Trial Promoter: A Web-Based Tool for Boosting the Promotion of Clinical Research Through Social Media.

PubMed

Reuter, Katja; Ukpolo, Francis; Ward, Edward; Wilson, Melissa L; Angyan, Praveen

2016-06-29

Scarce information about clinical research, in particular clinical trials, is among the top reasons why potential participants do not take part in clinical studies. Without volunteers, on the other hand, clinical research and the development of novel approaches to preventing, diagnosing, and treating disease are impossible. Promising digital options such as social media have the potential to work alongside traditional methods to boost the promotion of clinical research. However, investigators and research institutions are challenged to leverage these innovations while saving time and resources. To develop and test the efficiency of a Web-based tool that automates the generation and distribution of user-friendly social media messages about clinical trials. Trial Promoter is developed in Ruby on Rails, HTML, cascading style sheet (CSS), and JavaScript. In order to test the tool and the correctness of the generated messages, clinical trials (n=46) were randomized into social media messages and distributed via the microblogging social media platform Twitter and the social network Facebook. The percent correct was calculated to determine the probability with which Trial Promoter generates accurate messages. During a 10-week testing phase, Trial Promoter automatically generated and published 525 user-friendly social media messages on Twitter and Facebook. On average, Trial Promoter correctly used the message templates and substituted the message parameters (text, URLs, and disease hashtags) 97.7% of the time (1563/1600). Trial Promoter may serve as a promising tool to render clinical trial promotion more efficient while requiring limited resources. It supports the distribution of any research or other types of content. The Trial Promoter code and installation instructions are freely available online.

Trial Promoter: A Web-Based Tool for Boosting the Promotion of Clinical Research Through Social Media

PubMed Central

Ukpolo, Francis; Ward, Edward; Wilson, Melissa L

2016-01-01

Background Scarce information about clinical research, in particular clinical trials, is among the top reasons why potential participants do not take part in clinical studies. Without volunteers, on the other hand, clinical research and the development of novel approaches to preventing, diagnosing, and treating disease are impossible. Promising digital options such as social media have the potential to work alongside traditional methods to boost the promotion of clinical research. However, investigators and research institutions are challenged to leverage these innovations while saving time and resources. Objective To develop and test the efficiency of a Web-based tool that automates the generation and distribution of user-friendly social media messages about clinical trials. Methods Trial Promoter is developed in Ruby on Rails, HTML, cascading style sheet (CSS), and JavaScript. In order to test the tool and the correctness of the generated messages, clinical trials (n=46) were randomized into social media messages and distributed via the microblogging social media platform Twitter and the social network Facebook. The percent correct was calculated to determine the probability with which Trial Promoter generates accurate messages. Results During a 10-week testing phase, Trial Promoter automatically generated and published 525 user-friendly social media messages on Twitter and Facebook. On average, Trial Promoter correctly used the message templates and substituted the message parameters (text, URLs, and disease hashtags) 97.7% of the time (1563/1600). Conclusions Trial Promoter may serve as a promising tool to render clinical trial promotion more efficient while requiring limited resources. It supports the distribution of any research or other types of content. The Trial Promoter code and installation instructions are freely available online. PMID:27357424

Feasibility of Extracting Key Elements from ClinicalTrials.gov to Support Clinicians' Patient Care Decisions.

PubMed

Kim, Heejun; Bian, Jiantao; Mostafa, Javed; Jonnalagadda, Siddhartha; Del Fiol, Guilherme

2016-01-01

Motivation: Clinicians need up-to-date evidence from high quality clinical trials to support clinical decisions. However, applying evidence from the primary literature requires significant effort. Objective: To examine the feasibility of automatically extracting key clinical trial information from ClinicalTrials.gov. Methods: We assessed the coverage of ClinicalTrials.gov for high quality clinical studies that are indexed in PubMed. Using 140 random ClinicalTrials.gov records, we developed and tested rules for the automatic extraction of key information. Results: The rate of high quality clinical trial registration in ClinicalTrials.gov increased from 0.2% in 2005 to 17% in 2015. Trials reporting results increased from 3% in 2005 to 19% in 2015. The accuracy of the automatic extraction algorithm for 10 trial attributes was 90% on average. Future research is needed to improve the algorithm accuracy and to design information displays to optimally present trial information to clinicians.

An assessment of the utilization of the preclinical rodent model literature in clinical trials of putative therapeutics for the treatment of alcohol use disorders.

PubMed

Barajaz, Ashley M; Kliethermes, Christopher L

2017-12-01

Rodent models of Alcohol Use Disorders (AUD) are used extensively by preclinical researchers to develop new therapeutics for the treatment of AUD. Although these models play an important role in the development of novel, targeted therapeutics, their role in bringing therapeutics to clinical trials is unclear, as off-label use of existing medications not approved for the treatment of AUD is commonly seen in the clinic and clinical trials. In the current study, we used the Clinicaltrials.gov database to obtain a list of drugs that have been tested for efficacy in a clinical trial between 1997 and 2017. We then conducted a set of literature searches to determine which of the 98 unique drugs we identified had shown efficacy in a rodent model of an AUD prior to being tested in a clinical trial. We found that slightly less than half of the drugs tested in clinical trials (48%) had shown prior efficacy in any rodent model of an AUD, while the remaining 52% of drugs were used off-label, or in some cases, following non-published studies. This study raises the question of how clinical researchers incorporate results from preclinical studies in the decision to bring a drug to a clinical trial. Our results underscore the need for ongoing communication among preclinical and clinical researchers. Copyright © 2017 Elsevier B.V. All rights reserved.

A Pilot Study of a Culturally Targeted Video Intervention to Increase Participation of African American Patients in Cancer Clinical Trials

PubMed Central

Libin, Alexander V.; Wang, Hong; Swain, Sandra M.

2012-01-01

Purpose. Barriers to clinical trial participation among African American cancer patients are well characterized in the literature. Attitudinal barriers encompassing fear, distrust, and concerns about ethical misconduct are also well documented. To increase trial accrual, these attitudes must be adequately addressed, yet there remains a lack of targeted interventions toward this end. We developed a 15-minute culturally targeted video designed to impact six specific attitudes of African American cancer patients toward therapeutic trials. We conducted a pilot study to test in the first such intervention to increase intention to enroll. Patients and Methods. The primary study outcome was self-reported likelihood to participate in a therapeutic trial. Using a mixed methods approach, we developed the Attitudes and Intention to Enroll in Therapeutic Clinical Trials (AIET) instrument, a 30-item questionnaire measuring six attitudinal barriers to African American trial participation. We enrolled 108 eligible active treatment patients at a large urban cancer institute. McNemar's test for matched pairs was used to assess changes in attitudes and likelihood to enroll in a clinical trial at baseline and immediately after the video. Pre- and post-video AIET summative scores were analyzed by paired t-test for each attitudinal barrier. Results. Patients' likelihood of enrolling in a clinical trial significantly increased post-video with 36% of the sample showing positive changes in intention [McNemar's χ2 = 33.39, p < .001]. Paired t-tests showed significant changes in all six attitudinal barriers measured via AIET summative scores from pre- to post-video. Conclusion. These data suggest utility of our video for increasing African American participation in clinical trials. PMID:22639112

Linear Combinations of Multiple Outcome Measures to Improve the Power of Efficacy Analysis ---Application to Clinical Trials on Early Stage Alzheimer Disease

PubMed Central

Xiong, Chengjie; Luo, Jingqin; Morris, John C; Bateman, Randall

2018-01-01

Modern clinical trials on Alzheimer disease (AD) focus on the early symptomatic stage or even the preclinical stage. Subtle disease progression at the early stages, however, poses a major challenge in designing such clinical trials. We propose a multivariate mixed model on repeated measures to model the disease progression over time on multiple efficacy outcomes, and derive the optimum weights to combine multiple outcome measures by minimizing the sample sizes to adequately power the clinical trials. A cross-validation simulation study is conducted to assess the accuracy for the estimated weights as well as the improvement in reducing the sample sizes for such trials. The proposed methodology is applied to the multiple cognitive tests from the ongoing observational study of the Dominantly Inherited Alzheimer Network (DIAN) to power future clinical trials in the DIAN with a cognitive endpoint. Our results show that the optimum weights to combine multiple outcome measures can be accurately estimated, and that compared to the individual outcomes, the combined efficacy outcome with these weights significantly reduces the sample size required to adequately power clinical trials. When applied to the clinical trial in the DIAN, the estimated linear combination of six cognitive tests can adequately power the clinical trial. PMID:29546251

A mixed methods study to assess the feasibility of a randomised controlled trial of invasive urodynamic testing versus clinical assessment and non-invasive tests prior to surgery for stress urinary incontinence in women: the INVESTIGATE-I study.

PubMed

Hilton, Paul; Armstrong, Natalie; Brennand, Catherine; Howel, Denise; Shen, Jing; Bryant, Andrew; Tincello, Douglas G; Lucas, Malcolm G; Buckley, Brian S; Chapple, Christopher R; Homer, Tara; Vale, Luke; McColl, Elaine

2015-09-08

The position of invasive urodynamic testing (IUT) in diagnostic pathways for urinary incontinence is unclear, and systematic reviews have called for further trials evaluating clinical utility. The objective of this study was to inform the decision whether to proceed to a definitive randomised trial of IUT compared to clinical assessment with non-invasive tests, prior to surgery in women with stress urinary incontinence (SUI) or stress-predominant mixed urinary incontinence (MUI). A mixed methods study comprising a pragmatic multicentre randomised pilot trial, a qualitative face-to face interview study with patients eligible for the trial, an exploratory economic evaluation including value of information study, a survey of clinicians' views about IUT, and qualitative telephone interviews with purposively sampled survey respondents. Only the first and second of these elements are reported here. Trial participants were randomised to either clinical assessment with non-invasive tests (control arm) or clinical assessment with non-invasive tests plus IUT (intervention arm). The main outcome measures of these feasibility studies were confirmation that units can identify and recruit eligible women, acceptability of investigation strategies and data collection tools, and acquisition of outcome data to determine the sample size for a definitive trial. The primary outcome proposed for a definitive trial was ICIQ-FLUTS (total score) 6 months after surgery or the start of nonsurgical treatment. Of 284 eligible women, 222 (78%) were recruited, 165/219 (75%) returned questionnaires at baseline, and 125/200 returned them (63%) at follow-up. Most women underwent surgery; management plans were changed in 19 (19%) participants following IUT. Participants interviewed were positive about the trial and the associated documentation. All elements of a definitive trial were rehearsed. Such a trial would require between 232 and 922 participants, depending on the target difference in the primary outcome. We identified possible modifications to our protocol for application in a definitive trial including clarity over inclusion/exclusions, screening processes, reduction in secondary outcomes, and modification to patient questionnaire booklets and bladder diaries. A definitive trial of IUT versus clinical assessment prior to surgery for SUI or stress predominant MUI is feasible and remains relevant. Current Controlled Trials: ISRCTN 71327395, registered 7 June 2010.

Managing multicentre clinical trials with open source.

PubMed

Raptis, Dimitri Aristotle; Mettler, Tobias; Fischer, Michael Alexander; Patak, Michael; Lesurtel, Mickael; Eshmuminov, Dilmurodjon; de Rougemont, Olivier; Graf, Rolf; Clavien, Pierre-Alain; Breitenstein, Stefan

2014-03-01

Multicentre clinical trials are challenged by high administrative burden, data management pitfalls and costs. This leads to a reduced enthusiasm and commitment of the physicians involved and thus to a reluctance in conducting multicentre clinical trials. The purpose of this study was to develop a web-based open source platform to support a multi-centre clinical trial. We developed on Drupal, an open source software distributed under the terms of the General Public License, a web-based, multi-centre clinical trial management system with the design science research approach. This system was evaluated by user-testing and well supported several completed and on-going clinical trials and is available for free download. Open source clinical trial management systems are capable in supporting multi-centre clinical trials by enhancing efficiency, quality of data management and collaboration.

DNA Vaccination Against Metastatic Breast Cancer

DTIC Science & Technology

2001-07-01

cells. Although DNA vaccines have shown effectiveness in clinical trials , it is essential to demonstrate pre- clinical effectiveness for anti-tumor... clinical trials for infectious diseases (4), it is essential to (5-7)demonstrate pre- clinical effectiveness for anti-tumor vaccines before clinical testing...Program Clinical Translational Research (CTR) award to perform a Phase I clinical trial of ELVIS2-neu. Our preliminary application was selected for

Feasibility of Extracting Key Elements from ClinicalTrials.gov to Support Clinicians’ Patient Care Decisions

PubMed Central

Kim, Heejun; Bian, Jiantao; Mostafa, Javed; Jonnalagadda, Siddhartha; Del Fiol, Guilherme

2016-01-01

Motivation: Clinicians need up-to-date evidence from high quality clinical trials to support clinical decisions. However, applying evidence from the primary literature requires significant effort. Objective: To examine the feasibility of automatically extracting key clinical trial information from ClinicalTrials.gov. Methods: We assessed the coverage of ClinicalTrials.gov for high quality clinical studies that are indexed in PubMed. Using 140 random ClinicalTrials.gov records, we developed and tested rules for the automatic extraction of key information. Results: The rate of high quality clinical trial registration in ClinicalTrials.gov increased from 0.2% in 2005 to 17% in 2015. Trials reporting results increased from 3% in 2005 to 19% in 2015. The accuracy of the automatic extraction algorithm for 10 trial attributes was 90% on average. Future research is needed to improve the algorithm accuracy and to design information displays to optimally present trial information to clinicians. PMID:28269867

Searching for cures: Inner-city and rural patients' awareness and perceptions of cancer clinical trials.

PubMed

Geana, Mugur; Erba, Joseph; Krebill, Hope; Doolittle, Gary; Madhusudhana, Sheshadri; Qasem, Abdulraheem; Malomo, Nikki; Sharp, Denise

2017-03-01

Fewer than 5% of cancer patients participate in clinical trials, making it challenging to test new therapies or interventions for cancer. Even within that small number, patients living in inner-city and rural areas are underrepresented in clinical trials. This study explores cancer patients' awareness and perceptions of cancer clinical trials, as well as their perceptions of patient-provider interactions related to discussing cancer clinical trials in order to improve accrual in cancer clinical trials. Interviews with 66 former and current in inner-city and rural cancer patients revealed a lack of awareness and understanding about clinical trials, as well as misconceptions about what clinical trials entail. Findings also revealed that commercials and television shows play a prominent role in forming inner-city and rural patients' attitudes and/or misconceptions about clinical trials. However, rural patients were more likely to hold unfavorable views about clinical trials than inner-city patients. Patient-provider discussions emerged as being crucial for increasing awareness of clinical trials among patients and recruiting them to trials. Findings from this study will inform communication strategies to enhance recruitment to cancer clinical trials by increasing awareness and countering misconceptions about clinical trials.

Activities of Tannins--From In Vitro Studies to Clinical Trials.

PubMed

Sieniawska, Elwira

2015-11-01

Tannins are considered as valuable plant secondary metabolites providing many benefits for human health. In this review information was gathered about bioactivity in vitro and in vivo, as well as about conducted clinical trials. The literature research was based on ScienceDirect, Scopus, and Cochrane databases and presents a wide range of tested activities of tannins. The described clinical trials verify laboratory tests and show the effective health benefits taken from supplementation with tannins.

Harnessing Cerebrospinal Fluid Biomarkers in Clinical Trials for Treating Alzheimer's and Parkinson's Diseases: Potential and Challenges

PubMed Central

Kim, Dana; Kim, Young-Sam; Shin, Dong Wun; Park, Chang-Shin

2016-01-01

No disease-modifying therapies (DMT) for neurodegenerative diseases (NDs) have been established, particularly for Alzheimer's disease (AD) and Parkinson's disease (PD). It is unclear why candidate drugs that successfully demonstrate therapeutic effects in animal models fail to show disease-modifying effects in clinical trials. To overcome this hurdle, patients with homogeneous pathologies should be detected as early as possible. The early detection of AD patients using sufficiently tested biomarkers could demonstrate the potential usefulness of combining biomarkers with clinical measures as a diagnostic tool. Cerebrospinal fluid (CSF) biomarkers for NDs are being incorporated in clinical trials designed with the aim of detecting patients earlier, evaluating target engagement, collecting homogeneous patients, facilitating prevention trials, and testing the potential of surrogate markers relative to clinical measures. In this review we summarize the latest information on CSF biomarkers in NDs, particularly AD and PD, and their use in clinical trials. The large number of issues related to CSF biomarker measurements and applications has resulted in relatively few clinical trials on CSF biomarkers being conducted. However, the available CSF biomarker data obtained in clinical trials support the advantages of incorporating CSF biomarkers in clinical trials, even though the data have mostly been obtained in AD trials. We describe the current issues with and ongoing efforts for the use of CSF biomarkers in clinical trials and the plans to harness CSF biomarkers for the development of DMT and clinical routines. This effort requires nationwide, global, and multidisciplinary efforts in academia, industry, and regulatory agencies to facilitate a new era. PMID:27819412

Harnessing Cerebrospinal Fluid Biomarkers in Clinical Trials for Treating Alzheimer's and Parkinson's Diseases: Potential and Challenges.

