that investigated iron chelation treatments, including retrospective and prospective non-randomised clinical trials, suggested that mortality, due mainly to cardiac damage, was reduced or completely absent in patients treated with deferiprone (DFP) alone or a combined deferiprone-deferoxamine (DFP-DFO) chelation treatment. However, no survival analysis has been reported for a long-term randomised control trial. Here, we performed a multicenter, long-term, randomised control trial that compared deferoxamine (DFO) versus DFP alone, sequential DFP-DFO, or combined DFP-DFO iron chelation treatments. The trial included 265 patients with thalassemia major, with 128 (48.3%) females and 137 (51.7%) males. No deaths occurred with the DFP-alone or the combined DFP-DFO treatments. One death occurred due to graft versus host disease (GVHD) in a patient that had undergone bone marrow transplantation; this patient was censored at the time of transplant. Only one death occurred with the DFP-DFO sequential treatment in a patient that had experienced an episode of heart failure one year earlier. Ten deaths occurred with the deferoxamine treatment. The main factors that correlated with an increase in the hazard ratio for death were: cirrhosis, arrhythmia, previous episode of heart failure, diabetes, hypogonadism, and hypothyroidism. In a Cox regression model, the interaction effect of sex and age was statistically significant (p-value<0.013). For each increasing year of age, the hazard ratio for males was 1.03 higher than that for females (p-value<0.013). In conclusion, the results of this study show that the risk factors for predicting mortality in patients with thalassemia major are deferoxamine

  10. The MANDELA study: A multicenter, randomized, open-label, parallel group trial to refine the use of everolimus after heart transplantation.

    PubMed

    Deuse, Tobias; Bara, Christoph; Barten, Markus J; Hirt, Stephan W; Doesch, Andreas O; Knosalla, Christoph; Grinninger, Carola; Stypmann, Jörg; Garbade, Jens; Wimmer, Peter; May, Christoph; Porstner, Martina; Schulz, Uwe

    2015-11-01

    In recent years a series of trials has sought to define the optimal protocol for everolimus-based immunosuppression in heart transplantation, with the goal of minimizing exposure to calcineurin inhibitors (CNIs) and harnessing the non-immunosuppressive benefits of everolimus. Randomized studies have demonstrated that immunosuppressive potency can be maintained in heart transplant patients receiving everolimus despite marked CNI reduction, although very early CNI withdrawal may be inadvisable. A potential renal advantage has been shown for everolimus, but the optimal time for conversion and the adequate reduction in CNI exposure remain to be defined. Other reasons for use of everolimus include a substantial reduction in the risk of cytomegalovirus infection, and evidence for inhibition of cardiac allograft vasculopathy, a major cause of graft loss. The ongoing MANDELA study is a 12-month multicenter, randomized, open-label, parallel-group study in which efficacy, renal function and safety are compared in approximately 200 heart transplant patients. Patients receive CNI therapy, steroids and everolimus or mycophenolic acid during months 3 to 6 post-transplant, and are then randomized at month 6 post-transplant (i) to convert to CNI-free immunosuppression with everolimus and mycophenolic acid or (ii) to continue reduced-exposure CNI, with concomitant everolimus. Patients are then followed to month 18 post-transplant The rationale and expectations for the trial and its methodology are described herein.

  11. Reflections 1 year into the 21-Center National Institutes of Health--funded WRIST study: a primer on conducting a multicenter clinical trial.

    PubMed

    2013-06-01

    The Wrist and Radius Injury Surgery Trial (WRIST) study group is a collaboration of 21 hand surgery centers in the United States, Canada, and Singapore, to showcase the interest and capability of hand surgeons to conduct a multicenter clinical trial. The WRIST study group was formed in response to the seminal systematic review by Margaliot et al and the Cochrane report that indicated marked deficiency in the quality of evidence in the distal radius fracture literature. Since the initial description of this fracture by Colles in 1814, over 2,000 studies have been published on this subject; yet, high-level studies based on the principles of evidence-based medicine are lacking. As we continue to embrace evidence-based medicine to raise the quality of research, the lessons learned during the organization and conduct of WRIST can serve as a template for others contemplating similar efforts. This article traces the course of WRIST by sharing the triumphs and, more important, the struggles faced in the first year of this study.

  12. Effectiveness and Safety of Electroacupuncture on Poststroke Urinary Incontinence: Study Protocol of a Pilot Multicentered, Randomized, Parallel, Sham-Controlled Trial

    PubMed Central

    2016-01-01

    This pilot multicentered, randomized, parallel, sham-controlled trial is intended to evaluate the effectiveness and safety of electroacupuncture therapy for poststroke patients with urinary incontinence. Forty stroke survivors aged >19 years will be recruited in 2 hospitals in the Republic of Korea. Patients who experienced stroke within 2 years and satisfy criteria of urinary frequencies ≥2 with either 3 to 4 points on the Patient Perception of Intensity of Urgency Scale or 13 points or more on the Korean version of the International Prostate Symptom Scale (K-IPSS) will be identified, along with other eligibility criteria. Patients will be randomly allocated to either a treatment or control group to receive 10 sessions of electroacupuncture or sham therapies, respectively. Patients and outcome assessors will be blinded. The primary outcome is the change of Total Urgency and Frequency Score between the baseline and the trial endpoint. The K-IPSS, the International Consultation on Incontinence Questionnaire for Urinary Incontinence Short Form, and the Lower Urinary Tract Symptoms Outcome Score will be evaluated for effectiveness assessment. Adverse events will be reported after every session. The Blinding Index will also be calculated. Data will be statistically analyzed with 0.05 significance levels by 2-sided testing. PMID:28042304

  13. A review of the 2001 Volvo Award winner in clinical studies: lumbar fusion versus nonsurgical treatment for chronic low back pain: a multicenter randomized controlled trial from the Swedish lumbar spine study group.

    PubMed

    Kwon, Brian; Katz, Jeffrey N; Kim, David H; Jenis, Louis G

    2006-01-15

    The current debate over the efficacy of lumbar fusion for low back pain has not been settled. Fritzell et al published a landmark paper entitled "Lumbar fusion versus nonsurgical treatment for chronic low back pain: a multicenter randomized controlled trial from the Swedish lumbar spine study group." Their goal was to provide objective evidence supporting lumbar fusion. While it was well designed and important to our knowledge base, it has limitations. We set out to review their work in an unbiased yet critical manner. Our goals are to summarize the strengths and weaknesses of the paper, place it in the context of current knowledge, and highlight its significance for present-day practice and research. From technical and study design perspectives, Fritzell et al were able to validate the use of lumbar fusion for the treatment of low back pain. However, their use of "usual nonoperative" care and nonspecific definition of low back pain precluded a truly genuine comparison of operative and nonoperative groups. We commend the Swedish lumbar spine study group and their remarkable efforts; they elevated the sophistication of spine research and spawned many more excellent works to help settle the ongoing controversy on the ideal treatment of low back pain.

  14. Rare cancer trial design: lessons from FDA approvals.

    PubMed

    Gaddipati, Himabindu; Liu, Ke; Pariser, Anne; Pazdur, Richard

    2012-10-01

    A systematic analysis of clinical trials supporting rare cancer drug approvals may identify concepts and terms that can inform the effective design of prospective clinical trials for rare cancers. In this article, using annual incidence ≤6 of 100,000 individuals to define "rare cancer," we identified clinical trials for rare cancers, supporting U.S. Food and Drug Administration (FDA) drug approvals for rare cancer indications between December 1987 and May 2011. We characterized each selected trial for study design, sample size, primary efficacy endpoints, and statistical comparisons. We also profiled trials with regard to type of submission, review designation, and approval type. Our results indicated that, of 99 trials that supported the approvals of 45 drugs for 68 rare cancer indications, one third of these trials were randomized; 69% of approvals relied on objective response rate as the primary efficacy endpoint; and 63% were based on a single trial. Drugs granted accelerated approval appeared more likely to be associated with postmarketing safety findings, relative to drugs approved under the regular approval. Data collected across clinical trials were robust: Use of different lower incidence rates in analyzing these trials did not have effects on trial characteristics. The absolute number of drug approvals for rare cancer indications increased markedly over time. We concluded that one third of clinical trials supporting drug approvals for rare cancer indications were randomized, affirming the feasibility and value of randomized trial design to evaluate drugs for rare cancers. Postmarketing safety data may relate to trial design and approval type. An operational definition of "rare cancer" can be useful for the analysis of trial data and for the path toward harmonizing the terminology in the area of clinical research on rare cancers.

  15. Water exchange for screening colonoscopy increases adenoma detection rate: a multicenter, double-blinded, randomized controlled trial.

    PubMed

    Cadoni, Sergio; Falt, Přemysl; Rondonotti, Emanuele; Radaelli, Franco; Fojtik, Petr; Gallittu, Paolo; Liggi, Mauro; Amato, Arnaldo; Paggi, Silvia; Smajstrla, Vit; Urban, Ondřej; Erriu, Matteo; Koo, Malcolm; Leung, Felix W

    2017-03-10

    per procedure was significantly higher with water exchange (P = 0.04). Water exchange achieved the highest cleanliness scores (overall and in the right colon). These variables were comparable between water immersion and air insufflation. Conclusions The design with blinded observers strengthens the validity of the observation that water exchange, but not water immersion, can achieve significantly higher adenoma detection than air insufflation. Based on this evidence, the use of water exchange should be encouraged.Trial registered at ClinicalTrials.gov (NCT02041507).

  16. Design and conduct of clinical trials in osteoarthritis.

    PubMed

    Altman, R D

    1990-01-01

    Clinical features of osteoarthritis (OA) require that general recommendations for the design and conduct of clinical trials be modified in order to apply these concepts to clinical trials in OA. A format has been devised for design of clinical trials in OA. In order to assess the applicability of this format, it has been compared to a published clinical trial: chondroprotective agents versus standard treatment of OA of the knee. The published study appeared reliably designed and conducted in a manner that provided an answer to most of the questions posed. The study appears to form a sound basis for additional studies.

  17. Effects of Two Chinese Herbal Formulae for the Treatment of Moderate to Severe Stable Chronic Obstructive Pulmonary Disease: A Multicenter, Double-Blind, Randomized Controlled Trial

    PubMed Central

    Cao, Yuxue; Du, Yijie; Zhang, Hongying; Luo, Qingli; Li, Bei; Wu, Jinfeng; Lv, Yubao; Sun, Jing; Jin, Hualiang; Wei, Kai; Zhao, Zhengxiao; Kong, Lingwen; Zhou, Xianmei; Miao, Qing; Wang, Gang; Zhou, Qingwei; Dong, Jingcheng

    2014-01-01

    Objective The study aims to evaluate the efficacy and safety of two Chinese herbal formulae for the treatment of stable COPD. Methods A multicenter, double-blind, double-dummy, and randomized controlled trial (RCT) was conducted. All groups were treated with additional conventional medicines. There were a 6-month treatment and a 12-month follow-up for 5 times. Primary outcomes included lung function test, exacerbation frequency, score of SGRQ. Second outcomes consisted of 6MWD, BODE index, psychological field score, inflammatory factors and cortisol. Results A total of 331 patients were randomly divided into two active treatment groups (Bushen Yiqi (BY) granule group, n = 109; Bushen Fangchuan (BF) tablet group, n = 109) and a placebo group (n = 113). Finally 262 patients completed the study. BY granule & BF tablet increased the values of VC, FEV1 (%) and FEV1/FVC (%), compared with placebo. BY granule improved PEF. Both treatments reduced acute exacerbation frequency (P = 0.067), BODE index and psychological field score, while improved 6MWD. In terms of descent rang of SGRQ score, both treatments increased (P = 0.01). Both treatments decreased inflammatory cytokines, such as IL-8, and IL-17(P = 0.0219). BY granule obviously descended IL-17(P<0.05), IL-1β (P = 0.05), IL-6, compared with placebo. They improved the level of IL-10 and cortisol. BY granule raised cortisol (P = 0.07) and decreased TNF-α. Both treatments slightly descended TGF-β1. In terms of safety, subject compliance and drug combination, there were no differences (P>0.05) among three groups. Conclusions BY granule and BF tablet were positively effective for the treatment of COPD, and the former performed better in general. Trial Registration Chinese Clinical Trial Register center ChiCTR-TRC-09000530 PMID:25118962

  18. Prospective Multicenter Phase II Trial of Systemic ADH-1 in Combination With Melphalan via Isolated Limb Infusion in Patients With Advanced Extremity Melanoma

    PubMed Central

    Beasley, Georgia M.; Riboh, Jonathan C.; Augustine, Christina K.; Zager, Jonathan S.; Hochwald, Steven N.; Grobmyer, Stephen R.; Peterson, Bercedis; Royal, Richard; Ross, Merrick I.; Tyler, Douglas S.

    2011-01-01

    Purpose Isolated limb infusion (ILI) with melphalan (M-ILI) dosing corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit melanoma with a 29% complete response rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes. In a preclinical animal model, systemic ADH-1 given with regional melphalan demonstrated synergistic antitumor activity, and in a phase I trial with M-ILI it had minimal toxicity. Patients and Methods Patients with American Joint Committee on Cancer (AJCC) stage IIIB or IIIC extremity melanoma were treated with 4,000 mg of ADH-1, administered systemically on days 1 and 8, and with M-ILI corrected for IBW on day 1. Drug pharmacokinetics and N-cadherin immunohistochemical staining were performed on pretreatment tumor. The primary end point was response at 12 weeks determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Results In all, 45 patients were enrolled over 15 months at four institutions. In-field responses included 17 patients with complete responses (CRs; 38%), 10 with partial responses (22%), six with stable disease (13%), eight with progressive disease (18%), and four (9%) who were not evaluable. Median duration of in-field response among the 17 CRs was 5 months, and median time to in-field progression among 41 evaluable patients was 4.6 months (95% CI, 4.0 to 7.1 months). N-cadherin was detected in 20 (69%) of 29 tumor samples. Grade 4 toxicities included creatinine phosphokinase increase (four patients), arterial injury (one), neutropenia (one), and pneumonitis (one). Conclusion To the best of our knowledge, this phase II trial is the first prospective multicenter ILI trial and the first to incorporate a targeted agent in an attempt to augment antitumor responses to regional chemotherapy. Although targeting N-cadherin may improve melanoma sensitivity to chemotherapy, no difference in response to treatment was seen in this study. PMID:21343562

  19. Is Surgery for Displaced, Midshaft Clavicle Fractures in Adults Cost-Effective? Results Based on a Multicenter Randomized Controlled Trial

    PubMed Central

    2010-01-01

    Objectives To determine the cost-effectiveness of open reduction internal fixation (ORIF) of displaced, midshaft clavicle fractures in adults. Design Formal cost-effectiveness analysis based on a prospective, randomized controlled trial. Setting Eight hospitals in Canada (seven university affiliated and one community hospital) Patients/Participants 132 adults with acute, completely displaced, midshaft clavicle fractures Intervention Clavicle ORIF versus nonoperative treatment Main Outcome Measurements Utilities derived from SF-6D Results The base-case cost per quality adjusted life year (QALY) gained for ORIF was $65,000. Cost-effectiveness improved to $28,150/QALY gained when the functional benefit from ORIF was assumed to be permanent, with cost per QALY gained falling below $50,000 when the functional advantage persisted for 9.3 years or more. In other sensitivity analyses, the cost per QALY gained for ORIF fell below $50,000 when ORIF cost less than $10,465 (base case cost $13,668) or the long-term utility difference between nonoperative treatment and ORIF was greater than 0.034 (base-case difference 0.014). Short-term disutility associated with fracture healing also affected cost-effectiveness, with the cost per QALY gained for ORIF falling below $50,000 when the utility of a fracture treated nonoperatively prior to union was less than 0.617 (base-case utility 0.706) or when nonoperative treatment increased the time to union by 20 weeks (base-case difference 12 weeks). Conclusions The cost-effectiveness of ORIF after acute clavicle fracture depended on the durability of functional advantage for ORIF compared to nonoperative treatment. When functional benefits persisted for more than 9 years, ORIF had favorable value compared with many accepted health interventions. PMID:20577073

  20. Reinforcement learning design for cancer clinical trials

    PubMed Central

    Zhao, Yufan; Kosorok, Michael R.; Zeng, Donglin

    2009-01-01

    Summary We develop reinforcement learning trials for discovering individualized treatment regimens for life-threatening diseases such as cancer. A temporal-difference learning method called Q-learning is utilized which involves learning an optimal policy from a single training set of finite longitudinal patient trajectories. Approximating the Q-function with time-indexed parameters can be achieved by using support vector regression or extremely randomized trees. Within this framework, we demonstrate that the procedure can extract optimal strategies directly from clinical data without relying on the identification of any accurate mathematical models, unlike approaches based on adaptive design. We show that reinforcement learning has tremendous potential in clinical research because it can select actions that improve outcomes by taking into account delayed effects even when the relationship between actions and outcomes is not fully known. To support our claims, the methodology's practical utility is illustrated in a simulation analysis. In the immediate future, we will apply this general strategy to studying and identifying new treatments for advanced metastatic stage IIIB/IV non-small cell lung cancer, which usually includes multiple lines of chemotherapy treatment. Moreover, there is significant potential of the proposed methodology for developing personalized treatment strategies in other cancers, in cystic fibrosis, and in other life-threatening diseases. PMID:19750510

  1. Personalized radiotherapy: concepts, biomarkers and trial design

    PubMed Central

    Redalen, K R

    2015-01-01

    In the past decade, and pointing onwards to the immediate future, clinical radiotherapy has undergone considerable developments, essentially including technological advances to sculpt radiation delivery, the demonstration of the benefit of adding concomitant cytotoxic agents to radiotherapy for a range of tumour types and, intriguingly, the increasing integration of targeted therapeutics for biological optimization of radiation effects. Recent molecular and imaging insights into radiobiology will provide a unique opportunity for rational patient treatment, enabling the parallel design of next-generation trials that formally examine the therapeutic outcome of adding targeted drugs to radiation, together with the critically important assessment of radiation volume and dose-limiting treatment toxicities. In considering the use of systemic agents with presumed radiosensitizing activity, this may also include the identification of molecular, metabolic and imaging markers of treatment response and tolerability, and will need particular attention on patient eligibility. In addition to providing an overview of clinical biomarker studies relevant for personalized radiotherapy, this communication will highlight principles in addressing clinical evaluation of combined-modality-targeted therapeutics and radiation. The increasing number of translational studies that bridge large-scale omics sciences with quality-assured phenomics end points—given the imperative development of open-source data repositories to allow investigators the access to the complex data sets—will enable radiation oncology to continue to position itself with the highest level of evidence within existing clinical practice. PMID:25989697

  2. Personalized radiotherapy: concepts, biomarkers and trial design.

    PubMed

    Ree, A H; Redalen, K R

    2015-07-01

    In the past decade, and pointing onwards to the immediate future, clinical radiotherapy has undergone considerable developments, essentially including technological advances to sculpt radiation delivery, the demonstration of the benefit of adding concomitant cytotoxic agents to radiotherapy for a range of tumour types and, intriguingly, the increasing integration of targeted therapeutics for biological optimization of radiation effects. Recent molecular and imaging insights into radiobiology will provide a unique opportunity for rational patient treatment, enabling the parallel design of next-generation trials that formally examine the therapeutic outcome of adding targeted drugs to radiation, together with the critically important assessment of radiation volume and dose-limiting treatment toxicities. In considering the use of systemic agents with presumed radiosensitizing activity, this may also include the identification of molecular, metabolic and imaging markers of treatment response and tolerability, and will need particular attention on patient eligibility. In addition to providing an overview of clinical biomarker studies relevant for personalized radiotherapy, this communication will highlight principles in addressing clinical evaluation of combined-modality-targeted therapeutics and radiation. The increasing number of translational studies that bridge large-scale omics sciences with quality-assured phenomics end points-given the imperative development of open-source data repositories to allow investigators the access to the complex data sets-will enable radiation oncology to continue to position itself with the highest level of evidence within existing clinical practice.

  3. Validation of a real-time PCR based method for detection of Clostridium botulinum types C, D and their mosaic variants C-D and D-C in a multicenter collaborative trial.

    PubMed

    Woudstra, Cedric; Skarin, Hanna; Anniballi, Fabrizio; Auricchio, Bruna; De Medici, Dario; Bano, Luca; Drigo, Ilenia; Hansen, Trine; Löfström, Charlotta; Hamidjaja, Raditijo; van Rotterdam, Bart J; Koene, Miriam; Bäyon-Auboyer, Marie-Hélène; Buffereau, Jean-Philippe; Fach, Patrick

    2013-08-01

    Two real-time PCR arrays based on the GeneDisc(®) cycler platform (Pall-GeneDisc Technologies) were evaluated in a multicenter collaborative trial for their capacity to specifically detect and discriminate Clostridium botulinum types C, D and their mosaic variants C-D and D-C that are associated with avian and mammalian botulism. The GeneDisc(®) arrays developed as part of the DG Home funded European project 'AnibioThreat' were highly sensitive and specific when tested on pure isolates and naturally contaminated samples (mostly clinical specimen from avian origin). Results of the multicenter collaborative trial involving eight laboratories in five European Countries (two laboratories in France, Italy and The Netherlands, one laboratory in Denmark and Sweden), using DNA extracts issued from 33 pure isolates and 48 naturally contaminated samples associated with animal botulism cases, demonstrated the robustness of these tests. Results showed a concordance among the eight laboratories of 99.4%-100% for both arrays. The reproducibility of the tests was high with a relative standard deviation ranging from 1.1% to 7.1%. Considering the high level of agreement achieved between the laboratories these PCR arrays constitute robust and suitable tools for rapid detection of C. botulinum types C, D and mosaic types C-D and D-C. These are the first tests for C. botulinum C and D that have been evaluated in a European multicenter collaborative trial.

  4. Advances in designs for Alzheimer's disease clinical trials.

    PubMed

    Cummings, Jeffrey; Gould, Heath; Zhong, Kate

    2012-01-01

    There is an urgent need to identify new treatments for the rapidly growing population of people with Alzheimer's disease (AD). Innovations in clinical trial designs many help to reduce development time, provide more definitive answers regarding drug efficacy, and facilitate prioritizing compounds to be advanced to Phase III clinical trials. Standard designs compare drug and placebo changes from baseline on a rating scale. Baysian adaptive clinical trials allow the use of data collected in the trial to modify doses, sample size, trial duration, and entry criteria in an ongoing way as the data are collected. Disease-modification is supported by findings on staggered start and delayed withdrawal designs. Futility designs can use historical controls and may shorten trial duration. Combination therapy designs may allow investigation of additive or synergistic treatment effects. Novel trial selection criteria allow investigation of treatment effects in asymptomatic or minimally symptomatic, prodromal AD populations. The Clinical Dementia Rating-Sum of Boxes (CDR-SOB) can be considered as a single trial outcome in early disease populations. Alternate forms of the Alzheimer's Disease Assessment Scale-Cognitive Portion (ADAS-cog), computerized measures, and pharmacoeconomic scales provide new and relevant information on drug effects. Comparative dose strategies are used in trials of symptomatic agents, and novel methods including withdrawal designs, symptom emergence analyses, and sequential designs are being utilized to assess the efficacy of putative psychotropic agents. The choice of trial design is driven by the question to be answered by the clinical trial; an increasing number of design approaches are available and may be useful in accelerating and refining AD drug development.

  5. Advances in designs for Alzheimer’s disease clinical trials

    PubMed Central

    Cummings, Jeffrey; Gould, Heath; Zhong, Kate

    2012-01-01

    There is an urgent need to identify new treatments for the rapidly growing population of people with Alzheimer’s disease (AD). Innovations in clinical trial designs many help to reduce development time, provide more definitive answers regarding drug efficacy, and facilitate prioritizing compounds to be advanced to Phase III clinical trials. Standard designs compare drug and placebo changes from baseline on a rating scale. Baysian adaptive clinical trials allow the use of data collected in the trial to modify doses, sample size, trial duration, and entry criteria in an ongoing way as the data are collected. Disease-modification is supported by findings on staggered start and delayed withdrawal designs. Futility designs can use historical controls and may shorten trial duration. Combination therapy designs may allow investigation of additive or synergistic treatment effects. Novel trial selection criteria allow investigation of treatment effects in asymptomatic or minimally symptomatic, prodromal AD populations. The Clinical Dementia Rating-Sum of Boxes (CDR-SOB) can be considered as a single trial outcome in early disease populations. Alternate forms of the Alzheimer’s Disease Assessment Scale-Cognitive Portion (ADAS-cog), computerized measures, and pharmacoeconomic scales provide new and relevant information on drug effects. Comparative dose strategies are used in trials of symptomatic agents, and novel methods including withdrawal designs, symptom emergence analyses, and sequential designs are being utilized to assess the efficacy of putative psychotropic agents. The choice of trial design is driven by the question to be answered by the clinical trial; an increasing number of design approaches are available and may be useful in accelerating and refining AD drug development. PMID:23383393

  6. Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life.

    PubMed

    Saccardi, Riccardo; Mancardi, Gian Luigi; Solari, Alessandra; Bosi, Alberto; Bruzzi, Paolo; Di Bartolomeo, Paolo; Donelli, Amedea; Filippi, Massimo; Guerrasio, Angelo; Gualandi, Francesca; La Nasa, Giorgio; Murialdo, Alessandra; Pagliai, Francesca; Papineschi, Federico; Scappini, Barbara; Marmont, Alberto M

    2005-03-15

    Hematopoietic stem cell transplantation (HSCT) has been proposed for the treatment of severe multiple sclerosis (MS). In a phase 2 multicenter study we selected 19 non-primary progressive MS patients showing high disease activity on the basis of both brain magnetic resonance imaging (MRI) and sustained clinical deterioration despite conventional treatments. After stem cell mobilization with cyclophosphamide (CY) and filgrastim, patients were conditioned with BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea), cytosine arabinoside, etoposide, and melphalan (BEAM) followed by antithymocyte globulin (ATG). Unmanipulated peripheral blood stem cells (PBSCs) were then infused. No maintenance treatment was administered with a median follow-up of 36 months (range, 12 to 72 months). All patients showed clinical stabilization or improvement; 3 subsequently deteriorated, 1 beyond the baseline. No MRI active lesions were detected after the HSCT except in 1 patient who showed a new lesion at 4.5 years. Infections were limited and restricted to 3 months after HSCT. Health-related quality of life was assessed through the 54-item MS quality of life (MSQOL-54) questionnaire, showing a statistically significant improvement in both composite scores and in most of the individual domains. HSCT is able to induce a prolonged clinical stabilization in severe progressive MS patients, resulting in both sustained treatment-free periods and quality of life improvement.

  7. Safety of Daily Albuterol in Infants with a History of Bronchospasm: A Multi-Center Placebo Controlled Trial§

    PubMed Central

    Hedrick, James A; Baker, James W; Atlas, Arthur B; Naz, Aftab A; Lincourt, William R; Trivedi, Roopa; Ellworth, Anna; Davis, Angela M

    2009-01-01

    Introduction: Inhaled short-acting bronchodilators are recommended for the quick relief of bronchospasm symptoms in children including those less than five years of age. However, limited safety data is available in this young population. Methods: Safety data were analyzed from a randomized, double-blind, parallel group, placebo-controlled multicenter, study evaluating albuterol HFA 90µg or 180µg versus placebo three times a day for 4 weeks using a valved holding chamber, Aerochamber Plus and facemask in children birth ≤24 months old with a history of bronchospasm. Results: The overall incidence of adverse events (AE) during treatment was: albuterol 90µg (59%), albuterol 180µg (76%) and placebo (71%). The most frequently reported AEs were pyrexia in 7 (24%), 2 (7%), and 3 (11%) subjects in the albuterol 180µg, albuterol 90µg, and placebo groups, respectively. Upper respiratory tract infection (URTI) occurred in 5 (17%) and 3 (11%) subjects in the albuterol 180µg and placebo groups, respectively. Sinus tachycardia occurred in 5 (17%), 2 (7%) and 2 (7%) subjects receiving albuterol 180µg, albuterol 90µg and placebo, respectively. One subject in each of the albuterol treatment groups experienced drug related agitation and/or restlessness or mild sinus arrhythmia. No drug-related QT prolongation or abnormal serum potassium and glucose levels were reported in the albuterol treatment groups. Conclusion: This study provides additional albuterol HFA safety information for the treatment of children aged birth ≤24 months with a history of bronchospasm. PMID:19639035

  8. Autologous whole blood versus corticosteroid local injection in treatment of plantar fasciitis: A randomized, controlled multicenter clinical trial.

    PubMed

    Karimzadeh, Afshin; Raeissadat, Seyed Ahmad; Erfani Fam, Saleh; Sedighipour, Leyla; Babaei-Ghazani, Arash

    2017-03-01

    Plantar fasciitis is the most common cause of heel pain. Local injection modalities are among treatment options in patients with resistant pain. The aim of the present study was to evaluate the effect of local autologous whole blood compared with corticosteroid local injection in treatment of plantar fasciitis. In this randomized controlled multicenter study, 36 patients with chronic plantar fasciitis were recruited. Patients were allocated randomly into three treatment groups: local autologous blood, local corticosteroid injection, and control groups receiving no injection. Patients were assessed with visual analog scale (VAS), pressure pain threshold (PPT), and plantar fasciitis pain/disability scale (PFPS) before treatment, as well as 4 and 12 weeks post therapy. Variables of pain and function improved significantly in both corticosteroid and autologous blood groups compared to control group. At 4 weeks following treatment, patients in corticosteroid group had significantly lower levels of pain than patients in autologous blood and control groups (higher PPT level, lower PFPS, and VAS). After 12 weeks of treatment, both corticosteroid and autologous blood groups had lower average levels of pain than control group. The corticosteroid group showed an early sharp and then more gradual improvement in pain scores, but autologous blood group had a steady gradual drop in pain. Autologous whole blood and corticosteroid local injection can both be considered as effective methods in the treatment of chronic plantar fasciitis. These treatments decrease pain and significantly improve function compared to no treatment.

  9. End points and clinical trial design in pulmonary arterial hypertension.

    PubMed

    McLaughlin, Vallerie V; Badesch, David B; Delcroix, Marion; Fleming, Thomas R; Gaine, Sean P; Galiè, Nazzareno; Gibbs, J Simon R; Kim, Nick H; Oudiz, Ronald J; Peacock, Andrew; Provencher, Steeve; Sitbon, Olivier; Tapson, Victor F; Seeger, Werner

    2009-06-30

    New and emerging therapies might provide benefit in patients with pulmonary arterial hypertension. Their efficacy and safety will be compared with existing combination therapies in randomized clinical trials. Appropriate end points for these trials need to be identified: these will include exercise testing, the composite end point of time to clinical worsening, and hemodynamic markers, including advanced imaging modalities and biomarkers. Quality-of-life questionnaires are useful and important secondary end points; pulmonary arterial hypertension-specific questionnaires are currently being developed. Advantages and disadvantages of various trial designs, including placebo-controlled monotherapy or add-on trials, noninferiority studies, and withdrawal trials are also discussed.

  10. Assessing the effectiveness and cost effectiveness of subcutaneous nerve stimulation in patients with predominant back pain due to failed back surgery syndrome (SubQStim study): study protocol for a multicenter randomized controlled trial

    PubMed Central

    2013-01-01

    Background Chronic radicular pain can be effectively treated with spinal cord stimulation, but this therapy is not always sufficient for chronic back pain. Subcutaneous nerve stimulation (SQS) refers to the placement of percutaneous leads in the subcutaneous tissue within the area of pain. Case series data show that failed back surgery syndrome (FBSS) patients experience clinically important levels of pain relief following SQS and may also reduce their levels of analgesic therapy and experience functional well-being. However, to date, there is no randomized controlled trial evidence to support the use of SQS in FBSS. Methods/Design The SubQStim study is a multicenter randomized controlled trial comparing SQS plus optimized medical management (‘SQS arm’) versus optimized medical management alone (‘OMM arm’) in patients with predominant back pain due to FBSS. Up to 400 patients will be recruited from approximately 33 centers in Europe and Australia and will be randomized 1:1 to the SQS or OMM arms. After 9 months, patients who fail to reach the primary outcome will be allowed to switch treatments. Patients will be evaluated at baseline (prior to randomization) and at 1, 3, 6, 9, 12, 18, 24, and 36 months after randomization. The primary outcome is the proportion of patients at 9 months with a ≥50% reduction in back pain intensity compared to baseline. The secondary outcomes are: back and leg pain intensity score, functional disability, health-related quality of life, patient satisfaction, patient global impression of change, healthcare resource utilization/costs, cost-effectiveness analysis and adverse events. Outcomes arms will be compared between SQS and OMM arms at all evaluation points up to and including 9 months. After the 9-month assessment visit, the main analytic focus will be to compare within patient changes in outcomes relative to baseline. Discussion The SubQStim trial began patient recruitment in November 2012. Recruitment is expected to close

  11. Evaluation of Cross-Calibrated 68Ge/68Ga Phantoms for Assessing PET/CT Measurement Bias in Oncology Imaging for Single- and Multicenter Trials

    PubMed Central

    Byrd, Darrin W.; Doot, Robert K.; Allberg, Keith C.; MacDonald, Lawrence R.; McDougald, Wendy A.; Elston, Brian F.; Linden, Hannah M.; Kinahan, Paul E.