PubMed

Kim, Dana; Kim, Young Sam; Shin, Dong Wun; Park, Chang Shin; Kang, Ju Hee

2016-10-01

No disease-modifying therapies (DMT) for neurodegenerative diseases (NDs) have been established, particularly for Alzheimer's disease (AD) and Parkinson's disease (PD). It is unclear why candidate drugs that successfully demonstrate therapeutic effects in animal models fail to show disease-modifying effects in clinical trials. To overcome this hurdle, patients with homogeneous pathologies should be detected as early as possible. The early detection of AD patients using sufficiently tested biomarkers could demonstrate the potential usefulness of combining biomarkers with clinical measures as a diagnostic tool. Cerebrospinal fluid (CSF) biomarkers for NDs are being incorporated in clinical trials designed with the aim of detecting patients earlier, evaluating target engagement, collecting homogeneous patients, facilitating prevention trials, and testing the potential of surrogate markers relative to clinical measures. In this review we summarize the latest information on CSF biomarkers in NDs, particularly AD and PD, and their use in clinical trials. The large number of issues related to CSF biomarker measurements and applications has resulted in relatively few clinical trials on CSF biomarkers being conducted. However, the available CSF biomarker data obtained in clinical trials support the advantages of incorporating CSF biomarkers in clinical trials, even though the data have mostly been obtained in AD trials. We describe the current issues with and ongoing efforts for the use of CSF biomarkers in clinical trials and the plans to harness CSF biomarkers for the development of DMT and clinical routines. This effort requires nationwide, global, and multidisciplinary efforts in academia, industry, and regulatory agencies to facilitate a new era.

Breast Cancer: Treatment Options

MedlinePlus

... A clinical trial is a research study that tests a new approach to treatment. Doctors want to learn whether the new treatment is safe, effective, and possibly better than the standard treatment. Clinical trials can test a new drug and how often it should ...

Home-based versus clinic-based specimen collection in the management of Chlamydia trachomatis and Neisseria gonorrhoeae infections.

PubMed

Fajardo-Bernal, Luisa; Aponte-Gonzalez, Johanna; Vigil, Patrick; Angel-Müller, Edith; Rincon, Carlos; Gaitán, Hernando G; Low, Nicola

2015-09-29

Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) are the most frequent causes of bacterial sexually transmitted infections (STIs). Management strategies that reduce losses in the clinical pathway from infection to cure might improve STI control and reduce complications resulting from lack of, or inadequate, treatment. To assess the effectiveness and safety of home-based specimen collection as part of the management strategy for Chlamydia trachomatis and Neisseria gonorrhoeae infections compared with clinic-based specimen collection in sexually-active people. We searched the Cochrane Sexually Transmitted Infections Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and LILACS on 27 May 2015, together with the World Health Organization International Clinical Trials Registry (ICTRP) and ClinicalTrials.gov. We also handsearched conference proceedings, contacted trial authors and reviewed the reference lists of retrieved studies. Randomized controlled trials (RCTs) of home-based compared with clinic-based specimen collection in the management of C. trachomatis and N. gonorrhoeae infections. Three review authors independently assessed trials for inclusion, extracted data and assessed risk of bias. We contacted study authors for additional information. We resolved any disagreements through consensus. We used standard methodological procedures recommended by Cochrane. The primary outcome was index case management, defined as the number of participants tested, diagnosed and treated, if test positive. Ten trials involving 10,479 participants were included. There was inconclusive evidence of an effect on the proportion of participants with index case management (defined as individuals tested, diagnosed and treated for CT or NG, or both) in the group with home-based (45/778, 5.8%) compared with clinic-based (51/788, 6.5%) specimen collection (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.60 to 1.29; 3 trials, I² = 0%, 1566 participants, moderate quality). Harms of home-based specimen collection were not evaluated in any trial. All 10 trials compared the proportions of individuals tested. The results for the proportion of participants completing testing had high heterogeneity (I² = 100%) and were not pooled. We could not combine data from individual studies looking at the number of participants tested because the proportions varied widely across the studies, ranging from 30% to 96% in home group and 6% to 97% in clinic group (low-quality evidence). The number of participants with positive test was lower in the home-based specimen collection group (240/2074, 11.6%) compared with the clinic-based group (179/967, 18.5%) (RR 0.72, 95% CI 0.61 to 0.86; 9 trials, I² = 0%, 3041 participants, moderate quality). Home-based specimen collection could result in similar levels of index case management for CT or NG infection when compared with clinic-based specimen collection. Increases in the proportion of individuals tested as a result of home-based, compared with clinic-based, specimen collection are offset by a lower proportion of positive results. The harms of home-based specimen collection compared with clinic-based specimen collection have not been evaluated. Future RCTs to assess the effectiveness of home-based specimen collection should be designed to measure biological outcomes of STI case management, such as proportion of participants with negative tests for the relevant STI at follow-up.

Two Decades of Cardiovascular Trials With Primary Surrogate Endpoints: 1990-2011.

PubMed

Bikdeli, Behnood; Punnanithinont, Natdanai; Akram, Yasir; Lee, Ike; Desai, Nihar R; Ross, Joseph S; Krumholz, Harlan M

2017-03-21

Surrogate endpoint trials test strategies more efficiently but are accompanied by uncertainty about the relationship between changes in surrogate markers and clinical outcomes. We identified cardiovascular trials with primary surrogate endpoints published in the New England Journal of Medicine , Lancet , and JAMA: Journal of the American Medical Association from 1990 to 2011 and determined the trends in publication of surrogate endpoint trials and the success of the trials in meeting their primary endpoints. We tracked for publication of clinical outcome trials on the interventions tested in surrogate trials. We screened 3016 articles and identified 220 surrogate endpoint trials. From the total of 220 surrogate trials, 157 (71.4%) were positive for their primary endpoint. Only 59 (26.8%) surrogate trials had a subsequent clinical outcomes trial. Among these 59 trials, 24 outcomes trial results validated the positive surrogates, whereas 20 subsequent outcome trials were negative following positive results on a surrogate. We identified only 3 examples in which the surrogate trial was negative but a subsequent outcomes trial was conducted and showed benefit. Findings were consistent in a sample cohort of 383 screened articles inclusive of 37 surrogate endpoint trials from 6 other high-impact journals. Although cardiovascular surrogate outcomes trials frequently show superiority of the tested intervention, they are infrequently followed by a prominent outcomes trial. When there was a high-profile clinical outcomes study, nearly half of the positive surrogate trials were not validated. Cardiovascular surrogate outcome trials may be more appropriate for excluding benefit from the patient perspective than for identifying it. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Clinical Trials Using Anti-CD19/CD28/CD3zeta CAR Gammaretroviral Vector-transduced Autologous T Lymphocytes KTE-C19

Cancer.gov

NCI supports clinical trials that test new and more effective ways to treat cancer. Find clinical trials studying anti-cd19/cd28/cd3zeta car gammaretroviral vector-transduced autologous t lymphocytes kte-c19.

The clinical utility of lung clearance index in early cystic fibrosis lung disease is not impacted by the number of multiple-breath washout trials

PubMed Central

Foong, Rachel E.; Harper, Alana J.; King, Louise; Turkovic, Lidija; Davis, Miriam; Clem, Charles C.; Davis, Stephanie D.; Ranganathan, Sarath; Hall, Graham L.

2018-01-01

The lung clearance index (LCI) from the multiple-breath washout (MBW) test is a promising surveillance tool for pre-school children with cystic fibrosis (CF). Current guidelines for MBW testing recommend that three acceptable trials are required. However, success rates to achieve these criteria are low in children aged <7 years and feasibility may improve with modified pre-school criteria that accepts tests with two acceptable trials. This study aimed to determine if relationships between LCI and clinical outcomes of CF lung disease differ when only two acceptable MBW trials are assessed. Healthy children and children with CF aged 3–6 years were recruited for MBW testing. Children with CF also underwent bronchoalveolar lavage fluid collection and a chest computed tomography scan. MBW feasibility increased from 46% to 75% when tests with two trials were deemed acceptable compared with tests where three acceptable trials were required. Relationships between MBW outcomes and markers of pulmonary inflammation, infection and structural lung disease were not different between tests with three acceptable trials compared with tests with two acceptable trials. This study indicates that pre-school MBW data from two acceptable trials may provide sufficient information on ventilation distribution if three acceptable trials are not possible. PMID:29707562

Improved participants' understanding of research information in real settings using the SIDCER informed consent form: a randomized-controlled informed consent study nested with eight clinical trials.

PubMed

Koonrungsesomboon, Nut; Tharavanij, Thipaporn; Phiphatpatthamaamphan, Kittichet; Vilaichone, Ratha-Korn; Manuwong, Sudsayam; Curry, Parichat; Siramolpiwat, Sith; Punchaipornpon, Thanachai; Kanitnate, Supakit; Tammachote, Nattapol; Yamprasert, Rodsarin; Chanvimalueng, Waipoj; Kaewkumpai, Ruchirat; Netanong, Soiphet; Kitipawong, Peerapong; Sritipsukho, Paskorn; Karbwang, Juntra

2017-02-01

This study aimed to test the applicability and effectiveness of the principles and informed consent form (ICF) template proposed by the Strategic Initiative for Developing Capacity in Ethical Review (SIDCER) across multiple clinical trials involving Thai research participants with various conditions. A single-center, randomized-controlled study nested with eight clinical trials was conducted at Thammasat University Hospital, Thailand. A total of 258 participants from any of the eight clinical trials were enrolled and randomly assigned to read either the SIDCER ICF (n = 130) or the conventional ICF (n = 128) of the respective trial. Their understanding of necessary information was assessed using the post-test questionnaire; they were allowed to consult a given ICF while completing the questionnaire. The primary endpoint was the proportion of the participants who had the post-test score of ≥80%, and the secondary endpoint was the total score of the post-test. The proportion of the participants in the SIDCER ICF group who achieved the primary endpoint was significantly higher than that of the conventional ICF group (60.8 vs. 41.4%, p = 0.002). The total score of the post-test was also significantly higher among the participants who read the SIDCER ICF than those who read the conventional ICF (83.3 vs. 76.0%, p < 0.001). The present study demonstrated that the SIDCER ICF was applicable and effective to improve Thai research participants' understanding of research information in diverse clinical trials. Using the SIDCER ICF methodology, clinical researchers can improve the quality of ICFs for their trials.

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.

Improving Decision Making about Genetic Testing in the Clinic: An Overview of Effective Knowledge Translation Interventions.

PubMed

Légaré, France; Robitaille, Hubert; Gane, Claire; Hébert, Jessica; Labrecque, Michel; Rousseau, François

2016-01-01

Knowledge translation (KT) interventions are attempts to change behavior in keeping with scientific evidence. While genetic tests are increasingly available to healthcare consumers in the clinic, evidence about their benefits is unclear and decisions about genetic testing are thus difficult for all parties. We sought to identify KT interventions that involved decisions about genetic testing in the clinical context and to assess their effectiveness for improving decision making in terms of behavior change, increased knowledge and wellbeing. We searched for trials assessing KT interventions in the context of genetic testing up to March 2014 in all systematic reviews (n = 153) published by two Cochrane review groups: Effective Practice and Organisation of Care (EPOC) and Consumers and Communication. We retrieved 2473 unique trials of which we retained only 28 (1%). Two EPOC reviews yielded two trials of KT interventions: audit and feedback (n = 1) and educational outreach (n = 1). Both targeted health professionals and the KT intervention they assessed was found to be effective. Four Consumers and Communication reviews yielded 26 trials: decision aids (n = 15), communication of DNA-based disease risk estimates (n = 7), personalized risk communication (n = 3) and mobile phone messaging (n = 1). Among these, 25 trials targeted only health consumers or patients and the KT interventions were found to be effective in four trials, partly effective in seven, and ineffective in four. Lastly, only one trial targeted both physicians and patients and was found to be effective. More research on the effectiveness of KT interventions regarding genetic testing in the clinical context may contribute to patients making informed value-based decisions and drawing the maximum benefit from clinical applications of genetic and genomic innovations.

Biomarker-Guided Adaptive Trial Designs in Phase II and Phase III: A Methodological Review

PubMed Central

Antoniou, Miranta; Jorgensen, Andrea L; Kolamunnage-Dona, Ruwanthi

2016-01-01

Background Personalized medicine is a growing area of research which aims to tailor the treatment given to a patient according to one or more personal characteristics. These characteristics can be demographic such as age or gender, or biological such as a genetic or other biomarker. Prior to utilizing a patient’s biomarker information in clinical practice, robust testing in terms of analytical validity, clinical validity and clinical utility is necessary. A number of clinical trial designs have been proposed for testing a biomarker’s clinical utility, including Phase II and Phase III clinical trials which aim to test the effectiveness of a biomarker-guided approach to treatment; these designs can be broadly classified into adaptive and non-adaptive. While adaptive designs allow planned modifications based on accumulating information during a trial, non-adaptive designs are typically simpler but less flexible. Methods and Findings We have undertaken a comprehensive review of biomarker-guided adaptive trial designs proposed in the past decade. We have identified eight distinct biomarker-guided adaptive designs and nine variations from 107 studies. Substantial variability has been observed in terms of how trial designs are described and particularly in the terminology used by different authors. We have graphically displayed the current biomarker-guided adaptive trial designs and summarised the characteristics of each design. Conclusions Our in-depth overview provides future researchers with clarity in definition, methodology and terminology for biomarker-guided adaptive trial designs. PMID:26910238

How Imaging Can Impact Clinical Trial Design: Molecular Imaging as a Biomarker for Targeted Cancer Therapy.

PubMed

Mankoff, David A; Farwell, Michael D; Clark, Amy S; Pryma, Daniel A

2015-01-01

The ability to measure biochemical and molecular processes to guide cancer treatment represents a potentially powerful tool for trials of targeted cancer therapy. These assays have traditionally been performed by analysis of tissue samples. However, more recently, functional and molecular imaging has been developed that is capable of in vivo assays of cancer biochemistry and molecular biology and is highly complementary to tissue-based assays. Cancer imaging biomarkers can play a key role in increasing the efficacy and efficiency of therapeutic clinical trials and also provide insight into the biologic mechanisms that bring about a therapeutic response. Future progress will depend on close collaboration between imaging scientists and cancer physicians and on public and commercial sponsors, to take full advantage of what imaging has to offer for clinical trials of targeted cancer therapy. This review will provide examples of how molecular imaging can inform targeted cancer clinical trials and clinical decision making by (1) measuring regional expression of the therapeutic target, (2) assessing early (pharmacodynamic) response to treatment, and (3) predicting therapeutic outcome. The review includes a discussion of basic principles of molecular imaging biomarkers in cancer, with an emphasis on those methods that have been tested in patients. We then review clinical trials designed to evaluate imaging tests as integrated markers embedded in a therapeutic clinical trial with the goal of validating the imaging tests as integral markers that can aid patient selection and direct response-adapted treatment strategies. Examples of recently completed multicenter trials using imaging biomarkers are highlighted.

Characteristics of clinical trials that require participants to be fluent in English

PubMed Central

Egleston, Brian L; Pedraza, Omar; Wong, Yu-Ning; Dunbrack, Roland L; Griffin, Candace L; Ross, Eric A; Beck, J Robert

2015-01-01

Background/Aims Diverse samples in clinical trials can make findings more generalizable. We sought to characterize the prevalence of clinical trials in the United States that required English fluency for participants to enroll in the trial. Methods We randomly chose over 10,000 clinical trial protocols registered with ClinicalTrials.gov and examined the inclusion and exclusion criteria of the trials. We compared the relationship of clinical trial characteristics with English fluency inclusion requirements. We merged the ClinicalTrials.gov data with U.S. Census and American Community Survey data to investigate the association of English language restrictions with ZIP-code level demographic characteristics of participating institutions. We used Chi-squared tests, t-tests, and logistic regression models for analyses. Results English fluency requirements have been increasing over time, from 1.7% of trials having such requirements before 2000 to 9.0% after 2010 (p<0.001 from Chi-squared test). Industry sponsored trials had low rates of English fluency requirements (1.8%) while behavioral trials had high rates (28.4%). Trials opening in the Northeast of the U.S. had the highest regional English requirement rates (10.7%) while trials opening in more than one region had the lowest (3.3%, p<0.001). Since 1995, trials opening in ZIP-codes with larger Hispanic populations were less likely to have English fluency requirements (OR=0.92 for each 10 percent increase in proportion of Hispanics, 95% CI 0.86–0.98, p=0.013). Trials opening in ZIP-codes with more residents self-identifying as Black/African American (OR=1.87, 95% CI 1.36–2.58, p<0.001 for restricted cubic spline term) or Asian (OR=1.16 for linear term, 95% CI 1.07–1.25, p<0.001) were more likely to have English fluency requirements. ZIP-codes with higher poverty rates had trials with more English language restrictions (OR=1.06 for a 10 percent poverty rate increase, 95% CI 1.001–1.11, p=0.045). There was a statistically significant interaction between year and intervention type, such that the increase in English fluency requirements was more common for some interventions than for others. Conclusions The proportion of clinical trials registered with ClinicalTrials.gov that have English fluency requirements for study inclusion has been increasing over time. English language restrictions are associated with a number of characteristics, including the demographic characteristics of communities in which the sponsoring institutions are located. PMID:26152834

Characteristics of clinical trials that require participants to be fluent in English.

PubMed

Egleston, Brian L; Pedraza, Omar; Wong, Yu-Ning; Dunbrack, Roland L; Griffin, Candace L; Ross, Eric A; Beck, J Robert

2015-12-01

Diverse samples in clinical trials can make findings more generalizable. We sought to characterize the prevalence of clinical trials in the United States that required English fluency for participants to enroll in the trial. We randomly chose over 10,000 clinical trial protocols registered with ClinicalTrials.gov and examined the inclusion and exclusion criteria of the trials. We compared the relationship of clinical trial characteristics with English fluency inclusion requirements. We merged the ClinicalTrials.gov data with US Census and American Community Survey data to investigate the association of English-language restrictions with ZIP-code-level demographic characteristics of participating institutions. We used Chi-squared tests, t-tests, and logistic regression models for analyses. English fluency requirements have been increasing over time, from 1.7% of trials having such requirements before 2000 to 9.0% after 2010 (p < 0.001 from Chi-squared test). Industry-sponsored trials had low rates of English fluency requirements (1.8%), while behavioral trials had high rates (28.4%). Trials opening in the Northeast of the United States had the highest regional English requirement rates (10.7%), while trials opening in more than one region had the lowest (3.3%, p<0.001). Since 1995, trials opening in ZIP codes with larger Hispanic populations were less likely to have English fluency requirements (odds ratio=0.92 for each 10% increase in proportion of Hispanics, 95% confidence interval=0.86-0.98, p=0.013). Trials opening in ZIP codes with more residents self-identifying as Black/African American (odds ratio=1.87, 95% confidence interval=1.36-2.58, p<0.001 for restricted cubic spline term) or Asian (odds ratio=1.16 for linear term, 95% confidence interval=1.07-1.25, p<0.001) were more likely to have English fluency requirements. ZIP codes with higher poverty rates had trials with more English-language restrictions (odds ratio=1.06 for a 10% poverty rate increase, 95% confidence interval=1.001-1.11, p=0.045). There was a statistically significant interaction between year and intervention type, such that the increase in English fluency requirements was more common for some interventions than for others. The proportion of clinical trials registered with ClinicalTrials.gov that have English fluency requirements for study inclusion has been increasing over time. English-language restrictions are associated with a number of characteristics, including the demographic characteristics of communities in which the sponsoring institutions are located. © The Author(s) 2015.

Design and implementation of a controlled clinical trial to evaluate the effectiveness and efficiency of routine opt-out rapid human immunodeficiency virus screening in the emergency department.

PubMed

Haukoos, Jason S; Hopkins, Emily; Byyny, Richard L; Conroy, Amy A; Silverman, Morgan; Eisert, Sheri; Thrun, Mark; Wilson, Michael; Boyett, Brian; Heffelfinger, James D

2009-08-01

In 2006, the Centers for Disease Control and Prevention (CDC) released revised recommendations for performing human immunodeficiency virus (HIV) testing in health care settings, including implementing routine rapid HIV screening, the use of an integrated opt-out consent, and limited prevention counseling. Emergency departments (EDs) have been a primary focus of these efforts. These revised CDC recommendations were primarily based on feasibility studies and have not been evaluated through the application of rigorous research methods. This article describes the design and implementation of a large prospective controlled clinical trial to evaluate the CDC's recommendations in an ED setting. From April 15, 2007, through April 15, 2009, a prospective quasi-experimental equivalent time-samples clinical trial was performed to compare the clinical effectiveness and efficiency of routine (nontargeted) opt-out rapid HIV screening (intervention) to physician-directed diagnostic rapid HIV testing (control) in a high-volume urban ED. In addition, three nested observational studies were performed to evaluate the cost-effectiveness and patient and staff acceptance of the two rapid HIV testing methods. This article describes the rationale, methodologies, and study design features of this program evaluation clinical trial. It also provides details regarding the integration of the principal clinical trial and its nested observational studies. Such ED-based trials are rare, but serve to provide valid comparisons between testing approaches. Investigators should consider similar methodology when performing future ED-based health services research.

New clinical trial tests prime-and-boost vaccine delivery for advanced solid tumors | Center for Cancer Research

Cancer.gov

Researchers are testing a prime-and-boost approach to safely direct the immune system to kill tumor cells that express brachyury, a protein expressed in high levels in some cancers. A new clinical trial is testing an experimental vaccine in patients whose cancers have not responded to standard treatments.

Clinical trials attitudes and practices of Latino physicians.

PubMed

Ramirez, Amelie G; Wildes, Kimberly; Talavera, Greg; Nápoles-Springer, Anna; Gallion, Kipling; Pérez-Stable, Eliseo J

2008-07-01

Ethnic differences in physicians' attitudes and behaviors related to clinical trials might partially account for disparities in clinical trial participation among Latino patients. Literature regarding Latino physicians' clinical trials attitudes and practices, in comparison to White physicians, was lacking. Cross-sectional data from randomly selected physicians (N=695), stratified by ethnicity, were analyzed to test associations of ethnicity with physicians' participation in and attitudes toward referral of patients to clinical trials. Chi-square analyses showed significant (p<0.05) associations of physician race/ethnicity and clinical trials involvement, type of trial for which the physician is likely to recommend a patient, belief in scientific value, and factors that would influence recommendation for a patient to participate. Multivariate analyses resulted in several significant (p<0.05) predictors of clinical trials outcomes, including physician race/ethnicity. Latino physicians were significantly less involved in clinical trials than White physicians and found less scientific value in them, highlighting areas for future education and intervention.

Correcting for multiple-testing in multi-arm trials: is it necessary and is it done?

PubMed

Wason, James M S; Stecher, Lynne; Mander, Adrian P

2014-09-17

Multi-arm trials enable the evaluation of multiple treatments within a single trial. They provide a way of substantially increasing the efficiency of the clinical development process. However, since multi-arm trials test multiple hypotheses, some regulators require that a statistical correction be made to control the chance of making a type-1 error (false-positive). Several conflicting viewpoints are expressed in the literature regarding the circumstances in which a multiple-testing correction should be used. In this article we discuss these conflicting viewpoints and review the frequency with which correction methods are currently used in practice. We identified all multi-arm clinical trials published in 2012 by four major medical journals. Summary data on several aspects of the trial design were extracted, including whether the trial was exploratory or confirmatory, whether a multiple-testing correction was applied and, if one was used, what type it was. We found that almost half (49%) of published multi-arm trials report using a multiple-testing correction. The percentage that corrected was higher for trials in which the experimental arms included multiple doses or regimens of the same treatments (67%). The percentage that corrected was higher in exploratory than confirmatory trials, although this is explained by a greater proportion of exploratory trials testing multiple doses and regimens of the same treatment. A sizeable proportion of published multi-arm trials do not correct for multiple-testing. Clearer guidance about whether multiple-testing correction is needed for multi-arm trials that test separate treatments against a common control group is required.

Current clinical trials testing combinations of immunotherapy and radiation.

PubMed

Crittenden, Marka; Kohrt, Holbrook; Levy, Ronald; Jones, Jennifer; Camphausen, Kevin; Dicker, Adam; Demaria, Sandra; Formenti, Silvia

2015-01-01

Preclinical evidence of successful combinations of ionizing radiation with immunotherapy has inspired testing the translation of these results to the clinic. Interestingly, the preclinical work has consistently predicted the responses encountered in clinical trials. The first example came from a proof-of-principle trial started in 2001 that tested the concept that growth factors acting on antigen-presenting cells improve presentation of tumor antigens released by radiation and induce an abscopal effect. Granulocyte-macrophage colony-stimulating factor was administered during radiotherapy to a metastatic site in patients with metastatic solid tumors to translate evidence obtained in a murine model of syngeneic mammary carcinoma treated with cytokine FLT-3L and radiation. Subsequent clinical availability of vaccines and immune checkpoint inhibitors has triggered a wave of enthusiasm for testing them in combination with radiotherapy. Examples of ongoing clinical trials are described in this report. Importantly, most of these trials include careful immune monitoring of the patients enrolled and will generate important data about the proimmunogenic effects of radiation in combination with a variety of immune modulators, in different disease settings. Results of these studies are building a platform of evidence for radiotherapy as an adjuvant to immunotherapy and encourage the growth of this novel field of radiation oncology. Copyright © 2015 Elsevier Inc. All rights reserved.

Design and analysis of three-arm trials with negative binomially distributed endpoints.

PubMed

Mütze, Tobias; Munk, Axel; Friede, Tim

2016-02-20

A three-arm clinical trial design with an experimental treatment, an active control, and a placebo control, commonly referred to as the gold standard design, enables testing of non-inferiority or superiority of the experimental treatment compared with the active control. In this paper, we propose methods for designing and analyzing three-arm trials with negative binomially distributed endpoints. In particular, we develop a Wald-type test with a restricted maximum-likelihood variance estimator for testing non-inferiority or superiority. For this test, sample size and power formulas as well as optimal sample size allocations will be derived. The performance of the proposed test will be assessed in an extensive simulation study with regard to type I error rate, power, sample size, and sample size allocation. For the purpose of comparison, Wald-type statistics with a sample variance estimator and an unrestricted maximum-likelihood estimator are included in the simulation study. We found that the proposed Wald-type test with a restricted variance estimator performed well across the considered scenarios and is therefore recommended for application in clinical trials. The methods proposed are motivated and illustrated by a recent clinical trial in multiple sclerosis. The R package ThreeArmedTrials, which implements the methods discussed in this paper, is available on CRAN. Copyright © 2015 John Wiley & Sons, Ltd.

Exact tests using two correlated binomial variables in contemporary cancer clinical trials.

PubMed

Yu, Jihnhee; Kepner, James L; Iyer, Renuka

2009-12-01

New therapy strategies for the treatment of cancer are rapidly emerging because of recent technology advances in genetics and molecular biology. Although newer targeted therapies can improve survival without measurable changes in tumor size, clinical trial conduct has remained nearly unchanged. When potentially efficacious therapies are tested, current clinical trial design and analysis methods may not be suitable for detecting therapeutic effects. We propose an exact method with respect to testing cytostatic cancer treatment using correlated bivariate binomial random variables to simultaneously assess two primary outcomes. The method is easy to implement. It does not increase the sample size over that of the univariate exact test and in most cases reduces the sample size required. Sample size calculations are provided for selected designs.

Effects of an Art-Based Curriculum on Clinical Trials Attitudes and Breast Cancer Prevention Knowledge

ERIC Educational Resources Information Center

Herman, Patricia M.; Larkey, Linda K.

2006-01-01

Although Latinos now comprise the largest minority in the U.S. population, they continue to be seriously underrepresented in clinical trials. A nonrandomized controlled study of an innovative community-developed clinical trial and breast cancer education program targeting Latinas tested whether use of an art-based curriculum could increase…

Clinical trials of a personal electrocardiograph

NASA Astrophysics Data System (ADS)

Boyakhchyan, A.; Lezhnina, I.; Overchuk, K.; Perchatkin, V.; Lvova, A.; Alexander, U.

2018-05-01

The article describes the results of a clinical trial at the Cardiology Research Institute in Tomsk. Clinical trials were conducted to identify different important information for diagnosis. These tests were also conducted to remotely monitor the treatment of patients who had already been discharged from the hospital.The study involved 15 patients, the most interesting cases are described in this article.

A Randomized Clinical Trial of Alternative Stress Management Interventions in Persons with HIV Infection

ERIC Educational Resources Information Center

McCain, Nancy L.; Gray, D. Patricia; Elswick, R. K., Jr.; Robins, Jolynne W.; Tuck, Inez; Walter, Jeanne M.; Rausch, Sarah M.; Ketchum, Jessica McKinney

2008-01-01

Research in psychoneuroimmunology suggests that immunosuppression associated with perceived stress may contribute to disease progression in persons with HIV infection. While stress management interventions may enhance immune function, few alternative approaches have yet been tested. This randomized clinical trial was conducted to test effects of…

Remune trial will stop; new trials planned.

PubMed

James, J S

1999-05-21

A clinical trial using remune, the anti-HIV vaccine developed by the late Dr. Jonas Salk, has been ended. The study is a clinical-endpoint trial which looks for statistically significant differences in AIDS sickness or death between patients who add remune to their treatment regimens versus those who use a placebo. Agouron Pharmaceuticals and the Immune Response Corporation who were conducting the trial announced their decision to stop it after an analysis by the Data Safety Monitoring Board. No differences in clinical endpoints were found and it was projected that continuing the trial would likely not find any. The companies are now planning two new Phase III trials using viral load testing rather than clinical endpoints as study criteria.

Can the FDA improve oversight of foreign clinical trials?: Closing the information gap and moving towards a globalized regulatory scheme.

PubMed

Ourso, André

2012-01-01

Currently, pharmaceutical companies' utilization of foreign clinical trial data is a ubiquitous and indispensable aspect of gaining approval to market drugs in the United States. Cost benefits, a larger pool of ready volunteer subjects, and greater efficiency in clinical testing are some of the reasons for conducting clinical trials overseas. Despite these advantages, lack of proper oversight may have serious public health implications regarding the integrity of clinical research, ethical treatment of human subjects, and drug safety. Due to the expansive global nature of foreign clinical trials, there are concerns with the FDA's ability to monitor and regulate these trials. This article examines the FDA's oversight of foreign clinical trials and the agency's limitations regulating these trials. In addition to looking at steps the FDA is taking to address these limitations, the article examines other potential regulatory and cooperative actions that can be taken to effectively monitor foreign clinical trials and to ensure data integrity and patient safety.

Driving CAR T-cells forward.

PubMed

Jackson, Hollie J; Rafiq, Sarwish; Brentjens, Renier J

2016-06-01

The engineered expression of chimeric antigen receptors (CARs) on the surface of T cells enables the redirection of T-cell specificity. Early clinical trials using CAR T cells for the treatment of patients with cancer showed modest results, but the impressive outcomes of several trials of CD19-targeted CAR T cells in the treatment of patients with B-cell malignancies have generated an increased enthusiasm for this approach. Important lessons have been derived from clinical trials of CD19-specific CAR T cells, and ongoing clinical trials are testing CAR designs directed at novel targets involved in haematological and solid malignancies. In this Review, we discuss these trials and present strategies that can increase the antitumour efficacy and safety of CAR T-cell therapy. Given the fast-moving nature of this field, we only discuss studies with direct translational application currently or soon-to-be tested in the clinical setting.

Driving CAR T-cells forward

PubMed Central

Jackson, Hollie J.; Rafiq, Sarwish; Brentjens, Renier J.

2017-01-01

The engineered expression of chimeric antigen receptors (CARs) on the surface of T cells enables the redirection of T-cell specificity. Early clinical trials using CAR T cells for the treatment of patients with cancer showed modest results, but the impressive outcomes of several trials of CD19-targeted CAR T cells in the treatment of patients with B-cell malignancies have generated an increased enthusiasm for this approach. Important lessons have been derived from clinical trials of CD19-specific CAR T cells, and ongoing clinical trials are testing CAR designs directed at novel targets involved in haematological and solid malignancies. In this Review, we discuss these trials and present strategies that can increase the antitumour efficacy and safety of CAR T-cell therapy. Given the fast-moving nature of this field, we only discuss studies with direct translational application currently or soon-to-be tested in the clinical setting. PMID:27000958

Weighted re-randomization tests for minimization with unbalanced allocation.

PubMed

Han, Baoguang; Yu, Menggang; McEntegart, Damian

2013-01-01

Re-randomization test has been considered as a robust alternative to the traditional population model-based methods for analyzing randomized clinical trials. This is especially so when the clinical trials are randomized according to minimization, which is a popular covariate-adaptive randomization method for ensuring balance among prognostic factors. Among various re-randomization tests, fixed-entry-order re-randomization is advocated as an effective strategy when a temporal trend is suspected. Yet when the minimization is applied to trials with unequal allocation, fixed-entry-order re-randomization test is biased and thus compromised in power. We find that the bias is due to non-uniform re-allocation probabilities incurred by the re-randomization in this case. We therefore propose a weighted fixed-entry-order re-randomization test to overcome the bias. The performance of the new test was investigated in simulation studies that mimic the settings of a real clinical trial. The weighted re-randomization test was found to work well in the scenarios investigated including the presence of a strong temporal trend. Copyright © 2013 John Wiley & Sons, Ltd.

Optical ensemble analysis of intraocular lens performance through a simulated clinical trial with ZEMAX.

PubMed

Zhao, Huawei

2009-01-01

A ZEMAX model was constructed to simulate a clinical trial of intraocular lenses (IOLs) based on a clinically oriented Monte Carlo ensemble analysis using postoperative ocular parameters. The purpose of this model is to test the feasibility of streamlining and optimizing both the design process and the clinical testing of IOLs. This optical ensemble analysis (OEA) is also validated. Simulated pseudophakic eyes were generated by using the tolerancing and programming features of ZEMAX optical design software. OEA methodology was verified by demonstrating that the results of clinical performance simulations were consistent with previously published clinical performance data using the same types of IOLs. From these results we conclude that the OEA method can objectively simulate the potential clinical trial performance of IOLs.

Evaluation of eligibility and recruitment in breast cancer clinical trials.

PubMed

Lemieux, Julie; Forget, Geneviève; Brochu, Olyvia; Provencher, Louise; Cantin, Guy; Desbiens, Christine; Doyle, Catherine; Poirier, Brigitte; Camden, Stéphanie; Durocher, Martin

2014-08-01

Objectives of the study were to measure recruitment rates in clinical trials and to identify patients, physicians or trials characteristics associated with higher recruitment rates. Among patients who had a clinical trial available for their cancer, 83.5% (345/413) met the eligibility criteria to at least one clinical trial. At least one trial was proposed to 33.1% (113/341) of the eligible patients and 19.7% (68/345) were recruited. Overall recruitment was 16.5% (68/413). In multivariate analyses, trial proposal and enrollment were lower for elderly patients and higher in high cancer stages. Trials from pharmaceutical industry had higher recruitment rates and trials testing hormonal therapy enrolled more patients. Breast cancer patients' accrual to a clinical trial could be improved by trying to systematically identify all eligible patients and propose a trial to those eligible and to whom the treatment is planned to be equivalent to the standard arm of the trial. Copyright © 2014 Elsevier Ltd. All rights reserved.