    2016-01-01

    Quantitative PET imaging is an important tool for clinical trials evaluating the response of cancers to investigational therapies. The standardized uptake value, used as a quantitative imaging biomarker, is dependent on multiple parameters that may contribute bias and variability. The use of long-lived, sealed PET calibration phantoms offers the advantages of known radioactivity activity concentration and simpler use than aqueous phantoms. We evaluated scanner and dose calibrator sources from two batches of commercially available kits, together at a single site and distributed across a local multicenter PET imaging network. We found that radioactivity concentration was uniform within the phantoms. Within the regions of interest drawn in the phantom images, coefficients of variation of voxel values were less than 2%. Across phantoms, coefficients of variation for mean signal were close to 1%. Biases of the standardized uptake value estimated with the kits varied by site and were seen to change in time by approximately ±5%. We conclude that these biases cannot be assumed constant over time. The kits provide a robust method to monitor PET scanner and dose calibrator biases, and resulting biases in standardized uptake values. PMID:28066807

  12. Efficacy and Tolerability of Paliperidone Extended-release in the Treatment of First-episode Psychosis: An Eight-week, Open-label, Multicenter Trial

    PubMed Central

    Kang, Nam-In; Koo, Bon-Hoon; Kim, Sung-Wan; Kim, Jong-Hoon; Nam, Beomwoo; Lee, Bong-Ju; Lee, Sang-Hyuk; Lee, Seung Jae; Lee, Seung-Hwan; Jung, Myung Hun; Hahn, Sang Woo; Chung, Young-Chul

    2016-01-01

    Objective We investigated the efficacy and tolerability of paliperidone extended-release (ER) tablets in patients with first-episode psychosis (n=75). Methods This was an 8-week, open-label, multicenter trial. The primary outcome variable was scores on the Positive and Negative Syndrome Scale (PANSS); secondary measures included the Scale for the Assessment of Negative Symptoms (SANS), the Cognitive Assessment Interview (CAI), and the Global Assessment of Functioning (GAF). To assess safety, we measured drug-related adverse events, weight, lipid-related variables, and prolactin and administered the Simpson–Angus Rating Scale (SARS), the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia Scale (BAS), the Arizona Sexual Experiences Scale (ASEX), and the Udvalg for Kliniske Undersogelser side effect rating scale (UKU). Results The administration of paliperidone ER resulted in significant improvement in the PANSS, SANS, CAI, and GAF scores (p<0.001) over time. This improvement was evident as early as 1 week. The most frequent adverse events were akathisia, somnolence, anxiety, and sedation, which were well tolerated. Modest increases in weight and lipid profiles were also noted. Prolactin levels were substantially increased at the endpoint in both male and female patients. Conclusion These results indicate that paliperidone ER is effective and is characterized by good tolerability in the treatment of positive and negative symptoms and cognitive functioning in first-episode psychosis. PMID:27489380

  13. Comparable Renal Function at 6 Months with Tacrolimus Combined with Fixed-Dose Sirolimus or MMF: Results of a Randomized Multicenter Trial in Renal Transplantation.

    PubMed

    Van Gurp, Eveline; Bustamante, Jesus; Franco, Antonio; Rostaing, Lionel; Becker, Thomas; Rondeau, Eric; Czajkowski, Zenon; Rydzewski, Andrzej; Alarcon, Antonio; Bachleda, Petr; Samlik, Jiri; Burmeister, Dirk; Pallardo, Luis; Moal, Marie-Christine; Rutkowski, Boleslaw; Wlodarczyk, Zbigniew

    2010-01-01

    In a multicenter trial, renal transplant recipients were randomized to tacrolimus with fixed-dose sirolimus (Tac/SRL, N = 318) or tacrolimus with MMF (Tac/MMF, N = 316). Targeted tacrolimus trough levels were lower in the Tac/SRL group after day 14. The primary endpoint was renal function at 6 months using creatinine clearance (Cockcroft-Gault) and was comparable at 66.4 mL/min (SE 1.4) with Tac/SRL and at 65.2mL/min (SE 1.3) with Tac/MMF (completers). Biopsy-confirmed acute rejection was 15.1% (Tac/SRL) and 12.3% (Tac/MMF). In both groups, graft survival was 93% and patient survival was 99.0%. Premature withdrawal due to an adverse event was twice as high in the Tac/SRL group, 15.1% versus 6.3%. Hypercholesterolemia incidence was higher with Tac/SRL (P < .05) while CMV, leukopenia, and diarrhea incidences were higher with Tac/MMF (P < .05). The incidence of any antidiabetic treatment for >30 consecutive days in previously nondiabetic patients was 17.8%, Tac/SRL, and 24.8%, Tac/MMF. Evaluation at 6 months showed comparable renal function using tacrolimus/sirolimus and tacrolimus/MMF regimens.

  14. Novel therapies for resistant focal segmental glomerulosclerosis (FONT) phase II clinical trial: study design

    PubMed Central

    2011-01-01

    Background The lack of adequate randomized clinical trials (RCT) has hindered identification of new therapies that are safe and effective for patients with primary focal segmental glomerulosclerosis (FSGS), especially in patients who fail to respond to corticosteroids and immunosuppressive therapies. Recent basic science advances have led to development of alternative treatments that specifically target aberrant pathways of fibrosis which are relevant to disease progression in FSGS. There is a need for a flexible Phase II study design which will test such novel antifibrotic strategies in order to identify agents suitable for phase III testing. Methods/Design The Novel Therapies for Resistant Focal Segmental Glomerulosclerosis (FONT) project is a multicenter Phase I/II RCT designed to investigate the potential efficacy of novel therapies for resistant FSGS. Adalimumab and galactose will be evaluated against conservative therapy consisting of the combination of lisinopril, losartan and atorvastatin. The sample size is defined to assure that if one of the treatments has a superior response rate compared to that of the other treatments, it will be selected with high probability for further evaluation. Comparison of primary and secondary endpoints in each study arm will enable a choice to be made of which treatments are worthy of further study in future Phase III RCT. Discussion This report highlights the key features of the FONT II RCT including the two-step outcome analysis that will expedite achievement of the study objectives. The proposed phase II study design will help to identify promising agents for further testing while excluding ineffective agents. This staged approach can help to prevent large expenditures on unworthy therapeutic agents in the management of serious but rare kidney diseases Trial Registration ClinicalTrials.gov, NCT00814255 PMID:21310077

  15. Evaluation of performance of the Omni mode for detecting video capsule endoscopy images: A multicenter randomized controlled trial

    PubMed Central

    Hosoe, Naoki; Watanabe, Kenji; Miyazaki, Takako; Shimatani, Masaaki; Wakamatsu, Takahiro; Okazaki, Kazuichi; Esaki, Motohiro; Matsumoto, Takayuki; Abe, Takayuki; Kanai, Takanori; Ohtsuka, Kazuo; Watanabe, Mamoru; Ikeda, Keiichi; Tajiri, Hisao; Ohmiya, Naoki; Nakamura, Masanao; Goto, Hidemi; Tsujikawa, Tomoyuki; Ogata, Haruhiko

    2016-01-01

    Background and study aims: Olympus recently developed a new algorithm called Omni mode that discards redundant video capsule endoscopy (VCE) images. The current study aimed to demonstrate the non-inferiority of the Omni mode in terms of true positives (TPs) and the superiority of the Omni mode with regard to reading time against a control (ordinary ES-10 system). Patients and methods: This multicenter prospective study included 40 patients with various small bowel diseases. VCE images were evaluated by 7 readers and 3 judging committee members. Two randomly allocated readers assessed the VCE images obtained using the 2 modalities for each patient. The order of the modalities was switched between the 2 readers and the interval between readings by the same reader was 2 weeks. The judging committee predefined clinically relevant lesions as major lesions and irrelevant lesions as minor lesions. The number of TPs for major and minor lesions and the reading times were compared between the modalities. The predefined non-inferiority margin for the TP ratio of the Omni mode compared with the control was 0.9. Results: The estimated TP ratios and 95 % confidence intervals for total, major, and minor lesions were 0.87 (0.80 – 0.95), 0.93 (0.83 – 1.04), and 0.83 (0.74 – 0.94), respectively. Although non-inferiority was not demonstrated, the rate of detection of major lesions was not significantly different between the modalities. The reading time was significantly lower when using the Omni mode than when using the control. Conclusions: The Omni mode may be only appropriate for the assessment of major lesions. PMID:27540577

  16. Intravenous Penciclovir for Treatment of Herpes Simplex Infections in Immunocompromised Patients: Results of a Multicenter, Acyclovir-Controlled Trial

    PubMed Central

    Lazarus, Hillard M.; Belanger, Robert; Candoni, Anna; Aoun, Mickaël; Jurewicz, Regina; Marks, Lynn

    1999-01-01

    The efficacy and safety of penciclovir (PCV) for the treatment of herpes simplex virus (HSV) infections in immunocompromised (IC) patients were studied in a double-blind, acyclovir (ACV)-controlled, multicenter study. A total of 342 patients with mucocutaneous HSV infections received 5 mg of PCV per kg every 12 or 8 h (q12h or q8h) or 5 mg of ACV per kg q8h, beginning within 72 h of lesion onset and continuing for up to 7 days. The mean age of the patients was 49 years; 94% were white and 52% were female. The main reasons for their IC states were hematologic disorder (63%) and transplant plus hematologic disorder (16%). Clinical and virological assessments were performed daily during the 7-day treatment and then every other day until lesion healing. The primary efficacy parameter addressed new lesion formation. Secondary end points focused on viral shedding, healing, and pain. Approximately 20% of patients in each treatment group developed new lesions during therapy; thus, equivalence with ACV (defined prospectively) was demonstrated for both q12h and q8h PCV regimens. For all three treatment groups, the median time to the cessation of viral shedding was 4 days and the median time to complete healing was 8 days; there were no statistically significant differences in the rates of complete healing or the cessation of viral shedding when the results for PCV q12h and q8h were compared with those for ACV q8h. In addition, there was no statistically significant difference between PCV q12h or q8h, compared with ACV q8h, for the resolution of pain. PCV was well tolerated, with an adverse event profile comparable to that of ACV. In conclusion, PCV q12h is a well-tolerated and effective therapy for mucocutaneous HSV infection in IC patients and offers a reduced frequency of dosing compared with ACV q8h. PMID:10223935

  17. Efficacy of Magnesium Trihydrate of Ursodeoxycholic Acid and Chenodeoxycholic Acid for Gallstone Dissolution: A Prospective Multicenter Trial

    PubMed Central

    Hyun, Jong Jin; Lee, Hong Sik; Kim, Chang Duck; Dong, Seok Ho; Lee, Seung-Ok; Ryu, Ji Kon; Lee, Don Haeng; Jeong, Seok; Kim, Tae Nyeun; Lee, Jin; Koh, Dong Hee; Park, Eun Taek; Lee, Inseok; Yoo, Byung Moo; Kim, Jin Hong

    2015-01-01

    Background/Aims Cholecystectomy is necessary for the treatment of symptomatic or complicated gallbladder (GB) stones, but oral litholysis with bile acids is an attractive alternative therapeutic option for asymptomatic or mildly symptomatic patients. This study was conducted to evaluate the efficacy of magnesium trihydrate of ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on gallstone dissolution and to investigate improvements in gallstone-related symptoms. Methods A prospective, multicenter, phase 4 clinical study to determine the efficacy of orally administered magnesium trihydrate of UDCA and CDCA was performed from January 2011 to June 2013. The inclusion criteria were GB stone diameter ≤15 mm, GB ejection fraction ≥50%, radiolucency on plain X-ray, and asymptomatic/mildly symptomatic patients. The patients were prescribed one capsule of magnesium trihydrate of UDCA and CDCA at breakfast and two capsules at bedtime for 6 months. The dissolution rate, response rate, and change in symptom score were evaluated. Results A total of 237 subjects were enrolled, and 195 subjects completed the treatment. The dissolution rate was 45.1% and the response rate was 47.2% (92/195) after 6 months of administration of magnesium trihydrate of UDCA and CDCA. Only the stone diameter was significantly associated with the response rate. Both the symptom score and the number of patients with symptoms significantly decreased regardless of stone dissolution. Adverse events necessitating discontinuation of the drug, surgery, or endoscopic management occurred in 2.5% (6/237) of patients. Conclusions Magnesium trihydrate of UDCA and CDCA is a well-tolerated bile acid that showed similar efficacy for gallstone dissolution and improvement of gallstone-related symptoms as that shown in previous studies. PMID:26087862

  18. Are explanatory trials ethical? Shifting the burden of justification in clinical trial design.

    PubMed

    Borgerson, Kirstin

    2013-08-01

    Most phase III clinical trials today are explanatory. Because explanatory, or efficacy, trials test hypotheses under "ideal" conditions, they are not well suited to providing guidance on decisions made in most clinical care contexts. Pragmatic trials, which test hypotheses under "usual" conditions, are often better suited to this task. Yet, pragmatic, or effectiveness, trials are infrequently carried out. This mismatch between the design of clinical trials and the needs of health care professionals is frustrating for everyone involved, and explains some of the challenges inherent in attempts to enhance knowledge translation and encourage evidence-based practice. The situation is more than simply frustrating, however; it is potentially unethical. Clinical trials must be socially valuable in order to (1) warrant the risks they impose on human research subjects and (2) fairly and efficiently assess new clinical interventions. Most bioethicists would agree that trials that have no social value, for instance, because their results do not have the potential to advance clinical care, should not be performed. What is less widely appreciated is that given limited research resources, trials that are more socially valuable should be preferred to trials that are less socially valuable when all else is equal. With respect to clinical trial design, I argue that while explanatory trials often have some social value, many have less social value than their pragmatic counterparts. On the basis of this general ethical assessment, I provide a preliminary defense of the position that clinical researchers should aim to conduct pragmatic trials, that is, that researchers face a burden of justification related to any idealizing elements added to trial designs.

  19. Pleiotropic effects of sitagliptin versus voglibose in patients with type 2 diabetes inadequately controlled via diet and/or a single oral antihyperglycemic agent: a multicenter, randomized trial

    PubMed Central

    Matsushima, Yukiko; Takeshita, Yumie; Kita, Yuki; Otoda, Toshiki; Kato, Ken-ichiro; Toyama-Wakakuri, Hitomi; Akahori, Hiroshi; Shimizu, Akiko; Hamaguchi, Erika; Nishimura, Yasuyuki; Kanamori, Takehiro; Kaneko, Shuichi; Takamura, Toshinari

    2016-01-01

    Purpose A step-up strategy for diet therapy and/or single oral antihyperglycemic agent (OHA) regimens has not yet been established. The aim of this study was to evaluate hemoglobin A1c (HbA1c) as a primary end point, and the pleiotropic effects on metabolic and cardiovascular parameters as secondary end points, of sitagliptin versus voglibose in patients with type 2 diabetes with inadequate glycemic control while on diet therapy and/or treatment with a single OHA. Methods In this multicenter, randomized, open-label, parallel-group trial, a total of 260 patients with inadequately controlled type 2 diabetes (HbA1c levels >6.9%) were randomly assigned to receive either sitagliptin (50 mg, once daily) or voglibose (0.6 mg, thrice daily) for 12 weeks. The primary end point was HbA1c levels. Results Patients receiving sitagliptin showed a significantly greater decrease in HbA1c levels (−0.78±0.69%) compared with those receiving voglibose (−0.30±0.78%). Sitagliptin treatment also lowered serum alkaline phosphatase levels and increased serum creatinine, uric acid, cystatin-C and homeostasis model assessment-β values. Voglibose increased low-density lipoprotein-cholesterol levels and altered serum levels of several fatty acids, and increased Δ-5 desaturase activity. Both drugs increased serum adiponectin. The incidence of adverse events (AEs) was significantly lower in the sitagliptin group, due to the decreased incidence of gastrointestinal AEs. Conclusions Sitagliptin shows superior antihyperglycemic effects compared with voglibose as a first-line or second-line therapy. However, both agents possess unique pleiotropic effects that lead to reduced cardiovascular risk in Japanese people with type 2 diabetes. Trial registration number UMIN 000003503. PMID:27110370

  20. Phase II, randomized, multicenter, double-blind, placebo-controlled trial of a polyclonal anti-Staphylococcus aureus capsular polysaccharide immune globulin in treatment of Staphylococcus aureus bacteremia.

    PubMed

    Rupp, Mark E; Holley, H Preston; Lutz, Jon; Dicpinigaitis, Peter V; Woods, Christopher W; Levine, Donald P; Veney, Naomi; Fowler, Vance G

    2007-12-01

    New treatment modalities are needed for the treatment of infections due to multidrug-resistant Staphylococcus aureus. S. aureus capsular polysaccharide immune globulin (Altastaph) is a polyclonal immune globulin preparation that is being developed as adjunctive therapy for persons with S. aureus infections complicated by bacteremia. In a phase II, multicenter, randomized, double-blind, placebo-controlled trial, 40 subjects with documented S. aureus bacteremia received standard therapy plus either Altastaph at 200 mg/kg of body weight in each of two infusions 24 h apart or placebo. During the 42-day observation period, antibody pharmacokinetics and safety were the primary characteristics studied. Information regarding the resolution of bacteremia and fever was also analyzed. Anti-type-5 and anti-type-8 capsular antibody levels peaked after the second infusion at 550 mug/ml and 419 mug/ml, respectively, and remained above 100 mug/ml at day 28. A total of 316 adverse events were noted in 39 of 40 subjects. Infusion-related adverse events in Altastaph recipients were infrequent and similar to those among recipients of commercial intravenously administered immunoglobulin G products. Five of 21 (23%) subjects in the Altastaph group died, whereas 2 of 18 (11%) subjects in the placebo group died (P = 0.42). Compared to the control patients, the Altastaph recipients had a shorter median time to the resolution of fever (2 days and 7 days, respectively; P = 0.09) and a shorter length of hospital stay (9 days and 14 days, respectively; P = 0.03). However, these findings are exploratory, and there were few differences in the other variables measured. High levels of opsonizing antibodies were maintained for the initial 4 weeks. Although the study was not powered to show efficacy, these preliminary findings and safety profile suggest that Altastaph may be an effective adjunct to antibiotics and warrants further investigation (ClinicalTrials.gov number NCT00063089).

  1. Preoperative Chemotherapy in Patients With Intermediate-Risk Rectal Adenocarcinoma Selected by High-Resolution Magnetic Resonance Imaging: The GEMCAD 0801 Phase II Multicenter Trial

    PubMed Central

    Brown, Gina; Estevan, Rafael; Salud, Antonieta; Montagut, Clara; Maurel, Joan; Safont, Maria Jose; Aparicio, Jorge; Feliu, Jaime; Vera, Ruth; Alonso, Vicente; Gallego, Javier; Martin, Marta; Pera, Miguel; Sierra, Enrique; Serra, Javier; Delgado, Salvadora; Roig, Jose V.; Santos, Jesus; Pericay, Carles

    2014-01-01

    Background. The need for preoperative chemoradiation or short-course radiation in all T3 rectal tumors is a controversial issue. A multicenter phase II trial was undertaken to evaluate the efficacy and safety of neoadjuvant capecitabine and oxaliplatin combined with bevacizumab in patients with intermediate-risk rectal adenocarcinoma. Methods. We recruited 46 patients with T3 rectal adenocarcinoma selected by magnetic resonance imaging (MRI) who were candidates for (R0) resection located in the middle third with clear mesorectal fascia and who were selected by pelvic MRI. Patients received four cycles of neoadjuvant capecitabine and oxaliplatin combined with bevacizumab (final cycle without bevacizumab) before total mesorectal excision (TME). In case of progression, preoperative chemoradiation was planned. The primary endpoint was overall response rate (ORR). Results. On an intent-to-treat analysis, the ORR was 78% (n = 36; 95% confidence interval [CI]: 63%–89%) and no progression was detected. Pathologic complete response was observed in nine patients (20%; 95% CI: 9–33), and T downstaging was observed in 48%. Forty-four patients proceeded to TME, and all had R0 resection. During preoperative therapy, two deaths occurred as a result of pulmonary embolism and diarrhea, respectively, and one patient died after surgery as a result of peritonitis secondary to an anastomotic leak (AL). A 13% rate of AL was higher than expected. The 24-month disease-free survival rate was 75% (95% CI: 60%–85%), and the 2-year local relapse rate was 2% (95% CI: 0%–11%). Conclusion. In this selected population, initial chemotherapy results in promising activity, but the observed toxicity does not support further investigation of this specific regimen. Nevertheless, these early results warrant further testing of this strategy in an enriched population and in randomized trials. PMID:25209376

  2. A Multicenter, Randomized Clinical Trial of a Cognitive Remediation Program for Childhood Survivors of a Pediatric Malignancy

    ERIC Educational Resources Information Center

    Butler, Robert W.; Copeland, Donna R.; Fairclough, Diane L.; Mulhern, Raymond K.; Katz, Ernest R.; Kazak, Anne E.; Noll, Robert B.; Patel, Sunita K.; Sahler, Olle Jane Z.

    2008-01-01

    Survivors of childhood cancer whose malignancy and/or treatment involved the central nervous system may demonstrate a consistent pattern of neurocognitive deficits. The present study evaluated a randomized clinical trial of the Cognitive Remediation Program (CRP). Participants were 6- to 17-year-old survivors of childhood cancer (N = 161; 35%…

  3. Trial design innovations: Clinical trials for treatment of neuropsychiatric symptoms in Alzheimer's Disease

    PubMed Central

    Zhong, K

    2015-01-01

    Neuropsychiatric symptoms are common in Alzheimer's disease (AD) and other neurodegenerative disorders. Recent progress has been made with clinical trials, advancing new therapies for psychosis in Parkinson's disease (PD), agitation in AD, and apathy in AD. Definitions have emerged for agitation and apathy in patients with cognitive impairment, facilitating recruitment of clinical trial populations. Progress in clinical trial design and the agents being assessed promise to advance therapies for disabling symptoms and improve quality of life for patients and caregivers. PMID:26206713

  4. Trial design innovations: Clinical trials for treatment of neuropsychiatric symptoms in Alzheimer's Disease.

    PubMed

    Cummings, J; Zhong, K

    2015-11-01

    Neuropsychiatric symptoms are common in Alzheimer's disease (AD) and other neurodegenerative disorders. Recent progress has been made with clinical trials, advancing new therapies for psychosis in Parkinson's disease (PD), agitation in AD, and apathy in AD. Definitions have emerged for agitation and apathy in patients with cognitive impairment, facilitating recruitment of clinical trial populations. Progress in clinical trial design and the agents being assessed promise to advance therapies for disabling symptoms and improve quality of life for patients and caregivers.

  5. Maintenance nifedipine therapy for preterm symptomatic placenta previa: A randomized, multicenter, double-blind, placebo-controlled trial

    PubMed Central

    Verspyck, Eric; de Vienne, Claire; Muszynski, Charles; Bubenheim, Michael; Chanavaz-Lacheray, Isabella; Dreyfus, Michel; Deruelle, Philippe; Benichou, Jacques

    2017-01-01

    Objective To assess the impact of maintenance nifedipine therapy on pregnancy duration in women with preterm placenta previa bleeding. Methods PPADAL was a randomized, double-blind, placebo-controlled trial conducted between 05/2008 and 05/2012 in five French hospitals. The trial included 109 women, aged ≥ 18 years, with at least one episode of placenta previa bleeding, intact membranes and no other pregnancy complication, at gestational age 24 to 34 weeks and after 48 hours of complete acute tocolysis. Women were randomly allocated to receive either 20 mg of slow-release nifedipine three times daily (n = 54) or placebo (n = 55) until 36 + 6 weeks of gestation. The primary outcome for the trial was length of pregnancy measured in days after enrolment. Main secondary outcomes were rates of recurrent bleeding, cesarean delivery due to hemorrhage, blood transfusion, maternal side effects, gestational age at delivery and adverse perinatal outcomes (perinatal death, chronic lung disease, neonatal sepsis, intraventricular hemorrhage > grade 2, perventricular leukomalacia > grade 1, or necrotizing enterocolitis). Analysis was by intention to treat. Results Mean (SD) prolongation of pregnancy was not different between the nifedipine (n = 54) and the placebo (n = 55) group; 42.5 days ± 23.8 versus 44.2 days ± 24.5, p = 0.70. Cesarean due to hemorrhage performed before 37 weeks occurred more frequently in the nifedipine group in comparison with the placebo group (RR, 1.66; 95% confidence interval, 1.05–2.72). Adverse perinatal outcomes were comparable between groups; 3.8% for nifedipine versus 5.5% for placebo (relative risk, 0.52; 95% confidence interval 0.10–2.61). No maternal mortality or perinatal death occurred. Conclusion Maintenance oral nifedipine neither prolongs duration of pregnancy nor improves maternal or perinatal outcomes. Trial registration ClinicalTrials.gov NCT00620724 PMID:28333939

  6. A MULTI-CENTER CLUSTER-RANDOMIZED TRIAL OF A MULTI-FACTORIAL INTERVENTION TO IMPROVE ANTIHYPERTENSIVE MEDICATION ADHERENCE AND BLOOD PRESSURE CONTROL AMONG PATIENTS AT HIGH CARDIOVASCULAR RISK (The COM99 study)*

    PubMed Central

    Pladevall, Manel; Brotons, Carlos; Gabriel, Rafael; Arnau, Anna; Suarez, Carmen; de la Figuera, Mariano; Marquez, Emilio; Coca, Antonio; Sobrino, Javier; Divine, George; Heisler, Michele; Williams, L Keoki

    2010-01-01

    Background Medication non-adherence is common and results in preventable disease complications. This study assesses the effectiveness of a multifactorial intervention to improve both medication adherence and blood pressure control and to reduce cardiovascular events. Methods and Results In this multi-center, cluster-randomized trial, physicians from hospital-based hypertension clinics and primary care centers across Spain were randomized to receive and provide the intervention to their high-risk patients. Eligible patients were ≥50 years of age, had uncontrolled hypertension, and had an estimated 10-year cardiovascular risk greater than 30%. Physicians randomized to the intervention group counted patients’ pills, designated a family member to support adherence behavior, and provided educational information to patients. The primary outcome was blood pressure control at 6 months. Secondary outcomes included both medication adherence and a composite end-point of all cause mortality and cardiovascular-related hospitalizations. Seventy-nine physicians and 877 patients participated in the trial. The mean duration of follow-up was 39 months. Intervention patients were less likely to have an uncontrolled systolic blood pressure (odds ratio 0.62; 95% confidence interval [CI] 0.50–0.78) and were more likely to be adherent (OR 1.91; 95% CI 1.19–3.05) when compared with control group patients at 6 months. After five years 16% of the patients in the intervention group and 19% in the control group met the composite end-point (hazard ratio 0.97; 95% CI 0.67–1.39). Conclusions A multifactorial intervention to improve adherence to antihypertensive medication was effective in improving both adherence and blood pressure control, but it did not appear to improve long-term cardiovascular events. PMID:20823391

  7. A Multicenter, Open Labeled, Randomized, Phase III Study Comparing Lopinavir/Ritonavir Plus Atazanavir to Lopinavir/Ritonavir Plus Zidovudine and Lamivudine in Naive HIV-1-Infected Patients: 48-Week Analysis of the LORAN Trial

    PubMed Central

    Ulbricht, K.U; Behrens, G.M; Stoll, M; Salzberger, B; Jessen, H; Jessen, A.B; Kuhlmann, B; Heiken, H; Trein, A; Schmidt, R.E

    2011-01-01

    Objective: The primary aim of the study was to compare the metabolic side effects of a nucleoside analogue-containing regimen with a nucleoside analogue-sparing double protease inhibitor regimen. A secondary goal was to test for efficacy of a double-PI regimen. Design: Multicenter, randomized, open-label, phase III clinical trial. Subjects: Adult HIV-1-infected individuals naïve to antiretroviral therapy with viral load above 400 HIV-RNA copies/ml were randomized (1:1) to either 400 mg lopinavir /100 mg ritonavir (LPV/r) BID plus 150 mg lamivudine/300 mg zidovudine (CBV) BID versus LPV/r BID plus 300 mg atazanavir (ATV) QD. Main outcome measure was the virologic failure in both groups, defined as viral load ≥50 copies/ml at week 48. Results: In the CBV/LPV/r-arm, 29 out of 35 patients [(83%; 95% confidence interval (CI) 66.9-92.2%] and 18 out of 40 patients (45%; 95% CI 29.7-61.5%) in the ATV/LPV/r-arm had a HIV-RNA level <50 copies/ml at week 48. The intent-to-treat analysis revealed inferior virologic response in the ATV/LPV/r arm (Chi-Q and Fisher´s Exact Test p<0.001) and resulted in premature termination of the trial. Eleven patients in the ATV/LPV/r-arm discontinued therapy because of virological failure. These failures mostly presented with low level replication (<1,000 copies/ml). Increases in CD4 cell counts was significantly more rapid in the ATV/LPV/r arm (p=0.02), but comparable at week 48. Conclusions: ATV/LPV/r had less virologic efficacy than the conventional RTI-based regimen and resulted in a high virological failure rate with low level replication. PMID:21643422

  8. Regadenoson-stress myocardial CT perfusion and single-photon emission CT: rationale, design, and acquisition methods of a prospective, multicenter, multivendor comparison.

    PubMed

    Cury, Ricardo C; Kitt, Therese M; Feaheny, Kathleen; Akin, Jamie; George, Richard T

    2014-01-01

    Pharmacologic stress myocardial CT perfusion (CTP) has been reported to be a viable imaging modality for detection of myocardial ischemia compared with single-photon emission CT (SPECT) in several single-center studies. However, regadenoson-stress CTP has not previously been compared with SPECT in a multicenter, multivendor study. The rationale and design of a phase 2, randomized, cross-over study of regadenoson-stress myocardial perfusion imaging by CTP compared with SPECT are described herein. The study will be conducted at approximately 25 sites by using 6 different CT scanner models, including 64-, 128-, 256-, and 320-slice systems. Subjects with known/suspected coronary artery disease will be randomly assigned to 1 of 2 imaging procedure sequences; rest and regadenoson-stress SPECT on day 1, then regadenoson-stress CTP and rest CTP/coronary CT angiography (same acquisition) on day 2; or regadenoson-stress CTP and rest CTP/CT angiography on day 1, then rest and regadenoson-stress SPECT on day 2. The prespecified primary analysis examines the agreement rate between CTP and SPECT for detecting or excluding ischemia (≥2 or 0-1 reversible defects, respectively), as assessed by 3 independent blinded readers for each modality. Non-inferiority will be indicated if the lower boundary of the 95% CI for the agreement rate is within 0.15 of 0.78 (the observed agreement rate in the regadenoson pivotal trials). The protocol described herein will support the first evaluation of regadenoson-stress CTP by using multiple scanner types compared with SPECT.

  9. Long-term outcomes of palliative colonic stenting versus emergency surgery for acute proximal malignant colonic obstruction: a multicenter trial

    PubMed Central

    Siddiqui, Ali; Cosgrove, Natalie; Yan, Linda H.; Brandt, Daniel; Janowski, Raymond; Kalra, Ankush; Zhan, Tingting; Baron, Todd H.; Repici, Allesandro; Taylor, Linda Jo; Adler, Douglas. G.

    2017-01-01

    Background and study aims Long-term data are limited regarding clinical outcomes of self-expanding metal stents as an alternative for surgery in the treatment of acute proximal MBO. The aim of this study was to compare the long-term outcomes of stenting to surgery for palliation in patients with incurable obstructive CRC for lesions proximal to the splenic flexure. Patients and methods Retrospective multicenter cohort study of obstructing proximal CRC patients with who underwent insertion of a SEMS (n = 69) or surgery (n = 36) from 1999 to 2014. The primary endpoint was relief of obstruction. Secondary endpoints included technical success, duration of hospital stay, early and late adverse events (AEs) and survival. Results Technical success was achieved in 62/69 (89.8 %) patients in the SEMS group and in 36 /36 (100 %) patients who underwent surgery (P = 0.09). In the SEMS group, 10 patients underwent stenting as a bridge to surgery and 59 underwent stent placement for palliation. Clinical relief was achieved in 78 % of patients with stenting and in 100 % of patients who underwent surgery (P < 0.001). Patients with SEMS had significantly less acute AEs compared to the surgery group (7.2 % vs. 30.5 %, P = 0.003). Hospital mortality for the SEMS group was 0 % compared to 5.6 % in the surgery group (P = 0.11). Patients in the SEMS group had a significantly shorter median hospital stay (4 days) as compared to the surgery group (8 days) (P < 0.01). Maintenance of decompression without the recurrence of bowel obstruction until death or last follow-up was lower in the SEMS group (73.9 %) than the surgery group (97.3 %; P = 0.003). SEMS placement was associated with higher long-term complication rates compared to surgery (21 % and 11 % P = 0.27). Late SEMS AEs included occlusion (10 %), migration (5 %), and colonic ulcer (6 %). At 120 weeks, survival in the SEMS group was 5.6 % vs. 0 % in the

  10. Cerebrolysin in vascular dementia: improvement of clinical outcome in a randomized, double-blind, placebo-controlled multicenter trial.

    PubMed

    Guekht, Alla B; Moessler, Herbert; Novak, Philipp H; Gusev, Evgenyi I

    2011-01-01

    No drug to treat vascular dementia (VaD) has yet been approved by the American or European authorities, leaving a large population of patients without effective therapy. Cerebrolysin has a long record of safety and might be efficacious in this condition. We conducted a large, multicenter, double-blind, placebo-controlled study in 242 patients meeting the criteria for VaD. The primary endpoint was the combined outcome of cognition (based on Alzheimer's Disease Assessment Scale Cognitive Subpart, Extended Version [ADAS-cog+] score) and overall clinical functioning (based on Clinician's Interview-Based Impression of Change plus Caregiver Input [CIBIC+] score) assessed after 24 weeks of treatment. Intravenous Cerebrolysin 20 mL was administered once daily over the course of 2 treatment cycles as add-on therapy to basic treatment with acetylsalicylic acid. The addition of Cerebrolysin was associated with significant improvement in both primary parameters. At week 24, ADAS-cog+ score improved by 10.6 points in the Cerebrolysin group, compared with 4.4 points in the placebo group (least squares mean difference, -6.17; P < .0001 vs placebo). CIBIC+ showed a mean improvement of 2.84 in the treatment arm and 3.68 in the placebo arm, a treatment difference of 0.84 (P < .0001 vs placebo). These findings were confirmed by responder analyses demonstrating higher rates in the Cerebrolysin group (ADAS-cog+ improvement of ≥4 points from baseline, 82.1% vs 52.2%; CIBIC+ score of <4 at week 24, 75.3% vs 37.4%; combined response in ADAS-cog+ and CIBIC+, 67.5% vs 27.0%). For Cerebrolysin, the odds ratio for achieving a favorable CIBIC+ response was 5.08 (P < .05), and that for achieving a favorable combined response was 5.63 (P < .05). Our data indicate that the addition of Cerebrolysin significantly improved clinical outcome, and that the benefits persisted for at least 24 weeks. Cerebrolysin was safe and well tolerated.

  11. Collaborative translational research leading to multicenter clinical trials in Duchenne muscular dystrophy: the Cooperative International Neuromuscular Research Group (CINRG).

    PubMed

    Escolar, Diana M; Henricson, Erik K; Pasquali, Livia; Gorni, Ksenija; Hoffman, Eric P

    2002-10-01

    Progress in the development of rationally based therapies for Duchenne muscular dystrophy has been accelerated by encouraging multidisciplinary, multi-institutional collaboration between basic science and clinical investigators in the Cooperative International Research Group. We combined existing research efforts in pathophysiology by a gene expression profiling laboratory with the efforts of animal facilities capable of conducting high-throughput drug screening and toxicity testing to identify safe and effective drug compounds that target different parts of the pathophysiologic cascade in a genome-wide drug discovery approach. Simultaneously, we developed a clinical trial coordinating center and an international network of collaborating physicians and clinics where those drugs could be tested in large-scale clinical trials. We hope that by bringing together investigators at these facilities and providing the infrastructure to support their research, we can rapidly move new bench discoveries through animal model screening and into therapeutic testing in humans in a safe, timely and cost-effective setting.