Designs and adaptive analysis plans for pivotal clinical trials of therapeutics and companion diagnostics.

PubMed

Simon, Richard

2008-06-01

Developments in genomics and biotechnology provide unprecedented opportunities for the development of effective therapeutics and companion diagnostics for matching the right drug to the right patient. Effective co-development involves many new challenges with increased opportunity for success as well as delay and failure. Clinical trial designs and adaptive analysis plans for the prospective design of pivotal trials of new therapeutics and companion diagnostics are reviewed. Effective co-development requires careful prospective planning of the design and analysis strategy for pivotal clinical trials. Randomized clinical trials continue to be important for evaluating the effectiveness of new treatments, but the target populations for analysis should be prospectively specified based on the companion diagnostic. Post hoc analyses of traditionally designed randomized clinical trials are often deeply problematic. Clear separation is generally required of the data used for developing the diagnostic test, including their threshold of positivity, from the data used for evaluating treatment effectiveness in subsets determined by the test. Adaptive analysis can be used to provide flexibility to the analysis but the use of such methods requires careful planning and prospective definition in order to assure that the pivotal trial adequately limits the chance of erroneous conclusions.

Comparison of Survival Outcomes Among Cancer Patients Treated In and Out of Clinical Trials

PubMed Central

2014-01-01

Background Clinical trials test the efficacy of a treatment in a select patient population. We examined whether cancer clinical trial patients were similar to nontrial, “real-world” patients with respect to presenting characteristics and survival. Methods We reviewed the SWOG national clinical trials consortium database to identify candidate trials. Demographic factors, stage, and overall survival for patients in the standard arms were compared with nontrial control subjects selected from the Surveillance, Epidemiology, and End Results program. Multivariable survival analyses using Cox regression were conducted. The survival functions from aggregate data across all studies were compared separately by prognosis (≥50% vs <50% average 2-year survival). All statistical tests were two-sided. Results We analyzed 21 SWOG studies (11 good prognosis and 10 poor prognosis) comprising 5190 patients enrolled from 1987 to 2007. Trial patients were younger than nontrial patients (P < .001). In multivariable analysis, trial participation was not associated with improved overall survival for all 11 good-prognosis studies but was associated with better survival for nine of 10 poor-prognosis studies (P < .001). The impact of trial participation on overall survival endured for only 1 year. Conclusions Trial participation was associated with better survival in the first year after diagnosis, likely because of eligibility criteria that excluded higher comorbidity patients from trials. Similar survival patterns between trial and nontrial patients after the first year suggest that trial standard arm outcomes are generalizable over the long term and may improve confidence that trial treatment effects will translate to the real-world setting. Reducing eligibility criteria would improve access to clinical trials. PMID:24627276

Lab and Imaging Tests

MedlinePlus

... Grant Grant Finder Therapy Acceleration Program Academic Concierge Biotechnology Accelerator Clinical Trials Division Resources for HCPs Continuing ... Grant Grant Finder Therapy Acceleration Program Academic Concierge Biotechnology Accelerator Clinical Trials Division Resources for HCPs Continuing ...

In search of memory tests equivalent for experiments on animals and humans.

PubMed

Brodziak, Andrzej; Kołat, Estera; Różyk-Myrta, Alicja

2014-12-19

Older people often exhibit memory impairments. Contemporary demographic trends cause aging of the society. In this situation, it is important to conduct clinical trials of drugs and use training methods to improve memory capacity. Development of new memory tests requires experiments on animals and then clinical trials in humans. Therefore, we decided to review the assessment methods and search for tests that evaluate analogous cognitive processes in animals and humans. This review has enabled us to propose 2 pairs of tests of the efficiency of working memory capacity in animals and humans. We propose a basic set of methods for complex clinical trials of drugs and training methods to improve memory, consisting of 2 pairs of tests: 1) the Novel Object Recognition Test - Sternberg Item Recognition Test and 2) the Object-Location Test - Visuospatial Memory Test. We postulate that further investigations of methods that are equivalent in animals experiments and observations performed on humans are necessary.

Power analysis to detect treatment effects in longitudinal clinical trials for Alzheimer's disease.

PubMed

Huang, Zhiyue; Muniz-Terrera, Graciela; Tom, Brian D M

2017-09-01

Assessing cognitive and functional changes at the early stage of Alzheimer's disease (AD) and detecting treatment effects in clinical trials for early AD are challenging. Under the assumption that transformed versions of the Mini-Mental State Examination, the Clinical Dementia Rating Scale-Sum of Boxes, and the Alzheimer's Disease Assessment Scale-Cognitive Subscale tests'/components' scores are from a multivariate linear mixed-effects model, we calculated the sample sizes required to detect treatment effects on the annual rates of change in these three components in clinical trials for participants with mild cognitive impairment. Our results suggest that a large number of participants would be required to detect a clinically meaningful treatment effect in a population with preclinical or prodromal Alzheimer's disease. We found that the transformed Mini-Mental State Examination is more sensitive for detecting treatment effects in early AD than the transformed Clinical Dementia Rating Scale-Sum of Boxes and Alzheimer's Disease Assessment Scale-Cognitive Subscale. The use of optimal weights to construct powerful test statistics or sensitive composite scores/endpoints can reduce the required sample sizes needed for clinical trials. Consideration of the multivariate/joint distribution of components' scores rather than the distribution of a single composite score when designing clinical trials can lead to an increase in power and reduced sample sizes for detecting treatment effects in clinical trials for early AD.

Recruitment of subjects into clinical trials for Alzheimer disease.

PubMed

Knebl, Janice A; Patki, Deepti

2010-09-01

Alzheimer disease is a devastating neurodegenerative disorder affecting millions of Americans. It reduces the ability of the individual to remain independent, places a burden on caregivers, and substantially increases healthcare costs. New treatments are being tested in numerous clinical trials with the goal of preventing or delaying the onset of Alzheimer disease, slowing or modifying the disease's course, or finding a cure for patients with the disease. Alzheimer disease research can successfully proceed only if individuals who have this illness are willing to participate in clinical trials. However, recruitment and retention of subjects in clinical trials for Alzheimer disease is a challenging task. Furthermore, because of reductions in decision-making capacities of individuals with Alzheimer disease, clinical trials also need to involve caregivers. The present article delineates unique hurdles encountered in the recruitment process for Alzheimer disease clinical trials. The article also identifies strategies for effective recruitment of subjects in Alzheimer disease clinical trials, including guidelines to help principal investigators and clinical research coordinators reach recruitment goals.

Repeat testing of low-level HIV-1 RNA: assay performance and implementation in clinical trials.

PubMed

White, Kirsten; Garner, Will; Wei, Lilian; Eron, Joseph J; Zhong, Lijie; Miller, Michael D; Martin, Hal; Plummer, Andrew; Tran-Muchowski, Cecilia; Lindstrom, Kim; Porter, James; Piontkowsky, David; Light, Angela; Reiske, Heinz; Quirk, Erin

2018-05-15

Assess the performance of HIV-1 RNA repeat testing of stored samples in cases of low-level viremia during clinical trials. Prospective and retrospective analysis of randomized clinical trial samples and reference standards. To evaluate assay variability of the Cobas AmpliPrep/Cobas TaqMan HIV-1 Test, v2.0, three separate sources of samples were utilized: the World Health Organization (WHO) HIV reference standard (assayed using 50 independent measurements at six viral loads <200 copies/ml), retrospective analysis of four to six aliquots of plasma samples from four clinical trial participants, and prospective repeat testing of 120 samples from participants in randomized trials with low-level viremia. The TaqMan assay on the WHO HIV-1 RNA standards at viral loads <200 copies/ml performed within the expected variability according to assay specifications. However, standards with low viral loads of 36 and 18 copies/ml reported values of ≥ 50 copies/ml in 66 and 18% of tests, respectively. In participants treated with antiretrovirals who had unexpected viremia of 50-200 copies/ml after achieving <50 copies/ml, retesting of multiple aliquots of stored plasma found <50 copies/ml in nearly all cases upon retesting (14/15; 93%). Repeat testing was prospectively implemented in four clinical trials for all samples with virologic rebound of 50-200 copies/ml (n = 120 samples from 92 participants) from which 42% (50/120) had a retest result of less than 50 copies/ml and 58% (70/120) retested ≥ 50 copies/ml. The TaqMan HIV-1 RNA assay shows variability around 50 copies/ml that affects clinical trial results and may impact clinical practice. In participants with a history of viral load suppression, unexpected low-level viremia may be because of assay variability rather than low drug adherence or true virologic failure. Retesting a stored aliquot of the same sample may differentiate between assay variability and virologic failure as the source of viremia. This retesting strategy could save time, money, and anxiety for patients and their providers, as well as decrease follow-up clinic visits without increasing the risk of virologic failure and resistance development.

Methodological issues with adaptation of clinical trial design.

PubMed

Hung, H M James; Wang, Sue-Jane; O'Neill, Robert T

2006-01-01

Adaptation of clinical trial design generates many issues that have not been resolved for practical applications, though statistical methodology has advanced greatly. This paper focuses on some methodological issues. In one type of adaptation such as sample size re-estimation, only the postulated value of a parameter for planning the trial size may be altered. In another type, the originally intended hypothesis for testing may be modified using the internal data accumulated at an interim time of the trial, such as changing the primary endpoint and dropping a treatment arm. For sample size re-estimation, we make a contrast between an adaptive test weighting the two-stage test statistics with the statistical information given by the original design and the original sample mean test with a properly corrected critical value. We point out the difficulty in planning a confirmatory trial based on the crude information generated by exploratory trials. In regards to selecting a primary endpoint, we argue that the selection process that allows switching from one endpoint to the other with the internal data of the trial is not very likely to gain a power advantage over the simple process of selecting one from the two endpoints by testing them with an equal split of alpha (Bonferroni adjustment). For dropping a treatment arm, distributing the remaining sample size of the discontinued arm to other treatment arms can substantially improve the statistical power of identifying a superior treatment arm in the design. A common difficult methodological issue is that of how to select an adaptation rule in the trial planning stage. Pre-specification of the adaptation rule is important for the practicality consideration. Changing the originally intended hypothesis for testing with the internal data generates great concerns to clinical trial researchers.

Strategies and Challenges in Clinical Trials Targeting Human Aging

PubMed Central

Newman, John C.; Milman, Sofiya; Hashmi, Shahrukh K.; Austad, Steve N.; Kirkland, James L.; Halter, Jeffrey B.

2016-01-01

Interventions that target fundamental aging processes have the potential to transform human health and health care. A variety of candidate drugs have emerged from basic and translational research that may target aging processes. Some of these drugs are already in clinical use for other purposes, such as metformin and rapamycin. However, designing clinical trials to test interventions that target the aging process poses a unique set of challenges. This paper summarizes the outcomes of an international meeting co-ordinated by the NIH-funded Geroscience Network to further the goal of developing a translational pipeline to move candidate compounds through clinical trials and ultimately into use. We review the evidence that some drugs already in clinical use may target fundamental aging processes. We discuss the design principles of clinical trials to test such interventions in humans, including study populations, interventions, and outcomes. As examples, we offer several scenarios for potential clinical trials centered on the concepts of health span (delayed multimorbidity and functional decline) and resilience (response to or recovery from an acute health stress). Finally, we describe how this discussion helped inform the design of the proposed Targeting Aging with Metformin study. PMID:27535968

Visual scoring of non-cavitated caries lesions and clinical trial efficiency, testing xylitol in caries active adults

PubMed Central

Brown, JP; Amaechi, BT; Bader, JD; Gilbert, GH; Makhija, SK; Lozano-Pineda, J; Leo, MC; Chuhe, C; Vollmer, WM

2013-01-01

Objectives To better understand the effectiveness of xylitol in caries prevention in adults, and to attempt improved clinical trial efficiency. Methods As part of the Xylitol for Adult Caries Trial (X-ACT), non-cavitated and cavitated caries lesions were assessed in subjects who were experiencing the disease. The trial was a test of the effectiveness of 5 grams/day of xylitol, consumed by dissolving in the mouth five 1 gram lozenges spaced across each day, compared with a sucralose placebo. For this analysis, seeking trial efficiency, 538 subjects aged 21–80, with complete data for four dental examinations were selected from the 691 randomized into the three year trial, conducted at three sites. Acceptable inter and intra examiner reliability before and during the trial was quantified using the kappa statistic. Results The mean annualized non-cavitated plus cavitated lesion transition scores in coronal and root surfaces, from sound to carious favoured xylitol over placebo, during the three cumulative periods of 12, 24, and 33 months, but these clinically and statistically non-significant differences declined in magnitude over time. Restricting the present assessment to those subjects with a higher baseline lifetime caries experience showed possible but inconsistent benefit. Conclusions There was no clear and clinically relevant preventive effect of xylitol on caries in adults with adequate fluoride exposure when non-cavitated plus cavitated lesions were assessed. This conformed to the X-ACT trial result assessing cavitated lesions. Including non-cavitated lesion assessment in this full scale, placebo controlled, multi site, randomized, double blinded clinical trial in adults experiencing dental caries, did not achieve added trial efficiency or demonstrate practical benefit of xylitol. Trial Registration ClinicalTrials.Gov NCT00393055 PMID:24205951

INVESTIGATE-I (INVasive Evaluation before Surgical Treatment of Incontinence Gives Added Therapeutic Effect?): study protocol for a mixed methods study to assess the feasibility of a future randomised controlled trial of the clinical utility of invasive urodynamic testing

PubMed Central

2011-01-01

Background Urinary incontinence is an important health problem to the individual sufferer and to health services. Stress and stress predominant mixed urinary incontinence are increasingly managed by surgery due to advances in surgical techniques. Despite the lack of evidence for its clinical utility, most clinicians undertake invasive urodynamic testing (IUT) to confirm a functional diagnosis of urodynamic stress incontinence before offering surgery for this condition. IUT is expensive, embarrassing and uncomfortable for women and carries a small risk. Recent systematic reviews have confirmed the lack of high quality evidence of effectiveness. The aim of this pilot study is to test the feasibility of a future definitive randomised control trial that would address whether IUT alters treatment decisions and treatment outcome in these women and would test its clinical and cost effectiveness. Methods/design This is a mixed methods pragmatic multicentre feasibility pilot study with four components:- (a) A multicentre, external pilot randomised trial comparing basic clinical assessment with non-invasive tests and IUT. The outcome measures are rates of recruitment, randomisation and data completion. Data will be used to estimate sample size necessary for the definitive trial. (b) Qualitative interviews of a purposively sampled sub-set of women eligible for the pilot trial will explore willingness to participate, be randomised and their overall trial experience. (c) A national survey of clinicians to determine their views of IUT in this context, the main outcome being their willingness to randomise patients into the definitive trial. (d) Qualitative interviews of a purposively sampled group of these clinicians will explore whether and how they use IUT to inform their decisions. Discussion The pilot trial will provide evidence of feasibility and acceptability and therefore inform the decision whether to proceed to the definitive trial. Results will inform the design and conduct of the definitive trial and ensure its effectiveness in achieving its research aim. Trial registration number Current Controlled Trials ISRCTN71327395 assigned 7th June 2010. PMID:21733166

How many research nurses for how many clinical trials in an oncology setting? Definition of the Nursing Time Required by Clinical Trial-Assessment Tool (NTRCT-AT).

PubMed

Milani, Alessandra; Mazzocco, Ketti; Stucchi, Sara; Magon, Giorgio; Pravettoni, Gabriella; Passoni, Claudia; Ciccarelli, Chiara; Tonali, Alessandra; Profeta, Teresa; Saiani, Luisa

2017-02-01

Few resources are available to quantify clinical trial-associated workload, needed to guide staffing and budgetary planning. The aim of the study is to describe a tool to measure clinical trials nurses' workload expressed in time spent to complete core activities. Clinical trials nurses drew up a list of nursing core activities, integrating results from literature searches with personal experience. The final 30 core activities were timed for each research nurse by an outside observer during daily practice in May and June 2014. Average times spent by nurses for each activity were calculated. The "Nursing Time Required by Clinical Trial-Assessment Tool" was created as an electronic sheet that combines the average times per specified activities and mathematic functions to return the total estimated time required by a research nurse for each specific trial. The tool was tested retrospectively on 141 clinical trials. The increasing complexity of clinical research requires structured approaches to determine workforce requirements. This study provides a tool to describe the activities of a clinical trials nurse and to estimate the associated time required to deliver individual trials. The application of the proposed tool in clinical research practice could provide a consistent structure for clinical trials nursing workload estimation internationally. © 2016 John Wiley & Sons Australia, Ltd.

A Randomized Prospective Trial Comparing Paravertebral Block and General Anesthesia for Operative Treatment of Breast Cancer

DTIC Science & Technology

2001-10-01

block the anesthetic of choice for operative treatment of breast cancer. To test this hypothesis we proposed a prospective randomized clinical trial ...coordinators. Months 4-6. Status: Complete The study’s existing part-time Clinical Trial Coordinator, Mr. John Arbo, was enlisted full-time in June...of full-time Clinical Trial Coordinator for Mount Sinai. ■ Poster presentation by Mount Sinai staff of study goals and methods at a Department of

Does Cognitive Behavioral Therapy for Youth Anxiety Outperform Usual Care in Community Clinics? An Initial Effectiveness Test

ERIC Educational Resources Information Center

Southam-Gerow, Michael A.; Weisz, John R.; Chu, Brian C.; McLeod, Bryce D.; Gordis, Elana B.; Connor-Smith, Jennifer K.

2010-01-01

Objective: Most tests of cognitive behavioral therapy (CBT) for youth anxiety disorders have shown beneficial effects, but these have been efficacy trials with recruited youths treated by researcher-employed therapists. One previous (nonrandomized) trial in community clinics found that CBT did not outperform usual care (UC). The present study used…

Could home sexually transmitted infection specimen collection with e-prescription be a cost-effective strategy for clinical trials and clinical care?

PubMed

Blake, Diane R; Spielberg, Freya; Levy, Vivian; Lensing, Shelly; Wolff, Peter A; Venkatasubramanian, Lalitha; Acevedo, Nincoshka; Padian, Nancy; Chattopadhyay, Ishita; Gaydos, Charlotte A

2015-01-01

Results of a recent demonstration project evaluating feasibility, acceptability, and cost of a Web-based sexually transmitted infection (STI) testing and e-prescription treatment program (eSTI) suggest that this approach could be a feasible alternative to clinic-based testing and treatment, but the results need to be confirmed by a randomized comparative effectiveness trial. We modeled a decision tree comparing (1) cost of eSTI screening using a home collection kit and an e-prescription for uncomplicated treatment versus (2) hypothetical costs derived from the literature for referral to standard clinic-based STI screening and treatment. Primary outcome was number of STIs detected. Analyses were conducted from the clinical trial perspective and the health care system perspective. The eSTI strategy detected 75 infections, and the clinic referral strategy detected 45 infections. Total cost of eSTI was $94,938 ($1266/STI detected) from the clinical trial perspective and $96,088 ($1281/STI detected) from the health care system perspective. Total cost of clinic referral was $87,367 ($1941/STI detected) from the clinical trial perspective and $71,668 ($1593/STI detected) from the health care system perspective. Results indicate that eSTI will likely be more cost-effective (lower cost/STI detected) than clinic-based STI screening, both in the context of clinical trials and in routine clinical care. Although our results are promising, they are based on a demonstration project and estimates from other small studies. A comparative effectiveness research trial is needed to determine actual cost and impact of the eSTI system on identification and treatment of new infections and prevention of their sequelae.

Safety of phase I clinical trials with monoclonal antibodies in Germany--the regulatory requirements viewed in the aftermath of the TGN1412 disaster.

PubMed

Liedert, B; Bassus, S; Schneider, C K; Kalinke, U; Löwer, J

2007-01-01

This review summarizes scientific, ethical and regulatory aspects of Phase I clinical trials with monoclonal antibodies. The current standard requirements for pre-clinical testing and for clinical study design are presented. The scientific considerations discussed herein are generally applicable, the view on legal requirements for clinical trials refer to the German jurisdiction only. The adverse effects associated with the TGN1412 Phase I trial indicate that the predictive value of pre-clinical animal models requires reevaluation and that, in certain cases, some issues of clinical trial protocols such as dose fixing may need refinement or redesign. Concrete safety measures, which have been proposed as a consequence of the TGN1412 event include introduction of criteria for high-risk antibodies, sequential inclusion of trial participants and implementation of pre-Phase I studies where dose calculation is based on the pre-clinical No Effect Level instead of the No Observed Adverse Effect Level. The recently established European clinical trials database (EUDRACT Database) is a further safety tool to expedite the sharing of relevant information between scientific authorities.

Phase II cancer clinical trials for biomarker-guided treatments.

PubMed

Jung, Sin-Ho

2018-01-01

The design and analysis of cancer clinical trials with biomarker depend on various factors, such as the phase of trials, the type of biomarker, whether the used biomarker is validated or not, and the study objectives. In this article, we demonstrate the design and analysis of two Phase II cancer clinical trials, one with a predictive biomarker and the other with an imaging prognostic biomarker. Statistical testing methods and their sample size calculation methods are presented for each trial. We assume that the primary endpoint of these trials is a time to event variable, but this concept can be used for any type of endpoint.

Infant lung function tests as endpoints in the ISIS multicenter clinical trial in cystic fibrosis.

PubMed

Davis, Stephanie D; Ratjen, Felix; Brumback, Lyndia C; Johnson, Robin C; Filbrun, Amy G; Kerby, Gwendolyn S; Panitch, Howard B; Donaldson, Scott H; Rosenfeld, Margaret

2016-05-01

The Infant Study of Inhaled Saline (ISIS) in CF was the first multicenter clinical trial to utilize infant pulmonary function tests (iPFTs) as an endpoint. Secondary analysis of ISIS data was conducted in order to assess feasibility of iPFT measures and their associations with respiratory symptoms. Standard deviations were calculated to aid in power calculations for future clinical trials. Seventy-three participants enrolled, 70 returned for the final visit; 62 (89%) and 45 (64%) had acceptable paired functional residual capacity (FRC) and raised volume measurements, respectively. Mean baseline FEV0.5, FEF75 and FRC z-scores were 0.3 (SD: 1.2), -0.2 (SD: 2.0), and 1.8 (SD: 2.0). iPFTs are not appropriate primary endpoints for multicenter clinical trials due to challenges of obtaining acceptable data and near-normal average raised volume measurements. Raised volume measures have potential to serve as secondary endpoints in future clinical CF trials. Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Visual scoring of non cavitated caries lesions and clinical trial efficiency, testing xylitol in caries-active adults.

PubMed

Brown, John P; Amaechi, Bennett T; Bader, James D; Gilbert, Gregg H; Makhija, Sonia K; Lozano-Pineda, Juanita; Leo, Michael C; Chen, Chuhe; Vollmer, William M

2014-06-01

To better understand the effectiveness of xylitol in caries prevention in adults and to attempt improved clinical trial efficiency. As part of the Xylitol for Adult Caries Trial (X-ACT), non cavitated and cavitated caries lesions were assessed in subjects who were experiencing the disease. The trial was a test of the effectiveness of 5 g/day of xylitol, consumed by dissolving in the mouth five 1 g lozenges spaced across each day, compared with a sucralose placebo. For this analysis, seeking trial efficiency, 538 subjects aged 21-80, with complete data for four dental examinations, were selected from the 691 randomized into the 3-year trial, conducted at three sites. Acceptable inter- and intra-examiner reliability before and during the trial was quantified using the kappa statistic. The mean annualized noncavitated plus cavitated lesion transition scores in coronal and root surfaces, from sound to carious favoured xylitol over placebo, during the three cumulative periods of 12, 24, and 33 months, but these clinically and statistically nonsignificant differences declined in magnitude over time. Restricting the present assessment to those subjects with a higher baseline lifetime caries experience showed possible but inconsistent benefit. There was no clear and clinically relevant preventive effect of xylitol on caries in adults with adequate fluoride exposure when non cavitated plus cavitated lesions were assessed. This conformed to the X-ACT trial result assessing cavitated lesions. Including non cavitated lesion assessment in this full-scale, placebo-controlled, multisite, randomized, double-blinded clinical trial in adults experiencing dental caries did not achieve added trial efficiency or demonstrate practical benefit of xylitol. ClinicalTrials.Gov NCT00393055. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Clinician-led improvement in cancer care (CLICC) - testing a multifaceted implementation strategy to increase evidence-based prostate cancer care: phased randomised controlled trial - study protocol

PubMed Central

2014-01-01

Background Clinical practice guidelines have been widely developed and disseminated with the aim of improving healthcare processes and patient outcomes but the uptake of evidence-based practice remains haphazard. There is a need to develop effective implementation methods to achieve large-scale adoption of proven innovations and recommended care. Clinical networks are increasingly being viewed as a vehicle through which evidence-based care can be embedded into healthcare systems using a collegial approach to agree on and implement a range of strategies within hospitals. In Australia, the provision of evidence-based care for men with prostate cancer has been identified as a high priority. Clinical audits have shown that fewer than 10% of patients in New South Wales (NSW) Australia at high risk of recurrence after radical prostatectomy receive guideline recommended radiation treatment following surgery. This trial will test a clinical network-based intervention to improve uptake of guideline recommended care for men with high-risk prostate cancer. Methods/Design In Phase I, a phased randomised cluster trial will test a multifaceted intervention that harnesses the NSW Agency for Clinical Innovation (ACI) Urology Clinical Network to increase evidence-based care for men with high-risk prostate cancer following surgery. The intervention will be introduced in nine NSW hospitals over 10 months using a stepped wedge design. Outcome data (referral to radiation oncology for discussion of adjuvant radiotherapy in line with guideline recommended care or referral to a clinical trial of adjuvant versus salvage radiotherapy) will be collected through review of patient medical records. In Phase II, mixed methods will be used to identify mechanisms of provider and organisational change. Clinicians’ knowledge and attitudes will be assessed through surveys. Process outcome measures will be assessed through document review. Semi-structured interviews will be conducted to elucidate mechanisms of change. Discussion The study will be one of the first randomised controlled trials to test the effectiveness of clinical networks to lead changes in clinical practice in hospitals treating patients with high-risk cancer. It will additionally provide direction regarding implementation strategies that can be effectively employed to encourage widespread adoption of clinical practice guidelines. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12611001251910. PMID:24884877

Valx: A system for extracting and structuring numeric lab test comparison statements from text

PubMed Central

Hao, Tianyong; Liu, Hongfang; Weng, Chunhua

2017-01-01

Objectives To develop an automated method for extracting and structuring numeric lab test comparison statements from text and evaluate the method using clinical trial eligibility criteria text. Methods Leveraging semantic knowledge from the Unified Medical Language System (UMLS) and domain knowledge acquired from the Internet, Valx takes 7 steps to extract and normalize numeric lab test expressions: 1) text preprocessing, 2) numeric, unit, and comparison operator extraction, 3) variable identification using hybrid knowledge, 4) variable - numeric association, 5) context-based association filtering, 6) measurement unit normalization, and 7) heuristic rule-based comparison statements verification. Our reference standard was the consensus-based annotation among three raters for all comparison statements for two variables, i.e., HbA1c and glucose, identified from all of Type 1 and Type 2 diabetes trials in ClinicalTrials.gov. Results The precision, recall, and F-measure for structuring HbA1c comparison statements were 99.6%, 98.1%, 98.8% for Type 1 diabetes trials, and 98.8%, 96.9%, 97.8% for Type 2 Diabetes trials, respectively. The precision, recall, and F-measure for structuring glucose comparison statements were 97.3%, 94.8%, 96.1% for Type 1 diabetes trials, and 92.3%, 92.3%, 92.3% for Type 2 diabetes trials, respectively. Conclusions Valx is effective at extracting and structuring free-text lab test comparison statements in clinical trial summaries. Future studies are warranted to test its generalizability beyond eligibility criteria text. The open-source Valx enables its further evaluation and continued improvement among the collaborative scientific community. PMID:26940748

Valx: A System for Extracting and Structuring Numeric Lab Test Comparison Statements from Text.

PubMed

Hao, Tianyong; Liu, Hongfang; Weng, Chunhua

2016-05-17

To develop an automated method for extracting and structuring numeric lab test comparison statements from text and evaluate the method using clinical trial eligibility criteria text. Leveraging semantic knowledge from the Unified Medical Language System (UMLS) and domain knowledge acquired from the Internet, Valx takes seven steps to extract and normalize numeric lab test expressions: 1) text preprocessing, 2) numeric, unit, and comparison operator extraction, 3) variable identification using hybrid knowledge, 4) variable - numeric association, 5) context-based association filtering, 6) measurement unit normalization, and 7) heuristic rule-based comparison statements verification. Our reference standard was the consensus-based annotation among three raters for all comparison statements for two variables, i.e., HbA1c and glucose, identified from all of Type 1 and Type 2 diabetes trials in ClinicalTrials.gov. The precision, recall, and F-measure for structuring HbA1c comparison statements were 99.6%, 98.1%, 98.8% for Type 1 diabetes trials, and 98.8%, 96.9%, 97.8% for Type 2 diabetes trials, respectively. The precision, recall, and F-measure for structuring glucose comparison statements were 97.3%, 94.8%, 96.1% for Type 1 diabetes trials, and 92.3%, 92.3%, 92.3% for Type 2 diabetes trials, respectively. Valx is effective at extracting and structuring free-text lab test comparison statements in clinical trial summaries. Future studies are warranted to test its generalizability beyond eligibility criteria text. The open-source Valx enables its further evaluation and continued improvement among the collaborative scientific community.

Regulatory issues with multiplicity in drug approval: Principles and controversies in a changing landscape.

PubMed

Benda, Norbert; Brandt, Andreas

2018-01-01

Recently, new draft guidelines on multiplicity issues in clinical trials have been issued by European Medicine Agency (EMA) and Food and Drug Administration (FDA), respectively. Multiplicity is an issue in clinical trials, if the probability of a false-positive decision is increased by insufficiently accounting for testing multiple hypotheses. We outline the regulatory principles related to multiplicity issues in confirmatory clinical trials intended to support a marketing authorization application in the EU, describe the reasons for an increasing complexity regarding multiple hypotheses testing and discuss the specific multiplicity issues emerging within the regulatory context and being relevant for drug approval.

Regulation of Clinical Trials with Advanced Therapy Medicinal Products in Germany.

PubMed

Renner, Matthias; Anliker, Brigitte; Sanzenbacher, Ralf; Schuele, Silke

2015-01-01

In the European Union, clinical trials for Advanced Therapy Medicinal Products are regulated at the national level, in contrast to the situation for a Marketing Authorisation Application, in which a centralised procedure is foreseen for these medicinal products. Although based on a common understanding regarding the regulatory requirement to be fulfilled before conduct of a clinical trial with an Advanced Therapy Investigational Medicinal Product, the procedures and partly the scientific requirements for approval of a clinical trial application differ between the European Union Member States. This chapter will thus give an overview about the path to be followed for a clinical trial application and the subsequent approval process for an Advanced Therapy Investigational Medicinal Product in Germany and will describe the role of the stakeholders that are involved. In addition, important aspects of manufacturing, quality control and non-clinical testing of Advanced Therapy Medicinal Products in the clinical development phase are discussed. Finally, current and future approaches for harmonisation of clinical trial authorisation between European Union Member States are summarised.

Optimization of the decision-making process for the selection of therapeutics to undergo clinical testing for spinal cord injury in the North American Clinical Trials Network.

PubMed

Guest, James; Harrop, James S; Aarabi, Bizhan; Grossman, Robert G; Fawcett, James W; Fehlings, Michael G; Tator, Charles H

2012-09-01

The North American Clinical Trials Network (NACTN) includes 9 clinical centers funded by the US Department of Defense and the Christopher Reeve Paralysis Foundation. Its purpose is to accelerate clinical testing of promising therapeutics in spinal cord injury (SCI) through the development of a robust interactive infrastructure. This structure includes key committees that serve to provide longitudinal guidance to the Network. These committees include the Executive, Data Management, and Neurological Outcome Assessments Committees, and the Therapeutic Selection Committee (TSC), which is the subject of this manuscript. The NACTN brings unique elements to the SCI field. The Network's stability is not restricted to a single clinical trial. Network members have diverse expertise and include experts in clinical care, clinical trial design and methodology, pharmacology, preclinical and clinical research, and advanced rehabilitation techniques. Frequent systematic communication is assigned a high value, as is democratic process, fairness and efficiency of decision making, and resource allocation. This article focuses on how decision making occurs within the TSC to rank alternative therapeutics according to 2 main variables: quality of the preclinical data set, and fit with the Network's aims and capabilities. This selection process is important because if the Network's resources are committed to a therapeutic, alternatives cannot be pursued. A proposed methodology includes a multicriteria decision analysis that uses a Multi-Attribute Global Inference of Quality matrix to quantify the process. To rank therapeutics, the TSC uses a series of consensus steps designed to reduce individual and group bias and limit subjectivity. Given the difficulties encountered by industry in completing clinical trials in SCI, stable collaborative not-for-profit consortia, such as the NACTN, may be essential to clinical progress in SCI. The evolution of the NACTN also offers substantial opportunity to refine decision making and group dynamics. Making the best possible decisions concerning therapeutics selection for trial testing is a cornerstone of the Network's function.

An analysis of registered clinical trials in otolaryngology from 2007 to 2010: ClinicalTrials.gov.

PubMed

Witsell, David L; Schulz, Kristine A; Lee, Walter T; Chiswell, Karen

2013-11-01

To describe the conditions studied, interventions used, study characteristics, and funding sources of otolaryngology clinical trials from the ClinicalTrials.gov database; compare this otolaryngology cohort of interventional studies to clinical visits in a health care system; and assess agreement between clinical trials and clinical activity. Database analysis. Trial registration data downloaded from ClinicalTrials.gov and administrative data from the Duke University Medical Center from October 1, 2007 to September 27, 2010. Data extraction from ClinicalTrials.gov was done using MeSH and non-MeSH disease condition terms. Studies were subcategorized to create the following groupings for descriptive analysis: ear, nose, allergy, voice, sleep, head and neck cancer, thyroid, and throat. Duke Health System visits were queried by using selected ICD-9 codes for otolaryngology and non-otolaryngology providers. Visits were grouped similarly to ClinicalTrials.gov for further analysis. Chi-square tests were used to explore differences between groups. A total of 1115 of 40,970 registered interventional trials were assigned to otolaryngology. Head and neck cancer trials predominated. Study models most frequently incorporated parallel design (54.6%), 2 study groups (46.6%), and randomization (69.1%). Phase 2 or 3 studies constituted 46.4% of the cohort. Comparison of the ClinicalTrials.gov database with administrative health system visit data by disease condition showed discordance between national research activity and clinical visit volume for patients with otolaryngology complaints. Analysis of otolaryngology-related clinical research as listed in ClinicalTrials.gov can inform patients, physicians, and policy makers about research focus areas. The relative burden of otolaryngology-associated conditions in our tertiary health system exceeds research activity within the field.