  12. Clinical Trials in Peripheral Vascular Disease: Pipeline and Trial Designs: An Evaluation of the ClinicalTrials.gov Database

    PubMed Central

    Subherwal, Sumeet; Patel, Manesh R.; Chiswell, Karen; Tidemann-Miller, Beth A.; Jones, W. Schuyler; Conte, Michael S.; White, Christopher J.; Bhatt, Deepak L.; Laird, John R.; Hiatt, William R.; Tasneem, Asba; Califf, Robert M.

    2014-01-01

    Background Tremendous advances have occurred in therapies for peripheral vascular disease (PVD); however, until recently it has not been possible to examine the entire clinical trial portfolio of studies for treatment of PVD (both arterial and venous disease). Methods and Results We examined interventional trials registered in ClinicalTrials.gov from October 2007 through September 2010 (n=40,970) and identified 676 (1.7%) PVD trials (n=493 arterial only, n=170 venous only, n=13 both arterial and venous). Most arterial studies investigated lower extremity peripheral artery disease and acute stroke (35% and 24%, respectively), while most venous studies examined deep vein thrombosis/pulmonary embolus prevention (42%) or venous ulceration (25%). A placebo-controlled trial design was used in 27% of the PVD trials, and 4% of the PVD trials excluded patients aged >65 years. Enrollment in at least 1 US site decreased from 51% in 2007 to 41% of trials in 2010. Compared with non-cardiology disciplines, PVD trials were more likely to be double-blinded, investigate use of devices and procedures, and have industry sponsorship and assumed funding source, and less likely to investigate drug and behavioral therapies. Geographic access to PVD clinical trials within the United States is limited to primarily large metropolitan areas. Conclusions PVD studies represent a small group of trials registered in ClinicalTrials.gov, despite the high prevalence of vascular disease in the general population. This low number, compounded by the decreasing number of PVD trials in the United States, is concerning and may limit the ability to inform current clinical practice of patients with PVD. PMID:25239436

  13. OARSI Clinical Trials Recommendations: Design and conduct of clinical trials for hip osteoarthritis.

    PubMed

    Lane, N E; Hochberg, M C; Nevitt, M C; Simon, L S; Nelson, A E; Doherty, M; Henrotin, Y; Herontin, Y; Flechsenhar, K

    2015-05-01

    The ability to assess the efficacy and effectiveness of an intervention for the treatment of hip osteoarthritis (OA) requires strong clinical trial methodology. This consensus paper provides recommendations based on a narrative literature review and best judgment of the members of the committee for clinical trials of hip OA. We provide recommendations on clinical trial design, outcome measures, including structural (radiography), and patient and physician global assessments, performance based measures, molecular markers and experimental endpoints including MRI imaging. This information can be utilized by sponsors of trials for new therapeutic agents for hip OA.

  14. Optimal design of multi-arm multi-stage trials.

    PubMed

    Wason, James M S; Jaki, Thomas

    2012-12-30

    In drug development, there is often uncertainty about the most promising among a set of different treatments. Multi-arm multi-stage (MAMS) trials provide large gains in efficiency over separate randomised trials of each treatment. They allow a shared control group, dropping of ineffective treatments before the end of the trial and stopping the trial early if sufficient evidence of a treatment being superior to control is found. In this paper, we discuss optimal design of MAMS trials. An optimal design has the required type I error rate and power but minimises the expected sample size at some set of treatment effects. Finding an optimal design requires searching over stopping boundaries and sample size, potentially a large number of parameters. We propose a method that combines quick evaluation of specific designs and an efficient stochastic search to find the optimal design parameters. We compare various potential designs motivated by the design of a phase II MAMS trial. We also consider allocating more patients to the control group, as has been carried out in real MAMS studies. We show that the optimal allocation to the control group, although greater than a 1:1 ratio, is smaller than previously advocated and that the gain in efficiency is generally small.

  15. Effects of Poly-Bioactive Compounds on Lipid Profile and Body Weight in a Moderately Hypercholesterolemic Population with Low Cardiovascular Disease Risk: A Multicenter Randomized Trial

    PubMed Central

    Solà, Rosa; Valls, Rosa-M; Puzo, José; Calabuig, José-Ramón; Brea, Angel; Pedret, Anna; Moriña, David; Villar, José; Millán, Jesús; Anguera, Anna

    2014-01-01

    A dietary supplement (AP, Armolipid Plus) that combines red yeast rice extract, policosanol, berberine, folic acid, coenzyme Q10 and asthaxantine can have beneficial effects on cardiovascular disease (CVD) biomarkers. The aim of this study was to assess whether the intake of AP, in combination with dietary recommendations, reduces serum low density lipoprotein cholesterol (LDL-c) concentrations and other CVD biomarkers in patients with hypercholesterolemia. Eligible patients were recruited from the outpatient clinics of six Spanish hospitals Hospital Virgen del Rocío (Sevilla); Hospital San Jorge (Huesca); Hospital San Pedro (Logroño); Hospital Gregorio Marañón (Madrid), Hospital la Fe (Valencia) and Hospital Universitari Sant Joan (Reus) as recruiting and coordinating center. 102 participants (mean age ± SD; 50.91±11.61; 32 men) with low CVD, with mild-to-moderately elevated LDL-c (between 3.35 mmol/L and 4.88 mmol/L) without hypolipemic therapy were randomized in a double-blind, parallel, controlled, multicenter trial commencing January 2012 and ending December 2012. Among the exclusion criteria were any concomitant chronic disease, triglycerides (TG) >3.97 mmol/L, pregnant or lactating, and history of CVD. At 12 weeks, compared to placebo, AP reduced LDL-c by −6.9%, apolipoprotein (Apo) B-100 by −6.6% and total cholesterol/HDL-c ratio by −5.5%, the ApoB/ApoA1 ratio by −8.6%, while increasing ApoA1 by +2.5% (p<0.05). AP consumption was associated with modest mean weight loss of −0.93 kg (95%CI: -1.74 to -0.12; P = 0.02) compared with control group while dietary composition remained unchanged in the AP group. The AP product was well tolerated. In conclusion, AP, combined with dietary recommendations, reduced LDL-c levels as well as total cholesterol/HDL-c and ApoB/ApoA1 ratios, while increasing Apo A1, all of which are improvements in CVD risk indicators. AP is a product which could benefit patients having moderate hyperlipidemia and excess

  16. Design of treatment trials for functional gastrointestinal disorders

    PubMed Central

    van Zanten, S J O V.; Talley, N; Bytzer, P; Klein, K; Whorwell, P; Zinsmeister, A

    1999-01-01

    Until recently many clinical trials of functional gastrointestinal disorders (FGIDs) suffered from important weaknesses in trial design, study execution, and data analysis. This makes it difficult to determine whether truly efficacious therapies exist for these disorders. One of the important methodologic problems is the absence of validated outcome measures and lack of consensus among stakeholders on how to measure outcome. Currently much of the effort is being put into the development of validated outcome measures for several of the FGIDs. The randomized, controlled trial with parallel groups is the design of choice. In this report, guidelines are given for the basic architecture of intervention studies of FGIDs. Further studies on design issues are required to ensure the recommendations will become evidence based in the future.


Keywords: clinical trial; random allocation; functional gastrointestinal disorder(s); dyspepsia; functional dyspepsia; irritable bowel syndrome; evidence based medicine; study design; outcome measures; Rome II PMID:10457048

  17. Multifaceted Intervention to Prevent Venous Thromboembolism in Patients Hospitalized for Acute Medical Illness: A Multicenter Cluster-Randomized Trial

    PubMed Central

    Roy, Pierre-Marie; Rachas, Antoine; Meyer, Guy; Le Gal, Grégoire; Durieux, Pierre; El Kouri, Dominique; Honnart, Didier; Schmidt, Jeannot; Legall, Catherine; Hausfater, Pierre; Chrétien, Jean-Marie; Mottier, Dominique

    2016-01-01

    Background Misuse of thromboprophylaxis may increase preventable complications for hospitalized medical patients. Objectives To assess the net clinical benefit of a multifaceted intervention in emergency wards (educational lectures, posters, pocket cards, computerized clinical decision support systems and, where feasible, electronic reminders) for the prevention of venous thromboembolism. Patients/Methods Prospective cluster-randomized trial in 27 hospitals. After a pre-intervention period, centers were randomized as either intervention (n = 13) or control (n = 14). All patients over 40 years old, admitted to the emergency room, and hospitalized in a medical ward were included, totaling 1,402 (712 intervention and 690 control) and 15,351 (8,359 intervention and 6,992 control) in the pre-intervention and intervention periods, respectively. Results Symptomatic venous thromboembolism or major bleeding (primary outcome) occurred at 3 months in 3.1% and 3.2% of patients in the intervention and control groups, respectively (adjusted odds ratio: 1.02 [95% confidence interval: 0.78–1.34]). The rates of thromboembolism (1.9% vs. 1.9%), major bleedings (1.2% vs. 1.3%), and mortality (11.3% vs. 11.1%) did not differ between the groups. Between the pre-intervention and intervention periods, the proportion of patients who received prophylactic anticoagulant treatment more steeply increased in the intervention group (from 35.0% to 48.2%: +13.2%) than the control (40.7% to 44.1%: +3.4%), while the rate of adequate thromboprophylaxis remained stable in both groups (52.4% to 50.9%: -1.5%; 49.1% to 48.8%: -0.3%). Conclusions Our intervention neither improved adequate prophylaxis nor reduced the rates of clinical events. New strategies are required to improve thromboembolism prevention for hospitalized medical patients. Trial Registration ClinicalTrials.gov NCT01212393 PMID:27227406

  18. Design and execution of clinical trials in orthopaedic surgery

    PubMed Central

    Mundi, R.; Chaudhry, H.; Mundi, S.; Godin, K.; Bhandari, M.

    2014-01-01

    High-quality randomised controlled trials (RCTs) evaluating surgical therapies are fundamental to the delivery of evidence-based orthopaedics. Orthopaedic clinical trials have unique challenges; however, when these challenges are overcome, evidence from trials can be definitive in its impact on surgical practice. In this review, we highlight several issues that pose potential challenges to orthopaedic investigators aiming to perform surgical randomised controlled trials. We begin with a discussion on trial design issues, including the ethics of sham surgery, the importance of sample size, the need for patient-important outcomes, and overcoming expertise bias. We then explore features surrounding the execution of surgical randomised trials, including ethics review boards, the importance of organisational frameworks, and obtaining adequate funding. Cite this article: Bone Joint Res 2014;3:161–8. PMID:24869465

  19. A new design of a polysomnography-based multi-center treatment study for the restless legs syndrome.

    PubMed

    Penzel, T; Brandenburg, U; Peter, J H; Otto, R; Hundemer, H P; Lledo, A; Wetter, T C; Trenkwalder, C

    2002-04-01

    Periodic limb movements (PLM) cause sleep disorders and daytime symptoms and are frequently associated with restless legs syndrome (RLS). Treatment of RLS with increased PLM during sleep (PLMS) has been evaluated in studies limited in size, methodology and study length. This long-term, placebo-controlled, multi-center, study with polysomnography (PSG) recordings has been designed in order to assess efficacy and safety parameters of pergolide treatment in RLS. This novel approach for a study was created to assure consistently high quality of sleep recording and analysis. Using defined criteria, 21 sleep centers were approved for the study after a pilot phase. Seventeen centers with 16 different PSG systems randomized 100 patients. Digital sleep recordings from 4 visits (baseline, 6 weeks, 6 months, 1 year) were submitted to one central evaluation center following previously defined standardized operating procedures. Visual scoring of all recordings was performed by one independent scorer. Reliability of scoring was evaluated for 20 randomly selected baseline recordings. The mean epoch by epoch agreement for sleep stages was 88% (range 81-96%), mean arousal re-scoring differed by 0.5 (range: -16 to 20), and mean PLM index re-scoring differed by 0.1 (range: -1.5 to 2.1). Using one scorer with a demonstrated high reliability in PSG scoring for all sleep recordings was very effective in terms of study cost, study duration, and data quality.

  20. Some epidemiologic, clinical, microbiologic, and organizational assumptions that influenced the design and performance of the Global Enteric Multicenter Study (GEMS).

    PubMed

    Farag, Tamer H; Nasrin, Dilruba; Wu, Yukun; Muhsen, Khitam; Blackwelder, William C; Sommerfelt, Halvor; Panchalingam, Sandra; Nataro, James P; Kotloff, Karen L; Levine, Myron M

    2012-12-01

    The overall aim of the Global Enteric Multicenter Study-1 (GEMS-1) is to identify the etiologic agents associated with moderate-to-severe diarrhea (MSD) among children <5 years of age, and thereby the attributable pathogen-specific population-based incidence of MSD, to guide investments in research and public health interventions against diarrheal disease. To accomplish this, 9 core assumptions were vetted through widespread consultation: (1) a limited number of etiologic agents may be responsible for most MSD; (2) a definition of MSD can be crafted that encompasses cases that might otherwise be fatal in the community without treatment; (3) MSD seen at sentinel centers is a proxy for fatal diarrheal disease in the community; (4) matched case/control is the appropriate epidemiologic design; (5) methods across the sites can be standardized and rigorous quality control maintained; (6) a single 60-day postenrollment visit to case and control households creates mini-cohorts, allowing comparisons; (7) broad support for GEMS-1 messages can be achieved by incorporating advice from public health spokespersons; (8) results will facilitate the setting of investment and intervention priorities; and (9) wide acceptance and dissemination of the GEMS-1 results can be achieved.

  1. Some Epidemiologic, Clinical, Microbiologic, and Organizational Assumptions That Influenced the Design and Performance of the Global Enteric Multicenter Study (GEMS)

    PubMed Central

    Farag, Tamer H.; Nasrin, Dilruba; Wu, Yukun; Muhsen, Khitam; Blackwelder, William C.; Sommerfelt, Halvor; Panchalingam, Sandra; Nataro, James P.; Kotloff, Karen L.; Levine, Myron M.

    2012-01-01

    The overall aim of the Global Enteric Multicenter Study–1 (GEMS-1) is to identify the etiologic agents associated with moderate-to-severe diarrhea (MSD) among children <5 years of age, and thereby the attributable pathogen-specific population-based incidence of MSD, to guide investments in research and public health interventions against diarrheal disease. To accomplish this, 9 core assumptions were vetted through widespread consultation: (1) a limited number of etiologic agents may be responsible for most MSD; (2) a definition of MSD can be crafted that encompasses cases that might otherwise be fatal in the community without treatment; (3) MSD seen at sentinel centers is a proxy for fatal diarrheal disease in the community; (4) matched case/control is the appropriate epidemiologic design; (5) methods across the sites can be standardized and rigorous quality control maintained; (6) a single 60-day postenrollment visit to case and control households creates mini-cohorts, allowing comparisons; (7) broad support for GEMS-1 messages can be achieved by incorporating advice from public health spokespersons; (8) results will facilitate the setting of investment and intervention priorities; and (9) wide acceptance and dissemination of the GEMS-1 results can be achieved. PMID:23169935

  2. A Prospective Multi-center Trial of Escherichia coli Extract for the Prophylactic Treatment of Patients with Chronically Recurrent Cystitis

    PubMed Central

    Kim, Kun Suk; Kim, Ji-Yoon; Jeong, In Gab; Paick, Jae-Seung; Son, Hwancheol; Lim, Dae Jung; Shim, Hong Bang; Park, Won Hee; Jung, Hee Chang

    2010-01-01

    We have assessed the efficacy and safety of Escherichia coli extract (ECE; Uro-Vaxom®) which contains active immunostimulating fractions, in the prophylactic treatment of chronically recurrent cystitis. Forty-two patients with more than 2 episodes of cystitis in the proceeding 6 months were treated for 3 months with one capsule daily of ECE and observed for a further 6 months. The primary efficacy criterion was the number of episodes of recurrent cystitis during the 6 months after treatment compared to those during the 6 months before treatment. At the end of the 9-month trial, 34 patients (all women) were eligible for statistical analysis. Their mean age was 56.4 yr (range, 34-75 yr), and they had experienced recurrent urinary tract infections for 7.2±5.2 yr. The number of recurrences was significantly lower during the 6-month follow-up period than during the 6 months preceding the trial (0.35 vs. 4.26, P<0.001). During the follow-up, 28 (82.4%) patients had no recurrences and 4 (11.8%) had 1 each. In patients who relapsed, ECE alleviated cystitis symptoms, including painful voiding, frequency and urgency. There were no serious adverse events related to the study drug. Our study demonstrates the efficacy and safety of ECE in the prophylactic treatment of chronically recurrent cystitis. PMID:20191044

  3. Effects of Lactobacillus gasseri OLL2716 on Helicobacter pylori-Associated Dyspepsia: A Multicenter Randomized Double-Blind Controlled Trial

    PubMed Central

    Ozawa, Hideki; Uemura, Naomi; Inoue, Kazuhiko; Kawai, Takashi; Ohtsu, Toshihiro; Koga, Yasuhiro

    2016-01-01

    Some Lactobacillus spp. suppress Helicobacter pylori in the stomach and have potential therapeutic applications for the treatment of gastrointestinal conditions. In this study, the effects of Lactobacillus strains on functional dyspepsia associated with H. pylori infection were examined. Volunteers were screened using the 13C-urea breath test (UBT) and H. pylori stool test, and 131 participants who met the selection criteria (mean age: 48.9 years) were randomly given L. gasseri OLL2716-containing yogurt or placebo yogurt once daily for 12 weeks. Gastrointestinal symptoms (epigastric pain, bloating, postprandial fullness, nausea, and heartburn) and the levels of serum pepsinogen (PG), 13C-UBT, and H. pylori stool antigen were assessed. No significant differences were observed between the groups in UBT results, H. pylori stool antigens, or the serum PGI/II ratio. In the L. gasseri group, postprandial fullness was significantly lower at the end of the trial compared to the initial level (p < 0.05) and significantly fewer patients had a VAS score of >10 for bloating compared to the placebo group (p < 0.05). Dietary supplementation with L. gasseri OLL2716-containing yogurt may effectively suppress dyspeptic symptoms in H. pylori-infected patients. This study was registered at the University Hospital Medical Network Clinical Trial Registry (UMIN000016746). PMID:27478434

  4. Supported Telemonitoring and Glycemic Control in People with Type 2 Diabetes: The Telescot Diabetes Pragmatic Multicenter Randomized Controlled Trial

    PubMed Central

    Wild, Sarah H.; Hanley, Janet; Lewis, Stephanie C.; McKnight, John A.; Padfield, Paul L.; Parker, Richard A.; Pinnock, Hilary; Sheikh, Aziz; McKinstry, Brian

    2016-01-01

    Background Self-monitoring of blood glucose among people with type 2 diabetes not treated with insulin does not appear to be effective in improving glycemic control. We investigated whether health professional review of telemetrically transmitted self-monitored glucose results in improved glycemic control in people with poorly controlled type 2 diabetes. Methods and Findings We performed a randomized, parallel, investigator-blind controlled trial with centralized randomization in family practices in four regions of the United Kingdom among 321 people with type 2 diabetes and glycated hemoglobin (HbA1c) >58 mmol/mol. The supported telemonitoring intervention involved self-measurement and transmission to a secure website of twice-weekly morning and evening glucose for review by family practice clinicians who were not blinded to allocation group. The control group received usual care, with at least annual review and more frequent reviews for people with poor glycemic or blood pressure control. HbA1c assessed at 9 mo was the primary outcome. Intention-to-treat analyses were performed. 160 people were randomized to the intervention group and 161 to the usual care group between June 6, 2011, and July 19, 2013. HbA1c data at follow-up were available for 146 people in the intervention group and 139 people in the control group. The mean (SD) HbA1c at follow-up was 63.0 (15.5) mmol/mol in the intervention group and 67.8 (14.7) mmol/mol in the usual care group. For primary analysis, adjusted mean HbA1c was 5.60 mmol/mol / 0.51% lower (95% CI 2.38 to 8.81 mmol/mol/ 95% CI 0.22% to 0.81%, p = 0·0007). For secondary analyses, adjusted mean ambulatory systolic blood pressure was 3.06 mmHg lower (95% CI 0.56–5.56 mmHg, p = 0.017) and mean ambulatory diastolic blood pressure was 2.17 mmHg lower (95% CI 0.62–3.72, p = 0.006) among people in the intervention group when compared with usual care after adjustment for baseline differences and minimization strata. No significant

  5. Multi-modality neuro-monitoring: conventional clinical trial design.

    PubMed

    Georgiadis, Alexandros L; Palesch, Yuko Y; Zygun, David; Hemphill, J Claude; Robertson, Claudia S; Leroux, Peter D; Suarez, Jose I

    2015-06-01

    Multi-modal monitoring has become an integral part of neurointensive care. However, our approach is at this time neither standardized nor backed by data from randomized controlled trials. The goal of the second Neurocritical Care Research Conference was to discuss research priorities in multi-modal monitoring, what research tools are available, as well as the latest advances in clinical trial design. This section of the meeting was focused on how such a trial should be designed so as to maximize yield and avoid mistakes of the past.

  6. Design of Lifestyle Intervention Trials to Prevent Excessive Gestational Weight Gain in Women with Overweight or Obesity

    PubMed Central

    2015-01-01

    Objective The Lifestyle Interventions for Expectant Moms (LIFE-Moms) Consortium is designed to determine, in pregnant women with overweight or obesity, whether various behavioral and lifestyle interventions reduce excessive gestational weight gain (GWG) and subsequent adverse maternal and neonatal outcomes, and obesity in offspring. The design and planning process of the LIFE-Moms Consortium is described. Design and Methods The LIFE-Moms Consortium is a collaboration among seven clinical centers, a Research Coordinating Unit, and the NIH designed to support each clinical center’s conduct of a separate trial of a unique intervention. Specific common measures, procedures, and eligibility criteria are consistent across the 7 trials allowing data to be combined in exploratory analyses and/or compared readily. Results Numerous committees and working groups were created to define common measures and outcomes during pregnancy and through 1 year postpartum, develop Consortium policies and oversee progress of the trials. The primary outcome for the Consortium is excessive GWG. Secondary outcomes include maternal, neonatal and infant anthropometric measures, physical activity, sleep, and complications of pregnancy and delivery. Conclusion A multi-center consortium of independent, lifestyle interventions with common measures and outcomes may enhance the ability to identify promising interventions for improving outcomes in pregnant women and their offspring. PMID:26708836

  7. Improvement in Growth After 1 Year of Growth Hormone Therapy in Well-Nourished Infants with Growth Retardation Secondary to Chronic Renal Failure: Results of a Multicenter, Controlled, Randomized, Open Clinical Trial

    PubMed Central

    Moreno, M. Llanos; Neto, Arlete; Ariceta, Gema; Vara, Julia; Alonso, Angel; Bueno, Alberto; Afonso, Alberto Caldas; Correia, António Jorge; Muley, Rafael; Barrios, Vicente; Gómez, Carlos; Argente, Jesús

    2010-01-01

    Background and objectives: Our aim was to evaluate the growth-promoting effect of growth hormone (GH) treatment in infants with chronic renal failure (CRF) and persistent growth retardation despite adequate nutritional and metabolic management. Design, setting, participants, & measurements: The study design included randomized, parallel groups in an open, multicenter trial comparing GH (0.33 mg/kg per wk) with nontreatment with GH during 12 months. Sixteen infants who had growth retardation, were aged 12 ± 3 months, had CRF (GFR ≤60 ml/min per 1.73 m2), and had adequate nutritional intake and good metabolic control were recruited from eight pediatric nephrology departments from Spain and Portugal. Main outcome measures were body length, body weight, bone age, biochemical and hormonal analyses, renal function, bone mass, and adverse effects. Results: Length gain in infants who were treated with GH was statistically greater (P < 0.05) than that of nontreated children (14.5 versus 9.5 cm/yr; SD score 1.43 versus −0.11). The GH-induced stimulation of growth was associated with no undesirable effects on bone maturation, renal failure progression, or metabolic control. In addition, GH treatment improved forearm bone mass and increased serum concentrations of total and free IGF-I and IGF-binding protein 3 (IGFBP-3), whereas IGF-II, IGFBP-1, IGFBP-2, GH-binding protein, ghrelin, and leptin were not modified. Conclusions: Infants with CRF and growth retardation despite good metabolic and nutritional control benefit from GH treatment without adverse effects during 12 months of therapy. PMID:20522533

  8. Effects of a Clinician Referral and Exercise Program for Men Who Have Completed Active Treatment for Prostate Cancer: A Multicenter Cluster Randomized Controlled Trial (ENGAGE)

    PubMed Central

    Livingston, Patricia M; Craike, Melinda J; Salmon, Jo; Courneya, Kerry S; Gaskin, Cadeyrn J; Fraser, Steve F; Mohebbi, Mohammadreza; Broadbent, Suzanne; Botti, Mari; Kent, Bridie

    2015-01-01

    BACKGROUND The purpose of this study was to determine the efficacy of a clinician referral and exercise program in improving exercise levels and quality of life for men with prostate cancer. METHODS This was a multicenter cluster randomized controlled trial in Melbourne, Australia comprising 15 clinicians: 8 clinicians were randomized to refer eligible participants (n = 54) to a 12-week exercise program comprising 2 supervised gym sessions and 1 home-based session per week, and 7 clinicians were randomized to follow usual care (n = 93). The primary outcome was self-reported physical activity; the secondary outcomes were quality of life, anxiety, and symptoms of depression. RESULTS A significant intervention effect was observed for vigorous-intensity exercise (effect size: Cohen's d, 0.46; 95% confidence interval [CI], 0.09-0.82; P = .010) but not for combined moderate and vigorous exercise levels (effect size: d, 0.08; 95% CI, −0.28 to 0.45; P = .48). Significant intervention effects were also observed for meeting exercise guidelines (≥150 min/wk; odds ratio, 3.9; 95% CI, 1.9-7.8; P = .002); positive intervention effects were observed in the intervention group for cognitive functioning (effect size: d, 0.34; 95% CI, −0.02 to 0.70; P = .06) and depression symptoms (effect size: d, −0.35; 95% CI, −0.71 to 0.02; P = .06). Eighty percent of participants reported that the clinician's referral influenced their decision to participate in the exercise program. CONCLUSIONS The clinician referral and 12-week exercise program significantly improved vigorous exercise levels and had a positive impact on mental health outcomes for men living with prostate cancer. Further research is needed to determine the sustainability of the exercise program and its generalizability to other cancer populations. Cancer 2015;121:2646–2654. © 2015 American Cancer Society. PMID:25877784

  9. Decreased nonrelapse mortality after unrelated cord blood transplantation for acute myeloid leukemia using reduced-intensity conditioning: a prospective phase II multicenter trial.

    PubMed

    Rio, Bernard; Chevret, Sylvie; Vigouroux, Stéphane; Chevallier, Patrice; Fürst, Sabine; Sirvent, Anne; Bay, Jacques-Olivier; Socié, Gérard; Ceballos, Patrice; Huynh, Anne; Cornillon, Jérôme; Françoise, Sylvie; Legrand, Faezeh; Yakoub-Agha, Ibrahim; Michel, Gérard; Maillard, Natacha; Margueritte, Geneviève; Maury, Sébastien; Uzunov, Madalina; Bulabois, Claude Eric; Michallet, Mauricette; Clement, Laurence; Dauriac, Charles; Bilger, Karin; Gluckman, Eliane; Ruggeri, Annalisa; Buzyn, Agnès; Nguyen, Stéphanie; Simon, Tabassome; Milpied, Nöel; Rocha, Vanderson

    2015-03-01

    A prospective phase II multicenter trial was performed with the aim to obtain less than 25% nonrelapse mortality (NRM) after unrelated cord blood transplantation (UCBT) for adults with acute myeloid leukemia (AML) using a reduced-intensity conditioning regimen (RIC) consisting of total body irradiation (2 Gy), cyclophosphamide (50 mg/kg), and fludarabine (200 mg/m(2)). From 2007 to 2009, 79 UCBT recipients were enrolled. Patients who underwent transplantation in first complete remission (CR1) (n = 48) had a higher frequency of unfavorable cytogenetics and secondary AML and required more induction courses of chemotherapy to achieve CR1 compared with the others. The median infused total nucleated cells (TNC) was 3.4 × 10(7)/kg, 60% received double UCBT, 77% were HLA mismatched (4/6), and 40% had major ABO incompatibility. Cumulative incidence of neutrophil recovery at day 60 was 87% and the cumulative incidence of 100-day acute graft-versus-host disease (II to IV) was 50%. At 2 years, the cumulative incidence of NRM and relapse was 20% and 46%, respectively. In multivariate analysis, major ABO incompatibility (P = .001) and TNC (<3.4 × 10(7)/kg; P = .001) were associated with increased NRM, and use of 2 or more induction courses to obtain CR1 was associated with increased relapse incidence (P = .04). Leukemia-free survival (LFS) at 2 years was 35%, and the only factor associated with decreased LFS was secondary AML (P = .04). In conclusion, despite the decreased NRM observed, other RIC regimens with higher myelosuppression should be evaluated to decrease relapse in high-risk AML. (EUDRACT 2006-005901-67).

  10. Intra-articular glenohumeral injections of HYADD®4-G for the treatment of painful shoulder osteoarthritis: a prospective multicenter, open-label trial

    PubMed Central

    PORCELLINI, GIUSEPPE; MEROLLA, GIOVANNI; GIORDAN, NICOLA; PALADINI, PAOLO; BURINI, ANDREA; CESARI, EUGENIO; CASTAGNA, ALESSANDRO

    2015-01-01

    Purpose numerous experimental and clinical studies in osteoarthritis (OA) have demonstrated that intra-articular (IA) administration of hyaluronic acid can improve the altered rheological properties of the synovial fluid and exert protective and reparative effects on the joint structure. The objective of this study was to evaluate the safety and performance of HYADD®4-G (Hymovis®) in patients with glenohumeral joint OA. Methods forty-one patients with shoulder pain and limited shoulder function resulting from concentric glenohumeral joint OA were enrolled in a multicenter clinical trial. Patients received two HYADD®4-G injections administered one week apart. The main outcome measure was improvement in shoulder pain on movement at six months as assessed through a 100-mm visual analog scale (VAS), range of motion (ROM) values, and Constant-Murley Shoulder Outcome Score (CS). Results two IA injections of HYADD®4-G (Hymovis®) significantly decreased pain and improved shoulder function for up to six months from the first injection. The VAS score decreased (from 66.1 mm to 37.7 mm at six months) and improvements were recorded in the total CS and in the ROM values ( rotation decreased from a mean value of 54.2° at baseline to 63.2° at six months and internal rotation from a mean value of 44.0° at baseline to 45.7° at 26 weeks). No serious adverse events occurred. Conclusions the study results demonstrated that two IA injections of HYADD®4-G (Hymovis®) may be a safe and effective treatment option for shoulder pain associated with glenohumeral OA and that the effects of the injections are still present for up to six months after the treatment. Level of evidence Level IV, therapeutic case series. PMID:26889467

  11. Clinical and bacteriological efficacies of sitafloxacin against community-acquired pneumonia caused by Streptococcus pneumoniae: nested cohort within a multicenter clinical trial.

    PubMed

    Fujita, Jiro; Niki, Yoshihito; Kadota, Jun-Ichi; Yanagihara, Katsunori; Kaku, Mitsuo; Watanabe, Akira; Aoki, Nobuki; Hori, Seiji; Tanigawara, Yusuke; Cash, Haley L; Kohno, Shigeru

    2013-06-01

    We evaluated the clinical and bacteriological efficacy of oral sitafloxacin (STFX) in clinically diagnosed community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae. Additionally, we cultured these patient samples to test the minimal inhibitory concentrations (MICs) of levofloxacin (LVFX), moxifloxacin (MFLX), STFX, and penicillin G (PCG), as well as identified mutations in the quinolone resistance determinant regions (QRDRs) in LVFX-resistant strains. This study is a nested cohort from a prospective, multicenter clinical trial consisting of 139 patients with community-acquired pneumonia (CAP), from which 72 were included in this study. After diagnosis of CAP caused by S. pneumoniae, STFX (50 mg twice daily, or 100 mg once daily) was orally administered for 7 days. Sixty-five patient sputum samples were then cultured for MIC analysis. In a LVFX-resistant strain that was identified, mutations in the QRDRs of the gyrA, gyrB, parC, and parE genes were examined. Of 72 patients eligible for this study, S. pneumoniae was successfully cultured from the sputum of 65 patients, and only 7 patients were diagnosed by urinary antigen only. Clinical improvement of CAP was obtained in 65 of the 69 clinically evaluable patients (65/69, 94.2 %). Eradication of S. pneumoniae was observed in 62 patients of the 65 bacteriologically evaluable patients (62/65, 95.4 %). Additionally, STFX showed the lowest MIC distribution compared with LVFX, MFLX, and PCG, and no major adverse reactions were observed. STFX treatment in patients with CAP caused by S. pneumoniae was found to be highly effective both clinically (94.2 %) and bacteriologically (95.4 %).

  12. Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial

    PubMed Central

    von Mehren, Margaret; Jones, Robin L.; Hensley, Martee L.; Schuetze, Scott M.; Staddon, Arthur; Milhem, Mohammed; Elias, Anthony; Ganjoo, Kristen; Tawbi, Hussein; Van Tine, Brian A.; Spira, Alexander; Dean, Andrew; Khokhar, Nushmia Z.; Park, Youn Choi; Knoblauch, Roland E.; Parekh, Trilok V.; Maki, Robert G.; Patel, Shreyaskumar R.

    2016-01-01

    Purpose This multicenter study, to our knowledge, is the first phase III trial to compare trabectedin versus dacarbazine in patients with advanced liposarcoma or leiomyosarcoma after prior therapy with an anthracycline and at least one additional systemic regimen. Patients and Methods Patients were randomly assigned in a 2:1 ratio to receive trabectedin or dacarbazine intravenously every 3 weeks. The primary end point was overall survival (OS), secondary end points were disease control—progression-free survival (PFS), time to progression, objective response rate, and duration of response—as well as safety and patient-reported symptom scoring. Results A total of 518 patients were enrolled and randomly assigned to either trabectedin (n = 345) or dacarbazine (n = 173). In the final analysis of PFS, trabectedin administration resulted in a 45% reduction in the risk of disease progression or death compared with dacarbazine (median PFS for trabectedin v dacarbazine, 4.2 v 1.5 months; hazard ratio, 0.55; P < .001); benefits were observed across all preplanned subgroup analyses. The interim analysis of OS (64% censored) demonstrated a 13% reduction in risk of death in the trabectedin arm compared with dacarbazine (median OS for trabectedin v dacarbazine, 12.4 v 12.9 months; hazard ratio, 0.87; P = .37). The safety profiles were consistent with the well-characterized toxicities of both agents, and the most common grade 3 to 4 adverse effects were myelosuppression and transient elevation of transaminases in the trabectedin arm. Conclusion Trabectedin demonstrates superior disease control versus conventional dacarbazine in patients who have advanced liposarcoma and leiomyosarcoma after they experience failure of prior chemotherapy. Because disease control in advanced sarcomas is a clinically relevant end point, this study supports the activity of trabectedin for patients with these malignancies. PMID:26371143

  13. Efficacy and safety of a vaginal medicinal product containing three strains of probiotic bacteria: a multicenter, randomized, double-blind, and placebo-controlled trial

    PubMed Central

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

    2015-01-01

    Objective The main objective of this study was to evaluate whether vaginal administration of probiotic Lactobacillus results in their colonization and persistence in the vagina and whether Lactobacillus colonization promotes normalization and maintenance of pH and Nugent score. Patients and methods The study was a multicenter, randomized, double-blind, and placebo-controlled trial. Altogether, 376 women were assessed for eligibility, and signed informed consent. One hundred and sixty eligible women with abnormal, also called intermediate, vaginal microflora, as indicated by a Nugent score of 4–6 and pH >4.5 and zero or low Lactobacillus count, were randomized. Each participant was examined four times during the study. Women were randomly allocated to receive either the probiotic preparation inVag®, or a placebo (one capsule for seven consecutive days vaginally). The product inVag includes the probiotic strains Lactobacillus fermentum 57A, Lactobacillus plantarum 57B, and Lactobacillus gasseri 57C. We took vaginal swabs during visits I, III, and IV to determine the presence and abundance of bacteria from the Lactobacillus genus, measure the pH, and estimate the Nugent score. Drug safety evaluation was based on analysis of the types and occurrence of adverse events. Results Administration of inVag contributed to a significant decrease (between visits) in both vaginal pH (P<0.05) and Nugent score (P<0.05), and a significant increase in the abundance of Lactobacillus between visit I and visits III and IV (P<0.05). Molecular typing revealed the presence of Lactobacillus strains originating from inVag in 82% of women taking the drug at visit III, and 47.5% at visit IV. There was no serious adverse event related to inVag administration during the study. Conclusion The probiotic inVag is safe for administration to sustainably restore the healthy vaginal microbiota, as demonstrated by predominance of the Lactobacillus bacteria in vaginal microbiota. PMID:26451088

  14. Immunogenicity and safety assessment of a trivalent, inactivated split influenza vaccine in Korean children: Double-blind, randomized, active-controlled multicenter phase III clinical trial.

    PubMed

    Han, Seung Beom; Rhim, Jung-Woo; Shin, Hye Jo; Lee, Soo Young; Kim, Hyun-Hee; Kim, Jong-Hyun; Lee, Kyung-Yil; Ma, Sang Hyuk; Park, Joon Soo; Kim, Hwang Min; Kim, Chun Soo; Kim, Dong Ho; Choi, Young Youn; Cha, Sung-Ho; Hong, Young Jin; Kang, Jin Han

    2015-01-01

    A multicenter, double-blind, randomized, active-control phase III clinical trial was performed to assess the immunogenicity and safety of a trivalent, inactivated split influenza vaccine. Korean children between the ages of 6 months and 18 y were enrolled and randomized into a study (study vaccine) or a control vaccine group (commercially available trivalent, inactivated split influenza vaccine) in a 5:1 ratio. Antibody responses were determined using hemagglutination inhibition assay, and post-vaccination immunogenicity was assessed based on seroconversion and seroprotection rates. For safety assessment, solicited local and systemic adverse events up to 28 d after vaccination and unsolicited adverse events up to 6 months after vaccination were evaluated. Immunogenicity was assessed in 337 and 68 children of the study and control groups. In the study vaccine group, seroconversion rates against influenza A/H1N1, A/H3N2, and B strains were 62.0% (95% CI: 56.8-67.2), 53.4% (95% CI: 48.1-58.7), and 54.9% (95% CI: 48.1-60.2), respectively. The corresponding seroprotection rates were 95.0% (95% CI: 92.6-97.3), 93.8% (95% CI: 91.2-96.4), and 95.3% (95% CI: 93.0-97.5). The lower 95% CI limits of the seroconversion and seroprotection rates were over 40% and 70%, respectively, against all strains. Seroconversion and seroprotection rates were not significantly different between the study and control vaccine groups. Furthermore, the frequencies of adverse events were not significantly different between the 2 vaccine groups, and no serious vaccination-related adverse events were noted. In conclusion, the study vaccine exhibited substantial immunogenicity and safety in Korean children and is expected to be clinically effective.

  15. Effects of motion style acupuncture treatment in acute low back pain patients with severe disability: a multicenter, randomized, controlled, comparative effectiveness trial.

    PubMed

    Shin, Joon-Shik; Ha, In-Hyuk; Lee, Jinho; Choi, Youngkwon; Kim, Me-Riong; Park, Byoung-Yoon; Shin, Byung-Cheul; Lee, Myeong Soo

    2013-07-01

    Reviews of the efficacy of acupuncture as a treatment for acute low back pain (aLBP) have shown that there is insufficient evidence for its effect and that more research is needed. Motion style acupuncture treatment (MSAT) is novel in that it requires a part of the patient's body to move passively or actively while acupuncture needles are retained. A multicenter, randomized, comparative effectiveness trial was conducted to evaluate the effects of MSAT in aLBP with severe disability. A total of 58 aLBP patients with severe functional disability (defined per Oswestry Disability Index [ODI] ⩾60%) were recruited and assigned randomly to receive 1 session of either conventional diclofenac injection (n=29) or MSAT (n=29). The primary outcome measured improvement in LBP using the 10-point numerical rating scale of LBP, and the secondary outcome assessed disability using the Oswestry Disability Index at 30minutes and at 2, 4, and 24weeks after treatment. Analyses were by intention to treat. The numerical rating scale of the MSAT group decreased 3.12 (95% confidence interval=2.26, 3.98; P<.0001) more than that of the injection group and the Oswestry Disability Index of the MSAT group decreased 32.95% (95% confidence interval=26.88, 39.03; P<.0001) more than that of the injection group, respectively. The difference between the 2 groups maintained statistical significance at 2 and 4weeks after treatment. These results suggest that MSAT has positive effects on immediate pain relief and the functional recovery of aLBP patients with severe disability.

  16. Complete steroid avoidance is effective and safe in children with renal transplants: a multicenter randomized trial with three-year follow-up.

    PubMed

    Sarwal, M M; Ettenger, R B; Dharnidharka, V; Benfield, M; Mathias, R; Portale, A; McDonald, R; Harmon, W; Kershaw, D; Vehaskari, V M; Kamil, E; Baluarte, H J; Warady, B; Tang, L; Liu, J; Li, L; Naesens, M; Sigdel, T; Waskerwitz, Janie; Salvatierra, O

    2012-10-01

    To determine whether steroid avoidance in pediatric kidney transplantation is safe and efficacious, a randomized, multicenter trial was performed in 12 pediatric kidney transplant centers. One hundred thirty children receiving primary kidney transplants were randomized to steroid-free (SF) or steroid-based (SB) immunosuppression, with concomitant tacrolimus, mycophenolate and standard dose daclizumab (SB group) or extended dose daclizumab (SF group). Follow-up was 3 years posttransplant. Standardized height Z-score change after 3 years follow-up was -0.99 ± 2.20 in SF versus -0.93 ± 1.11 in SB; p = 0.825. In subgroup analysis, recipients under 5 years of age showed improved linear growth with SF compared to SB treatment (change in standardized height Z-score at 3 years -0.43 ± 1.15 vs. -1.07 ± 1.14; p = 0.019). There were no differences in the rates of biopsy-proven acute rejection at 3 years after transplantation (16.7% in SF vs. 17.1% in SB; p = 0.94). Patient survival was 100% in both arms; graft survival was 95% in the SF and 90% in the SB arms (p = 0.30) at 3 years follow-up. Over the 3 year follow-up period, the SF group showed lower systolic BP (p = 0.017) and lower cholesterol levels (p = 0.034). In conclusion, complete steroid avoidance is safe and effective in unsensitized children receiving primary kidney transplants.

  17. COMPLETE STEROID AVOIDANCE IS EFFECTIVE AND SAFE IN CHILDREN WITH RENAL TRANSPLANTS: A MULTICENTER RANDOMIZED TRIAL WITH 3 YEAR FOLLOW UP

    PubMed Central

    Sarwal, Minnie M.; Ettenger, Robert; Dharnidharka, Vikas; Benfield, Mark; Mathias, Robert; Portale, Anthony; McDonald, Ruth; Harmon, William; Kershaw, David; Vehaskari, V. Matti; Kamil, Elaine; Baluarte, H. Jorge; Warady, Bradley; Tang, Lily; Liu, Jun; Li, Li; Naesens, Maarten; Sigdel, Tara; Waskerwitz, Janie; Salvatierra, Oscar

    2012-01-01

    To determine whether steroid avoidance in pediatric kidney transplantation is safe and efficacious, a randomized, multicenter trial was performed in 12 pediatric kidney transplant centers. One hundred thirty children receiving primary kidney transplants were randomized to steroid-free (SF) or steroid-based (SB) immunosuppression, with concomitant tacrolimus, mycophenolate, and standard dose daclizumab (SB group) or extended dose daclizumab (SF group). Follow-up was 3 years post-transplant. Standardized height Z score change after 3 years follow-up was −0.99±2.20 in SF vs. −0.93±1.11 in SB; p=0.825. In subgroup analysis, recipients under 5 years of age showed improved linear growth with SF compared to SB treatment (change in standardized height Z score at 3 years −0.43±1.15 vs. −1.07±1.14; p=0.019). There were no differences in the rates of biopsy-proven acute rejection at 3 years after transplantation (16.7% in SF vs. 17.1% in SB; p=0.94). Patient survival was 100% in both arms; graft survival was 95% in the SF and 90% in the SB arms (p=0.30) at 3 years follow-up. Over the three year follow-up period, the SF group showed lower systolic BP (p=0.017) and lower cholesterol levels (p=0.034). In conclusion, complete steroid avoidance is safe and effective in unsensitized children receiving primary kidney transplants. PMID:22694755

  18. The Effect of Patient-Specific Cerebral Oxygenation Monitoring on Postoperative Cognitive Function: A Multicenter Randomized Controlled Trial

    PubMed Central

    Ellis, Lucy; Murphy, Gavin J; Culliford, Lucy; Dreyer, Lucy; Clayton, Gemma; Downes, Richard; Nicholson, Eamonn; Stoica, Serban; Reeves, Barnaby C

    2015-01-01

    Background Indices of global tissue oxygen delivery and utilization such as mixed venous oxygen saturation, serum lactate concentration, and arterial hematocrit are commonly used to determine the adequacy of tissue oxygenation during cardiopulmonary bypass (CPB). However, these global measures may not accurately reflect regional tissue oxygenation and ischemic organ injury remains a common and serious complication of CPB. Near-infrared spectroscopy (NIRS) is a noninvasive technology that measures regional tissue oxygenation. NIRS may be used alongside global measures to optimize regional perfusion and reduce organ injury. It may also be used as an indicator of the need for red blood cell transfusion in the presence of anemia and tissue hypoxia. However, the clinical benefits of using NIRS remain unclear and there is a lack of high-quality evidence demonstrating its efficacy and cost effectiveness. Objective The aim of the patient-specific cerebral oxygenation monitoring as part of an algorithm to reduce transfusion during heart valve surgery (PASPORT) trial is to determine whether the addition of NIRS to CPB management algorithms can prevent cognitive decline, postoperative organ injury, unnecessary transfusion, and reduce health care costs. Methods Adults aged 16 years or older undergoing valve or combined coronary artery bypass graft and valve surgery at one of three UK cardiac centers (Bristol, Hull, or Leicester) are randomly allocated in a 1:1 ratio to either a standard algorithm for optimizing tissue oxygenation during CPB that includes a fixed transfusion threshold, or a patient-specific algorithm that incorporates cerebral NIRS monitoring and a restrictive red blood cell transfusion threshold. Allocation concealment, Internet-based randomization stratified by operation type and recruiting center, and blinding of patients, ICU and ward care staff, and outcome assessors reduce the risk of bias. The primary outcomes are cognitive function 3 months after

  19. Large-Scale Prospective T Cell Function Assays in Shipped, Unfrozen Blood Samples: Experiences from the Multicenter TRIGR Trial

    PubMed Central

    Cheung, Roy K.; Becker, Dorothy J.; Girgis, Rose; Palmer, Jerry P.; Cuthbertson, David; Krischer, Jeffrey P.

    2014-01-01

    Broad consensus assigns T lymphocytes fundamental roles in inflammatory, infectious, and autoimmune diseases. However, clinical investigations have lacked fully characterized and validated procedures, equivalent to those of widely practiced biochemical tests with established clinical roles, for measuring core T cell functions. The Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR) type 1 diabetes prevention trial used consecutive measurements of T cell proliferative responses in prospectively collected fresh heparinized blood samples shipped by courier within North America. In this article, we report on the quality control implications of this simple and pragmatic shipping practice and the interpretation of positive- and negative-control analytes in our assay. We used polyclonal and postvaccination responses in 4,919 samples to analyze the development of T cell immunocompetence. We have found that the vast majority of the samples were viable up to 3 days from the blood draw, yet meaningful responses were found in a proportion of those with longer travel times. Furthermore, the shipping time of uncooled samples significantly decreased both the viabilities of the samples and the unstimulated cell counts in the viable samples. Also, subject age was significantly associated with the number of unstimulated cells and T cell proliferation to positive activators. Finally, we observed a pattern of statistically significant increases in T cell responses to tetanus toxin around the timing of infant vaccinations. This assay platform and shipping protocol satisfy the criteria for robust and reproducible long-term measurements of human T cell function, comparable to those of established blood biochemical tests. We present a stable technology for prospective disease-relevant T cell analysis in immunological diseases, vaccination medicine, and measurement of herd immunity. PMID:24334687

  20. Picking the Good Apples: Statistics versus Good Judgment in Choosing Stent Operators for a Multicenter Clinical Trial

    PubMed Central

    Howard, George; Voeks, Jenifer H.; Meschia, James F.; Howard, Virginia J.; Brott, Thomas G.

    2014-01-01

    Background and Purpose The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) was completed with a quite low stroke and death rate. A “lead-in” series of patients receiving carotid artery stenting (CAS) was used to select the physician-operators for the study, where performance was evaluated by complication rates and by peer review of cases. Herein, we assess the potential contribution of statistical evaluation of complication rates. Methods The ability to discriminate between stent operators who can successfully meet the published guideline of <3% combined rate of stroke and death is calculated under the binomial distribution, based upon a small consecutive case series (n = 24 patients). Results A criterion of ≤2 stroke or death events among the 24 patients (<8% event rate) was required of operators. Setting such a high criterion, however, ensures an inability to exclude operators who cannot meet the criteria. In fact, if a “good” operator is defined as having a 2% event rate, and a “poor” operator as a 6% event rate, even a series of 240 patients would (on average) still exclude 5.4% of the good operators and include 4.6% of the poor operators. Conclusions The low periprocedural event rates in the trial suggest success in separating skillful operators from less skillful. However, it seems unlikely that statistical assessment of event rates in the lead-in contributed to successful selection, but rather successful selection was more likely due to peer review of subjective and other factors including patient volume and technical approaches. PMID:25213339

  1. Efficacy and Safety of Intravenous Urapidil for Older Hypertensive Patients with Acute Heart Failure: A Multicenter Randomized Controlled Trial

    PubMed Central

    Yang, Wei; Zhou, Yu-Jie; Fu, Yan; Qin, Jian; Qin, Shu; Chen, Xiao-Min; Guo, Jin-Cheng; Wang, De-Zhao; Zhan, Hong; Li, Jing; He, Jing-Yu

    2017-01-01

    Purpose Urapidil is putatively effective for patients with hypertension and acute heart failure, although randomized controlled trials thereon are lacking. We investigated the efficacy and safety of intravenous urapidil relative to that of nitroglycerin in older patients with hypertension and heart failure in a randomized controlled trial. Materials and Methods Patients (>60 y) with hypertension and heart failure were randomly assigned to receive intravenous urapidil (n=89) or nitroglycerin (n=91) for 7 days. Hemodynamic parameters, cardiac function, and safety outcomes were compared. Results Patients in the urapidil group had significantly lower mean systolic blood pressure (110.1±6.5 mm Hg) than those given nitroglycerin (126.4±8.1 mm Hg, p=0.022), without changes in heart rate. Urapidil was associated with improved cardiac function as reflected by lower N terminal-pro B type natriuretic peptide after 7 days (3311.4±546.1 ng/mL vs. 4879.1±325.7 ng/mL, p=0.027) and improved left ventricular ejection fraction (62.2±3.4% vs. 51.0±2.4%, p=0.032). Patients given urapidil had fewer associated adverse events, specifically headache (p=0.025) and tachycardia (p=0.004). The one-month rehospitalization and all-cause mortality rates were similar. Conclusion Intravenous administration of urapidil, compared with nitroglycerin, was associated with better control of blood pressure and preserved cardiac function, as well as fewer adverse events, for elderly patients with hypertension and acute heart failure. PMID:27873502

  2. Large-scale prospective T cell function assays in shipped, unfrozen blood samples: experiences from the multicenter TRIGR trial.

    PubMed

    Hadley, David; Cheung, Roy K; Becker, Dorothy J; Girgis, Rose; Palmer, Jerry P; Cuthbertson, David; Krischer, Jeffrey P; Dosch, Hans-Michael

    2014-02-01

    Broad consensus assigns T lymphocytes fundamental roles in inflammatory, infectious, and autoimmune diseases. However, clinical investigations have lacked fully characterized and validated procedures, equivalent to those of widely practiced biochemical tests with established clinical roles, for measuring core T cell functions. The Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR) type 1 diabetes prevention trial used consecutive measurements of T cell proliferative responses in prospectively collected fresh heparinized blood samples shipped by courier within North America. In this article, we report on the quality control implications of this simple and pragmatic shipping practice and the interpretation of positive- and negative-control analytes in our assay. We used polyclonal and postvaccination responses in 4,919 samples to analyze the development of T cell immunocompetence. We have found that the vast majority of the samples were viable up to 3 days from the blood draw, yet meaningful responses were found in a proportion of those with longer travel times. Furthermore, the shipping time of uncooled samples significantly decreased both the viabilities of the samples and the unstimulated cell counts in the viable samples. Also, subject age was significantly associated with the number of unstimulated cells and T cell proliferation to positive activators. Finally, we observed a pattern of statistically significant increases in T cell responses to tetanus toxin around the timing of infant vaccinations. This assay platform and shipping protocol satisfy the criteria for robust and reproducible long-term measurements of human T cell function, comparable to those of established blood biochemical tests. We present a stable technology for prospective disease-relevant T cell analysis in immunological diseases, vaccination medicine, and measurement of herd immunity.

  3. Effect of acacia polyphenol on glucose homeostasis in subjects with impaired glucose tolerance: A randomized multicenter feeding trial

    PubMed Central

    OGAWA, SOSUKE; MATSUMAE, TOMOYUKI; KATAOKA, TAKESHI; YAZAKI, YOSHIKAZU; YAMAGUCHI, HIDEYO

    2013-01-01

    Numerous in vitro and animal studies, as well as clinical trials have indicated that plant-derived polyphenols exert beneficial effects on glucose intolerance or type 2 diabetes. This clinical study aimed to investigate the effects of acacia polyphenol (AP) on glucose and insulin responses to an oral glucose tolerance test (OGTT) in non-diabetic subjects with impaired glucose tolerance (IGT). A randomized, double-blind, placebo-controlled trial was conducted in a total of 34 enrolled subjects. The subjects were randomly assigned to the AP-containing dietary supplement (AP supplement; in a daily dose of 250 mg as AP; n=17) or placebo (n=17) and the intervention was continued for 8 weeks. Prior to the start of the intervention (baseline) and after 4 and 8 weeks of intervention, plasma glucose and insulin were measured during a two-hour OGTT. Compared with the baseline, plasma glucose and insulin levels at 90 and/or 120 min, as well as the total area under the curve values during the OGTT (AUC0→2h) for glucose and insulin, were significantly reduced in the AP group, but not in the placebo group after intervention for 8 weeks. The decline from baseline in plasma glucose and insulin at 90 or 120 min of the OGTT for the AP group was significantly greater compared with that of the placebo group after 8 weeks of intervention. No AP supplement-related adverse side-effects nor any abnormal changes in routine laboratory tests and anthropometric parameters were observed throughout the study period. The AP supplement may have the potential to improve glucose homeostasis in subjects with IGT. PMID:23837032

  4. Adaptive Design of Confirmatory Trials: Advances and Challenges

    PubMed Central

    Lai, Tze Leung; Lavori, Philip W.; Tsang, Ka Wai

    2015-01-01

    The past decade witnessed major developments in innovative designs of confirmatory clinical trials, and adaptive designs represent the most active area of these developments. We give an overview of the developments and associated statistical methods in several classes of adaptive designs of confirmatory trials. We also discuss their statistical difficulties and implementation challenges, and show how these problems are connected to other branches of mainstream Statistics, which we then apply to resolve the difficulties and bypass the bottlenecks in the development of adaptive designs for the next decade. PMID:26079372

  5. Quality assurance and its impact on ovarian visualization rates in the multicenter United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

    PubMed Central

    Sharma, A.; Burnell, M.; Gentry‐Maharaj, A.; Campbell, S.; Amso, N. N.; Seif, M. W.; Fletcher, G.; Brunell, C.; Turner, G.; Rangar, R.; Ryan, A.; Jacobs, I.

    2016-01-01

    ABSTRACT Objective To describe the quality assurance (QA) processes and their impact on visualization of postmenopausal ovaries in the ultrasound arm of a multicenter screening trial for ovarian cancer. Methods In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, 50 639 women aged 50–74 years were randomized to the ultrasound arm and underwent annual transvaginal ultrasound (TVS) examinations. QA processes were developed during the course of the trial and included regular monitoring of the visualization rate (VR) of the right ovary. Non‐subjective factors identified previously as impacting on VR of the right ovary were included in a generalized estimating equation model for binary outcomes to enable comparison of observed vs adjusted VR between individual sonographers who had undertaken > 1000 scans during the trial and comparison between centers. Observed and adjusted VRs of sonographers and centers were ranked according to the highest VR. Analysis of annual VRs of sonographers and those of the included centers was undertaken. Results Between June 2001 and December 2010, 48 230 of 50 639 women attended one of 13 centers for a total of 270 035 annual TVS scans. One or both ovaries were seen in 228 145 (84.5%) TVS scans. The right ovary was seen on 196 426 (72.7%) of the scans. For the 78 sonographers included in the model, the median difference between observed and adjusted VR was −0.7% (range, −7.9 to 5.9%) and the median change in VR rank after adjustment was 3 (range, 0–18). For the 13 centers, the median difference between observed and adjusted VR was −0.5% (range, −2.2 to 1%), with no change in ranking after adjustment. The median adjusted VR was 73% (interquartile range (IQR), 65–82%) for sonographers and 74.7% (IQR, 67.1–79.0%) for centers. Despite the increasing age of the women being scanned, there was a steady decrease in the number of sonographers with VR < 60% (21.4% in 2002 vs 2.0% in 2010) and an increase in

  6. Systemic Sclerosis Disease Modification Clinical Trials Design: Quo Vadis?

    PubMed Central

    Mendoza, Fabian A.; Keyes-Elstein, Lynette L.; Jimenez, Sergio A.

    2012-01-01

    The purpose of this manuscript is to discuss relevant aspects of clinical trials for Systemic Sclerosis (SSc) and to identify important considerations for the design of SSc disease modification clinical trials. Placebo randomized controlled trials with appropriate identification of SSc patients with diffuse progressive SSc skin involvement of recent onset, along with a rescue strategy for patients with worsening lung and skin involvement are suggested. If change in skin thickening is a major outcome of the study, the selection of patients with recent onset of disease and a predetermined degree of skin involvement are crucial requirements. The trial duration should be of at least 12 months. Sample size calculations should consider differences that exceed the Minimal Important Difference. Other relevant trial designs and potential threats to study validity are also discussed. Previous SSc-disease modifying trials have been beset by high dropout rates. Analyses on the subset of subjects completing the trial or applying the last-observation-carried-forward approach can potentially lead to biased estimates and false conclusions. Strategies for retention of subjects should be included at the design stage and analyses to account for missing data should be performed. PMID:22422541

  7. Optimal multistage designs for randomised clinical trials with continuous outcomes.

    PubMed

    Wason, James M S; Mander, Adrian P; Thompson, Simon G

    2012-02-20

    Multistage designs allow considerable reductions in the expected sample size of a trial. When stopping for futility or efficacy is allowed at each stage, the expected sample size under different possible true treatment effects (δ) is of interest. The δ-minimax design is the one for which the maximum expected sample size is minimised amongst all designs that meet the types I and II error constraints. Previous work has compared a two-stage δ-minimax design with other optimal two-stage designs. Applying the δ-minimax design to designs with more than two stages was not previously considered because of computational issues. In this paper, we identify the δ-minimax designs with more than two stages through use of a novel application of simulated annealing. We compare them with other optimal multistage designs and the triangular design. We show that, as for two-stage designs, the δ-minimax design has good expected sample size properties across a broad range of treatment effects but generally has a higher maximum sample size. To overcome this drawback, we use the concept of admissible designs to find trials which balance the maximum expected sample size and maximum sample size. We show that such designs have good expected sample size properties and a reasonable maximum sample size and, thus, are very appealing for use in clinical trials.

  8. Prevention of acute exacerbations of chronic obstructive bronchitis with carbocysteine lysine salt monohydrate: a multicenter, double-blind, placebo-controlled trial.

    PubMed

    Allegra, L; Cordaro, C I; Grassi, C

    1996-01-01

    The efficacy and safety of carbocysteine lysine salt monohydrate (SCMC-Lys) in the prevention of acute exacerbations associated with chronic obstructive bronchitis were evaluated in a multicenter double-blind, placebo-controlled, parallel group trial in 662 outpatients. After a 1-month run-in period, patients were randomized to three groups and assigned to receive one of the following oral treatments: continuous SCMC-Lys 2.7 g once daily, intermittent SCMC-Lys at the same dosage (1-week courses alternating with 1-week intervals on placebo) or placebo. Each treatment lasted for 6 months and spanned the cooler months of the year. Evaluation was based on a daily recording of relevant clinical symptoms and signs and subsequent evaluation of the collected data by three blinded independent physicians. A total of 146 patients (23%) failed to complete the 6-month treatment (mostly due to difficulties in complying with protocol requirements), without clear-cut differences in the dropout rate in the three groups. An intention-to-treat analysis revealed that the incidence of patients without exacerbations in the group assigned to continuous SCMC-Lys treatment was significantly higher than in the placebo-treated group (p < 0.001). The total number of patients with at least one exacerbation was 66 (29.6%) in the group treated with continuous SCMC-Lys compared with 100 (45.9%) with placebo. In the former group the time between initiation of treatment and first exacerbation was significantly prolonged. The average number of days with acute respiratory illness was significantly decreased in the group receiving continuous SCMC-Lys compared with the group receiving placebo, and this was associated with a significant reduction in the antibiotic consumption during the trial period. In patients assigned to intermittent treatment, results of the assessed endpoints did not differ significantly from those observed in the placebo group. No serious adverse effects were reported. It is

  9. Effect of an Echinacea-Based Hot Drink Versus Oseltamivir in Influenza Treatment: A Randomized, Double-Blind, Double-Dummy, Multicenter, Noninferiority Clinical Trial

    PubMed Central

    Rauš, Karel; Pleschka, Stephan; Klein, Peter; Schoop, Roland; Fisher, Peter

    2015-01-01

    Background Echinacea has antiviral activity against influenza viruses in vitro and has traditionally been used for treatment of colds and flu. Objectives This randomized, double-blind, double-dummy, multicenter, controlled clinical trial compared a new echinacea formulation with the neuraminidase inhibitor oseltamivir, the gold standard treatment for influenza. Methods Following informed consent, 473 patients with early influenza symptoms (≤48 hours) were recruited in primary care in the Czech Republic and randomized to either 5 days of oseltamivir followed by 5 days of placebo, or 10 days of an Echinacea purpurea-based formulation called Echinaforce Hotdrink (A. Vogel Bioforce AG, Roggwil, Switzerland). The proportion of recovered patients (influenza symptoms rated as absent or mild in the evening) was analyzed for noninferiority between treatment groups using a generalized Wilcoxon test with significance level α = 0.05 (2-sided) and using a CI approach in the per-protocol sample. Results Recovery from illness was comparable in the 2 treatment groups at 1.5% versus 4.1% after 1 day, 50.2% versus 48.8% after 5 days, and 90.1% versus 84.8% after 10 days of treatment with Echinaforce Hotdrink and oseltamivir, respectively. Noninferiority was demonstrated for each day and overall (95% CI, 0.487–0.5265 by generalized Wilcoxon test). Very similar results were obtained in the group with virologically confirmed influenza virus infections and in a retrospective analysis during the peak influenza period. The incidence of complications was lower with Echinaforce Hotdrink than with oseltamivir (2.46% vs 6.45%; P = 0.076) and fewer adverse events (particularly nausea and vomiting) were observed with Echinaforce Hotdrink. Conclusions Echinaforce Hotdrink is as effective as oseltamivir in the early treatment of clinically diagnosed and virologically confirmed influenza virus infections with a reduced risk of complications and adverse events. It appears to be an attractive

  10. [Evaluation of a modular out-patient education program for adult asthmatics with office-based specialists--results of a controlled, randomized multicenter trial].

    PubMed

    Dhein, York; Barczok, Michael; Breyer, Gerhard Otto; Hellmann, Andreas; Oblinger, Paul; Weber, Michael; Gaus, Wilhelm; Bulenda, Dietmar

    2006-01-01

    The efficacy of a modular education program for adult asthmatics was evaluated in a controlled, randomized multicenter trial under outpatient conditions for six months. The education was performed with material (patient handout and PowerPoint slides) of the MASA Program (i.e. a modular outpatient education program for adult asthmatics) according to the contents list of the NASA Program (i.e. a national education program for adult asthmatics). In total, 75 patients of seven asthma specialists were included. The complete data of 53 patients were obtained and evaluated. All patients had been diagnosed with asthma in the year before, most of them (54%) with moderately severe asthma. The patients in the intervention group attended a two-hour teaching program for three times; the control group once received a short introduction to the use of a peak-flow meter, an asthma diary and asthma emergency instructions. Compared to the control group, the intervention group patients showed significantly less mild asthma attacks. The mean requirement for inhalation of short-acting beta-agonists was 0.18 times vs. 1.5 times per week for the intervention and the control group, respectively (p = 0.0062). Another primary outcome was the number of unscheduled asthma-related visits to the doctor within six months. There was a trend to lower numbers in the intervention group, but due to the small number of patients the results did not reach significance. The same applies to the patients' estimation of their quality of life, measured by the SF-36 questionnaire. Patients in the intervention group had a significantly better knowledge about their disease (improvement in the number of correctly answered questions: 6.7 times in the intervention and 5.5 times in the control group; p = 0.0062) and showed a better adherence to their regular medication. In conclusion, this trial proves the quality of the MASA education program and its feasibility in the outpatient setting of a chest physician

  11. Comparison between nedaplatin and cisplatin plus docetaxel combined with intensity-modulated radiotherapy for locoregionally advanced nasopharyngeal carcinoma: a multicenter randomized phase II clinical trial

    PubMed Central

    Tang, Chunyuan; Wu, Fang; Wang, Rensheng; Lu, Heming; Li, Guisheng; Liu, Meilian; Zhu, Haisheng; Zhu, Jinxian; Zhang, Yong; Hu, Kai

    2016-01-01

    Nasopharyngeal carcinoma (NPC) is highly incident in southern China. Metastasis is the major cause of death in NPC patients. Concurrent chemoradiotherapy (CCRT) has been accepted as standard in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma (NPC). However, induction chemotherapy (IC) also has benefits in this disease, especially in the patients with certain high-risk factors such as bulky and/or extensive nodal disease. It has been presented that adding IC to CCRT might be a reasonable approach and need more work to confirm. The optimal chemotherapeutic regimen combined with radiotherapy has not been determined so far. It is important to explore high effective and low toxic chemotherapy for the patients. In the multicenter prospective study, 223 patients with locoregionally advanced untreated NPC were randomized into experimental group and control group. The patients received two cycles of induction chemotherapy (IC) with docetaxel (DOC) plus nedaplatin (NDP) in experimental group every 3 weeks, followed by IMRT concurrent with weekly NDP for six cycles, and NDP was replaced by cisplatin (CDDP) in control group. More patients in experimental group could receive full courses of IC and concurrent chemoradiotherapy (CCRT) (P=0.013). There was no significant difference between the two groups in the percentage of reduction of GTVnx and GTVnd after IC (P=0.207 and P=0.107) and CR rate three months after completion of chemoradiotherapy (P=0.565 and P=0.738). With a mean follow-up of 35.1 months, no statistically significant difference in the 3-year OS, LRFS, RRFS, DMFS, and PFS was found. During IC, more patients suffered vomiting in control group (P=0.001). During CCRT, grade 3/4 neutropenia/thrombocytopenia were more common in experimental group (P=0.028 and P=0.035); whereas, severe anemia and vomiting were more common in control group (P=0.0001 and P=0.023). In conclusions, patients with locoregionally advanced NPC showed good

  12. Effect of Parecoxib as an Adjunct to Patient-Controlled Epidural Analgesia after Abdominal Hysterectomy: A Multicenter, Randomized, Placebo-Controlled Trial

    PubMed Central

    Liu, Wei-Feng; Shu, Hai-Hua; Zhao, Guo-Dong; Peng, Shu-Ling; Xiao, Jin-Fang; Zhang, Guan-Rong; Liu, Ke-Xuan; Huang, Wen-Qi

    2016-01-01

    Objective This multicenter, randomized, placebo-controlled study evaluated the efficacy and side effects of parecoxib during patient-controlled epidural analgesia (PCEA) after abdominal hysterectomy. Methods A total of 240 patients who were scheduled for elective abdominal hysterectomy under combined spinal-epidural anesthesia received PCEA plus postoperative intravenous parecoxib 40 mg or saline every 12 h for 48 h after an initial preoperative dose of parecoxib 40 mg or saline. An epidural loading dose of a mixture of 6 mL of 0.25% ropivacaine and 2 mg morphine was administered 30 min before the end of surgery, and PCEA was initiated using 1.25 mg/mL ropivacaine and 0.05 mg/mL morphine with a 2-mL/h background infusion and 2-mL bolus with a 15-min lockout. The primary end point of this study was the quantification of the PCEA-sparing effect of parecoxib. Results Demographic data were similar between the two groups. Patients in the parecoxib group received significantly fewer self-administrated boluses (0 (0, 3) vs. 7 (2, 15), P < 0.001) and less epidural morphine (5.01 ± 0.44 vs. 5.95 ± 1.29 mg, P < 0.001) but experienced greater pain relief compared with the control group (P < 0.001). Patient global satisfaction was higher in the parecoxib group than the control group (P < 0.001). Length of hospitalization (9.50 ± 2.1, 95% CI 9.12~9.88 vs. 10.41 ± 2.6, 95% CI 9.95~10.87, P = 0.003) and postoperative vomiting (17% vs. 29%, P < 0.05) were also reduced in the parecoxib group. There were no serious adverse effects in either group. Conclusion Our data suggest that adjunctive parecoxib during PCEA following abdominal hysterectomy is safe and efficacious in reducing pain, requirements of epidural analgesics, and side effects. Trial Registration ClinicalTrials.gov (NCT01566669) PMID:27622453

  13. OARSI Clinical Trials Recommendations: Design and conduct of implementation trials of interventions for osteoarthritis.