Designing Trials for Testing the Efficacy of Pre- Pro- and Synbiotics

NASA Astrophysics Data System (ADS)

Lewis, Stephen; Atkinson, Charlotte

Providing an evidence base for the rational delivery of medicines and treatments is the cornerstone of modern health care delivery. Much of this evidence base is gained through conducting clinical trials. Superficially, designing a clinical trial seems straightforward. However, in practice many unforeseen difficulties arise with long setting up times, poor recruitment rates and patients or interventions not behaving in the way expected. Unfortunately, clinical trials examining the efficacy of pre-, pro- and synbiotics have developed a reputation for being published in low impact journals and reaching unconvincing conclusions. As a generalization, the reason for this poor reputation is that the trials have tended to be too small and have not used meaningful clinical endpoints.

An introduction to multiplicity issues in clinical trials: the what, why, when and how.

PubMed

Li, Guowei; Taljaard, Monica; Van den Heuvel, Edwin R; Levine, Mitchell Ah; Cook, Deborah J; Wells, George A; Devereaux, Philip J; Thabane, Lehana

2017-04-01

In clinical trials it is not uncommon to face a multiple testing problem which can have an impact on both type I and type II error rates, leading to inappropriate interpretation of trial results. Multiplicity issues may need to be considered at the design, analysis and interpretation stages of a trial. The proportion of trial reports not adequately correcting for multiple testing remains substantial. The purpose of this article is to provide an introduction to multiple testing issues in clinical trials, and to reduce confusion around the need for multiplicity adjustments. We use a tutorial, question-and-answer approach to address the key issues of why, when and how to consider multiplicity adjustments in trials. We summarize the relevant circumstances under which multiplicity adjustments ought to be considered, as well as options for carrying out multiplicity adjustments in terms of trial design factors including Population, Intervention/Comparison, Outcome, Time frame and Analysis (PICOTA). Results are presented in an easy-to-use table and flow diagrams. Confusion about multiplicity issues can be reduced or avoided by considering the potential impact of multiplicity on type I and II errors and, if necessary pre-specifying statistical approaches to either avoid or adjust for multiplicity in the trial protocol or analysis plan. © The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Review of ongoing clinical trials in non-small cell lung cancer: a status report for 2009 from the ClinicalTrials.gov website.

PubMed

Subramanian, Janakiraman; Madadi, Anusha R; Dandona, Monica; Williams, Kristina; Morgensztern, Daniel; Govindan, Ramaswamy

2010-08-01

Several new agents are being tested in clinical trials for patients with non-small cell lung cancer (NSCLC). A survey of ongoing clinical trials in NSCLC in the ClinicalTrials.gov website would help identify areas that require further attention in the future. We conducted a survey of ongoing clinical trials on NSCLC registered in the ClinicalTrials.gov website. The advanced search option was applied using the terms "non small cell lung cancer," "open studies," "interventional," and "adults 18 years or older." Of the 493 eligible trials, 77 (15.6%) were phase III, 92 (18.7%) were phase I, and 240 (48.7%) were phase II trials. Universities were listed as the primary sponsor for 224 (45.4%) trials and pharmaceutical industry for 166 (33.7%) trials. Majority of the trials were multicenter studies (56.8%) and were being conducted exclusively within the United States (51.3%). A large proportion of phase II and III clinical trials (77.2%) were focused on patients with advanced-stage disease. The most frequently used end points were progression-free survival (27.1%) followed by tumor response rate (22.9%) and overall survival (16.6%). Although biomarker analysis was included in 185 (37.5%) trials, only 39 (7.9%) trials used biomarkers for patient selection. Progression-free survival is the end point most commonly used to assess the effectiveness of experimental regimens, and biomarker-based patient selection is rarely used in ongoing clinical trials for NSCLC.

Designing clinical trials to test disease-modifying agents: application to the treatment trials of Alzheimer's disease.

PubMed

Xiong, Chengjie; van Belle, Gerald; Miller, J Philip; Morris, John C

2011-02-01

Therapeutic trials of disease-modifying agents on Alzheimer's disease (AD) require novel designs and analyses involving switch of treatments for at least a portion of subjects enrolled. Randomized start and randomized withdrawal designs are two examples of such designs. Crucial design parameters such as sample size and the time of treatment switch are important to understand in designing such clinical trials. The purpose of this article is to provide methods to determine sample sizes and time of treatment switch as well as optimum statistical tests of treatment efficacy for clinical trials of disease-modifying agents on AD. A general linear mixed effects model is proposed to test the disease-modifying efficacy of novel therapeutic agents on AD. This model links the longitudinal growth from both the placebo arm and the treatment arm at the time of treatment switch for these in the delayed treatment arm or early withdrawal arm and incorporates the potential correlation on the rate of cognitive change before and after the treatment switch. Sample sizes and the optimum time for treatment switch of such trials as well as optimum test statistic for the treatment efficacy are determined according to the model. Assuming an evenly spaced longitudinal design over a fixed duration, the optimum treatment switching time in a randomized start or a randomized withdrawal trial is half way through the trial. With the optimum test statistic for the treatment efficacy and over a wide spectrum of model parameters, the optimum sample size allocations are fairly close to the simplest design with a sample size ratio of 1:1:1 among the treatment arm, the delayed treatment or early withdrawal arm, and the placebo arm. The application of the proposed methodology to AD provides evidence that much larger sample sizes are required to adequately power disease-modifying trials when compared with those for symptomatic agents, even when the treatment switch time and efficacy test are optimally chosen. The proposed method assumes that the only and immediate effect of treatment switch is on the rate of cognitive change. Crucial design parameters for the clinical trials of disease-modifying agents on AD can be optimally chosen. Government and industry officials as well as academia researchers should consider the optimum use of the clinical trials design for disease-modifying agents on AD in their effort to search for the treatments with the potential to modify the underlying pathophysiology of AD.

Understanding clinical development of chimeric antigen receptor T cell therapies.

PubMed

de Wilde, Sofieke; Guchelaar, Henk-Jan; Zandvliet, Maarten Laurens; Meij, Pauline

2017-06-01

In the past decade, many clinical trials with gene- and cell-based therapies (GCTs) have been performed. Increased interest in the development of these drug products by various stakeholders has become apparent. Despite this growth in clinical studies, the number of therapies receiving marketing authorization approval (MAA) is lagging behind. To enhance the success rate of GCT development, it is essential to better understand the clinical development of these products. Chimeric antigen receptor (CAR) T cells are a GCT product subtype with promising efficacy in cancer treatment which are tested in many clinical trials, but have not yet received MAA. We generated an overview of the characteristics of CAR T-cell clinical development in the United States, Canada and Europe. Subsequently, the characteristics of clinical trials with CAR T-cell products that proceeded to a subsequent clinical trial, used as a proxy for success, were compared with those that did not proceed. From the U.S. and European Union clinical trial databases, 106 CAR T-cell trials were selected, from which 49 were linked to a subsequent trial and 57 were not. The majority of the trials had an academic sponsor from which most did not proceed, whereas most commercially sponsored trials were followed by another clinical trial. Furthermore, trials with a subsequent trial more frequently recruited large patient cohorts and were more often multicenter compared with trials that were not followed up. These characteristics can be used by investigators to better design clinical trials with CAR T cells. We encourage sponsors to plan clinical development ahead for a higher efficiency of product development and thereby achieving a higher success rate of development towards MAA. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Considerations of sex and gender differences in preclinical and clinical trials.

PubMed

Raz, Limor; Miller, Virginia M

2012-01-01

Women continue to be underrepresented in clinical trials, particularly in Phases I and II of experimental drug studies in spite of legislative guidelines in the USA, Canada, the European Union, Australia, and Japan requiring the inclusion of women in clinical trials. As such, women remain a vulnerable population subject to the adverse effects of pharmacological therapies. Thus, women experience higher rates of adverse drug reactions than do men and for women of reproductive age or who may be pregnant, therapeutic options may be limited. This chapter provides a brief history of inclusion of sex and gender as variables in clinical trials, summarizes governmental legislation for consideration of sex and gender in clinical trials and provides specific examples of drugs which have been withdrawn from the market because of side effects in women. Additional information related to sex and gender in preclinical testing, trial design, challenges to recruitment of women for clinical trials and statistical methods for analysis of data also is considered.

Home screening for sexually transmitted diseases in high‐risk young women: randomised controlled trial

PubMed Central

Cook, Robert L; Østergaard, Lars; Hillier, Sharon L; Murray, Pamela J; Chang, Chung‐Chou H; Comer, Diane M; Ness, Roberta B

2007-01-01

Objective Home screening tests could eliminate several barriers to testing sexually transmitted diseases (STDs). Aim To determine whether offering repeated home screening tests would increase the rate of testing for chlamydia and gonorrhoea in a high‐risk sample of young women. Methods In this randomised controlled trial, 403 young women (mean age 18.9 years, 70% black) with a recent STD or with STD‐related risk factors were enrolled. Participants were recruited from clinics and high‐prevalence neighbourhoods and then randomly assigned to receive either a home testing kit or an invitation to attend a medical clinic for testing at 6, 12 and 18 months after enrollment. Over 80% of women were followed for 2 years. The trial is registered with ClinicalTrials.gov, number NCT 00177437. Results Of 197 women in the intervention group, 140 (71%) returned at least one home test and 25 of 249 (10%) home tests were positive. Women who received home screening tests completed significantly more STD tests overall (1.94 vs 1.41 tests per woman‐year, p<0.001) and more STD tests in the absence of symptoms (1.18 vs 0.75 tests per woman‐year, p<0.001). More women in the intervention group completed at least one test when asymptomatic (162 (82.2%) vs 117 (61.3%), p<0.001). The intervention was most effective among women recruited outside medical clinics. There was no significant difference in the overall rate of STDs detected. Conclusions Home screening significantly increased the utilisation of chlamydia and gonorrhoea testing in this sample of high‐risk young women, and thus represents a feasible strategy to facilitate STD testing in young women. PMID:17301105

Expert Systems In Medical Studies - A New Twist

NASA Astrophysics Data System (ADS)

Slagle, James R.; Long, John M.; Wick, Michael R.; Matts, John P.; Leon, Arthur S.

1986-03-01

The use of experts to evaluate large amounts of trial data results in increasingly expensive and time consuming research. We are investigating the role expert systems can play in reducing the time and expense of research projects. Current methods in large clinical studies for evaluating data are often crude and superficial. We have developed, for a large clinical trial, an expert system for analysis of treadmill exercise ECG test results. In the cases we are studying, a patient is given a treadmill exercise ECG test once a year for five years. Pairs of these exercise tests are then evaluated by cardiologists to determine the condition of the patient's heart. The results of our system show great promise for the use of expert systems in reducing the time and expense of large clinical trials.

Using pathology-specific laboratory profiles in Clinical Pathology to reduce inappropriate test requesting: two completed audit cycles

PubMed Central

2012-01-01

Background Systematic reviews have shown that, although well prepared, the Consensus Guidelines have failed to change clinical practice. In the healthcare district of Castelnovo né Monti (Reggio Emilia, Italy), it became necessary for the GPs and Clinical Pathologists to work together to jointly define laboratory profiles. Methods Observational study with two cycles of retrospective audit on test request forms, in a primary care setting. Objectives of the study were to develop pathology-specific laboratory profiles and to increase the number of provisional diagnoses on laboratory test request forms. A Multiprofessional Multidisciplinary Inter-hospital Work Team developed pathology-specific laboratory profiles for more effective test requesting. After 8 training sessions that used a combined strategy with multifaceted interventions, the 23 General Practitioners (GPs) in the trial district (Castelnovo nè Monti) tested the profiles; the 21 GPs in the Puianello district were the control group; all GPs in both districts participated in the trial. All laboratory tests for both healthcare districts are performed at the Laboratory located in the trial district. A baseline and a 1-year audit were performed in both districts on the GPs’ request forms. Results Seven pathology-specific laboratory profiles for outpatients were developed. In the year after the first audit cycle: 1) the number of tests requested in the trial district was distinctly lower than that in the previous year, with a decrease of about 5% (p < 0.001); 2) the provisional diagnosis on the request forms was 52.8% in the trial district and 42% in the control district (P < 0.001); 3) the decrease of the number of tests on each request form was much more marked in the trial district (8.73 vs. 10.77; p < 0.001). Conclusions The first audit cycle showed a significant decrease in the number of tests ordered only in the trial district. The combined strategy used in this study improved the prescriptive compliance of most of the GPs involved. The presence of the clinical pathologist is seen as an added value. PMID:22759353

Using pathology-specific laboratory profiles in clinical pathology to reduce inappropriate test requesting: two completed audit cycles.

PubMed

Baricchi, Roberto; Zini, Michele; Nibali, Maria Grazia; Vezzosi, Walter; Insegnante, Vincenzo; Manfuso, Clotilde; Polese, Alessandra; Costoli, Valmer; Spelti, Antonio; Formisano, Debora; Orlandini, Danilo; Nicolini, Fausto; Poli, Antonio

2012-07-03

Systematic reviews have shown that, although well prepared, the Consensus Guidelines have failed to change clinical practice. In the healthcare district of Castelnovo né Monti (Reggio Emilia, Italy), it became necessary for the GPs and Clinical Pathologists to work together to jointly define laboratory profiles. Observational study with two cycles of retrospective audit on test request forms, in a primary care setting. Objectives of the study were to develop pathology-specific laboratory profiles and to increase the number of provisional diagnoses on laboratory test request forms. A Multiprofessional Multidisciplinary Inter-hospital Work Team developed pathology-specific laboratory profiles for more effective test requesting. After 8 training sessions that used a combined strategy with multifaceted interventions, the 23 General Practitioners (GPs) in the trial district (Castelnovo nè Monti) tested the profiles; the 21 GPs in the Puianello district were the control group; all GPs in both districts participated in the trial. All laboratory tests for both healthcare districts are performed at the Laboratory located in the trial district. A baseline and a 1-year audit were performed in both districts on the GPs' request forms. Seven pathology-specific laboratory profiles for outpatients were developed. In the year after the first audit cycle: 1) the number of tests requested in the trial district was distinctly lower than that in the previous year, with a decrease of about 5% (p < 0.001); 2) the provisional diagnosis on the request forms was 52.8% in the trial district and 42% in the control district (P < 0.001); 3) the decrease of the number of tests on each request form was much more marked in the trial district (8.73 vs. 10.77; p < 0.001). The first audit cycle showed a significant decrease in the number of tests ordered only in the trial district. The combined strategy used in this study improved the prescriptive compliance of most of the GPs involved. The presence of the clinical pathologist is seen as an added value.

Culinary Spice Plants in Dietary Supplement Products and Tested in Clinical Trials123

PubMed Central

Saldanha, Leila G; Dwyer, Johanna T; Betz, Joseph M

2016-01-01

Dried plant parts used as culinary spices (CSs) in food are permitted as dietary ingredients in dietary supplements (DSs) within certain constraints in the United States. We reviewed the amounts, forms, and nutritional support (structure/function) claims of DSs that contain CS plants listed in the Dietary Supplement Label Database (DSLD) and compared this label information with trial doses and health endpoints for CS plants that were the subject of clinical trials listed in clinicaltrials.gov. According to the DSLD, the CS plants occurring most frequently in DSs were cayenne, cinnamon, garlic, ginger, pepper, rosemary, and turmeric. Identifying the botanical species, categorizing the forms used, and determining the amounts from the information provided on DS labels was challenging. CS plants were typically added as a component of a blend, as the powered biomass, dried extracts, and isolated phytochemicals. The amounts added were declared on about 55% of the labels, rendering it difficult to determine the amount of the CS plant used in many DSs. Clinicaltrials.gov provided little information about the composition of test articles in the intervention studies. When plant names were listed on DS labels and in clinical trials, generally the common name and not the Latin binomial name was given. In order to arrive at exposure estimates and enable researchers to reproduce clinical trials, the Latin binomial name, form, and amount of the CS plant used in DSs and tested in clinical trials must be specified. PMID:26980817

Culinary Spice Plants in Dietary Supplement Products and Tested in Clinical Trials.

PubMed

Saldanha, Leila G; Dwyer, Johanna T; Betz, Joseph M

2016-03-01

Dried plant parts used as culinary spices (CSs) in food are permitted as dietary ingredients in dietary supplements (DSs) within certain constraints in the United States. We reviewed the amounts, forms, and nutritional support (structure/function) claims of DSs that contain CS plants listed in the Dietary Supplement Label Database (DSLD) and compared this label information with trial doses and health endpoints for CS plants that were the subject of clinical trials listed in clinicaltrials.gov. According to the DSLD, the CS plants occurring most frequently in DSs were cayenne, cinnamon, garlic, ginger, pepper, rosemary, and turmeric. Identifying the botanical species, categorizing the forms used, and determining the amounts from the information provided on DS labels was challenging. CS plants were typically added as a component of a blend, as the powered biomass, dried extracts, and isolated phytochemicals. The amounts added were declared on about 55% of the labels, rendering it difficult to determine the amount of the CS plant used in many DSs. Clinicaltrials.gov provided little information about the composition of test articles in the intervention studies. When plant names were listed on DS labels and in clinical trials, generally the common name and not the Latin binomial name was given. In order to arrive at exposure estimates and enable researchers to reproduce clinical trials, the Latin binomial name, form, and amount of the CS plant used in DSs and tested in clinical trials must be specified. © 2016 American Society for Nutrition.

First external quality assurance program for bloodstream Real-Time PCR monitoring of treatment response in clinical trials of Chagas disease.