    PubMed

    Allen, K D; Bierma-Zeinstra, S M A; Foster, N E; Golightly, Y M; Hawker, G

    2015-05-01

    Rigorous implementation research is important for testing strategies to improve the delivery of effective osteoarthritis (OA) interventions. The objective of this manuscript is to describe principles of implementation research, including conceptual frameworks, study designs and methodology, with specific recommendations for randomized clinical trials of OA treatment and management. This manuscript includes a comprehensive review of prior research and recommendations for implementation trials. The review of literature included identification of seminal articles on implementation research methods, as well as examples of previous exemplar studies using these methods. In addition to a comprehensive summary of this literature, this manuscript provides key recommendations for OA implementation trials. This review concluded that to date there have been relatively few implementation trials of OA interventions, but this is an emerging area of research. Future OA clinical trials should routinely consider incorporation of implementation aims to enhance translation of findings.

  14. Intravenous Ibuprofen for Treatment of Post-Operative Pain: A Multicenter, Double Blind, Placebo-Controlled, Randomized Clinical Trial

    PubMed Central

    Escontrela Rodriguez, Blanca; Planas Roca, Antonio; Martínez Ruiz, Alberto

    2016-01-01

    Background Non-steroidal anti-inflammatory drugs are often used as components of multimodal therapy for postoperative pain management, but their use is currently limited by its side effects. The specific objective of this study was to evaluate the efficacy and safety of a new formulation of intravenous (IV) ibuprofen for the management of postoperative pain in a European population. Methods and Findings A total of 206 patients from both abdominal and orthopedic surgery, were randomly assigned in 1:1 ratio to receive 800 mg IV-ibuprofen or placebo every 6 hours; all patients had morphine access through a patient controlled analgesia pump. The primary outcome measure was median morphine consumption within the first 24 hours following surgery. The mean±SEM of morphine requirements was reduced from 29,8±5,25 mg to 14,22±3,23 mg (p = 0,015) and resulted in a decrease in pain at rest (p = 0,02) measured by Visual Analog Scale (VAS) from mean±SEM 3.34±0,35 to 0.86±0.24, and also in pain during movement (p = 0,02) from 4.32±0,36 to 1.90±0,30 in the ibuprofen treatment arm; while in the placebo group VAS score at rest ranged from 4.68±0,40 to 2.12±0,42 and during movement from 5.66±0,42 to 3.38±0,44. Similar treatment-emergent adverse events occurred across both study groups and there was no difference in the overall incidence of these events. Conclusions Perioperative administration of IV-Ibuprofen 800 mg every 6 hours in abdominal surgery patient’s decreases morphine requirements and pain score. Furthermore IV-Ibuprofen was safe and well tolerate. Consequently we consider appropriate that protocols for management of postoperative pain include IV-Ibuprofen 800 mg every 6 hours as an option to offer patients an analgesic benefit while reducing the potentially risks associated with morphine consumption. Trial Registration EU Clinical Trials Register 2011-005007-33 PMID:27152748

  15. A French multicenter randomised trial comparing two dose-regimens of prothrombin complex concentrates in urgent anticoagulation reversal

    PubMed Central

    2013-01-01

    /kg group. No safety concerns were raised by the 40 IU/kg dose. Further trials are needed to evaluate the impact of the high dose of 4-factor PCC on functional outcomes and mortality. Trial registration Eudra CT number 2007-000602-73. PMID:23305460

  16. Prolonged release melatonin for improving sleep in totally blind subjects: a pilot placebo-controlled multicenter trial

    PubMed Central

    Roth, Thomas; Nir, Tali; Zisapel, Nava

    2015-01-01

    Introduction Melatonin, secreted by the pineal gland during the night phase, is a regulator of the biological clock and sleep tendency. Totally blind subjects frequently report severe, periodic sleep problems, with 50%–75% of cases displaying non-24-hour sleep–wake disorder (N24HSWD) due to inability to synchronize with the environmental day–night cycle. Melatonin immediate-release preparations are reportedly effective in N24HSWD. Here, we studied the efficacy and safety of prolonged-release melatonin (PRM), a registered drug for insomnia, for sleep disorders in totally blind subjects living in normal social environments. The primary endpoint was demonstration of clinically meaningful effects on sleep duration (upper confidence interval [CI] limit >20 minutes whether significant or not) to allow early decision-making on further drug development in this indication. Trial registration ClinicalTrials.gov registry – NCT00972075. Methods In a randomized, double-blind, placebo-controlled proof-of-principle study, 13 totally blind subjects had 2 weeks’ placebo run-in, 6 weeks’ randomized (1:1) PRM (Circadin®) or placebo nightly, and 2 weeks’ placebo run-out. Outcome measures included daily voice recorded sleep diary, Clinical Global Impression of Change (CGIC), WHO-Five Well-being Index (WHO-5), and safety. Results Mean nightly sleep duration improved by 43 minutes in the PRM and 16 minutes in the placebo group (mean difference: 27 minutes, 95% CI: −14.4 to 69 minutes; P=0.18; effect size: 0.82) meeting the primary endpoint. Mean sleep latency decreased by 29 minutes with PRM over placebo (P=0.13; effect size: 0.92) and nap duration decreased in the PRM but not placebo group. The variability in sleep onset/offset and latency tended to decrease during PRM but not placebo treatment. The potentially beneficial effects of PRM persisted during the 2 weeks of discontinuation period, consistent with clock stabilizing effects. PRM was well-tolerated, adverse

  17. Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial

    PubMed Central

    Geissler, Edward K.; Schnitzbauer, Andreas A.; Zülke, Carl; Lamby, Philipp E.; Proneth, Andrea; Duvoux, Christophe; Burra, Patrizia; Jauch, Karl-Walter; Rentsch, Markus; Ganten, Tom M.; Schmidt, Jan; Settmacher, Utz; Heise, Michael; Rossi, Giorgio; Cillo, Umberto; Kneteman, Norman; Adam, René; van Hoek, Bart; Bachellier, Philippe; Wolf, Philippe; Rostaing, Lionel; Bechstein, Wolf O.; Rizell, Magnus; Powell, James; Hidalgo, Ernest; Gugenheim, Jean; Wolters, Heiner; Brockmann, Jens; Roy, André; Mutzbauer, Ingrid; Schlitt, Angela; Beckebaum, Susanne; Graeb, Christian; Nadalin, Silvio; Valente, Umberto; Turrión, Victor Sánchez; Jamieson, Neville; Scholz, Tim; Colledan, Michele; Fändrich, Fred; Becker, Thomas; Söderdahl, Gunnar; Chazouillères, Olivier; Mäkisalo, Heikki; Pageaux, Georges-Philippe; Steininger, Rudolf; Soliman, Thomas; de Jong, Koert P.; Pirenne, Jacques; Margreiter, Raimund; Pratschke, Johann; Pinna, Antonio D.; Hauss, Johann; Schreiber, Stefan; Strasser, Simone; Klempnauer, Jürgen; Troisi, Roberto I.; Bhoori, Sherrie; Lerut, Jan; Bilbao, Itxarone; Klein, Christian G.; Königsrainer, Alfred; Mirza, Darius F.; Otto, Gerd; Mazzaferro, Vincenzo; Neuhaus, Peter; Schlitt, Hans J.

    2016-01-01

    Background We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). Methods In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor–free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor–free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. Results Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age ≤60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). Conclusions Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC. PMID:26555945

  18. Transdermal Wound Oxygen Therapy on Pressure Ulcer Healing: A Single-Blind Multi-Center Randomized Controlled Trial

    PubMed Central

    Azimian, Jalil; Dehghan Nayeri, Nahid; Pourkhaleghi, Enis; Ansari, Monireh

    2015-01-01

    Background: Although healthcare quality has considerably improved in many countries, pressure ulcer is still a major health challenge worldwide. Objectives: The current study aimed to evaluate the effects of TWOT on the healing of pressure ulcers. Patients and Methods: This study was a randomized controlled trial, and the convenient sample including 100 patients hospitalized in two university-affiliated medical-surgical intensive care units and one neurology unit located in Qazvin, Iran were studied. Patients with stage II-IV pressure ulcer on the sacral or ischial areas were randomly assigned to either the control or the experimental groups. The experimental group received a 12-day transdermal wound oxygen therapy. Wound status was assessed seven times before the intervention, as well as two, four, six, eight, ten, and twelve days after the intervention. Results: After 12 days of wound oxygen therapy, the number of patients with complete wound healing in the experimental group was significantly greater than that of the control group. Moreover, the total mean of wound area in the experimental group was significantly lower than that of the control group. Conclusions: Transdermal wound oxygen therapy can effectively promote wound healing in patients with pressure ulcers. PMID:26734476

  19. A multicenter randomized trial comparing rabeprazole and itopride in patients with functional dyspepsia in Japan: the NAGOYA study

    PubMed Central

    Kamiya, Takeshi; Shikano, Michiko; Kubota, Eiji; Mizoshita, Tsutomu; Wada, Tsuneya; Tanida, Satoshi; Kataoka, Hiromi; Adachi, Hiroshi; Hirako, Makoto; Okuda, Noriaki; Joh, Takashi

    2017-01-01

    The aims of this study were to compare the therapeutic effects of a proton pump inhibitor (PPI), rabeprazole (RPZ), and a prokinetic agent, itopride (ITO), and to investigate the role of PPI in the treatment strategy for Japanese functional dyspepsia (FD) patients. We randomly assigned 134 patients diagnosed by Rome III criteria to 4 weeks treatment with RPZ 10 mg/day (n = 69) or ITO 150 mg/day (n = 65). Dyspeptic symptoms were evaluated using FD scores at baseline and after 1, 2 and 4 weeks of treatment. We also divided subjects into predominantly epigastric pain syndrome (EPS) or postprandial distress syndrome (PDS), and evaluated the efficacy of RPZ and ITO respectively. RPZ showed a significant decrease in the Rate of Change (RC) in FD score within 1 week, which was maintained until after 4 weeks, with RPZ a significant effect compared with ITO at all evaluation points. In addition, RPZ showed a significant decrease in FD score in subjects with both EPS and PDS, whereas a significant decrease in the RC with ITO was only shown in those with predominant PDS. Acid-suppressive therapy with RPZ is useful for PDS as well EPS in Japanese FD patients (UMIN Clinical Trials Registry number: UMIN 000013962). PMID:28366993

  20. Enhancing kidney function with thrombolytic therapy following donation after cardiac death: a multicenter quasi-blinded prospective randomized trial.

    PubMed

    Woodside, Kenneth J; Goldfarb, David A; Rabets, John C; Sanchez, Edmund Q; Lebovitz, Daniel J; Schulak, James A; Fung, John J; Eghtesad, Bijan

    2015-12-01

    Kidneys from donors after cardiac death (DCD) are at risk for inferior outcomes, possibly due to microthrombi and additional warm ischemia. We describe an organ procurement organization-wide trial utilizing thrombolytic tissue plasminogen activator (tPA) during machine pulsatile perfusion (MPP). A kidney from each recovered kidney pair was prospectively randomized to receive tPA (50 mg Alteplase) or no tPA (control) in the MPP perfusate. From 2011 to 2013, 24 kidneys were placed with enrolled recipients from 19 DCD kidney donors. There were no significant differences for absolute values of flow or resistance while undergoing MPP between the groups, nor rates of achieving discrete flow and resistance targets. While there was a trend toward lower creatinine and higher glomerular filtration rates in the tPA group at 3, 6, 9, and 12 months, these differences were not significant. Delayed graft function (DGF) rates were 41.7% in the tPA group vs. 58.4% in the control group (OR 0.51, 95%CI 0.10-2.59, p = 0.68). Death-censored graft survival was similar between the groups. In this pilot study, encouraging trends are seen in kidney allograft function independent of MPP parameters following DCD kidney transplantation for those kidneys receiving thrombolytic tPA and MPP, compared with standard MPP.

  1. Deferiprone versus deferoxamine in thalassemia intermedia: Results from a 5-year long-term Italian multicenter randomized clinical trial.

    PubMed

    Calvaruso, Giuseppina; Vitrano, Angela; Di Maggio, Rosario; Lai, Eliana; Colletta, Grazia; Quota, Alessandra; Gerardi, Calogera; Rigoli, Luciana Concetta; Sacco, Massimiliano; Pitrolo, Lorella; Maggio, Aurelio

    2015-07-01

    In patients with thalassemia intermedia (TI), such as beta-TI, alpha-thalassemia (mainly HbH disease and mild/moderate forms of HbE/beta-thalassemia), iron overload is an important challenge in terms of diagnosis, monitoring, and treatment. Moreover, to date, the only possible chelators available are deferoxamine, deferasirox, and deferiprone. Here, we report the first 5-year long-term randomized clinical trial comparing the effectiveness of deferiprone versus deferoxamine in patients with TI. Body iron burden, which was determined by measuring serum ferritin levels in the same patient over 5 years and analyzed according to the generalized linear mixed model (GLMM), showed a linear decrease over time in the mean serum ferritin levels in both treatment groups (P-value = 0.035). The overall period of observation was 235.2 person-years for the deferiprone patients compared with 214.3 person-years for the deferoxamine patients. The results of the log-rank test suggested that the deferiprone treatment did not affect survival compared with the deferoxamine treatment (P-value = 0.360). The major adverse events observed included gastrointestinal symptoms and joint pain or arthralgia. Neutropenia and agranulocytosis were also detected, suggesting needing of strict hematological control. In conclusion, long-term iron chelation therapy with deferiprone is associated with an efficacy and safety similar to that of deferoxamine, suggesting that this drug is an alternative option in cases in which deferoxamine and deferasirox are contraindicated.

  2. Results of the AIEOP AML 2002/01 multicenter prospective trial for the treatment of children with acute myeloid leukemia.

    PubMed

    Pession, Andrea; Masetti, Riccardo; Rizzari, Carmelo; Putti, Maria Caterina; Casale, Fiorina; Fagioli, Franca; Luciani, Matteo; Lo Nigro, Luca; Menna, Giuseppe; Micalizzi, Concetta; Santoro, Nicola; Testi, Anna Maria; Zecca, Marco; Biondi, Andrea; Pigazzi, Martina; Rutella, Sergio; Rondelli, Roberto; Basso, Giuseppe; Locatelli, Franco

    2013-07-11

    We evaluated the outcome of 482 children with acute myeloid leukemia (AML) enrolled in the Associazione Italiana di Ematologia e Oncologia Pediatrica AML 2002/01 trial. Treatment was stratified according to risk group; hematopoietic stem cell transplantation (HSCT) was used in high-risk (HR) children. Patients with core binding factor leukemia achieving complete remission (CR) after the first induction course were considered standard risk (SR; 99 patients), whereas the others (n = 383) were assigned to the HR group. Allogeneic (ALLO) or autologous (AUTO) HSCT was employed, respectively, in 141 and 102 HR patients after consolidation therapy. CR, early death, and induction failure rates were 87%, 3%, and 10%, respectively. Relapse occurred in 24% of patients achieving CR. The 8-year overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 68%, 55%, and 63%, respectively. OS, EFS, and DFS for SR and HR patients were 83%, 63%, and 66% and 64%, 53%, and 62%. DFS was 63% and 73% for HR patients given AUTO-HSCT and ALLO-HSCT, respectively. In multivariate analysis, risk group, white blood cell >100 × 10(9)/L at diagnosis, and monosomal karyotype predicted poorer EFS. Risk-oriented treatment and broad use of HSCT result in a long-term EFS comparing favorably with previously published studies on childhood AML.

  3. An investment appraisal approach to clinical trial design.

    PubMed

    Backhouse, M E

    1998-11-01

    In this paper, a general investment appraisal model is presented which shows how pharmaceutical companies could take profit considerations into account when making decisions about the design of randomized controlled trials. A general model is presented based on the net present value method of investment appraisal. The approach is illustrated with a hypothetical example which shows how optimal (net present value maximizing) designs can be determined based on choices about sample size and endpoint measurement. The method could be extended to accommodate considerations about other trial design features, and could be used to determine a portfolio of studies which maximizes the expected return on a given development or trial budget. Furthermore, the approach could be used by pharmaceutical companies to evaluate the incremental costs and benefits of incorporating non-clinical objectives into trials, such as quality of life research and economic evaluation studies. A number of practical difficulties would need to be overcome to utilize the approach. Directions for further research are therefore highlighted centred on the key components of the model: a trial cost function, a product demand function, innovation diffusion processes and Bayesian approaches to trial design.

  4. Cost and accuracy of advanced breeding trial designs in apple

    PubMed Central

    Harshman, Julia M; Evans, Kate M; Hardner, Craig M

    2016-01-01

    Trialing advanced candidates in tree fruit crops is expensive due to the long-term nature of the planting and labor-intensive evaluations required to make selection decisions. How closely the trait evaluations approximate the true trait value needs balancing with the cost of the program. Designs of field trials of advanced apple candidates in which reduced number of locations, the number of years and the number of harvests per year were modeled to investigate the effect on the cost and accuracy in an operational breeding program. The aim was to find designs that would allow evaluation of the most additional candidates while sacrificing the least accuracy. Critical percentage difference, response to selection, and correlated response were used to examine changes in accuracy of trait evaluations. For the quality traits evaluated, accuracy and response to selection were not substantially reduced for most trial designs. Risk management influences the decision to change trial design, and some designs had greater risk associated with them. Balancing cost and accuracy with risk yields valuable insight into advanced breeding trial design. The methods outlined in this analysis would be well suited to other horticultural crop breeding programs. PMID:27019717

  5. Cerebrolysin Asian Pacific trial in acute brain injury and neurorecovery: design and methods.

    PubMed

    Poon, Wai; Vos, Pieter; Muresanu, Dafin; Vester, Johannes; von Wild, Klaus; Hömberg, Volker; Wang, Ernest; Lee, Tatia M C; Matula, Christian

    2015-04-15

    Traumatic brain injury (TBI) is one of the leading causes of injury-related death. In the United States alone, an estimated 1.7 million people sustain a TBI each year, and approximately 5.3 million people live with a TBI-related disability. The direct medical costs and indirect costs such as lost productivity of TBIs totaled an estimated $76.5 billion in the U.S. in the year 2000. Improving the limited treatment options for this condition remains challenging. However, recent reports from interdisciplinary working groups (consisting primarily of neurologists, neurosurgeons, neuropsychologists, and biostatisticians) have stated that to improve TBI treatment, important methodological lessons from the past must be taken into account in future clinical research. An evaluation of the neuroprotection intervention studies conducted over the last 30 years has indicated that a limited understanding of the underlying biological concepts and methodological design flaws are the major reasons for the failure of pharmacological agents to demonstrate efficacy. Cerebrolysin is a parenterally-administered neuro-peptide preparation that acts in a manner similar to endogenous neurotrophic factors. Cerebrolysin has a favorable adverse effect profile, and several meta-analyses have suggested that Cerebrolysin is beneficial as a dementia treatment. CAPTAIN is a randomized, double-blind, placebo-controlled, multi-center, multinational trial of the effects of Cerebrolysin on neuroprotection and neurorecovery after TBI using a multidimensional ensemble of outcome scales. The CAPTAIN trial will be the first TBI trial with a 'true' multidimensional approach based on full outcome scales, while avoiding prior weaknesses, such as loss of information through "dichotomization," or unrealistic assumptions such as "normal distribution."

  6. Rationale and design of the Early Sleeve gastrectomy In New Onset Diabetic Obese Patients (ESINODOP) trial.

    PubMed

    Trastulli, Stefano; Desiderio, Jacopo; Grandone, Ilenia; Fontana, Lucia; Paolini, Luisa; Altomare, Maria; D'Angelo, Paola; Palazzi, Mariangela; Cirocchi, Roberto; Leotta, Sergio; Fatati, Giuseppe; Parisi, Amilcare

    2017-03-01

    No randomized clinical trials (RCTs) have yet evaluated the bariatric surgery's efficacy and safety in patients newly diagnosed with type 2 diabetes mellitus (T2DM). The aim of this multicenter RCT is to compare bariatric surgery, particularly laparoscopic sleeve gastrectomy (LSG), with conventional medical therapy (CMT) in obese patients (body mass index between 30 and 42 kg/m(2)) newly diagnosed with T2DM and without any diabetes-related complications at any stage. A total of 100 eligible patients will be randomized at a 1:1 ratio to undergo one of the two planned treatments and will be followed for at least 6 years after randomization. The main objective of the ESINODOP trial is to investigate the efficacy of LSG compared with CMT alone in inducing and maintaining a remission of T2DM (defined as HbA1c levels ≤6.0 %, without active pharmacologic therapy after 1 year). The remission of T2DM will also be evaluated with the criteria provided by the American Diabetes Association (ADA), and the additional parameters such as adverse event rates, micro- and macrovascular complications, weight loss, gastrointestinal hormones, and quality of life will be compared. The study started on September 2015 and the planned recruitment period is 3 years. Patient recruitment and follow-up take place in the two diabetology and nutrition centers participating in the study, which are performed on a national basis. The ESINODOP trial is designed with the intent of comparing the efficacy of CMT alone to that of CMT in conjunction with LSG performed at the time of diabetes diagnosis in mildly obese diabetic patients. Currently, patients with these characteristics are not eligible for bariatric/metabolic surgery.

  7. Treatment of Nonalcoholic Fatty Liver Disease in Children: TONIC Trial Design

    PubMed Central

    2010-01-01

    Background Nonalcoholic fatty liver disease (NAFLD) in children can lead to steatohepatitis, cirrhosis, and end-stage liver disease. The cause of NAFLD is unknown, but it is commonly associated with obesity, insulin resistance, and dyslipidemia. Objectives TONIC is conducted to test whether treatment with metformin, an insulin sensitizer, or vitamin E, a naturally available antioxidant, will lead to improvements in biochemical and histological features of nondiabetic children with biopsy-proven NAFLD. Design TONIC is a randomized, multicenter, double-masked, placebo-controlled trial of 96 weeks of treatment with metformin or vitamin E. The primary outcome measure chosen for the trial is improvement in serum alanine aminotransferase (ALT) levels with treatment as compared to placebo. An improvement in ALT is defined as reduction in serum ALT levels to below 50% of the baseline values or into the normal range (40 U/L or less) during the last 48 weeks of treatment. Histological improvement is defined by changes in liver histology between a baseline and end-of-treatment liver biopsy in regards to (1) steatohepatitis, (2) NAFLD Activity Score, consisting of scores for steatosis, lobular inflammation, and hepatocellular injury (ballooning), and (3) fibrosis score. Methods Between September 2005 and September 2007, 173 children were enrolled into TONIC at 10 clinical centers in the United States. Participants were randomized to receive either metformin (500 mg b.i.d.), vitamin E (400 IU b.i.d.), or placebo for 96 weeks. This protocol was approved by all participating center Institutional Review Boards (IRBs) and an independent Data and Safety Monitoring Board (DSMB). (ClinicalTrials.gov number, NCT00063635.) PMID:19761871

  8. The citicoline brain injury treatment (COBRIT) trial: design and methods.

    PubMed

    Zafonte, Ross; Friedewald, William T; Lee, Shing M; Levin, Bruce; Diaz-Arrastia, Ramon; Ansel, Beth; Eisenberg, Howard; Timmons, Shelly D; Temkin, Nancy; Novack, Thomas; Ricker, Joseph; Merchant, Randall; Jallo, Jack

    2009-12-01

    Traumatic brain injury (TBI) is a major cause of death and disability. In the United States alone approximately 1.4 million sustain a TBI each year, of which 50,000 people die, and over 200,000 are hospitalized. Despite numerous prior clinical trials no standard pharmacotherapy for the treatment of TBI has been established. Citicoline, a naturally occurring endogenous compound, offers the potential of neuroprotection, neurorecovery, and neurofacilitation to enhance recovery after TBI. Citicoline has a favorable side-effect profile in humans and several meta-analyses suggest a benefit of citicoline treatment in stroke and dementia. COBRIT is a randomized, double-blind, placebo-controlled, multi-center trial of the effects of 90 days of citicoline on functional outcome in patients with complicated mild, moderate, and severe TBI. In all, 1292 patients will be recruited over an estimated 32 months from eight clinical sites with random assignment to citicoline (1000 mg twice a day) or placebo (twice a day), administered enterally or orally. Functional outcomes are assessed at 30, 90, and 180 days after the day of randomization. The primary outcome consists of a set of measures that will be analyzed as a composite measure using a global test procedure at 90 days. The measures comprise the following core battery: the California Verbal Learning Test II; the Controlled Oral Word Association Test; Digit Span; Extended Glasgow Outcome Scale; the Processing Speed Index; Stroop Test part 1 and Stroop Test part 2; and Trail Making Test parts A and B. Secondary outcomes include survival, toxicity, and rate of recovery.

  9. Parenteral Hydration in Patients With Advanced Cancer: A Multicenter, Double-Blind, Placebo-Controlled Randomized Trial

    PubMed Central

    Bruera, Eduardo; Hui, David; Dalal, Shalini; Torres-Vigil, Isabel; Trumble, Joseph; Roosth, Joseph; Krauter, Susan; Strickland, Carol; Unger, Kenneth; Palmer, J. Lynn; Allo, Julio; Frisbee-Hume, Susan; Tarleton, Kenneth

    2013-01-01

    Purpose The vast majority of patients with cancer at the end of life receive parenteral hydration in hospitals and no hydration in hospice, with limited evidence supporting either practice. In this randomized controlled trial, we determined the effect of hydration on symptoms associated with dehydration, quality of life, and survival in patients with advanced cancer. Patients and Methods We randomly assigned 129 patients with cancer from six hospices to receive parenteral hydration (normal saline 1 L per day) or placebo (normal saline 100 mL per day) daily over 4 hours. The primary outcome was change in the sum of four dehydration symptoms (fatigue, myoclonus, sedation and hallucinations, 0 = best and 40 = worst possible) between day 4 and baseline. Secondary outcomes included Edmonton Symptom Assessment Scale (ESAS), Memorial Delirium Assessment Scale (MDAS), Nursing Delirium Screening Scale (NuDESC), Unified Myoclonus Rating Scale (UMRS), Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F), Dehydration Assessment Scale, creatinine, urea, and overall survival. Intention-to-treat analysis was conducted to examine the change by day 4 ± 2 and day 7 ± 2 between groups. Results The hydration (n = 63) and placebo (n = 66) groups had similar baseline characteristics. We found no significant differences between the two groups for change in the sum of four dehydration symptoms (−3.3 v −2.8, P = .77), ESAS (all nonsignificant), MDAS (1 v 3.5, P = .084), NuDESC (0 v 0, P = .13), and UMRS (0 v 0, P = .54) by day 4. Results for day 7, including FACIT-F, were similar. Overall survival did not differ between the two groups (median, 21 v 15 days, P = .83). Conclusion Hydration at 1 L per day did not improve symptoms, quality of life, or survival compared with placebo. PMID:23169523

  10. Training Latin American primary care physicians in the WPA module on depression: results of a multicenter trial

    PubMed Central

    LEVAV, ITZHAK; KOHN, ROBERT; MONTOYA, IVAN; PALACIO, CARLOS; ROZIC, PABLO; SOLANO, IDA; VALENTINI, WILLIANS; VICENTE, BENJAMIN; MORALES, JORGE CASTRO; EIGUETA, FRANCISCO ESPEJO; SARAVANAN, YAMINI; MIRANDA, CLAUDIO T.; SARTORIUS, NORMAN

    2008-01-01

    Background In order to improve care for people with depressive disorders and to reduce the increasing burden of depression, the American Regional Office of the World Health Organization has launched a major region-wide initiative. A central part of this effort was directed to the primary care system where the diagnosis and treatment of depression are deficient in many countries. This study evaluated the materials developed by the World Psychiatric Association in a training program on depression among primary care physicians by measuring changes in their knowledge, attitudes, and practice (KAP). Method One hundred and seven physicians and 6174 patients from five Latin American countries participated in the trial. KAP were assessed 1 month before and 1 month following the training program. In addition, the presence of depressive symptoms was measured in patients who visited the clinic during a typical week at both times using the Zung Depression Scale and a DSM-IV/ICD-10 major depression checklist. Results The program slightly improved knowledge about depression and modified some attitudes, but had limited impact on actual practice. There was no evidence that the diagnosis of depression was made more frequently, nor was there an improvement in psychopharmacological management. The post-training agreement between physician diagnosis and that based on patient self-report remained low. The physicians, however, seemed more confident in treating depressed patients after training, and referred fewer patients to psychiatrists. Conclusions Traditional means of training primary care physicians in depression have little impact on clinical practice regardless of the quality of the teaching materials. PMID:15842027

  11. Rituximab in Children with Steroid-Dependent Nephrotic Syndrome: A Multicenter, Open-Label, Noninferiority, Randomized Controlled Trial

    PubMed Central

    Rossi, Roberta; Bonanni, Alice; Quinn, Robert R.; Sica, Felice; Bodria, Monica; Pasini, Andrea; Montini, Giovanni; Edefonti, Alberto; Belingheri, Mirco; De Giovanni, Donatella; Barbano, Giancarlo; Degl’Innocenti, Ludovica; Scolari, Francesco; Murer, Luisa; Reiser, Jochen; Fornoni, Alessia; Ghiggeri, Gian Marco

    2015-01-01

    Steroid-dependent nephrotic syndrome (SDNS) carries a high risk of toxicity from steroids or steroid-sparing agents. This open-label, noninferiority, randomized controlled trial at four sites in Italy tested whether rituximab is noninferior to steroids in maintaining remission in juvenile SDNS. We enrolled children age 1–16 years who had developed SDNS in the previous 6–12 months and were maintained in remission with high prednisone doses (≥0.7 mg/kg per day). We randomly assigned participants to continue prednisone alone for 1 month (control) or to add a single intravenous infusion of rituximab (375 mg/m2; intervention). Prednisone was tapered in both groups after 1 month. For noninferiority, rituximab had to permit steroid withdrawal and maintain 3-month proteinuria (mg/m2 per day) within a prespecified noninferiority margin of three times the levels among controls (primary outcome). We followed participants for ≥1 year to compare risk of relapse (secondary outcome). Fifteen children per group (21 boys; mean age, 7 years [range, 2.6–13.5 years]) were enrolled and followed for ≤60 months (median, 22 months). Three-month proteinuria was 42% lower in the rituximab group (geometric mean ratio, 0.58; 95% confidence interval, 0.18 to 1.95 [i.e., within the noninferiority margin of three times the levels in controls]). All but one child in the control group relapsed within 6 months; median time to relapse in the rituximab group was 18 months (95% confidence interval, 9 to 32 months). In the rituximab group, nausea and skin rash during infusion were common; transient acute arthritis occurred in one child. In conclusion, rituximab was noninferior to steroids for the treatment of juvenile SDNS. PMID:25592855

  12. Rituximab in Children with Steroid-Dependent Nephrotic Syndrome: A Multicenter, Open-Label, Noninferiority, Randomized Controlled Trial.

    PubMed

    Ravani, Pietro; Rossi, Roberta; Bonanni, Alice; Quinn, Robert R; Sica, Felice; Bodria, Monica; Pasini, Andrea; Montini, Giovanni; Edefonti, Alberto; Belingheri, Mirco; De Giovanni, Donatella; Barbano, Giancarlo; Degl'Innocenti, Ludovica; Scolari, Francesco; Murer, Luisa; Reiser, Jochen; Fornoni, Alessia; Ghiggeri, Gian Marco

    2015-09-01

    Steroid-dependent nephrotic syndrome (SDNS) carries a high risk of toxicity from steroids or steroid-sparing agents. This open-label, noninferiority, randomized controlled trial at four sites in Italy tested whether rituximab is noninferior to steroids in maintaining remission in juvenile SDNS. We enrolled children age 1-16 years who had developed SDNS in the previous 6-12 months and were maintained in remission with high prednisone doses (≥0.7 mg/kg per day). We randomly assigned participants to continue prednisone alone for 1 month (control) or to add a single intravenous infusion of rituximab (375 mg/m(2); intervention). Prednisone was tapered in both groups after 1 month. For noninferiority, rituximab had to permit steroid withdrawal and maintain 3-month proteinuria (mg/m(2) per day) within a prespecified noninferiority margin of three times the levels among controls (primary outcome). We followed participants for ≥1 year to compare risk of relapse (secondary outcome). Fifteen children per group (21 boys; mean age, 7 years [range, 2.6-13.5 years]) were enrolled and followed for ≤60 months (median, 22 months). Three-month proteinuria was 42% lower in the rituximab group (geometric mean ratio, 0.58; 95% confidence interval, 0.18 to 1.95 [i.e., within the noninferiority margin of three times the levels in controls]). All but one child in the control group relapsed within 6 months; median time to relapse in the rituximab group was 18 months (95% confidence interval, 9 to 32 months). In the rituximab group, nausea and skin rash during infusion were common; transient acute arthritis occurred in one child. In conclusion, rituximab was noninferior to steroids for the treatment of juvenile SDNS.

  13. Supplemental vibrational force does not reduce pain experience during initial alignment with fixed orthodontic appliances: a multicenter randomized clinical trial

    PubMed Central

    Woodhouse, Neil R.; DiBiase, Andrew T.; Papageorgiou, Spyridon N.; Johnson, Nicola; Slipper, Carmel; Grant, James; Alsaleh, Maryam; Cobourne, Martyn T.