PubMed

Ramírez, Juan C; Parrado, Rudy; Sulleiro, Elena; de la Barra, Anabelle; Rodríguez, Marcelo; Villarroel, Sandro; Irazu, Lucía; Alonso-Vega, Cristina; Alves, Fabiana; Curto, María A; García, Lineth; Ortiz, Lourdes; Torrico, Faustino; Gascón, Joaquim; Flevaud, Laurence; Molina, Israel; Ribeiro, Isabela; Schijman, Alejandro G

2017-01-01

Real-Time PCR (qPCR) testing is recommended as both a diagnostic and outcome measurement of etiological treatment in clinical practice and clinical trials of Chagas disease (CD), but no external quality assurance (EQA) program provides performance assessment of the assays in use. We implemented an EQA system to evaluate the performance of molecular biology laboratories involved in qPCR based follow-up in clinical trials of CD. An EQA program was devised for three clinical trials of CD: the E1224 (NCT01489228), a pro-drug of ravuconazole; the Sampling Study (NCT01678599), that used benznidazole, both conducted in Bolivia; and the CHAGASAZOL (NCT01162967), that tested posaconazole, conducted in Spain. Four proficiency testing panels containing negative controls and seronegative blood samples spiked with 1, 10 and 100 parasite equivalents (par. eq.)/mL of four Trypanosoma cruzi stocks, were sent from the Core Lab in Argentina to the participating laboratories located in Bolivia and Spain. Panels were analyzed simultaneously, blinded to sample allocation, at 4-month intervals. In addition, 302 random blood samples from both trials carried out in Bolivia were sent to Core Lab for retesting analysis. The analysis of proficiency testing panels gave 100% of accordance (within laboratory agreement) and concordance (between laboratory agreement) for all T. cruzi stocks at 100 par. eq./mL; whereas their values ranged from 71 to 100% and from 62 to 100% at 1 and 10 par. eq./mL, respectively, depending on the T. cruzi stock. The results obtained after twelve months of preparation confirmed the stability of blood samples in guanidine-EDTA buffer. No significant differences were found between qPCR results from Bolivian laboratory and Core Lab for retested clinical samples. This EQA program for qPCR analysis of CD patient samples may significantly contribute to ensuring the quality of laboratory data generated in clinical trials and molecular diagnostics laboratories of CD.

Comparative effectiveness and acceptability of home-based and clinic-based sampling methods for sexually transmissible infections screening in females aged 14-50 years: a systematic review and meta-analysis.

PubMed

Odesanmi, Tolulope Y; Wasti, Sharada P; Odesanmi, Omolola S; Adegbola, Omololu; Oguntuase, Olubukola O; Mahmood, Sajid

2013-12-01

Home-based sampling is a strategy to enhance uptake of sexually transmissible infection (STI) screening. This review aimed to compare the screening uptake levels of home-based self-sampling and clinic-based specimen collection for STIs (chlamydia (Chlamydia trachomatis), gonorrhoea (Neisseria gonorrhoeae) and trichomoniasis) in females aged 14-50 years. Acceptability and effect on specimen quality were determined. Sixteen electronic databases were searched from inception to September 2012. Randomised controlled trials (RCTs) comparing the uptake levels of home-based self-sampling and clinic-based sampling for chlamydia, gonorrhoea and trichomoniasis in females aged 14-50 years were eligible for inclusion. The risk of bias in the trials was assessed. Risk ratios (RRs) for dichotomous outcomes were meta-analysed. Of 3065 papers, six studies with seven RCTs contributed to the final review. Compared with clinic-based methods, home-based screening increased uptake significantly (P=0.001-0.05) in five trials and was substantiated in a meta-analysis (RR: 1.55; 95% confidence interval: 1.30-1.85; P=0.00001) of two trials. In three trials, a significant preference for home-based testing (P=0.001-0.05) was expressed. No significant difference was observed in specimen quality. Sampling was rated as easy by a significantly higher number of women (P=0.01) in the clinic group in one trial. The review provides evidence that home-based testing results in greater uptake of STI screening in females (14-50 years) than clinic-based testing without compromising quality in the developed world. Home collection strategies should be added to clinic-based screening programs to enhance uptake.

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.

Type 1 Diabetes TrialNet--an international collaborative clinical trials network.

PubMed

Skyler, Jay S; Greenbaum, Carla J; Lachin, John M; Leschek, Ellen; Rafkin-Mervis, Lisa; Savage, Peter; Spain, Lisa

2008-12-01

Type 1 Diabetes TrialNet is an international consortium of clinical research centers aimed at the prevention or delay of type 1 diabetes (T1D). The fundamental goal of TrialNet is to counter the T1D disease process by immune modulation and/or enhancement of beta cell proliferation and regeneration. To achieve this goal, TrialNet researchers are working to better understand the natural history of the disease, to identify persons at risk, and to clinically evaluate novel therapies that balance potential risks and benefits. The particular focus is on studies of preventive measures. In addition, TrialNet evaluates therapies in individuals with newly diagnosed T1D with preserved beta cell function to help determine the risk/benefit profile and gain an initial assessment of potential efficacy in preservation of beta cell function, so that promising agents can be studied in prevention trials. In addition, TrialNet evaluates methodologies that enhance the conduct of its clinical trials, which includes tests of outcome assessment methodology, the evaluation of surrogate markers, and mechanistic studies laying the foundation for future clinical trials.

Quantitative methods in assessment of neurologic function.

PubMed

Potvin, A R; Tourtellotte, W W; Syndulko, K; Potvin, J

1981-01-01

Traditionally, neurologists have emphasized qualitative techniques for assessing results of clinical trials. However, in recent years qualitative evaluations have been increasingly augmented by quantitative tests for measuring neurologic functions pertaining to mental state, strength, steadiness, reactions, speed, coordination, sensation, fatigue, gait, station, and simulated activities of daily living. Quantitative tests have long been used by psychologists for evaluating asymptomatic function, assessing human information processing, and predicting proficiency in skilled tasks; however, their methodology has never been directly assessed for validity in a clinical environment. In this report, relevant contributions from the literature on asymptomatic human performance and that on clinical quantitative neurologic function are reviewed and assessed. While emphasis is focused on tests appropriate for evaluating clinical neurologic trials, evaluations of tests for reproducibility, reliability, validity, and examiner training procedures, and for effects of motivation, learning, handedness, age, and sex are also reported and interpreted. Examples of statistical strategies for data analysis, scoring systems, data reduction methods, and data display concepts are presented. Although investigative work still remains to be done, it appears that carefully selected and evaluated tests of sensory and motor function should be an essential factor for evaluating clinical trials in an objective manner.

Web-based training and interrater reliability testing for scoring the Hamilton Depression Rating Scale.

PubMed

Rosen, Jules; Mulsant, Benoit H; Marino, Patricia; Groening, Christopher; Young, Robert C; Fox, Debra

2008-10-30

Despite the importance of establishing shared scoring conventions and assessing interrater reliability in clinical trials in psychiatry, these elements are often overlooked. Obstacles to rater training and reliability testing include logistic difficulties in providing live training sessions, or mailing videotapes of patients to multiple sites and collecting the data for analysis. To address some of these obstacles, a web-based interactive video system was developed. It uses actors of diverse ages, gender and race to train raters how to score the Hamilton Depression Rating Scale and to assess interrater reliability. This system was tested with a group of experienced and novice raters within a single site. It was subsequently used to train raters of a federally funded multi-center clinical trial on scoring conventions and to test their interrater reliability. The advantages and limitations of using interactive video technology to improve the quality of clinical trials are discussed.

Is a comparative clinical trial for breast cancer tumor markers to monitor disease recurrence warranted? A value of information analysis

PubMed Central

Thariani, Rahber; Henry, Norah Lynn; Ramsey, Scott D; Blough, David K; Barlow, Bill; Gralow, Julie R; Veenstra, David L

2014-01-01

Background Breast cancer tumor markers are used by some clinicians to screen for disease recurrence risk. Since there is limited evidence of benefit, additional research may be warranted. Aim To assess the potential value of a randomized clinical trial of breast tumor marker testing in routine follow-up of high-risk, stage II–III breast cancer survivors. Materials & methods We developed a decision-analytic model of tumor marker testing plus standard surveillance every 3–6 months for 5 years. The expected value of sample information was calculated using probabilistic simulations and was a function of: the probability of selecting the optimal monitoring strategy with current versus future information; the impact of choosing the nonoptimal strategy; and the size of the population affected. Results The value of information for a randomized clinical trial involving 9000 women was US$214 million compared with a cost of US$30–60 million to conduct such a trial. The probability of making an alternate, nonoptimal decision and choosing testing versus no testing was 32% with current versus future information from the trial. The impact of a nonoptimal decision was US$2150 and size of population impacted over 10 years was 308,000. The value of improved information on overall survival was US$105 million, quality of life US$37 million and test performance US$71 million. Conclusion Conducting a randomized clinical trial of breast cancer tumor markers appears to offer a good societal return on investment. Retrospective analyses to assess test performance and evaluation of patient quality of life using tumor markers may also offer valuable areas of research. However, alternative investments may offer even better returns in investments and, as such, the trial concept deserves further study as part of an overall research-portfolio evaluation. PMID:24236631

Challenges and perspective of drug repurposing strategies in early phase clinical trials.

PubMed

Kato, Shumei; Moulder, Stacy L; Ueno, Naoto T; Wheler, Jennifer J; Meric-Bernstam, Funda; Kurzrock, Razelle; Janku, Filip

2015-01-01

Despite significant investments in the development of new agents only 5% of cancer drugs entering Phase I clinical trials are ultimately approved for routine clinical cancer care. Drug repurposing strategies using novel combinations of previously tested anticancer agents could reduce the cost and improve treatment outcomes. At MD Anderson Cancer Center, early phase clinical trials with drug repurposing strategies demonstrated promising outcomes in patients with both rare and common treatment refractory advanced cancers. Despite clinical efficacy advancing drug repurposing strategies in the clinical trial trajectory beyond early phase studies has been challenging mainly due to lack of funding and interest from the pharmaceutical industry. In this review, we delineate our experience and challenges with drug repurposing strategies.

Same day ART initiation versus clinic-based pre-ART assessment and counselling for individuals newly tested HIV-positive during community-based HIV testing in rural Lesotho - a randomized controlled trial (CASCADE trial).

PubMed

Labhardt, Niklaus Daniel; Ringera, Isaac; Lejone, Thabo Ishmael; Masethothi, Phofu; Thaanyane, T'sepang; Kamele, Mashaete; Gupta, Ravi Shankar; Thin, Kyaw; Cerutti, Bernard; Klimkait, Thomas; Fritz, Christiane; Glass, Tracy Renée

2016-04-14

Achievement of the UNAIDS 90-90-90 targets in Sub-Sahara Africa is challenged by a weak care-cascade with poor linkage to care and retention in care. Community-based HIV testing and counselling (HTC) is widely used in African countries. However, rates of linkage to care and initiation of antiretroviral therapy (ART) in individuals who tested HIV-positive are often very low. A frequently cited reason for non-linkage to care is the time-consuming pre-ART assessment often requiring several clinic visits before ART-initiation. This two-armed open-label randomized controlled trial compares in individuals tested HIV-positive during community-based HTC the proposition of same-day community-based ART-initiation to the standard of care pre-ART assessment at the clinic. Home-based HTC campaigns will be conducted in catchment areas of six clinics in rural Lesotho. Households where at least one individual tested HIV positive will be randomized. In the standard of care group individuals receive post-test counselling and referral to the nearest clinic for pre-ART assessment and counselling. Once they have started ART the follow-up schedule foresees monthly clinic visits. Individuals randomized to the intervention group receive on the spot point-of-care pre-ART assessment and adherence counselling with the proposition to start ART that same day. Once they have started ART, follow-up clinic visits will be less frequent. First primary outcome is linkage to care (individual presents at the clinic at least once within 3 months after the HIV test). The second primary outcome is viral suppression 12 months after enrolment in the study. We plan to enrol a minimum of 260 households with 1:1 allocation and parallel assignment into both arms. This trial will show if in individuals tested HIV-positive during community-based HTC campaigns the proposition of same-day ART initiation in the community, combined with less frequent follow-up visits at the clinic could be a pragmatic approach to improve the care cascade in similar settings. NCT02692027 , registered February 21, 2016.

Assessing cognitive function in clinical trials: latest developments and future directions.

PubMed

Wesnes, Keith

2002-01-01

Properly developed automated test systems are of value for assessing changes in cognitive function in clinical trials. Besides the other advantages that automation brings to trials, such as increased reliability and utility, it is shown that such systems are also more sensitive to change in cognitive function than traditional nonautomated procedures. Data from a variety of topical areas in drug development are presented to illustrate the added value such techniques have brought. The latest developments in automation include remote testing via the Internet and telephone.

Development of an online clinical trial recruitment portal for the NIHR mental health BRC.

PubMed

Markham, Sarah

2016-01-01

In order to test whether or not new treatments for mental health disorders help patients get better according to clinician/patient selected criteria, it is often necessary to test them on patients under safe, carefully monitored conditions called clinical trials. It is necessary to find enough patients to take part in a clinical trial so that the results of the trial are reliable. The NIHR Mental Health BRC (here after abbreviated to BRC) is a centre for research in London which seeks to find out better ways to treat patients with mental health difficulties. The BRC has experienced problems trying to find sufficient numbers of patients to participate in its clinical trials as it appears that insufficient patients were being told by their doctor about opportunities to participate in clinical research. In order to help the BRC find enough patients to volunteer to take part in its clinical trials, the author (a patient representative) of this article and a clinical researcher in the nearby Institute of Psychiatry, Psychology and Neuroscience (IoPPN) decided to work together to try to find the best way to let patients know more about what clinical trials are, what it is like to take part in them and which clinical trials are seeking patients to take part. The author and researcher used a report by the Association of Medical Research Charities (AMRC) on patient difficulties in finding clinical trials to take part in, and the recommendations it made, to guide them in building a website to give such patients the information on clinical trials they wanted (including clinical trials run by the BRC). The author and researcher also asked patients, carers, staff at the IoPPN and BRC what they thought of the website and how to make it better. They used the ideas, suggestions and criticisms to improve the website. The author and researcher also asked mental health charities and research organisations if they would advertise the final version of this website on their own websites; many said yes, they would. The manager of the BRC on reviewing the website, agreed that a final version of the website with the NIHR Mental Health BRC logo would be paid for and will form part of a new main website for the BRC in early 2016. ᅟ. Public & patient recruitment to clinical trials is viewed as one of the main barriers to the implementation of clinical trials. This difficulty is often attributed to the working culture of the NHS, rapid turnover of staff and patients and poor-gatekeeping in referring patients to suitable clinical trials. In response to the recruitment difficulties experienced by the Psychosis Studies Clinical Academic Group at the NIHR Mental Health Biomedical Research Centre, Denmark Hill, London, a member of the Office of Psychosis Studies at King's College London and a member (the author) of the King's Clinical Trials Unit, King's College London developed an initiative to create an online clinical trial recruitment portal/information hub for the NIHR Mental Health BRC. The primary purpose of this initiative being to promote patient and public awareness of and interest in participating in clinical trials.

Clinical Trials Offer a Path to Better Care for AYAs with Cancer

Cancer.gov

The slow progress against adolescent and young adult cancers is due, in part, to this populations lack of participation in clinical trials. Researchers are testing innovative ways to enroll more AYAs in clinical trials—using expanded access, patient navigation, community outreach, and collaborations between academic and community doctors.

Compliance with mandatory reporting of clinical trial results on ClinicalTrials.gov: cross sectional study.

PubMed

Prayle, Andrew P; Hurley, Matthew N; Smyth, Alan R

2012-01-03

To examine compliance with mandatory reporting of summary clinical trial results (within one year of completion of trial) on ClinicalTrials.gov for studies that fall under the recent Food and Drug Administration Amendments Act (FDAAA) legislation. Registry based study of clinical trial summaries. ClinicalTrials.gov, searched on 19 January 2011, with cross referencing with Drugs@FDA to determine for which trials mandatory reporting was required within one year. Selection criteria Studies registered on ClinicalTrials.gov with US sites which completed between 1 January and 31 December 2009. Proportion of trials for which results had been reported. The ClinicalTrials.gov registry contained 83,579 entries for interventional trials, of which 5642 were completed within the timescale of interest. We identified trials as falling within the mandatory reporting rules if they were covered by the FDAAA (trials of a drug, device, or biological agent, which have at least one US site, and are of phase II or later) and if they investigated a drug that already had approval from the Food and Drug Administration. Of these, 163/738 (22%) had reported results within one year of completion of the trial compared with 76/727 (10%) trials that were not subject to mandatory reporting (95% confidence interval for the difference in proportions 7.8% to 15.5%; χ(2) test, P = 2.6 × 10(-9)). Later phase trials were more likely to report results (P = 4.4 × 10(-11)), as were industry funded trials (P = 2.2 × 10(-16)). Most trials subject to mandatory reporting did not report results within a year of completion.

Phase I clinical trial will test multi-targeted immunotherapy in common childhood cancer | Center for Cancer Research

Cancer.gov

Chimeric antigen receptor (CAR) T-cell immunotherapy targeting the protein CD19 has shown promise in treating acute lymphoblastic leukemia (ALL). CD22-CAR T-cell therapy has yielded similarly encouraging results, but many patients relapse after either therapy. In an upcoming phase I clinical trial, Center for Cancer Research investigators will test a new strategy—treating

How Can the Evidence from Global Large-scale Clinical Trials for Cardiovascular Diseases be Improved?