    2015-01-01

    This prospective randomized trial investigated the effect of supplemental vibrational force on orthodontic pain during alignment with fixed-appliances. Eighty-one subjects < 20 years-old undergoing extraction-based fixed-appliance treatment were randomly allocated to supplementary (20-minutes/day) use of an intra-oral vibrational device (AcceleDent®) (n = 29); an identical non-functional (sham) device (n = 25) or fixed-appliances only (n = 27). Each subject recorded pain intensity (using a 100-mm visual-analogue scale) and intake of oral analgesia in a questionnaire, following appliance-placement (T1) and first-adjustment (T2) for 1-week (immediately-after, 4, 24, 72-hours and at 1-week). Mean maximum-pain for the total sample was 72.96 mm [SD 21.59; 95%CI 68.19–77.74 mm] with no significant differences among groups (P = 0.282). Subjects taking analgesics reported slightly higher maximum-pain although this was not significant (P = 0.170). The effect of intervention was independent of analgesia (P = 0.883). At T1 and T2, a statistically and clinically significant increase in mean pain was seen at 4 and 24-hours, declining at 72-hours and becoming insignificant at 1-week. For mean alignment-rate, pain-intensity and use of analgesics, no significant differences existed between groups (P > 0.003). The only significant predictor for mean pain was time. Use of an AcceleDent vibrational device had no significant effect on orthodontic pain or analgesia consumption during initial alignment with fixed appliances. PMID:26610843

  14. Multicenter, Randomized Clinical Trial To Compare the Safety and Efficacy of LFF571 and Vancomycin for Clostridium difficile Infections

    PubMed Central

    Mullane, Kathleen; Lee, Christine; Bressler, Adam; Buitrago, Martha; Weiss, Karl; Dabovic, Kristina; Praestgaard, Jens; Leeds, Jennifer A.; Blais, Johanne

    2014-01-01

    Clostridium difficile infection causes serious diarrheal disease. Although several drugs are available for treatment, including vancomycin, recurrences remain a problem. LFF571 is a semisynthetic thiopeptide with potency against C. difficile in vitro. In this phase 2 exploratory study, we compared the safety and efficacy (based on a noninferiority analysis) of LFF571 to those of vancomycin used in adults with primary episodes or first recurrences of moderate C. difficile infection. Patients were randomized to receive 200 mg of LFF571 or 125 mg of vancomycin four times daily for 10 days. The primary endpoint was the proportion of clinical cures at the end of therapy in the per-protocol population. Secondary endpoints included clinical cures at the end of therapy in the modified intent-to-treat (mITT) population, the time to diarrhea resolution, and the recurrence rate. Seventy-two patients were randomized, with 46 assigned to receive LFF571. Based on the protocol-specified definition, the rate of clinical cure for LFF571 (90.6%) was noninferior to that of vancomycin (78.3%). The 30-day sustained cure rates for LFF571 and vancomycin were 56.7% and 65.0%, respectively, in the per-protocol population and 58.7% and 60.0%, respectively, in the modified intent-to-treat population. Using toxin-confirmed cases only, the recurrence rates were lower for LFF571 (19% versus 25% for vancomycin in the per-protocol population). LFF571 was generally safe and well tolerated. The incidence of adverse events (AEs) was higher for LFF571 (76.1% versus 69.2% for vancomycin), although more AEs in the vancomycin group were suspected to be related to the study drug (38.5% versus 32.6% for LFF571). One patient receiving LFF571 discontinued the study due to an AE. (This study has been registered at ClinicalTrials.gov under registration no. NCT01232595.) PMID:25534727

  15. Overcoming Disembodiment: The Effect of Movement Therapy on Negative Symptoms in Schizophrenia—A Multicenter Randomized Controlled Trial

    PubMed Central

    Martin, Lily A. L.; Koch, Sabine C.; Hirjak, Dusan; Fuchs, Thomas

    2016-01-01

    Objective: Negative symptoms of patients with Schizophrenia are resistant to medical treatment or conventional group therapy. Understanding schizophrenia as a form of disembodiment of the self, a number of scientists have argued that the approach of embodiment and associated embodied therapies, such as Dance and Movement Therapy (DMT) or Body Psychotherapy (BPT), may be more suitable to explain the psychopathology underlying the mental illness and to address its symptoms. Hence the present randomized controlled trial (DRKS00009828, http://apps.who.int/trialsearch/) aimed to examine the effectiveness of manualized movement therapy (BPT/DMT) on the negative symptoms of patients with schizophrenia. Method:A total of 68 out-patients with a diagnosis of a schizophrenia spectrum disorder were randomly allocated to either the treatment (n = 44, 20 sessions of BPT/DMT) or the control condition [n = 24, treatment as usual (TAU)]. Changes in negative symptom scores on the Scale for the Assessment of Negative Symptoms (SANS) were analyzed using Analysis of Covariance (ANCOVA) with Simpson-Angus Scale (SAS) scores as covariates in order to control for side effects of antipsychotic medication. Results:After 20 sessions of treatment (BPT/DMT or TAU), patients receiving movement therapy had significantly lower negative symptom scores (SANS total score, blunted affect, attention). Effect sizes were moderate and mean symptom reduction in the treatment group was 20.65%. Conclusion:The study demonstrates that embodied therapies, such as BPT/DMT, are highly effective in the treatment of patients with schizophrenia. Results strongly suggest that BPT/DMT should be embedded in the daily clinical routine. PMID:27064347

  16. A Multicenter Phase II Trial of S-1 With Concurrent Radiation Therapy for Locally Advanced Pancreatic Cancer

    SciTech Connect

    Ikeda, Masafumi; Ioka, Tatsuya; Ito, Yoshinori; Yonemoto, Naohiro; Nagase, Michitaka; Yamao, Kenji; Miyakawa, Hiroyuki; Ishii, Hiroshi; Furuse, Junji; Sato, Keiko; Sato, Tosiya; Okusaka, Takuji

    2013-01-01

    Purpose: The aim of this trial was to evaluate the efficacy and toxicity of S-1 and concurrent radiation therapy for locally advanced pancreatic cancer (PC). Methods and Materials: Locally advanced PC patients with histologically or cytologically confirmed adenocarcinoma or adenosquamous carcinoma, who had no previous therapy were enrolled. Radiation therapy was delivered through 3 or more fields at a total dose of 50.4 Gy in 28 fractions over 5.5 weeks. S-1 was administered orally at a dose of 80 mg/m{sup 2} twice daily on the day of irradiation during radiation therapy. After a 2- to 8-week break, patients received a maintenance dose of S-1 (80 mg/m{sup 2}/day for 28 consecutive days, followed by a 14-day rest period) was then administered until the appearance of disease progression or unacceptable toxicity. The primary efficacy endpoint was survival, and the secondary efficacy endpoints were progression-free survival, response rate, and serum carbohydrate antigen 19-9 (CA19-9) response; the safety endpoint was toxicity. Results: Of the 60 evaluable patients, 16 patients achieved a partial response (27%; 95% confidence interval [CI], 16%-40%). The median progression-free survival period, overall survival period, and 1-year survival rate of the evaluable patients were 9.7 months (95% CI, 6.9-11.6 months), 16.2 months (95% CI, 13.5-21.3 months), and 72% (95%CI, 59%-82%), respectively. Of the 42 patients with a pretreatment serum CA19-9 level of {>=}100 U/ml, 34 (81%) patients showed a decrease of greater than 50%. Leukopenia (6 patients, 10%) and anorexia (4 patients, 7%) were the major grade 3-4 toxicities with chemoradiation therapy. Conclusions: The effect of S-1 with concurrent radiation therapy in patients with locally advanced PC was found to be very favorable, with only mild toxicity.

  17. Design and Rationale of the PREVENT III Clinical Trial: Edifoligide for the Prevention of Infrainguinal Vein Graft Failure

    PubMed Central

    Conte, Michael S.; Lorenz, Todd J.; Bandyk, Dennis F.; Clowes, Alexander W.; Moneta, Gregory L.; Seely, B. Lynn

    2006-01-01

    Surgical bypass of peripheral arterial occlusive disease with autologous vein grafts provides an effective means of restoring blood flow to the lower extremity, and has been a standard therapy for patients with disabling claudication or critical limb ischemia (CLI). However, failure rates may run as high as 50% within 5 years. These graft failures occur as a result of neointimal hyperplasia, a ubiquitous biologic response of blood vessel walls to injury, which is characterized by the migration and proliferation of smooth muscle cells (SMC). The E2F family of transcription factors regulates the expression of genes controlling SMC proliferation. Edifoligide (E2F Decoy) is a novel therapy that inhibits E2F function, thus attenuating neointimal hyperplasia. Its use in conjunction with a patented drug delivery pressurization chamber is under investigation. Using this system, edifoligide is administered to vein grafts in a single, ex vivo treatment following vein harvest and before implantation, resulting in minimal systemic drug exposure and excellent patient compliance. This Phase 3, randomized, double-blind, multicenter clinical trial is designed to evaluate the safety and efficacy of edifoligide in a population of approximately 1400 patients with CLI undergoing infrainguinal bypass for peripheral arterial disease (PAD). The primary outcome measure will be the time to occurrence of non-technical graft failure resulting in either graft revision or major amputation at 12 months after enrollment. A governing Clinical Events Classification committee (CEC) will adjudicate each graft failure to determine its etiology. The PREVENT III trial is the largest multicenter trial ever performed in patients receiving autologous vein bypass grafts for CLI. This landmark study will determine if edifoligide is safe and effective at preventing vein graft failure in patients undergoing lower extremity bypass, but it also provides a unique opportunity to observe current treatment

  18. Alternative clinical trial design in neurocritical care.

    PubMed

    Lazaridis, Christos; Maas, Andrew I R; Souter, Michael J; Martin, Renee H; Chesnut, Randal M; DeSantis, Stacia M; Sung, Gene; Leroux, Peter D; Suarez, Jose I

    2015-06-01

    Neurocritical care involves the care of highly complex patients with combinations of physiologic derangements in the brain and in extracranial organs. The level of evidence underpinning treatment recommendations remains low due to a multitude of reasons including an incomplete understanding of the involved physiology; lack of good quality, prospective, standardized data; and the limited success of conventional randomized controlled trials. Comparative effectiveness research can provide alternative perspectives and methods to enhance knowledge and evidence within the field of neurocritical care; these include large international collaborations for generation and maintenance of high quality data, statistical methods that incorporate heterogeneity and individualize outcome prediction, and finally advanced bioinformatics that integrate large amounts of variable-source data into patient-specific phenotypes and trajectories.

  19. Adaptive Designs for Randomized Trials in Public Health

    PubMed Central

    Brown, C. Hendricks; Have, Thomas R. Ten; Jo, Booil; Dagne, Getachew; Wyman, Peter A.; Muthén, Bengt; Gibbons, Robert D.

    2009-01-01

    In this article, we present a discussion of two general ways in which the traditional randomized trial can be modified or adapted in response to the data being collected. We use the term adaptive design to refer to a trial in which characteristics of the study itself, such as the proportion assigned to active intervention versus control, change during the trial in response to data being collected. The term adaptive sequence of trials refers to a decision-making process that fundamentally informs the conceptualization and conduct of each new trial with the results of previous trials. Our discussion below investigates the utility of these two types of adaptations for public health evaluations. Examples are provided to illustrate how adaptation can be used in practice. From these case studies, we discuss whether such evaluations can or should be analyzed as if they were formal randomized trials, and we discuss practical as well as ethical issues arising in the conduct of these new-generation trials. PMID:19296774

  20. Comparison of F(ab')2 versus Fab antivenom for pit viper envenomation: A prospective, blinded, multicenter, randomized clinical trial

    PubMed Central

    Ruha, Anne-Michelle; Seifert, Steven A.; Morgan, David L.; Lewis, Brandon J.; Arnold, Thomas C.; Clark, Richard F.; Meggs, William J.; Toschlog, Eric A.; Borron, Stephen W.; Figge, Gary R.; Sollee, Dawn R.; Shirazi, Farshad M.; Wolk, Robert; de Chazal, Ives; Quan, Dan; García-Ubbelohde, Walter; Alagón, Alejandro; Gerkin, Richard D.; Boyer, Leslie V.

    2015-01-01

    Background. Crotalidae Polyvalent Immune Fab (Ovine) has been the only antivenom commercially available in the US since 2007 for treatment of Crotalinae envenomation. Late coagulopathy can occur or recur after clearance of Fab antivenom, often after hospital discharge, lasting in some cases more than 2 weeks. There have been serious, even fatal, bleeding complications associated with recurrence phenomena. Frequent follow-up is required, and additional intervention or hospitalization is often necessary. F(ab')2 immunoglobulin derivatives have longer plasma half life than do Fab. We hypothesized that F(ab')2 antivenom would be superior to Fab in the prevention of late coagulopathy following treatment of patients with Crotalinae envenomation. Methods. We conducted a prospective, double-blind, randomized clinical trial, comparing late coagulopathy in snakebitten patients treated with F(ab')2 with maintenance doses [F(ab')2/F(ab')2], or F(ab')2 with placebo maintenance doses [F(ab')2/placebo], versus Fab with maintenance doses [Fab/Fab]. The primary efficacy endpoint was coagulopathy (platelet count < 150 K/mm3, fibrinogen level < 150 mg/dL) between end of maintenance dosing and day 8. Results. 121 patients were randomized at 18 clinical sites and received at least one dose of study drug. 114 completed the study. Of these, 11/37 (29.7%) in the Fab/Fab cohort experienced late coagulopathy versus 4/39 (10.3%, p < 0.05) in the F(ab')2/F(ab')2 cohort and 2/38 (5.3%, p < 0.05) in the F(ab')2/placebo cohort. The lowest heterologous protein exposure was with F(ab')2/placebo. No serious adverse events were related to study drug. In each study arm, one patient experienced an acute serum reaction and one experienced serum sickness. Conclusions. In this study, management of coagulopathic Crotalinae envenomation with longer-half-life F(ab')2 antivenom, with or without maintenance dosing, reduced the risk of subacute coagulopathy and bleeding following treatment of envenomation

  1. Oral Ondansetron versus Domperidone for Acute Gastroenteritis in Pediatric Emergency Departments: Multicenter Double Blind Randomized Controlled Trial

    PubMed Central

    Bonati, Maurizio; Maestro, Alessandra; Zanon, Davide; Rovere, Francesca; Arrighini, Alberto; Barbi, Egidio; Bertolani, Paolo; Biban, Paolo; Da Dalt, Liviana; Guala, Andrea; Mazzoni, Elisa; Pazzaglia, Anna; Perri, Paolo Francesco; Reale, Antonino; Renna, Salvatore; Urbino, Antonio Francesco; Valletta, Enrico; Vitale, Antonio; Zangardi, Tiziana; Clavenna, Antonio

    2016-01-01

    The use of antiemetics for vomiting in acute gastroenteritis in children is still a matter of debate. We conducted a double-blind randomized trial to evaluate whether a single oral dose of ondansetron vs domperidone or placebo improves outcomes in children with gastroenteritis. After failure of initial oral rehydration administration, children aged 1–6 years admitted for gastroenteritis to the pediatric emergency departments of 15 hospitals in Italy were randomized to receive one oral dose of ondansetron (0.15 mg/kg) or domperidone (0.5 mg/kg) or placebo. The primary outcome was the percentage of children receiving nasogastric or intravenous rehydration. A p value of 0.014 was used to indicate statistical significance (and 98.6% CI were calculated) as a result of having carried out two interim analyses. 1,313 children were eligible for the first attempt with oral rehydration solution, which was successful for 832 (63.4%); 356 underwent randomization (the parents of 125 children did not give consent): 118 to placebo, 119 to domperidone, and 119 to ondansetron. Fourteen (11.8%) needed intravenous rehydration in the ondansetron group vs 30 (25.2%) and 34 (28.8%) in the domperidone and placebo groups, respectively. Ondansetron reduced the risk of intravenous rehydration by over 50%, both vs placebo (RR 0.41, 98.6% CI 0.20–0.83) and domperidone (RR 0.47, 98.6% CI 0.23–0.97). No differences for adverse events were seen among groups. In a context of emergency care, 6 out of 10 children aged 1–6 years with vomiting due to gastroenteritis and without severe dehydration can be managed effectively with administration of oral rehydration solution alone. In children who fail oral rehydration, a single oral dose of ondansetron reduces the need for intravenous rehydration and the percentage of children who continue to vomit, thereby facilitating the success of oral rehydration. Domperidone was not effective for the symptomatic treatment of vomiting during acute

  2. Randomized controlled trials – a matter of design

    PubMed Central

    Spieth, Peter Markus; Kubasch, Anne Sophie; Penzlin, Ana Isabel; Illigens, Ben Min-Woo; Barlinn, Kristian; Siepmann, Timo

    2016-01-01

    Randomized controlled trials (RCTs) are the hallmark of evidence-based medicine and form the basis for translating research data into clinical practice. This review summarizes commonly applied designs and quality indicators of RCTs to provide guidance in interpreting and critically evaluating clinical research data. It further reflects on the principle of equipoise and its practical applicability to clinical science with an emphasis on critical care and neurological research. We performed a review of educational material, review articles, methodological studies, and published clinical trials using the databases MEDLINE, PubMed, and ClinicalTrials.gov. The most relevant recommendations regarding design, conduction, and reporting of RCTs may include the following: 1) clinically relevant end points should be defined a priori, and an unbiased analysis and report of the study results should be warranted, 2) both significant and nonsignificant results should be objectively reported and published, 3) structured study design and performance as indicated in the Consolidated Standards of Reporting Trials statement should be employed as well as registration in a public trial database, 4) potential conflicts of interest and funding sources should be disclaimed in study report or publication, and 5) in the comparison of experimental treatment with standard care, preplanned interim analyses during an ongoing RCT can aid in maintaining clinical equipoise by assessing benefit, harm, or futility, thus allowing decision on continuation or termination of the trial. PMID:27354804

  3. Methods and outcomes of engaging stakeholders to design a comparative effectiveness trial in children with uncontrolled asthma

    PubMed Central

    Erwin, Kim; Martin, Molly A.; Flippin, Tara; Norell, Sarah; Shadlyn, Ariana; Yang, Jie; Falco, Paula; Rivera, Jaime; Ignoffo, Stacy; Kumar, Rajesh; Margellos-Anast, Helen; McDermott, Michael; McMahon, Kate; Mosnaim, Giselle; Nyenhuis, Sharmilee M.; Press, Valerie G.; Ramsay, Jessica E.; Soyemi, Kenneth; Thompson, Trevonne M.; Krishnan, Jerry A.

    2016-01-01

    Aim To present the methods and outcomes of stakeholder engagement in the development of interventions for children presenting to the emergency department (ED) for uncontrolled asthma. Methods We engaged stakeholders (caregivers, physicians, nurses, administrators) from six EDs in a three-phase process to: 1) Define design requirements; 2) Prototype and Refine; and 3) Evaluate. Results Interviews among 28 stakeholders yielded themes regarding in-home asthma management practices and ED discharge experiences. Quantitative and qualitative evaluation showed strong preference for the new discharge tool (CHICAGO Action Plan after ED discharge, CAPE) over current tools. Conclusions Engaging end-users in contextual inquiry resulted in CAPE, a new stakeholder-balanced discharge tool, which is being tested in a multi-center comparative effectiveness trial. PMID:26690579

  4. Evidence for the future – Designing a clinical trial

    PubMed Central

    Hajebrahimi, Sakineh; Mostafaie, Ali; Sadeghi-Bazargani, Homayoun

    2011-01-01

    The quality of the evidence is a keystone in the understanding of Evidence Based Medicine. Randomized controlled trials (RCTs) rank first among the research designs providing clinical evidence. Knowing about the design of clinical trials is not only the cornerstone of clinical research, but also is a requirement for any clinician who wants to learn about new findings of clinical research in his/her field. Many clinicians have good understanding as well as some misunderstandings about the design of clinical trials. This article is going to provide some crucial comments to be considered in conducting RCTs in order to help in production of better evidence for future of urology research through RCTs PMID:22279317

  5. OARSI Clinical Trials Recommendations: Design and conduct of clinical trials for hand osteoarthritis.

    PubMed

    Kloppenburg, M; Maheu, E; Kraus, V B; Cicuttini, F; Doherty, M; Dreiser, R-L; Henrotin, Y; Jiang, G-L; Mandl, L; Martel-Pelletier, J; Nelson, A E; Neogi, T; Pelletier, J-P; Punzi, L; Ramonda, R; Simon, L S; Wang, S

    2015-05-01

    Hand osteoarthritis (OA) is a very frequent disease, but yet understudied. However, a lot of works have been published in the past 10 years, and much has been done to better understand its clinical course and structural progression. Despite this new knowledge, few therapeutic trials have been conducted in hand OA. The last OARSI recommendations for the conduct of clinical trials in hand OA dates back to 2006. The present recommendations aimed at updating previous recommendations, by incorporating new data. The purpose of this expert opinion, consensus driven exercise is to provide evidence-based guidance on the design, execution and analysis of clinical trials in hand OA, where published evidence is available, supplemented by expert opinion, where evidence is lacking, to perform clinical trials in hand OA, both for symptom and for structure-modification. They indicate core outcome measurement sets for studies in hand OA, and list the methods and instruments that should be used to measure symptoms or structure. For both symptom- and structure-modification, at least pain, physical function, patient global assessment, HR-QoL, joint activity and hand strength should be assessed. In addition, for structure-modification trials, structural progression should be measured by radiographic changes. We also provide a research agenda listing many unsolved issues that seem to most urgently need to be addressed from the perspective of performing "good" clinical trials in hand OA. These updated OARSI recommendations should allow for better standardizing the conduct of clinical trials in hand OA in the next future.

  6. Serum VEGF-D concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial

    PubMed Central

    Young, Lisa R; Lee, Hye-Seung; Inoue, Yoshikazu; Moss, Joel; Singer, Lianne G; Strange, Charlie; Nakata, Koh; Barker, Alan F; Chapman, Jeffrey T; Brantly, Mark L; Stocks, James M; Brown, Kevin K; Lynch, Joseph P; Goldberg, Hilary J; Downey, Gregory P; Swigris, Jeffrey J; Taveira-DaSilva, Angelo M; Krischer, Jeffrey P; Trapnell, Bruce C; McCormack, Francis X

    2013-01-01

    Summary Background VEGF-D is a lymphangiogenic growth factor that has a key role in tumour metastasis. Serum VEGF-D concentrations are increased in most patients with lymphangioleiomyomatosis, a rare neoplasm associated with mTOR-activating tuberous sclerosis gene mutations, lymphadenopathy, metastatic spread, and pulmonary cyst formation. We used data from the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial to assess the usefulness of serum VEGF-D concentration as a marker of severity and therapeutic response to sirolimus in patients with lymphangioleiomyomatosis. Methods In the MILES trial, patients with lymphangioleiomyomatosis who had forced expiratory volume in 1 second (FEV1) of 70% or less of predicted were randomly assigned (1:1) to 12 months masked treatment with sirolimus or placebo. Serum VEGF-D concentrations were measured at baseline, 6 months, and 12 months. We used a linear regression model to assess associations of baseline VEGF-D concentrations with markers of disease severity, and a linear mixed effects model to assess the associations of VEGF-D concentrations with between-group differences in clinical, physiological, and patient-reported outcomes. Findings We included 42 patients from the placebo group and 45 from the sirolimus group in our analysis. Baseline VEGF-D concentrations in individual patients varied from 0·34 ng/mL to 16·7 ng/mL. Baseline VEGF-D concentrations were higher in patients who needed supplemental oxygen than in those who did not need supplemental oxygen (1·7 ng/mL [IQR 0·99–3·36] vs 0·84 ng/mL [0·52–1·39]; p<0·0001) and in those who had a bronchodilator response than in those who did not (2·01 ng/mL [0·99–2·86] vs 1·00 ng/mL [0·61–2·15]; 0·0273). Median serum VEGF-D concentrations were similar at baseline in the sirolimus and placebo groups, and fell from baseline at 6 and 12 months in the sirolimus group but remained roughly stable in the placebo group. Each one

  7. "Intelligent Design" Goes on Trial in Pennsylvania

    ERIC Educational Resources Information Center

    Cavanagh, Sean

    2005-01-01

    The question of whether "intelligent design" amounts to legitimate science, pseudo-science, or religion masquerading as science has underwent a potentially historic legal test, as a federal court in Pennsylvania considered whether a public school district can require that students be exposed to the controversial concept. Eleven parents…

  8. Modifications of sequential designs in bioequivalence trials.

    PubMed

    Zheng, Cheng; Zhao, Lihui; Wang, Jixian

    2015-01-01

    Bioequivalence (BE) studies are designed to show that two formulations of one drug are equivalent and they play an important role in drug development. When in a design stage, it is possible that there is a high degree of uncertainty on variability of the formulations and the actual performance of the test versus reference formulation. Therefore, an interim look may be desirable to stop the study if there is no chance of claiming BE at the end (futility), or claim BE if evidence is sufficient (efficacy), or adjust the sample size. Sequential design approaches specially for BE studies have been proposed previously in publications. We applied modification to the existing methods focusing on simplified multiplicity adjustment and futility stopping. We name our method modified sequential design for BE studies (MSDBE). Simulation results demonstrate comparable performance between MSDBE and the original published methods while MSDBE offers more transparency and better applicability. The R package MSDBE is available at https://sites.google.com/site/modsdbe/.

  9. The Efficacy and Safety of Wenxin Keli in Patients with Frequent Premature Ventricular Contractions: A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Trial

    PubMed Central

    Hua, Wei; Gao, Run-Lin; Zhao, Bu-Chang; Wang, Jing; Chen, Xu-Hua; Cai, Chi; Zhang, Shu

    2015-01-01

    Background: Premature ventricular contractions (PVCs) are common in the general population, and frequent PVCs may result in the poor quality of life or even the damage of cardiac function. We examined the efficacy and safety of a traditional Chinese medicine Wenxin Keli for the treatment of frequent PVCs among a relatively large Chinese cohort. Methods: We performed a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. A total of 1200 eligible participants were randomly assigned in a ratio of 1:1 to receive Wenxin Keli or the placebo for 4 weeks. The primary and secondary endpoint was the change of PVC numbers and PVC-related symptoms after a 4-week treatment compared with baseline, respectively. In addition, vital signs, laboratory values, and electrocardiographic parameters were assessed in a safety analysis. Results: At the initial evaluation, no significant differences in the baseline characteristics were observed between the Wenxin Keli group and the placebo group. A smaller number of PVCs was observed after the 4-week treatment than at baseline, in both the Wenxin Keli group (5686 ± 5940 vs. 15,138 ± 7597 beats/d, P < 0.001) and the placebo group (10,592 ± 8009 vs. 14,529 ± 5929 beats/d, P < 0.001); moreover, the Wenxin Keli group demonstrated a significantli greater reduction in the frequency of PVCs than the placebo group (P < 0.001). In a full analysis set, patients in the Wenxin Keli group exhibited significantly higher total effective responses in the reduction of PVCs compared to those in the placebo group (83.8% vs. 43.5%, P < 0.001). The per-protocol analysis yielded similar results (83.0% vs. 39.3%, P < 0.001). Treatment with Wenxin Keli also demonstrated superior performance compared to the placebo with respect to PVC-related symptoms. No severe adverse effects attributable to Wenxin Keli were reported. Conclusions: Wenxin Keli treatment effectively reduced the overall number of PVCs and alleviated PVC

  10. Needle Sensation and Personality Factors Influence Therapeutic Effect of Acupuncture for Treating Bell's Palsy: A Secondary Analysis of a Multicenter Randomized Controlled Trial

    PubMed Central

    Zhang, Chen-Yan; Xu, Sha-Bei; Huang, Bo; Du, Peng; Zhang, Gui-Bin; Luo, Xiang; Huang, Guang-Ying; Xie, Min-Jie; Zhou, Zong-Kui; Wang, Wei

    2016-01-01

    Background: It has not been solved what kind of needle sensation might influence outcomes of acupuncture treatment. Effects of personality factors on the therapeutic effect of acupuncture have not been investigated. This study aimed to find the effects of the traits of personality on the objective outcome when different acupuncture techniques were used in treating patients with Bell's palsy. Methods: We performed a secondary analysis of a prospective multicenter randomized controlled trial of acupuncture for Bell's palsy. Patients were randomly assigned to the de qi and control groups, respectively. The primary outcome was facial nerve function at month 6. The intensity of each needle sensation was rated by a visual analog scale. Psychosocial factors were assessed by the pretreatment mediator questionnaire; 16 Personality Factor Questionnaire (16PF) was used for assessing personality factors and digit cancellation test for assessing attention. Results: After 6 months, patients in the de qi group had better facial function (adjusted odds ratio [OR]: 4.16, 95% confidence interval [CI]: 2.23–7.78). Path analysis showed that intensity of needle sensation of fullness had direct effect on House-Brackmann (HB) score at month 6. In de qi group, the low HB score on day 1 (OR: 0.13, 95% CI: 0.03–0.45) and the low Social Boldness score (OR: 0.63, 95% CI: 0.41–0.97) in 16PF were associated with better facial function. In control group, low HB score on day 1 (OR: 0.25, 95% CI: 0.13–0.50), low Vigilance score (OR: 0.66, 95% CI: 0.50–0.88), and high Tension score (OR: 1.41, 95% CI: 1.12–1.77) in 16PF were related to better facial function. Conclusions: The needle sensation of fullness could predict better facial function and personality traits might influence outcomes of acupuncture treatment. Both of them should be considered seriously in acupuncture treatment and research. PMID:27453226

  11. Treatment of severe pneumonia in hospitalized patients: results of a multicenter, randomized, double-blind trial comparing intravenous ciprofloxacin with imipenem-cilastatin. The Severe Pneumonia Study Group.

    PubMed Central

    Fink, M P; Snydman, D R; Niederman, M S; Leeper, K V; Johnson, R H; Heard, S O; Wunderink, R G; Caldwell, J W; Schentag, J J; Siami, G A

    1994-01-01

    Intravenously administered ciprofloxacin was compared with imipenem for the treatment of severe pneumonia. In this prospective, randomized, double-blind, multicenter trial, which included an intent-to-treat analysis, a total of 405 patients with severe pneumonia were enrolled. The mean APACHE II score was 17.6, 79% of the patients required mechanical ventilation, and 78% had nosocomial pneumonia. A subgroup of 205 patients (98 ciprofloxacin-treated patients and 107 imipenem-treated patients) were evaluable for the major efficacy endpoints. Patients were randomized to receive intravenous treatment with either ciprofloxacin (400 mg every 8 h) or imipenem (1,000 mg every 8 h), and doses were adjusted for renal function. The primary and secondary efficacy endpoints were bacteriological and clinical responses at 3 to 7 days after completion of therapy. Ciprofloxacin-treated patients had a higher bacteriological eradication rate than did imipenem-treated patients (69 versus 59%; 95% confidence interval of -0.6%, 26.2%; P = 0.069) and also a significantly higher clinical response rate (69 versus 56%; 95% confidence interval of 3.5%, 28.5%; P = 0.021). The greatest difference between ciprofloxacin and imipenem was in eradication of members of the family Enterobacteriaceae (93 versus 65%; P = 0.009). Stepwise logistic regression analysis demonstrated the following factors to be associated with bacteriological eradication: absence of Pseudomonas aeruginosa (P < 0.01), higher weight (P < 0.01), a low APACHE II score (P = 0.03), and treatment with ciprofloxacin (P = 0.04). When P. aeruginosa was recovered from initial respiratory tract cultures, failure to achieve bacteriological eradication and development of resistance during therapy were common in both treatment groups (67 and 33% for ciprofloxacin and 59 and 53% for imipenem, respectively). Seizures were observed more frequently with imipenem than with ciprofloxacin (6 versus 1%; P = 0.028). These results demonstrate that

  12. Interactions between Obesity Status and Dietary Intake of Monounsaturated and Polyunsaturated Oils on Human Gut Microbiome Profiles in the Canola Oil Multicenter Intervention Trial (COMIT)

    PubMed Central

    Pu, Shuaihua; Khazanehei, Hamidreza; Jones, Peter J.; Khafipour, Ehsan

    2016-01-01

    Long-term dietary fatty acid intake is believed to induce changes in the human gut microbiome which might be associated with human health or obesity status; however, considerable debate remains regarding the most favorable ratios of fatty acids to optimize these processes. The objective of this sub-study of a double-blinded randomized crossover clinical study, the canola oil multi-center intervention trial, was to investigate effects of five different novel oil blends fed for 30 days each on the intestinal microbiota in 25 volunteers with risk of metabolic syndrome. The 60 g treatments included three MUFA-rich diets: (1) conventional canola oil (Canola); (2) DHA-enriched high oleic canola oil (CanolaDHA); (3) high oleic canola oil (CanolaOleic); and two PUFA-rich diets: (4) a blend of corn/safflower oil (25:75) (CornSaff); and (5) a blend of flax/safflower oil (60:40) (FlaxSaff). Stool samples were collected at the end of each period. DNA was extracted and amplified for 16S rRNA gene pyrosequencing. A total of 17 phyla and 187 genera were identified. While five novel oil treatments failed to alter bacterial phyla composition, obese participants resulted in a higher proportion of Firmicutes to Bacteroidetes than overweight or normal weight groups (P = 0.01). Similarly at the genus level, overall bacterial distribution was highly associated with subjects’ body mass index (BMI). Treatment effects were observed between MUFA- and PUFA-rich diets, with the three MUFA diets elevating Parabacteroides, Prevotella, Turicibacter, and Enterobacteriaceae’s populations, while the two PUFA-rich diets favored the higher abundance of Isobaculum. High MUFA content feedings also resulted in an increase of Parabacteroides and a decrease of Isobaculum in obese, but not overweight subjects. Data suggest that BMI is a predominant factor in characterization of human gut microbiota profile, and that MUFA-rich and PUFA-rich diets impact the composition of gut microbiota at lower

  13. International multicenter comparative trial of endoscopic ultrasonography-guided gastroenterostomy versus surgical gastrojejunostomy for the treatment of malignant gastric outlet obstruction

    PubMed Central

    Khashab, Mouen A.; Bukhari, Majidah; Baron, Todd H.; Nieto, Jose; El Zein, Mohamad; Chen, Yen-I; Chavez, Yamile Haito; Ngamruengphong, Saowanee; Alawad, Ahmad S.; Kumbhari, Vivek; Itoi, Takao

    2017-01-01

    Background and study aims EUS-guided gastroenterostomy (EUS-GE) is a novel procedure that potentially offers long-lasting luminal patency without the risk of tumor ingrowth/overgrowth. This study compared the clinical success, technical success, adverse events (AEs), length of hospital stay (LOHS) and symptom recurrence in EUS-GE versus SGJ. Methods This was a multicenter international retrospective comparative study of EUS-GE and SGJ in patients with malignant gastric outlet obstruction (GOO) who underwent either EUS-GE or SGJ. EUS-GE was performed using lumen apposing metal stents. Results A total of 93 patients with malignant GOO treated with either EUS-GE (n = 30) or SGJ (n = 63) were identified. Peritoneal carcinomatosis was present in 13 (43 %) patients in the EUS-GE group and 7 (11 %) patients in the SGJ group (P < 0.001). Although the technical success rate was significantly higher in the SGJ group as compared to the EUS-GE group (100 % vs. 87 %, P = 0.009), the clinical success rate was not different (90 % vs. 87 %, P = 0.18, OR 0.8, 95 %CI 0.44 – 7.07). The rate of AEs was lower in the EUS-GE group, but the difference was not statistically significant (16 % vs 25 %, P = 0.3). The mean LOHS was similar in the EUS-GE group compared to SGJ (P = 0.35). The rate of recurrent GOO was not different between the two groups (3 % vs. 14 %, P = 0.08). Similarly, the mean time to reintervention was similar (88 days vs. 121 days, P = 0.83). Conclusions EUS-GE is associated with equivalent efficacy and safety as compared to surgical GJ. This is the first comparative trial between both techniques and suggests EUS-GE as a non-inferior but less invasive alter to surgery. PMID:28382326

  14. Protocol for the Cognitive Interventions and Nutritional Supplements (CINS) trial: A randomized controlled multicenter trial of a brief intervention (BI) versus a BI plus cognitive behavioral treatment (CBT) versus nutritional supplements for patients with long-lasting muscle and back pain

    PubMed Central

    2011-01-01

    Abstract Background Brief intervention programs are clinically beneficial, and cost efficient treatments for low back pain, when offered at 8-12 weeks, compared with treatment as usual. However, about 30% of the patients do not return to work. The European Guidelines for treatment of chronic low back pain recommends Cognitive Behavioral Therapy (CBT), but conclude that further research is needed to evaluate the effectiveness of CBT for chronic low back pain. Methods/Design The aim of the multicenter CINS trial (Cognitive Interventions and Nutritional Supplements) is to compare the effectiveness of 4 different interventions; Brief Intervention, Brief Intervention and CBT, Brief Intervention and nutritional supplements of seal oil, and Brief Intervention and nutritional supplements of soy oil. All participants will be randomly assigned to the interventions. The nutritional supplements will be tested in a double blind design. 400 patients will be recruited from a population of chronic low back pain patients that have been sick listed for 2-10 months. Four outpatient clinics, located in different parts of Norway, will participate in recruitment and treatment of the patients. The Brief Intervention is a one session cognitive, clinical examination program based on a non-injury model, where return to normal activity and work is the main goal, and is followed by two booster sessions. The CBT is a tailored treatment involving 7 sessions, following a detailed manual. The nutritional supplements consist of a dosage of 10 grams of either soy or seal oil (capsules) per day for 3 months, administered in a double blind design. All patients will be followed up with questionnaires after 3, 6 and 12 months, while sick leave data will be collected up to at least 24 months after randomization. The primary outcome of the study is sick leave and will be based on register data from the National Insurance Administration. Secondary outcomes include self-reported data on disability, pain

  15. Safety of Early Discharge for Low-Risk Patients With Febrile Neutropenia: A Multicenter Randomized Controlled Trial

    PubMed Central

    Talcott, James A.; Yeap, Beow Y.; Clark, Jack A.; Siegel, Robert D.; Loggers, Elizabeth Trice; Lu, Charles; Godley, Paul A.

    2011-01-01

    Purpose Febrile neutropenia commonly complicates cancer chemotherapy. Outpatient treatment may reduce costs and improve patient comfort but risk progression of undetected medical problems. Patients and Methods By using our validated algorithm, we identified medically stable inpatients admitted for febrile neutropenia (neutrophils < 500/μL) after chemotherapy and randomly assigned them to continued inpatient antibiotic therapy or early discharge to receive identical antibiotic treatment at home. Our primary outcome was the occurrence of any serious medical complication, defined as evidence of medical instability requiring urgent medical attention. Results We enrolled 117 patients with 121 febrile neutropenia episodes before study termination for poor accrual. We excluded five episodes as ineligible and three because of inadequate documentation of the study outcome. Treatment groups were clinically similar, but sociodemographic imbalances occurred because of block randomization. The median presenting absolute neutrophil count was 100/μL. Hematopoietic growth factors were used in 38% of episodes. The median neutropenia duration was 4 days (range, 1 to 15 days). Five outpatients were readmitted to the hospital. Major medical complications occurred in five episodes (8%) in the hospital arm and four (9%) in the home arm (95% CI for the difference, −10% to 13%; P = .56). No study patient died. Patient-reported quality of life was similar on both arms. Conclusion We found no evidence of adverse medical consequences from home care, despite a protocol designed to detect evidence of clinical deterioration. These results should reassure clinicians who elect to treat rigorously characterized low-risk patients with febrile neutropenia in suitable outpatient settings with appropriate surveillance for unexpected clinical deterioration. PMID:21931024

  16. The FDA and designing clinical trials for chronic cutaneous ulcers.

    PubMed

    Maderal, Andrea D; Vivas, Alejandra C; Eaglstein, William H; Kirsner, Robert S

    2012-12-01

    Treatment of chronic wounds can present a challenge, with many patients remaining refractory to available advanced therapies. As such, there is a strong need for the development of new products. Unfortunately, despite this demand, few new wound-related drugs have been approved over the past decade. This is in part due to unsuccessful clinical trials and subsequent lack of Food and Drug Administration (FDA) approval. In this article, we discuss the FDA approval process, how it relates to chronic wound trials, common issues that arise, and how best to manage them. Additionally, problems encountered specific to diabetic foot ulcers (DFU) and venous leg ulcers (VLU) are addressed. Careful construction of a clinical trial is necessary in order to achieve the best possible efficacy outcomes and thereby, gain FDA approval. How to design an optimal trial is outlined.

  17. Concordance of assays designed for the quantification of JAK2V617F: a multicenter study

    PubMed Central

    Lippert, Eric; Girodon, François; Hammond, Emma; Jelinek, Jaroslav; Reading, N. Scott; Fehse, Boris; Hanlon, Katy; Hermans, Mirjam; Richard, Céline; Swierczek, Sabina; Ugo, Valérie; Carillo, Serge; Harrivel, Véronique; Marzac, Christophe; Pietra, Daniela; Sobas, Marta; Mounier, Morgane; Migeon, Marina; Ellard, Sian; Kröger, Nicolaus; Herrmann, Richard; Prchal, Josef T.; Skoda, Radek C.; Hermouet, Sylvie

    2009-01-01

    Background Many different techniques have been designed for the quantification of JAK2V617F allelic burden, sometimes producing discrepant results. Design and Methods JAK2V617F quantification techniques were compared among 16 centers using 11 assays based on quantitative polymerase chain reaction (with mutation-specific primers or probes, or fluorescent resonance energy transfer/melting curve analysis), allele-specific polymerase chain reaction, conventional sequencing or pyrosequencing. Results A first series of blinded samples (granulocyte DNA, n=29) was analyzed. Seven assays (12 centers) reported values inside the mean±2SD; the mean coefficient of variation was 31%. Sequencing techniques lacked sensitivity, and strong discrepancies were observed with four techniques, which could be attributed to inadequate standards or to different modes of expression of results. Indeed, quantification of JAK2V617F in relation to another control gene produced higher than expected values, suggesting the possibility of more than two JAK2 copies/cell. After calibration of assays with common 1% to 100% JAK2V617F standards (dilutions of UKE-1 cells in normal leukocytes), 14 centers tested ten new samples. JAK2V617F allelic burdens greater or equal than 1% were then reliably quantified by five techniques – one allele specific-polymerase chain reaction and four TaqMan allele-specific quantitative polymerase chain reaction assays, including one previously giving results outside the mean±2SD – with a lower mean coefficient of variation (21%). Of these, only the two TaqMan allele-specific quantitative polymerase chain reaction assays with primer-based specificity could detect 0.2% JAK2V617F. Conclusions Techniques expressing the allelic burden as JAK2V617F/total JAK2 and using a common set of standards produced similar quantification results but with variable sensitivity. Calibration to a reference standard improved reproducibility. PMID:19001280

  18. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods.

    PubMed

    Buse, John B; Bigger, J Thomas; Byington, Robert P; Cooper, Lawton S; Cushman, William C; Friedewald, William T; Genuth, Saul; Gerstein, Hertzel C; Ginsberg, Henry N; Goff, David C; Grimm, Richard H; Margolis, Karen L; Probstfield, Jeffrey L; Simons-Morton, Denise G; Sullivan, Mark D

    2007-06-18

    Most patients with type 2 diabetes mellitus develop cardiovascular disease (CVD), with substantial loss of life expectancy. Nonfatal CVD contributes greatly to excess healthcare costs and decreased quality of life in patients with diabetes. The current epidemic of obesity has raised expectations that CVD associated with type 2 diabetes will become an even greater public health challenge. Despite the importance of this health problem, there is a lack of definitive data on the effects of the intensive control of glycemia and other CVD risk factors on CVD event rates in patients with type 2 diabetes. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is a randomized, multicenter, double 2 x 2 factorial design study involving 10,251 middle-aged and older participants with type 2 diabetes who are at high risk for CVD events because of existing CVD or additional risk factors. ACCORD is testing the effects of 3 medical treatment strategies to reduce CVD morbidity and mortality. All participants are in the glycemia trial, which is testing the hypothesis that a therapeutic strategy that targets a glycosylated hemoglobin (HbA1c) level of <6.0% will reduce the rate of CVD events more than a strategy that targets an HbA1c level of 7.0%-7.9%. The lipid trial includes 5,518 of the participants, who receive either fenofibrate or placebo in a double-masked fashion to test the hypothesis of whether, in the context of good glycemic control, a therapeutic strategy that uses a fibrate to increase high-density lipoprotein cholesterol and lower triglyceride levels together with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) to lower low-density lipoprotein cholesterol will reduce the rate of CVD events compared with a strategy that uses a statin plus a placebo. The blood pressure trial includes the remaining 4,733 participants and tests the hypothesis that a therapeutic strategy that targets a systolic blood pressure of <120 mm Hg in the context

  19. The Effect of Trimosan© Gel on Pessary-Associated Bacterial Vaginosis: A Multi-Center, Randomized, Controlled Trial

    PubMed Central

    Meriwether, Kate V.; Rogers, Rebecca G.; Craig, Ellen; Peterson, Sean D.; Gutman, Robert E.; Iglesia, Cheryl B.

    2015-01-01

    Objectives Pessaries are important options for women with pelvic floor disorders, but many pessary users experience bacterial vaginosis (BV). The aim of this study was to evaluate the effect of TrimoSan© gel on BV prevalence among pessary users. Study Design Women presenting for a pessary fitting completed questionnaires on vaginal symptoms and hormone therapy (HT) use and underwent a BV® BLUE test and slide collection for BV analysis by Nugent's criteria. Following pessary fitting, women were randomized to either standard pessary care with the use of TrimoSan© placed vaginally twice weekly or to standard pessary care without TrimoSan© gel. Women returned 2 weeks and 3 months later for repeat slide collection for Gram stain, BV® BLUE testing, and completion of questionnaires on vaginal symptoms and desire to continue the pessary. Results There were 184 women randomized after successful fitting (92 to the TrimoSan© group), and 147 (79%) presented for 3 month follow up. Mean age was 56 ± 16 years; patients were mostly Caucasian (57%) or Hispanic (23%) and 36% were using HT. The groups did not differ in the prevalence of BV by Nugent's criteria at 2 weeks (20% TrimoSan© vs 26% no gel, p=0.46) or 3 months (24% TrimoSan© vs 23% no gel, p=0.82), nor did they differ in BV by BV® BLUE testing at 2 weeks (0%TrimoSan©vs 4% no gel, p=0.12) or 3 months (3% TrimoSan© vs 0% no gel, p=0.15). The prevalence of at least one vaginal symptom did not differ between groups at 2 weeks (44% TrimoSan© vs 45% no gel, p=0.98) or 3 months (42% TrimoSan© vs 32% no gel, p=0.30). The TrimoSan© group was equally likely to want to continue their pessary use compared to the standard care group at 2 weeks (90% vs 86%, p=0.64) and 3 months (63% vs 60%, p=0.76). Conclusions TrimoSan© gel in the first 3 months of pessary use does not decrease the prevalence of BV or vaginal symptoms and does not alter the likelihood of a woman desiring to continue pessary use. PMID:25935783

  20. GOST: A generic ordinal sequential trial design for a treatment trial in an emerging pandemic

    PubMed Central

    Whitehead, John

    2017-01-01

    Background Conducting clinical trials to assess experimental treatments for potentially pandemic infectious diseases is challenging. Since many outbreaks of infectious diseases last only six to eight weeks, there is a need for trial designs that can be implemented rapidly in the face of uncertainty. Outbreaks are sudden and unpredictable and so it is essential that as much planning as possible takes place in advance. Statistical aspects of such trial designs should be evaluated and discussed in readiness for implementation. Methodology/Principal findings This paper proposes a generic ordinal sequential trial design (GOST) for a randomised clinical trial comparing an experimental treatment for an emerging infectious disease with standard care. The design is intended as an off-the-shelf, ready-to-use robust and flexible option. The primary endpoint is a categorisation of patient outcome according to an ordinal scale. A sequential approach is adopted, stopping as soon as it is clear that the experimental treatment has an advantage or that sufficient advantage is unlikely to be detected. The properties of the design are evaluated using large-sample theory and verified for moderate sized samples using simulation. The trial is powered to detect a generic clinically relevant difference: namely an odds ratio of 2 for better rather than worse outcomes. Total sample sizes (across both treatments) of between 150 and 300 patients prove to be adequate in many cases, but the precise value depends on both the magnitude of the treatment advantage and the nature of the ordinal scale. An advantage of the approach is that any erroneous assumptions made at the design stage about the proportion of patients falling into each outcome category have little effect on the error probabilities of the study, although they can lead to inaccurate forecasts of sample size. Conclusions/Significance It is important and feasible to pre-determine many of the statistical aspects of an efficient trial

  1. Optimal design of clinical trials with computer simulation based on results of earlier trials, illustrated with a lipodystrophy trial in HIV patients.

    PubMed

    Abbas, Ismail; Rovira, Joan; Casanovas, Josep; Greenfield, Tony

    2008-12-01

    The designer of a clinical trial needs to make many assumptions about real-life practice based on prior knowledge. Simulation allows us to learn from experience by using the information obtained from a trial to improve the original estimators of population parameters. We propose using data from a previous trial to formulate assumptions that can be used to simulate trials and thus improve the design of new trials. To demonstrate our method, we used data from a real clinical trial which had been designed to evaluate cholesterol level changes as a surrogate marker for lipodystrophy in HIV patients. We were able to identify the optimal design that would have minimised the cost of a trial subject to a statistical power constraint which could then be used to design a new trial. In particular, we focused on three factors: the distribution of cholesterol levels in HIV patients, trial recruitment rates and trial dropout rates. We were able to verify our hypothesis that the total cost resulting from carrying out a clinical trial can be minimised by applying simulation models as an alternative to conventional approaches. In our findings the simulation model proved to be very intuitive and a useful method for testing the performance of investigators' assumptions and generating an optimal clinical trial design before being put into practice in the real world. In addition, we concluded that simulation models provide a more accurate determination of power than conventional approaches, thus minimising the total cost of clinical trials.

  2. Taking the Blood Bank to the Field: The Design and Rationale of the Prehospital Air Medical Plasma (PAMPer) Trial.

    PubMed

    Brown, Joshua B; Guyette, Francis X; Neal, Matthew D; Claridge, Jeffrey A; Daley, Brian J; Harbrecht, Brian G; Miller, Richard S; Phelan, Herb A; Adams, Peter W; Early, Barbara J; Peitzman, Andrew B; Billiar, Timothy R; Sperry, Jason L

    2015-01-01

    Hemorrhage and trauma induced coagulopathy remain major drivers of early preventable mortality in military and civilian trauma. Interest in the use of prehospital plasma in hemorrhaging patients as a primary resuscitation agent has grown recently. Trauma center-based damage control resuscitation using early and aggressive plasma transfusion has consistently demonstrated improved outcomes in hemorrhaging patients. Additionally, plasma has been shown to have several favorable immunomodulatory effects. Preliminary evidence with prehospital plasma transfusion has demonstrated feasibility and improved short-term outcomes. Applying state-of-the-art resuscitation strategies to the civilian prehospital arena is compelling. We describe here the rationale, design, and challenges of the Prehospital Air Medical Plasma (PAMPer) trial. The primary objective is to determine the effect of prehospital plasma transfusion during air medical transport on 30-day mortality in patients at risk for traumatic hemorrhage. This study is a multicenter cluster randomized clinical trial. The trial will enroll trauma patients with profound hypotension (SBP ≤ 70 mmHg) or hypotension (SBP 71-90 mmHg) and tachycardia (HR ≥ 108 bpm) from six level I trauma center air medical transport programs. The trial will also explore the effects of prehospital plasma transfusion on the coagulation and inflammatory response following injury. The trial will be conducted under exception for informed consent for emergency research with an investigational new drug approval from the U.S. Food and Drug Administration utilizing a multipronged community consultation process. It is one of three ongoing Department of Defense-funded trials aimed at expanding our understanding of the optimal therapeutic approaches to coagulopathy in the hemorrhaging trauma patient.

  3. Factorial designs: an overview with applications to orthodontic clinical trials.

    PubMed

    Pandis, Nikolaos; Walsh, Tanya; Polychronopoulou, Argy; Katsaros, Christos; Eliades, Theodore

    2014-06-01

    Factorial designs for clinical trials are often encountered in medical, dental, and orthodontic research. Factorial designs assess two or more interventions simultaneously and the main advantage of this design is its efficiency in terms of sample size as more than one intervention may be assessed on the same participants. However, the factorial design is efficient only under the assumption of no interaction (no effect modification) between the treatments under investigation and, therefore, this should be considered at the design stage. Conversely, the factorial study design may also be used for the purpose of detecting an interaction between two interventions if the study is powered accordingly. However, a factorial design powered to detect an interaction has no advantage in terms of the required sample size compared to a multi-arm parallel trial for assessing more than one intervention. It is the purpose of this article to highlight the methodological issues that should be considered when planning, analysing, and reporting the simplest form of this design, which is the 2 × 2 factorial design. An example from the field of orthodontics using two parameters (bracket type and wire type) on maxillary incisor torque loss will be utilized in order to explain the design requirements, the advantages and disadvantages of this design, and its application in orthodontic research.

  4. 78 FR 58318 - Clinical Trial Design for Intravenous Fat Emulsion Products; Public Workshop

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-23

    ... HUMAN SERVICES Food and Drug Administration Clinical Trial Design for Intravenous Fat Emulsion Products... ``Clinical Trial Design for Intravenous Fat Emulsion Products.'' This workshop will provide a forum to discuss trial design of clinical trials intended to support registration of intravenous fat...

  5. Development of Design-a-Trial, a knowledge-based critiquing system for authors of clinical trial protocols.

    PubMed

    Wyatt, J C; Altman, D G; Heathfield, H A; Pantin, C F

    1994-06-01

    Many published clinical trials are poorly designed, suggesting that the protocol was incomplete, disorganised or contained errors. This fact, doctors' limited statistical skills and the shortage of medical statisticians, prompted us to develop a knowledge-based aid, Design-a-Trial, for authors of clinical trial protocols. This interviews a physician, prompts them with suitable design options, comments on the statistical rigour and feasibility of their proposed design and generates a 6-page draft protocol document. This paper outlines the process used to develop Design-a-Trial, presents preliminary evaluation results, and discusses lessons we learned which may apply to the developed of other medical decision-aids.

  6. Adaptive design clinical trials and trial logistics models in CNS drug development.

    PubMed

    Wang, Sue-Jane; Hung, H M James; O'Neill, Robert

    2011-02-01

    In central nervous system therapeutic areas, there are general concerns with establishing efficacy thought to be sources of high attrition rate in drug development. For instance, efficacy endpoints are often subjective and highly variable. There is a lack of robust or operational biomarkers to substitute for soft endpoints. In addition, animal models are generally poor, unreliable or unpredictive. To increase the probability of success in central nervous system drug development program, adaptive design has been considered as an alternative designs that provides flexibility to the conventional fixed designs and has been viewed to have the potential to improve the efficiency in drug development processes. In addition, successful implementation of an adaptive design trial relies on establishment of a trustworthy logistics model that ensures integrity of the trial conduct. In accordance with the spirit of the U.S. Food and Drug Administration adaptive design draft guidance document recently released, this paper enlists the critical considerations from both methodological aspects and regulatory aspects in reviewing an adaptive design proposal and discusses two general types of adaptations, sample size planning and re-estimation, and two-stage adaptive design. Literature examples of adaptive designs in central nervous system are used to highlight the principles laid out in the U.S. FDA draft guidance. Four logistics models seen in regulatory adaptive design applications are introduced. In general, complex adaptive designs require simulation studies to access the design performance. For an adequate and well-controlled clinical trial, if a Learn-and-Confirm adaptive selection approach is considered, the study-wise type I error rate should be adhered to. However, it is controversial to use the simulated type I error rate to address a strong control of the study-wise type I error rate.

  7. Design innovations and baseline findings in a long-term Parkinson’s trial: NET-PD LS-1

    PubMed Central

    2012-01-01

    Background Based on the pre-clinical and the results of a phase 2 futility study, creatine was selected for an efficacy trial in Parkinson’s disease (PD). We present the design rationale and a description of the study cohort at baseline. Methods A randomized, multicenter, double-blind, parallel group, placebo controlled Phase 3 study of creatine (10 gm daily) in participants with early, treated PD, the Long-term Study – 1 (LS-1) is being conducted by the NINDS Exploratory Trials in Parkinson’s Disease (NET-PD) network. The study utilizes a global statistical test (GST) encompassing multiple clinical rating scales to provide a multidimensional assessment of disease progression. Results A total of 1,741 PD participants from 45 sites in the U.S. and Canada were randomized 1:1 to either 10-gm creatine/day or matching placebo. Participants are being evaluated for a minimum of 5 years. The LS-1 baseline cohort includes participants treated with dopaminergic therapy and generally mild PD. Conclusions LS-1 represents the largest cohort of patients with early treated PD ever enrolled in a clinical trial. The GST approach should provide high power to test the hypothesis that daily administration of creatine (10gm/day) is more effective than placebo in slowing clinical decline in PD between baseline and the 5 year follow-up visit against the background of dopaminergic therapy and best PD care. PMID:23079770

  8. Two-stage designs for cross-over bioequivalence trials.

    PubMed

    Kieser, Meinhard; Rauch, Geraldine

    2015-07-20

    The topic of applying two-stage designs in the field of bioequivalence studies has recently gained attention in the literature and in regulatory guidelines. While there exists some methodological research on the application of group sequential designs in bioequivalence studies, implementation of adaptive approaches has focused up to now on superiority and non-inferiority trials. Especially, no comparison of the features and performance characteristics of these designs has been performed, and therefore, the question of which design to employ in this setting remains open. In this paper, we discuss and compare 'classical' group sequential designs and three types of adaptive designs that offer the option of mid-course sample size recalculation. A comprehensive simulation study demonstrates that group sequential designs can be identified, which show power characteristics that are similar to those of the adaptive designs but require a lower average sample size. The methods are illustrated with a real bioequivalence study example.

  9. Randomized controlled trial design in rheumatoid arthritis: the past decade

    PubMed Central

    Strand, Vibeke; Sokolove, Jeremy

    2009-01-01

    Much progress has occurred over the past decade in rheumatoid arthritis trial design. Recognized challenges have led to the establishment of a clear regulatory pathway to demonstrate efficacy of a new therapeutic. The use of pure placebo beyond 12 to 16 weeks has been demonstrated to be unethical and thus background therapy and/or early rescue has become regular practice. Goals of remission and 'treating to targets' may prove more relevant to identify real-world use of new and existing therapeutics. Identification of rare adverse events associated with new therapies has resulted in intensive safety evaluation during randomized controlled trials and emphasis on postmarketing surveillance and use of registries. PMID:19232061

  10. OARSI Clinical Trials Recommendations: Design and conduct of clinical trials of surgical interventions for osteoarthritis

    PubMed Central

    Katz, J.N.; Losina, E.; Lohmander, L.S.

    2015-01-01

    summary To highlight methodological challenges in the design and conduct of randomized trials of surgical interventions and to propose strategies for addressing these challenges. This paper focuses on three broad areas: enrollment; intervention; and assessment including implications for analysis. For each challenge raised in the paper, we propose potential solutions. Enrollment poses challenges in maintaining investigator equipoise, managing conflict of interest and anticipating that patient preferences for specific treatments may reduce enrollment. Intervention design and implementation pose challenges relating to obsolescence, fidelity of intervention delivery, and adherence and crossover. Assessment and analysis raise questions regarding blinding and clustering of observations. This paper describes methodological problems in the design and conduct of surgical randomized trials and proposes strategies for addressing these challenges. PMID:25952350

  11. Frequentist evaluation of group sequential clinical trial designs.

    PubMed

    Emerson, Scott S; Kittelson, John M; Gillen, Daniel L

    2007-12-10

    Group sequential stopping rules are often used as guidelines in the monitoring of clinical trials in order to address the ethical and efficiency issues inherent in human testing of a new treatment or preventive agent for disease. Such stopping rules have been proposed based on a variety of different criteria, both scientific (e.g. estimates of treatment effect) and statistical (e.g. frequentist type I error, Bayesian posterior probabilities, stochastic curtailment). It is easily shown, however, that a stopping rule based on one of these criteria induces a stopping rule on all other criteria. Thus, the basis used to initially define a stopping rule is relatively unimportant so long as the operating characteristics of the stopping rule are fully investigated. In this paper we describe how the frequentist operating characteristics of a particular stopping rule might be evaluated to ensure that the selected clinical trial design satisfies the constraints imposed by the many different disciplines represented by the clinical trial collaborators.

  12. Standardization of sensitive human immunodeficiency virus coculture procedures and establishment of a multicenter quality assurance program for the AIDS Clinical Trials Group. The NIH/NIAID/DAIDS/ACTG Virology Laboratories.

    PubMed Central

    Hollinger, F B; Bremer, J W; Myers, L E; Gold, J W; McQuay, L

    1992-01-01

    An independent quality assurance program has been established by the Division of AIDS, National Institute of Allergy and Infectious Diseases, for monitoring virologic assays performed by nearly 40 laboratories participating in multicenter clinical trials in the United States. Since virologic endpoints are important in evaluating the timing and efficacy of therapeutic interventions, it is imperative that virologic measurements be accurate and uniform. When the quality assurance program was initially created, fewer than 40% of the laboratories could consistently recover human immunodeficiency virus (HIV) from peripheral blood mononuclear cells (PBMCs) of HIV-infected patients. By comparing coculture procedures in the more competent laboratories with those in laboratories who were struggling to isolate virus, optimal conditions were established and nonessential reagents and practices were eliminated. Changes were rapidly introduced into a laboratory when experience dictated that such modifications would result in a favorable outcome. Isolation of HIV was enhanced by optimizing the numbers and ratios of patient and donor cells used in cultures, by standardizing PBMC separation procedures, by using fresh rather than frozen donor PBMCs, by processing whole blood within 24 h, and by using natural delectinated interleukin 2 instead of recombinant interleukin 2 products in existence at that time. Delays of more than 8 h in the addition of phytohemagglutinin-stimulated donor cells to freshly separated patient PBMCs reduced recovery. Phytohemagglutinin in cocultures and the addition of Polybrene and anti-human alpha interferon to media were not important in HIV isolation. The introduction of a consensus protocol based on this information brought most laboratories quickly into compliance. In addition, monthly monitoring has successfully maintained proficiency among the laboratories, a process that is critical for the scientific integrity of collaborative multicenter trials

  13. Design of clinical trials in acute kidney injury: report from an NIDDK workshop on trial methodology.

    PubMed

    Palevsky, Paul M; Molitoris, Bruce A; Okusa, Mark D; Levin, Adeera; Waikar, Sushrut S; Wald, Ron; Chertow, Glenn M; Murray, Patrick T; Parikh, Chirag R; Shaw, Andrew D; Go, Alan S; Faubel, Sarah G; Kellum, John A; Chinchilli, Vernon M; Liu, Kathleen D; Cheung, Alfred K; Weisbord, Steven D; Chawla, Lakhmir S; Kaufman, James S; Devarajan, Prasad; Toto, Robert M; Hsu, Chi-yuan; Greene, Tom; Mehta, Ravindra L; Stokes, John B; Thompson, Aliza M; Thompson, B Taylor; Westenfelder, Christof S; Tumlin, James A; Warnock, David G; Shah, Sudhir V; Xie, Yining; Duggan, Emily G; Kimmel, Paul L; Star, Robert A

    2012-05-01

    Acute kidney injury (AKI) remains a complex clinical problem associated with significant short-term morbidity and mortality and lacking effective pharmacologic interventions. Patients with AKI experience longer-term risks for progressive chronic ESRD, which diminish patients' health-related quality of life and create a larger burden on the healthcare system. Although experimental models have yielded numerous promising agents, translation into clinical practice has been unsuccessful, possibly because of issues in clinical trial design, such as delayed drug administration, masking of therapeutic benefit by adverse events, and inadequate sample size. To address issues of clinical trial design, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a workshop titled "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers" in December 2010. Workshop participants included representatives from academia, industry, and government agencies whose areas of expertise spanned basic science, clinical nephrology, critical care medicine, biostatistics, pharmacology, and drug development. This document summarizes the discussions of collaborative workgroups that addressed issues related to patient selection, study endpoints, the role of novel biomarkers, sample size and power calculations, and adverse events and pilot/feasibility studies in prevention and treatment of AKI. Companion articles outline the discussions of workgroups for model trials related to prevention or treatment of established AKI in different clinical settings, such as in patients with sepsis.

  14. Prostate cancer chemoprevention: Strategies for designing efficient clinical trials.

    PubMed

    Lieberman, R

    2001-04-01

    A chemoprevention (CP) strategy has evolved for conducting efficient clinical trials for prostate cancer (PCa) prevention. It integrates five key components, including agents, biomarkers, cohorts, designs, and endpoints. The rationale for the CP strategy relates to the natural history of prostate cancer. There is a wide array of natural and synthetic agents that hold promise for inhibiting, reversing, or modulating the transition from normal to precancer and from precancer to cancer. These agent classes include antiandrogens, antiestrogens, phytoestrogens, antioxidants, anti-inflammatory (proapoptotic) agents, antiproliferation/antidifferentiation agents, signal transduction modulators of receptor tyrosine kinase and ras farnesylation, antiangiogenesis agents, insulinlike growth factor (IGF)-1, peroxisome proliferator-activator receptor modulators (-gamma and -delta), and gene-based interventions. Biomarkers and endpoints are guided by the level of evidence required (eg, phase 1, 2, 3). Two candidate surrogate endpoints (SE) based on histology are high-grade prostatic intraepithelial neoplasia (HGPIN) and computer-assisted image analysis of dysplastic lesions. Phase 1 trials use standard endpoints of safety, pharmacokinetics and limited pharmacodynamics. Phase 2 trials use endpoints of modulation of biomarkers and correlation with histology. Phase 3 trials use endpoints of clinical benefit, such as cancer incidence reduction and quality of life. Validation of a biomarker as a SE involves correlation of the biomarker with clinical benefit. Cohorts (target populations) for phase 2/3 trials include the general population of men over age 50 with a normal prostate-specific antigen (PSA), subjects with a strong family history of PCa, subjects with elevated PSA/negative biopsy, and subjects with HGPIN/negative biopsy. These at-risk populations reflect key individual risk factors (age, race, serum PSA [free/total]; serum IGF-1/IGF binding protein (IGFBP)-3; 1, 25(OH)(2) D3

  15. Design of Treatment Trials for Functional Gastrointestinal Disorders.

    PubMed

    Irvine, E Jan; Tack, Jan; Crowell, Michael D; Gwee, Kok Ann; Ke, Meiyun; Schmulson, Max J; Whitehead, William E; Spiegel, Brennan

    2016-05-01

    This article summarizes recent progress and regulatory guidance on design of trials to assess the efficacy of new therapies for functional gastrointestinal disorders (FGIDs). The double-masked, placebo-controlled, parallel-group design remains the accepted standard for evaluating treatment efficacy. A control group is essential, and a detailed description of the randomization process and concealed allocation method must be included in the study report. The control will most often be placebo, but for therapeutic procedures and for behavioral treatment trials, respectively, a sham procedure and control intervention with similar expectation of benefit, but lacking the treatment principle, are recommended. Investigators should be aware of, and attempt to minimize, expectancy effects (placebo, nocebo, precebo). The primary analysis should be based on the proportion of patients in each treatment arm who satisfy a treatment responder definition or a prespecified clinically meaningful change in a patient-reported outcome measure. Data analysis should use the intention-to-treat principle. Reporting of results should follow the Consolidated Standards for Reporting Trials guidelines and include secondary outcome measures to support or explain the primary outcome and an analysis of harms data. Trials should be registered in a public location before initiation and results should be published regardless of outcome.

  16. Design of clinical trials of gene therapy in Parkinson disease.

    PubMed

    Lewis, Travis B; Standaert, David G

    2008-01-01

    No current therapy for Parkinson disease has been shown to slow or reverse the progressive course of the disease. As a departure from traditional treatments, gene therapy approaches provide a new hope for realizing this long-sought goal; but before they can be widely employed for use in patients, they must first be submitted to the rigorous safety and efficacy standards of the clinical trial. Some of the challenges of gene therapy clinical trial design are similar to those in studies of conventional pharmacological agents and include addressing the heterogeneity of the disease, the need for clinical and surrogate endpoints, and the issue of distinguishing "symptomatic" from "neuroprotective" effects. Gene therapy trials also raise the issues of the risks of viral therapy, issues of dose-response, the need for sham surgery, and the long duration of risks and benefits. We conclude that the most feasible designs are for those treatments that are expected to produce a rapid improvement in directly observable symptoms. Trials of agents which are expected to produce only a slowing of progression and not a reversal of the disease course are likely to take much longer and will require the development of methods to assess quality of life and other non-motor aspects of the disease.

  17. Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

    PubMed Central

    2012-01-01

    Background Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH2O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure ≤30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this

  18. Combining radiotherapy and angiogenesis inhibitors: Clinical trial design

    SciTech Connect

    Citrin, Deborah . E-mail: citrind@mail.nih.gov; Menard, Cynthia; Camphausen, Kevin

    2006-01-01

    Radiotherapy (RT) plays a vital role in the multimodality treatment of cancer. Recent advances in RT have primarily involved improvements in dose delivery. Future improvements in tumor control and disease outcomes will likely involve the combination of RT with targeted therapies. Preclinical evaluations of angiogenesis inhibitors in combination with RT have yielded promising results with increased tumor 'cure.' It remains to be seen whether these improvements in tumor control in the laboratory will translate into improved outcomes in the clinic. Multiple differences between these agents and cytotoxic chemotherapy must be taken into account when designing clinical trials evaluating their effectiveness in combination with RT. We discuss important considerations for designing clinical trials of angiogenesis inhibitors with RT.

  19. Randomized controlled trials and challenge trials: design and criterion for validity.

    PubMed

    Sargeant, J M; Kelton, D F; O'Connor, A M

    2014-06-01

    This article is the third of six articles addressing systematic reviews in animal agriculture and veterinary medicine. This article provides an overview of clinical trials, both randomized controlled trials (RCTs) and challenge trials, where the disease outcome is deliberately induced by the investigator. RCTs are not the only study design used in systematic reviews, but are preferred when available as the gold standard for evaluating interventions under real-world conditions. RCTs are planned experiments, which involve diseased or at-risk study subjects and are designed to evaluate interventions (therapeutic treatments or preventive strategies, including antibiotics, vaccines, management practices, dietary changes, management changes or lifestyle changes). Key components of the RCT are the use of one or more comparison (control) groups and investigator control over intervention allocation. Important design features in RCTs include as follows: how the population is selected, approach to allocation of intervention and control group subjects, how allocation is concealed prior to enrolment of study subjects, how outcomes are defined, how allocation to group is concealed (blinding) and how withdrawals from the study are managed. Guidelines for reporting important features of RCTs have been published and are useful tools for writing, reviewing and reading reports of RCTs.

  20. Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

    PubMed

    Nicholson, Katharine A; Cudkowicz, Merit E; Berry, James D

    2015-04-01

    The last 2 decades have seen a surge in the number of amyotrophic lateral sclerosis (ALS) clinical trials with the hope of finding successful treatments. Clinical trialists aim to repurpose existing drugs and test novel compounds to target potential ALS disease pathophysiology. Recent technological advancements have led to the discovery of new causative genetic agents and modes of delivering potential therapy, calling for increasingly sophisticated trial design. The standard ALS clinical trial design may be modified depending on study needs: type of therapy; route of therapy delivery; phase of therapy development; applicable subpopulation; market availability of therapy; and utility of telemedicine. Novel biomarkers of diagnostic, predictive, prognostic, and pharmacodynamic value are undergoing development and validation for use in clinical trials. Design modifications build on the traditional clinical trial design and may be employed in either the learning or confirming trial phase. Novel designs aim to minimize patient risk, study duration, and sample size, while improving efficiency and promoting statistical power to herald an exciting era for clinical research in ALS.

  1. Design and analysis of crossover trials for absorbing binary endpoints.

    PubMed

    Nason, Martha; Follmann, Dean

    2010-09-01

    The crossover is a popular and efficient trial design used in the context of patient heterogeneity to assess the effect of treatments that act relatively quickly and whose benefit disappears with discontinuation. Each patient can serve as her own control as within-individual treatment and placebo responses are compared. Conventional wisdom is that these designs are not appropriate for absorbing binary endpoints, such as death or HIV infection. We explore the use of crossover designs in the context of these absorbing binary endpoints and show that they can be more efficient than the standard parallel group design when there is heterogeneity in individuals' risks. We also introduce a new two-period design where first period "survivors" are rerandomized for the second period. This design combines the crossover design with the parallel design and achieves some of the efficiency advantages of the crossover design while ensuring that the second period groups are comparable by randomization. We discuss the validity of the new designs and evaluate both a mixture model and a modified Mantel-Haenszel test for inference. The mixture model assumes no carryover or period effects while the Mantel-Haenszel approach conditions out period effects. Simulations are used to compare the different designs and an example is provided to explore practical issues in implementation.

  2. Alternative trial design in amyotrophic lateral sclerosis saves time and patients.

    PubMed

    Groeneveld, Geert Jan; Graf, Michael; van der Tweel, Ingeborg; van den Berg, Leonard H; Ludolph, Albert C

    2007-10-01

    A sequential trial design is an alternative for the classical trial design with a fixed sample size, that permits stopping a trial as soon as enough evidence for a treatment effect, or a lack thereof, is obtained. This study aimed to determine the difference in efficiency of time and patient number between a classical trial design and a sequential trial design. In this study we re-analysed a previously published classically designed clinical trial according to a sequential trial design. We subsequently determined the difference in total running time and patient number. We found that the sequential analysis offered a gain in time of 38%. We conclude that the sequential trial design may in certain situations be superior to the classical design.

  3. Bayesian Optimal Interval Design: A Simple and Well-Performing Design for Phase I Oncology Trials.

    PubMed

    Yuan, Ying; Hess, Kenneth R; Hilsenbeck, Susan G; Gilbert, Mark R

    2016-09-01

    Despite more than two decades of publications that offer more innovative model-based designs, the classical 3 + 3 design remains the most dominant phase I trial design in practice. In this article, we introduce a new trial design, the Bayesian optimal interval (BOIN) design. The BOIN design is easy to implement in a way similar to the 3 + 3 design, but is more flexible for choosing the target toxicity rate and cohort size and yields a substantially better performance that is comparable with that of more complex model-based designs. The BOIN design contains the 3 + 3 design and the accelerated titration design as special cases, thus linking it to established phase I approaches. A numerical study shows that the BOIN design generally outperforms the 3 + 3 design and the modified toxicity probability interval (mTPI) design. The BOIN design is more likely than the 3 + 3 design to correctly select the MTD and allocate more patients to the MTD. Compared with the mTPI design, the BOIN design has a substantially lower risk of overdosing patients and generally a higher probability of correctly selecting the MTD. User-friendly software is freely available to facilitate the application of the BOIN design. Clin Cancer Res; 22(17); 4291-301. ©2016 AACR.

  4. OARSI Clinical Trials Recommendations: Design, conduct, and reporting of clinical trials for knee osteoarthritis.

    PubMed

    McAlindon, T E; Driban, J B; Henrotin, Y; Hunter, D J; Jiang, G-L; Skou, S T; Wang, S; Schnitzer, T

    2015-05-01

    The goal of this document is to update the original OARSI recommendations specifically for the design, conduct, and reporting of clinical trials that target symptom or structure modification among individuals with knee osteoarthritis (OA). To develop recommendations for the design, conduct, and reporting of clinical trials for knee OA we initially drafted recommendations through an iterative process. Members of the working group included representatives from industry and academia. After the working group members reviewed a final draft, they scored the appropriateness for recommendations. After the members voted we calculated the median score among the nine members of the working group who completed the score. The document includes 25 recommendations regarding randomization, blocking and stratification, blinding, enhancing accuracy of patient-reported outcomes (PRO), selecting a study population and index knee, describing interventions, patient-reported and physical performance measures, structural outcome measures, biochemical biomarkers, and reporting recommendations. In summary, the working group identified 25 recommendations that represent the current best practices regarding clinical trials that target symptom or structure modification among individuals with knee OA. These updated recommendations incorporate novel technologies (e.g., magnetic resonance imaging (MRI)) and strategies to address the heterogeneity of knee OA.

  5. Challenges and opportunities in designing clinical trials for neuromyelitis optica

    PubMed Central

    Barron, Gerard; Behne, Jacinta M.; Bennett, Jeffery L.; Chin, Peter S.; Cree, Bruce A.C.; de Seze, Jerome; Flor, Armando; Fujihara, Kazuo; Greenberg, Benjamin; Higashi, Sayumi; Holt, William; Khan, Omar; Knappertz, Volker; Levy, Michael; Melia, Angela T.; Palace, Jacqueline; Smith, Terry J.; Sormani, Maria Pia; Van Herle, Katja; VanMeter, Susan; Villoslada, Pablo; Walton, Marc K.; Wasiewski, Warren; Wingerchuk, Dean M.; Yeaman, Michael R.

    2015-01-01

    Current management of neuromyelitis optica (NMO) is noncurative and only partially effective. Immunosuppressive or immunomodulatory agents are the mainstays of maintenance treatment. Safer, better-tolerated, and proven effective treatments are needed. The perceived rarity of NMO has impeded clinical trials for this disease. However, a diagnostic biomarker and recognition of a wider spectrum of NMO presentations has expanded the patient population from which study candidates might be recruited. Emerging insights into the pathogenesis of NMO have provided rationale for exploring new therapeutic targets. Academic, pharmaceutical, and regulatory communities are increasingly interested in meeting the unmet needs of patients with NMO. Clinical trials powered to yield unambiguous outcomes and designed to facilitate rapid evaluation of an expanding pipeline of experimental agents are needed. NMO-related disability occurs incrementally as a result of attacks; thus, limiting attack frequency and severity are critical treatment goals. Yet, the severity of NMO and perception that currently available agents are effective pose challenges to study design. We propose strategies for NMO clinical trials to evaluate agents targeting recovery from acute attacks and prevention of relapses, the 2 primary goals of NMO treatment. Aligning the interests of all stakeholders is an essential step to this end. PMID:25841026

  6. Improving venous ulcer healing: designing and reporting randomised controlled trials.

    PubMed

    Weller, Carolina D; McNeil, John; Evans, Sue; Reid, Christopher

    2010-02-01

    The randomised controlled trial (RCT) is often considered the gold standard for judging the benefits of treatments. The application of randomised controlled clinical trials to treatments of venous ulcer healing has lagged behind that of other areas of medicine. To interpret the results of an RCT, readers must understand a variety of aspects of their design, analysis and interpretation. Venous ulcer disease has a high prevalence and has a significant socioeconomic impact in most parts of the world. The management of venous ulcers causes a considerable strain on the health system and is likely to worsen in future. The multi-layer high compression system is described as the current gold standard for treating venous ulcers. A recent meta-analysis of bandaging systems found that multi-layer compression bandages appeared to be superior to single-layer bandages in promoting venous ulcer healing. However, it was noted that many of the studies had small sample sizes and the quality of research in the area was poor. The consolidating standards of reporting trials (CONSORT) statement can help clinicians to discern high-quality studies from ones of poorer quality. This paper discusses how CONSORT can help clinicians and researchers to design and report quality studies to contribute to evidence-based venous ulcer healing.

  7. Challenges and opportunities in designing clinical trials for neuromyelitis optica.

    PubMed

    Weinshenker, Brian G; Barron, Gerard; Behne, Jacinta M; Bennett, Jeffery L; Chin, Peter S; Cree, Bruce A C; de Seze, Jerome; Flor, Armando; Fujihara, Kazuo; Greenberg, Benjamin; Higashi, Sayumi; Holt, William; Khan, Omar; Knappertz, Volker; Levy, Michael; Melia, Angela T; Palace, Jacqueline; Smith, Terry J; Sormani, Maria Pia; Van Herle, Katja; VanMeter, Susan; Villoslada, Pablo; Walton, Marc K; Wasiewski, Warren; Wingerchuk, Dean M; Yeaman, Michael R

    2015-04-28

    Current management of neuromyelitis optica (NMO) is noncurative and only partially effective. Immunosuppressive or immunomodulatory agents are the mainstays of maintenance treatment. Safer, better-tolerated, and proven effective treatments are needed. The perceived rarity of NMO has impeded clinical trials for this disease. However, a diagnostic biomarker and recognition of a wider spectrum of NMO presentations has expanded the patient population from which study candidates might be recruited. Emerging insights into the pathogenesis of NMO have provided rationale for exploring new therapeutic targets. Academic, pharmaceutical, and regulatory communities are increasingly interested in meeting the unmet needs of patients with NMO. Clinical trials powered to yield unambiguous outcomes and designed to facilitate rapid evaluation of an expanding pipeline of experimental agents are needed. NMO-related disability occurs incrementally as a result of attacks; thus, limiting attack frequency and severity are critical treatment goals. Yet, the severity of NMO and perception that currently available agents are effective pose challenges to study design. We propose strategies for NMO clinical trials to evaluate agents targeting recovery from acute attacks and prevention of relapses, the 2 primary goals of NMO treatment. Aligning the interests of all stakeholders is an essential step to this end.

  8. An adequate design for regression analysis of yield trials.

    PubMed

    Gusmão, L

    1985-12-01

    Based on theoretical demonstrations and illustrated with a numerical example from triticale yield trials in Portugal, the Completely Randomized Design is proposed as the one suited for Regression Analysis. When trials are designed in Complete Randomized Blocks the regression of plot production on block mean instead of the regression of cultivar mean on the overall mean of the trial is proposed as the correct procedure for regression analysis. These proposed procedures, in addition to providing a better agreement with the assumptions for regression and the philosophy of the method, induce narrower confidence intervals and attenuation of the hyperbolic effect. The increase in precision is brought about by both a decrease in the t Student values by an increased number of degrees of freedom, and by a decrease in standard error by a non proportional increase of residual variance and non proportional increase of the sum of squares of the assumed independent variable. The new procedures seem to be promising for a better understanding of the mechanism of specific instability.

  9. Futility rules in bioequivalence trials with sequential designs.

    PubMed

    Fuglsang, Anders

    2014-01-01

    Health Canada, the US Food and Drug Administration, as well as the European Medicines Agency consider sequential designs acceptable for bioequivalence studies as long as the type I error is controlled at 5%. The EU guideline explicitly asks for specification of stopping rules, so the goal of this work is to investigate how stopping rules may affect type I errors and power for recently published sequential bioequivalence trial designs. Using extensive trial simulations, five different futility rules were evaluated for their effect on type I error rates and power in two-stage scenarios. Under some circumstances, notably low sample size in stage 1 and/or high variability power may be very severely affected by the stopping rules, whereas type I error rates appear less affected. Because applicants may initiate sequential studies when the variability is not known in advance, achieving sufficient power and thereby complying with certain guideline requirements may be challenging and application of optimistic futility rules could possibly be unethical. This is the first work to investigate how futility rules affect type I errors and power in sequential bioequivalence trials.

  10. Comparison of the long-term skeletal stability between a biodegradable and a titanium fixation system following BSSO advancement - a cohort study based on a multicenter randomised controlled trial.

    PubMed

    van Bakelen, N B; Boermans, B D A; Buijs, G J; Jansma, J; Pruim, G J; Hoppenreijs, Th J M; Bergsma, J E; Stegenga, B; Bos, R R M

    2014-10-01

    Biodegradable fixation systems could reduce or eliminate the problems associated with removal of titanium plates. A multicenter randomised controlled trial (RCT) was performed in the Netherlands from December 2006-July 2009, and originally 230 injured and orthognathic patients were included. The patients were randomly assigned to either a titanium control group (KLS Martin) or to a biodegradable test group (Inion CPS). The aim of the present study was to compare the long-term skeletal stability of advancement bilateral sagittal split osteotomies (BSSO) of a biodegradable system and a titanium system. Only patients from the original RCT who were at least 18 years old and who had a BSSO advancement osteotomy were included. Those who had simultaneous Le Fort I osteotomy or genioplasty were excluded. Analysis of skeletal stability was made by digital tracing of lateral cephalograms. Long-term skeletal stability in BSSO advancement did not differ significantly between patients treated with biodegradable plates and screws and those treated with titanium plates and screws. Given the comparable amount of relapse, the general use of Inion CPS in the treatment of BSSO advancement should not be discouraged. On the basis of other properties a total picture of the clinical use can be obtained; the short-term stability, the intraoperative switches, the number of plates removed and cost-effectiveness. Trial registration of original RCT: http://www.controlled-trials.com; ISRCTN 44212338.

  11. Design of clinical trials for therapeutic cancer vaccines development.

    PubMed

    Mackiewicz, Jacek; Mackiewicz, Andrzej

    2009-12-25

    Advances in molecular and cellular biology as well as biotechnology led to definition of a group of drugs referred to as medicinal products of advanced technologies. It includes gene therapy products, somatic cell therapeutics and tissue engineering. Therapeutic cancer vaccines including whole cell tumor cells vaccines or gene modified whole cells belong to somatic therapeutics and/or gene therapy products category. The drug development is a multistep complex process. It comprises of two phases: preclinical and clinical. Guidelines on preclinical testing of cell based immunotherapy medicinal products have been defined by regulatory agencies and are available. However, clinical testing of therapeutic cancer vaccines is still under debate. It presents a serious problem since recently clinical efficacy of the number of cancer vaccines has been demonstrated that focused a lot of public attention. In general clinical testing in the current form is very expensive, time consuming and poorly designed what may lead to overlooking of products clinically beneficial for patients. Accordingly regulatory authorities and researches including Cancer Vaccine Clinical Trial Working Group proposed three regulatory solutions to facilitate clinical development of cancer vaccines: cost-recovery program, conditional marketing authorization, and a new development paradigm. Paradigm includes a model in which cancer vaccines are investigated in two types of clinical trials: proof-of-principle and efficacy. The proof-of-principle trial objectives are: safety; dose selection and schedule of vaccination; and demonstration of proof-of-principle. Efficacy trials are randomized clinical trials with objectives of demonstrating clinical benefit either directly or through a surrogate. The clinical end points are still under debate.

  12. Staying well after depression: trial design and protocol

    PubMed Central

    2010-01-01

    Background Depression is often a chronic relapsing condition, with relapse rates of 50-80% in those who have been depressed before. This is particularly problematic for those who become suicidal when depressed since habitual recurrence of suicidal thoughts increases likelihood of further acute suicidal episodes. Therefore the question how to prevent relapse is of particular urgency in this group. Methods/Design This trial compares Mindfulness-Based Cognitive Therapy (MBCT), a novel form of treatment combining mindfulness meditation and cognitive therapy for depression, with both Cognitive Psycho-Education (CPE), an equally plausible cognitive treatment but without meditation, and treatment as usual (TAU). It will test whether MBCT reduces the risk of relapse in recurrently depressed patients and the incidence of suicidal symptoms in those with a history of suicidality who do relapse. It recruits participants, screens them by telephone for main inclusion and exclusion criteria and, if they are eligible, invites them to a pre-treatment session to assess eligibility in more detail. This trial allocates eligible participants at random between MBCT and TAU, CPE and TAU, and TAU alone in a ratio of 2:2:1, stratified by presence of suicidal ideation or behaviour and current anti-depressant use. We aim to recruit sufficient participants to allow for retention of 300 following attrition. We deliver both active treatments in groups meeting for two hours every week for eight weeks. We shall estimate effects on rates of relapse and suicidal symptoms over 12 months following treatment and assess clinical status immediately after treatment, and three, six, nine and twelve months thereafter. Discussion This will be the first trial of MBCT to investigate whether MCBT is effective in preventing relapse to depression when compared with a control psychological treatment of equal plausibility; and to explore the use of MBCT for the most severe recurrent depression - that in people who

  13. A randomized controlled trial of acupuncture and moxibustion to treat Bell's palsy according to different stages: design and protocol.

    PubMed

    Chen, Xiaoqin; Li, Ying; Zheng, Hui; Hu, Kaming; Zhang, Hongxing; Zhao, Ling; Li, Yan; Liu, Lian; Mang, Lingling; Yu, Shuyuan

    2009-07-01

    Acupuncture to treat Bell's palsy is one of the most commonly used methods in China. There are a variety of acupuncture treatment options to treat Bell's palsy in clinical practice. Since Bell's palsy has three different path-stages (acute stage, resting stage and restoration stage), so whether acupuncture is effective in the different path-stages and which acupuncture treatment is the best method are major issues in acupuncture clinical trials about Bell's palsy. In this article, we report the design and protocol of a large sample multi-center randomized controlled trial to treat Bell's palsy with acupuncture. There are five acupuncture groups, with four according to different path-stages and one not. In total, 900 patients with Bell's palsy are enrolled in this study. These patients are randomly assigned to receive one of the following four treatment groups according to different path-stages, i.e. 1) staging acupuncture group, 2) staging acupuncture and moxibustion group, 3) staging electro-acupuncture group, 4) staging acupuncture along yangming musculature group or non-staging acupuncture control group. The outcome measurements in this trial are the effect comparison achieved among these five groups in terms of House-Brackmann scale (Global Score and Regional Score), Facial Disability Index scale, Classification scale of Facial Paralysis, and WHOQOL-BREF scale before randomization (baseline phase) and after randomization. The result of this trial will certify the efficacy of using staging acupuncture and moxibustion to treat Bell's palsy, and to approach a best acupuncture treatment among these five different methods for treating Bell's palsy.

  14. Effects of a Psychological Intervention in a Primary Health Care Center for Caregivers of Dependent Relatives: A Randomized Trial

    ERIC Educational Resources Information Center

    Rodriguez-Sanchez, Emiliano; Patino-Alonso, Maria C.; Mora-Simon, Sara; Gomez-Marcos, Manuel A.; Perez-Penaranda, Anibal; Losada-Baltar, Andres; Garcia-Ortiz, Luis

    2013-01-01

    Purpose: To assess, in the context of Primary Health Care (PHC), the effect of a psychological intervention in mental health among caregivers (CGs) of dependent relatives. Design and Methods: Randomized multicenter, controlled clinical trial. The 125 CGs included in the trial were receiving health care in PHC. Inclusion criteria: Identifying…

  15. A Prospective, Multicenter, Randomized Phase II Study to Evaluate the Efficacy and Safety of Eculizumab in Patients with Guillain-Barré Syndrome (GBS): Protocol of Japanese Eculizumab Trial for GBS (JET-GBS)

    PubMed Central

    Yamaguchi, Nobuko; Sato, Yasunori; Nagashima, Kengo; Katayama, Kanako; Sekiguchi, Yukari; Iwai, Yuta; Amino, Hiroshi; Suichi, Tomoki; Yokota, Takanori; Nishida, Yoichiro; Kohara, Nobuo; Hirata, Koichi; Nishiyama, Kazutoshi; Yabe, Ichiro; Kaida, Ken-Ichi; Suzuki, Norihiro; Nodera, Hiroyuki; Tsuji, Shoji; Koike, Haruki; Kira, Jun-Ichi; Hanaoka, Hideki; Kusunoki, Susumu; Kuwabara, Satoshi

    2016-01-01

    Background Guillain-Barré syndrome (GBS) is an immune-mediated neuropathy that causes acute flaccid paralysis. Immunoglobulin and plasma exchange are established treatments for GBS; however, a substantial number of patients, particularly those with severe disease, have poor recovery and residual deficits. Recent studies suggest that complement activation plays a pivotal role in GBS-associated axonal degeneration, and eculizumab is a humanized monoclonal antibody that specifically binds to complement component 5 and potently inhibits complement activation. Objective This clinical trial aims to evaluate the efficacy and safety of eculizumab, a humanized monoclonal antibody directed against complement component 5, for treatment of GBS. Methods The Japanese Eculizumab Trial for GBS (JET-GBS) is a prospective, multicenter, placebo-controlled, double-blind, randomized phase II study conducted at 13 tertiary neurology centers and is funded by the Japan Agency for Medical Research and Development. A total of 33 GBS patients unable to walk independently within 2 weeks from symptom onset (Hughes functional grade 3-5) were randomized at a 2:1 ratio to receive either intravenous eculizumab (900 mg/day) or placebo once weekly for 4 weeks, followed by 20 weeks of follow-up. The primary endpoint for efficacy is the proportion of patients who regain their ability to walk without aid at 4 weeks after the first dose of the study treatment, while primary safety outcomes are the incidence of adverse events and serious adverse events during the trial. Results Enrollment for the trial began in August 2015. This trial is still ongoing. All participants have been enrolled, and follow-up will be completed in October 2016. Conclusions This study is the first to investigate the efficacy and safety of eculizumab for GBS. In case of a positive result, we will plan a phase III trial to investigate this issue in a larger number of patients. ClinicalTrial UMIN Clinical Trials Registry UMIN

  16. Clinical trial designs for testing biomarker-based personalized therapies

    PubMed Central

    Lai, Tze Leung; Lavori, Philip W; Shih, Mei-Chiung I; Sikic, Branimir I

    2014-01-01

    Background Advances in molecular therapeutics in the past decade have opened up new possibilities for treating cancer patients with personalized therapies, using biomarkers to determine which treatments are most likely to benefit them, but there are difficulties and unresolved issues in the development and validation of biomarker-based personalized therapies. We develop a new clinical trial design to address some of these issues. The goal is to capture the strengths of the frequentist and Bayesian approaches to address this problem in the recent literature and to circumvent their limitations. Methods We use generalized likelihood ratio tests of the intersection null and enriched strategy null hypotheses to derive a novel clinical trial design for the problem of advancing promising biomarker-guided strategies toward eventual validation. We also investigate the usefulness of adaptive randomization (AR) and futility stopping proposed in the recent literature. Results Simulation studies demonstrate the advantages of testing both the narrowly focused enriched strategy null hypothesis related to validating a proposed strategy and the intersection null hypothesis that can accommodate to a potentially successful strategy. AR and early termination of ineffective treatments offer increased probability of receiving the preferred treatment and better response rates for patients in the trial, at the expense of more complicated inference under small-to-moderate total sample sizes and some reduction in power. Limitations The binary response used in the development phase may not be a reliable indicator of treatment benefit on long-term clinical outcomes. In the proposed design, the biomarker-guided strategy (BGS) is not compared to ‘standard of care’, such as physician’s choice that may be informed by patient characteristics. Therefore, a positive result does not imply superiority of the BGS to ‘standard of care’. The proposed design and tests are valid asymptotically

  17. Heterotopic ossification following single-level anterior cervical discectomy and fusion: results from the prospective, multicenter, historically controlled trial comparing allograft to an optimized dose of rhBMP-2.

    PubMed

    Arnold, Paul M; Anderson, Karen K; Selim, Abdulhafez; Dryer, Randall F; Kenneth Burkus, J

    2016-09-01

    OBJECTIVE Heterotopic ossification (HO) has been reported following total hip, knee, cervical, and lumbar arthroplasty, as well as following posterolateral lumbar fusion using recombinant human bone morphogenetic protein-2 (rhBMP-2). Data regarding HO following anterior cervical discectomy and fusion (ACDF) with rhBMP-2 are sparse. A subanalysis was done of the prospective, multicenter, investigational device exemption trial that compared rhBMP-2 on an absorbable collagen sponge (ACS) versus allograft in ACDF for patients with symptomatic single-level cervical degenerative disc disease. METHODS To assess differences in types of HO observed in the treatment groups and effects of HO on functional and efficacy outcomes, clinical outcomes from previous disc replacement studies were compared between patients who received rhBMP-2/ACS versus allograft. Rate, location, grade, and size of ossifications were assessed preoperatively and at 24 months, and correlated with clinical outcomes. RESULTS Heterotopic ossification was primarily anterior in both groups. Preoperatively in both groups, and including osteophytes in the target regions, HO rates were high at 40.9% and 36.9% for the rhBMP-2/ACS and allograft groups, respectively (p = 0.350). At 24 months, the rate of HO in the rhBMP-2/ACS group was higher than in the allograft group (78.6% vs 59.2%, respectively; p < 0.001). At 24 months, the rate of superior-anterior adjacent-level Park Grade 3 HO was 4.2% in both groups, whereas the rate of Park Grade 2 HO was 19.0% in the rhBMP-2/ACS group compared with 9.8% in the allograft group. At 24 months, the rate of inferior-anterior adjacent-level Park Grade 2/3 HO was 11.9% in the rhBMP-2/ACS group compared with 5.9% in the allograft group. At 24 months, HO rates at the target implant level were similar (p = 0.963). At 24 months, the mean length and anteroposterior diameter of HO were significantly greater in the rhBMP-2/ACS group compared with the allograft group (p = 0.033 and

  18. Adaptive designs undertaken in clinical research: a review of registered clinical trials.

    PubMed

    Hatfield, Isabella; Allison, Annabel; Flight, Laura; Julious, Steven A; Dimairo, Munyaradzi

    2016-03-19

    Adaptive designs have the potential to improve efficiency in the evaluation of new medical treatments in comparison to traditional fixed sample size designs. However, they are still not widely used in practice in clinical research. Little research has been conducted to investigate what adaptive designs are being undertaken. This review highlights the current state of registered adaptive designs and their characteristics. The review looked at phase II, II/III and III trials registered on ClinicalTrials.gov from 29 February 2000 to 1 June 2014, supplemented with trials from the National Institute for Health Research register and known adaptive trials. A range of adaptive design search terms were applied to the trials extracted from each database. Characteristics of the adaptive designs were then recorded including funder, therapeutic area and type of adaptation. The results in the paper suggest that the use of adaptive designs has increased. They seem to be most often used in phase II trials and in oncology. In phase III trials, the most popular form of adaptation is the group sequential design. The review failed to capture all trials with adaptive designs, which suggests that the reporting of adaptive designs, such as in clinical trials registers, needs much improving. We recommend that clinical trial registers should contain sections dedicated to the type and scope of the adaptation and that the term 'adaptive design' should be included in the trial title or at least in the brief summary or design sections.

  19. Rationale and design of A Trial of Sertraline vs. Cognitive Behavioral Therapy for End-stage Renal Disease Patients with Depression (ASCEND).

    PubMed

    Hedayati, S Susan; Daniel, Divya M; Cohen, Scott; Comstock, Bryan; Cukor, Daniel; Diaz-Linhart, Yaminette; Dember, Laura M; Dubovsky, Amelia; Greene, Tom; Grote, Nancy; Heagerty, Patrick; Katon, Wayne; Kimmel, Paul L; Kutner, Nancy; Linke, Lori; Quinn, Davin; Rue, Tessa; Trivedi, Madhukar H; Unruh, Mark; Weisbord, Steven; Young, Bessie A; Mehrotra, Rajnish

    2016-03-01

    Major Depressive Disorder (MDD) is highly prevalent in patients with End Stage Renal Disease (ESRD) treated with maintenance hemodialysis (HD). Despite the high prevalence and robust data demonstrating an independent association between depression and poor clinical and patient-reported outcomes, MDD is under-treated when identified in such patients. This may in part be due to the paucity of evidence confirming the safety and efficacy of treatments for depression in this population. It is also unclear whether HD patients are interested in receiving treatment for depression. ASCEND (Clinical Trials Identifier Number NCT02358343), A Trial of Sertraline vs. Cognitive Behavioral Therapy (CBT) for End-stage Renal Disease Patients with Depression, was designed as a multi-center, 12-week, open-label, randomized, controlled trial of prevalent HD patients with comorbid MDD or dysthymia. It will compare (1) a single Engagement Interview vs. a control visit for the probability of initiating treatment for comorbid depression in up to 400 patients; and (2) individual chair-side CBT vs. flexible-dose treatment with a selective serotonin reuptake inhibitor, sertraline, for improvement of depressive symptoms in 180 of the up to 400 patients. The evolution of depressive symptoms will also be examined in a prospective longitudinal cohort of 90 HD patients who choose not to be treated for depression. We discuss the rationale and design of ASCEND, the first large-scale randomized controlled trial evaluating efficacy of non-pharmacologic vs. pharmacologic treatment of depression in HD patients for patient-centered outcomes.

  20. Antiosteoporotic Activity of Genistein Aglycone in Postmenopausal Women: Evidence from a Post-Hoc Analysis of a Multicenter Randomized Controlled Trial.

    PubMed

    Arcoraci, Vincenzo; Atteritano, Marco; Squadrito, Francesco; D'Anna, Rosario; Marini, Herbert; Santoro, Domenico; Minutoli, Letteria; Messina, Sonia; Altavilla, Domenica; Bitto, Alessandra

    2017-02-22

    Genistein has a preventive role against bone mass loss during menopause. However, experimental data in animal models of osteoporosis suggest an anti-osteoporotic potential for this isoflavone. We performed a post-hoc analysis of a previously published trial investigating the effects of genistein in postmenopausal women with low bone mineral density. The parent study was a randomized, double-blind, placebo-controlled trial involving postmenopausal women with a femoral neck (FN) density <0.795 g/cm². A cohort of the enrolled women was, in fact, identified at the baseline as osteoporotic (n = 121) on the basis of their T-score and analyzed thereafter for the 24 months' treatment with either 1000 mg of calcium and 800 IU vitamin D3 (placebo; n = 59); or calcium, vitamin D3, and Genistein aglycone (54 mg/day; genistein; n = 62). According to the femoral neck T-scores, 31.3% of the genistein and 30.9% of the placebo recipients were osteoporotic at baseline. In the placebo and genistein groups, the 10-year hip fracture probability risk assessed by Fracture Risk Assessment tool (FRAX) was 4.1 ± 1.9 (SD) and 4.2 ± 2.1 (SD), respectively. Mean bone mineral density (BMD) at the femoral neck increased from 0.62 g/cm² at baseline to 0.68 g/cm² at 1 year and 0.70 g/cm² at 2 years in genistein recipients, and decreased from 0.61 g/cm² at baseline to 0.60 g/cm² at 1 year and 0.57 g/cm² at 2 years in placebo recipients. At the end of the study only 18 postmenopausal women had osteoporosis in the genistein group with a prevalence of 12%, whereas in the placebo group the number of postmenopausal women with osteoporosis was unchanged, after 24 months. This post-hoc analysis is a proof-of concept study suggesting that genistein may be useful not only in postmenopausal osteopenia but also in osteoporosis. However, this proof-of concept study needs to be confirmed by a large, well designed, and appropriately focused randomized clinical trial in a population at high risk of

  1. Efficacy and Safety of Tangshen Formula on Patients with Type 2 Diabetic Kidney Disease: A Multicenter Double-Blinded Randomized Placebo-Controlled Trial

    PubMed Central

    Li, Ping; Chen, Yiping; Liu, Jianping; Hong, Jing; Deng, Yueyi; Yang, Fang; Jin, Xiuping; Gao, Jing; Li, Jing; Fang, Hui; Liu, Geling; Shi, Liping; Du, Jinhang; Li, Yang; Yan, Meihua; Wen, Yumin; Yang, Wenying

    2015-01-01

    Background Persons with diabetes are at high risk of developing diabetic kidney disease (DKD), which is associated with high morbidity and mortality. Current drug therapies for DKD, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are not entirely satisfactory. This study aimed to evaluate the additional benefit and safety of the Chinese herbal granule Tangshen Formula (TSF) in treating DKD. Methods The study was designed as a six-center randomized, double-blind, placebo-controlled trial. From April 2007 through December 2009, 180 patients with DKD were enrolled. In addition to conventional treatment with ACEIs or ARBs, 122 participants were randomly assigned to receive TSF and 58 participants to receive placebo for 24 weeks. Primary outcome was urinary protein level, measured by urinary albumin excretion rate (UAER) for participants with microalbuminuria, 24-hour urinary protein (24h UP) for participants with macroalbuminuria. Secondary outcomes included renal function, serum lipids, quality of life, symptoms, and adverse events. Findings After 24 weeks of treatment, no statistically significant difference in UAER (TSF −19.53 μg/min compared with placebo −7.01 μg/min, with a mean difference of −12.52 μg/min; 95%CI, −68.67 to 43.63, P = 0.696) was found between TSF and placebo groups. However, TSF displayed a statistically significant decrease in 24h UP (TSF−0.21 g compared with placebo 0.36 g, wi