PubMed

Sawata, Hiroshi; Tsutani, Kiichiro

2011-06-29

Clinical investigations are important for obtaining evidence to improve medical treatment. Large-scale clinical trials with thousands of participants are particularly important for this purpose in cardiovascular diseases. Conducting large-scale clinical trials entails high research costs. This study sought to investigate global trends in large-scale clinical trials in cardiovascular diseases. We searched for trials using clinicaltrials.gov (URL: http://www.clinicaltrials.gov/) using the key words 'cardio' and 'event' in all fields on 10 April, 2010. We then selected trials with 300 or more participants examining cardiovascular diseases. The search revealed 344 trials that met our criteria. Of 344 trials, 71% were randomized controlled trials, 15% involved more than 10,000 participants, and 59% were funded by industry. In RCTs whose results were disclosed, 55% of industry-funded trials and 25% of non-industry funded trials reported statistically significant superiority over control (p = 0.012, 2-sided Fisher's exact test). Our findings highlighted concerns regarding potential bias related to funding sources, and that researchers should be aware of the importance of trial information disclosures and conflicts of interest. We should keep considering management and training regarding information disclosures and conflicts of interest for researchers. This could lead to better clinical evidence and further improvements in the development of medical treatment worldwide.

A pragmatic cluster randomised controlled trial to evaluate the safety, clinical effectiveness, cost effectiveness and satisfaction with point of care testing in a general practice setting - rationale, design and baseline characteristics.

PubMed

Laurence, Caroline; Gialamas, Angela; Yelland, Lisa; Bubner, Tanya; Ryan, Philip; Willson, Kristyn; Glastonbury, Briony; Gill, Janice; Shephard, Mark; Beilby, Justin

2008-08-06

Point of care testing (PoCT) may be a useful adjunct in the management of chronic conditions in general practice (GP). The provision of pathology test results at the time of the consultation could lead to enhanced clinical management, better health outcomes, greater convenience and satisfaction for patients and general practitioners (GPs), and savings in costs and time. It could also result in inappropriate testing, increased consultations and poor health outcomes resulting from inaccurate results. Currently there are very few randomised controlled trials (RCTs) in GP that have investigated these aspects of PoCT. The Point of Care Testing in General Practice Trial (PoCT Trial) was an Australian Government funded multi-centre, cluster randomised controlled trial to determine the safety, clinical effectiveness, cost effectiveness and satisfaction of PoCT in a GP setting.The PoCT Trial covered an 18 month period with the intervention consisting of the use of PoCT for seven tests used in the management of patients with diabetes, hyperlipidaemia and patients on anticoagulant therapy. The primary outcome measure was the proportion of patients within target range, a measure of therapeutic control. In addition, the PoCT Trial investigated the safety of PoCT, impact of PoCT on patient compliance to medication, stakeholder satisfaction, cost effectiveness of PoCT versus laboratory testing, and influence of geographic location. The paper provides an overview of the Trial Design, the rationale for the research methodology chosen and how the Trial was implemented in a GP environment. The evaluation protocol and data collection processes took into account the large number of patients, the broad range of practice types distributed over a large geographic area, and the inclusion of pathology test results from multiple pathology laboratories.The evaluation protocol developed reflects the complexity of the Trial setting, the Trial Design and the approach taken within the funding provided. The PoCT Trial is regarded as a pragmatic RCT, evaluating the effectiveness of implementing PoCT in GP and every effort was made to ensure that, in these circumstances, internal and external validity was maintained. 12612605000272695.

Success rates for product development strategies in new drug development.

PubMed

Dahlin, E; Nelson, G M; Haynes, M; Sargeant, F

2016-04-01

While research has examined the likelihood that drugs progress across phases of clinical trials, no research to date has examined the types of product development strategies that are the most likely to be successful in clinical trials. This research seeks to identify the strategies that are most likely to reach the market-those generated using a novel product development strategy or strategies that combine a company's expertise with both drugs and indications, which we call combined experience strategies. We evaluate the success of product development strategies in the drug development process for a sample of 2562 clinical trials completed by 406 US pharmaceutical companies. To identify product development strategies, we coded each clinical trial according to whether it consisted of an indication or a drug that was new to the firm. Accordingly, a clinical trial that consists of both an indication and a drug that were both new to the firm represents a novel product development strategy; indication experience is a product development strategy that consists of an indication that a firm had tested previously in a clinical trial, but with a drug that was new to the firm; drug experience is a product development strategy that consists of a drug that the firm had prior experience testing in clinical trials, but with an indication that was new to the firm; combined experience consists of both a drug and an indication that the firm had experience testing in clinical trials. Success rates for product development strategies across clinical phases were calculated for the clinical trials in our sample. Combined experience strategies had the highest success rate. More than three and a half percent (0·036) of the trials that combined experience with drugs and indications eventually reached the market. The next most successful strategy is drug experience (0·025) with novel strategies trailing closely (0·024). Indication experience strategies are the least successful (0·008). These differences are statistically significant. The primary contribution of this study is that product development strategies combining experience with drugs and indications strategies are the most likely to reach the market, even though they are least common strategy. Therefore, combined experience strategies remain underutilized. The findings also suggest a promising path for pursuing combined experience strategies: gaining expertise with drugs is likely to be a more effective path to gaining the expertise necessary for developing subsequent recombination strategies. © 2016 John Wiley & Sons Ltd.

The Design of Phase II Clinical Trials Testing Cancer Therapeutics: Consensus Recommendations from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee

PubMed Central

Seymour, Lesley; Ivy, S. Percy; Sargent, Daniel; Spriggs, David; Baker, Laurence; Rubinstein, Larry; Ratain, Mark J; Le Blanc, Michael; Stewart, David; Crowley, John; Groshen, Susan; Humphrey, Jeffrey S; West, Pamela; Berry, Donald

2010-01-01

The optimal design of phase II studies continues to be the subject of vigorous debate, especially with regards to studies of newer molecularly targeted agents. The observations that many new therapeutics ‘fail’ in definitive phase III studies, coupled with the numbers of new agents to be tested as well as the increasing costs and complexity of clinical trials further emphasizes the critical importance of robust and efficient phase II design. The Clinical Trial Design Task Force(CTD-TF)of the NCI Investigational Drug Steering Committee (IDSC) has published a series of discussion papers on Phase II trial design in Clinical Cancer Research. The IDSC has developed formal recommendations regarding aspects of phase II trial design which are the subject of frequent debate such as endpoints(response vs. progression free survival), randomization(single arm designs vs. randomization), inclusion of biomarkers, biomarker based patient enrichment strategies, and statistical design(e.g. two stage designs vs. multiple-group adaptive designs). While these recommendations in general encourage the use of progression-free survival as the primary endpoint, the use of randomization, the inclusion of biomarkers and the incorporation of newer designs, we acknowledge that objective response as an endpoint, and single arm designs, remain relevant in certain situations. The design of any clinical trial should always be carefully evaluated and justified based on the characteristic specific to the situation. PMID:20215557

Randomization in cancer clinical trials: permutation test and development of a computer program.

PubMed Central

Ohashi, Y

1990-01-01

When analyzing cancer clinical trial data where the treatment allocation is done using dynamic balancing methods such as the minimization method for balancing the distribution of important prognostic factors in each arm, conservativeness occurs if such a randomization scheme is ignored and a simple unstratified analysis is carried out. In this paper, the above conservativeness is demonstrated by computer simulation, and the development of a computer program that carries out permutation tests of the log-rank statistics for clinical trial data where the allocation is done by the minimization method or a stratified permuted block design is introduced. We are planning to use this program in practice to supplement a usual stratified analysis and model-based methods such as the Cox regression. The most serious problem in cancer clinical trials in Japan is how to carry out the quality control or data management in trials that are initiated and conducted by researchers without support from pharmaceutical companies. In the final section of this paper, one international collaborative work for developing international guidelines on data management in clinical trials of bladder cancer is briefly introduced, and the differences between the system adopted in US/European statistical centers and the Japanese system is described. PMID:2269216

Novel end points for clinical trials in young children with cystic fibrosis.

PubMed

Simpson, Shannon J; Mott, Lauren S; Esther, Charles R; Stick, Stephen M; Hall, Graham L

2013-06-01

Cystic fibrosis (CF) lung disease commences early in the disease progression and is the most common cause of mortality. While new CF disease-modifying agents are currently undergoing clinical trial evaluation, the implementation of such trials in young children is limited by the lack of age-appropriate clinical trial end points. Advances in infant and preschool lung function testing, imaging of the chest and the development of biochemical biomarkers have led to increased possibility of quantifying mild lung disease in young children with CF and objectively monitoring disease progression over the course of an intervention. Despite this, further standardization and development of these techniques is required to provide robust objective measures for clinical trials in this age group.

Have Clinical Trials Properly Assessed c-Met Inhibitors?

PubMed

Hughes, Veronica S; Siemann, Dietmar W

2018-02-01

The c-Met/HGF pathway is implicated in cancer progression and dissemination. Many inhibitors have been developed to target this pathway. Unfortunately, most trials have failed to demonstrate efficacy. However, clinical trials have not adequately tested the concept of c-Met pathway inhibition due to the lack of appropriate patient selection criteria. Copyright © 2017 Elsevier Inc. All rights reserved.

Stem cells in clinical trials for treatment of retinal degeneration.

PubMed

Klassen, Henry

2016-01-01

After decades of basic science research involving the testing of regenerative strategies in animal models of retinal degenerative diseases, a number of clinical trials are now underway, with additional trials set to begin shortly. These efforts will evaluate the safety and preliminary efficacy of cell-based products in the eyes of patients with a number of retinal conditions, notably including age-related macular degeneration, retinitis pigmentosa and Stargardt's disease. This review considers the scientific work and early trials with fetal cells and tissues that set the stage for the current clinical investigatory work, as well the trials themselves, specifically those either now completed, underway or close to initiation. The cells of interest include retinal pigment epithelial cells derived from embryonic stem or induced pluripotent stem cells, undifferentiated neural or retinal progenitors or cells from the vascular/bone marrow compartment or umbilical cord tissue. Degenerative diseases of the retina represent a popular target for emerging cell-based therapeutics and initial data from early stage clinical trials suggest that short-term safety objectives can be met in at least some cases. The question of efficacy will require additional time and testing to be adequately resolved.

INVESTIGATE-I (INVasive Evaluation before Surgical Treatment of Incontinence Gives Added Therapeutic Effect?): a mixed-methods study to assess the feasibility of a future randomised controlled trial of invasive urodynamic testing prior to surgery for stress urinary incontinence in women.

PubMed

Hilton, Paul; Armstrong, Natalie; Brennand, Catherine; Howel, Denise; Shen, Jing; Bryant, Andrew; Tincello, Douglas G; Lucas, Malcolm G; Buckley, Brian S; Chapple, Christopher R; Homer, Tara; Vale, Luke; McColl, Elaine

2015-02-01

The position of invasive urodynamic testing in the diagnostic pathway for urinary incontinence (UI) is unclear. Systematic reviews have called for further trials evaluating clinical utility, although a preliminary feasibility study was considered appropriate. To inform the decision whether or not to proceed to a definitive randomised trial of invasive urodynamic testing compared with clinical assessment with non-invasive tests, prior to surgery in women with stress UI (SUI) or stress predominant mixed UI (MUI). A mixed-methods study comprising a pragmatic multicentre randomised pilot trial; economic evaluation; survey of clinicians' views about invasive urodynamic testing; qualitative interviews with clinicians and trial participants. Urogynaecology, female urology and general gynaecology units in Newcastle, Leicester, Swansea, Sheffield, Northumberland, Gateshead and South Tees. Trial recruits were women with SUI or stress predominant MUI who were considering surgery after unsuccessful conservative treatment. Relevant clinicians completed two online surveys. Subsets of survey respondents and trial participants took part in separate qualitative interview studies. Pilot trial participants were randomised to undergo clinical assessment with non-invasive tests (control arm); or assessment as controls, plus invasive urodynamic testing (intervention arm). Confirmation that units can identify and recruit eligible women; acceptability of investigation strategies and data collection tools; acquisition of outcome data to determine the sample size for a definitive trial. The proposed primary outcome for the definitive trial was International Consultation on Incontinence Modular Questionnaire (ICIQ) Female Lower Urinary Tract Symptoms (ICIQ-FLUTS) (total score) 6 months after surgery or the start of non-surgical treatment; secondary outcomes included: ICIQ-FLUTS (subscales); ICIQ Urinary Incontinence Short Form; ICIQ Lower Urinary Tract Symptoms Quality of Life; Urogenital Distress Inventory; EuroQol-5D; costs, quality-adjusted life-years (QALYs) and incremental cost per QALY, Short Form 12; 3-day bladder diary. Of 284 eligible women, 222 (78%) were recruited; 165/219 (75%) returned questionnaires at baseline and 125/200 (63%) who were sent questionnaires at follow-up. There were few missing data items in returned questionnaires, with individual outcome scales calculable for 81%-94%. Most women underwent surgery; management plans were changed in 19 (19%) participants following invasive urodynamic testing. Participant Costs Questionnaires were returned by 53% 6 months after treatment; complete data to undertake cost-utility analysis were available in 27% (intervention) and 47% (control). While insufficient to recommend changes in practice, the results suggest further research would be valuable. All clinicians responding to the survey had access to invasive urodynamic testing, and most saw it as essential prior to surgery in women with SUI with or without other symptoms; nevertheless, 70% considered the research question underlying INVESTIGATE important and most were willing to randomise patients in a definitive trial. Participants interviewed were positive about the trial and associated documentation; the desire of some women to avoid invasive urodynamic testing contrasted with opinions expressed by clinicians through both survey and interview responses. All elements of a definitive trial and economic evaluation were rehearsed; several areas for protocol modification were identified. Such a trial would require to 400-900 participants, depending on the difference in primary outcome sought. A definitive trial of invasive urodynamic testing versus clinical assessment prior to surgery for SUI or stress predominant MUI should be undertaken. Current Controlled Trials ISRCTN71327395. The National Institute for Health Research Health Technology Assessment programme.

Rapid diagnostic tests versus clinical diagnosis for managing people with fever in malaria endemic settings.

PubMed

Odaga, John; Sinclair, David; Lokong, Joseph A; Donegan, Sarah; Hopkins, Heidi; Garner, Paul

2014-04-17

In 2010, the World Health Organization recommended that all patients with suspected malaria are tested for malaria before treatment. In rural African settings light microscopy is often unavailable. Diagnosis has relied on detecting fever, and most people were given antimalarial drugs presumptively. Rapid diagnostic tests (RDTs) provide a point-of-care test that may improve management, particularly of people for whom the RDT excludes the diagnosis of malaria. To evaluate whether introducing RDTs into algorithms for diagnosing and treating people with fever improves health outcomes, reduces antimalarial prescribing, and is safe, compared to algorithms using clinical diagnosis. We searched the Cochrane Infectious Disease Group Specialized Register; CENTRAL (The Cochrane Library); MEDLINE; EMBASE; CINAHL; LILACS; and the metaRegister of Controlled Trials for eligible trials up to 10 January 2014. We contacted researchers in the field and reviewed the reference lists of all included trials to identify any additional trials. Individual or cluster randomized trials (RCTs) comparing RDT-supported algorithms and algorithms using clinical diagnosis alone for diagnosing and treating people with fever living in malaria-endemic settings. Two authors independently applied the inclusion criteria and extracted data. We combined data from individually and cluster RCTs using the generic inverse variance method. We presented all outcomes as risk ratios (RR) with 95% confidence intervals (CIs), and assessed the quality of evidence using the GRADE approach. We included seven trials, enrolling 17,505 people with fever or reported history of fever in this review; two individually randomized trials and five cluster randomized trials. All trials were conducted in rural African settings.In most trials the health workers diagnosing and treating malaria were nurses or clinical officers with less than one week of training in RDT supported diagnosis. Health worker prescribing adherence to RDT results was highly variable: the number of participants with a negative RDT result who received antimalarials ranged from 0% to 81%.Overall, RDT supported diagnosis had little or no effect on the number of participants remaining unwell at four to seven days after treatment (6990 participants, five trials, low quality evidence); but using RDTs reduced prescribing of antimalarials by up to three-quarters (17,287 participants, seven trials, moderate quality evidence). As would be expected, the reduction in antimalarial prescriptions was highest where health workers adherence to the RDT result was high, and where the true prevalence of malaria was lower.Using RDTs to support diagnosis did not have a consistent effect on the prescription of antibiotics, with some trials showing higher antibiotic prescribing and some showing lower prescribing in the RDT group (13,573 participants, five trials, very low quality evidence).One trial reported malaria microscopy on all enrolled patients in an area of moderate endemicity, so we could compare the number of patients in the RDT and clinical diagnosis groups that actually had microscopy confirmed malaria infection but did not receive antimalarials. No difference was detected between the two diagnostic strategies (1280 participants, one trial, low quality evidence). Algorithms incorporating RDTs can substantially reduce antimalarial prescribing if health workers adhere to the test results. Introducing RDTs has not been shown to improve health outcomes for patients, but adherence to the test result does not seem to result in worse clinical outcomes than presumptive treatment.Concentrating on improving the care of RDT negative patients could improve health outcomes in febrile children.

Raising Public Awareness of Clinical Trials: Development of Messages for a National Health Communication Campaign.

PubMed

Massett, Holly A; Dilts, David M; Bailey, Robert; Berktold, Jennifer; Ledsky, Rebecca; Atkinson, Nancy L; Mishkin, Grace; Denicoff, Andrea; Padberg, Rose Mary; Allen, Marin P; Silver, Karen; Carrington, Kelli; Johnson, Lenora E

2017-05-01

Clinical trials are essential for developing new and effective treatments and improving patient quality of life; however, many trials cannot answer their primary research questions because they fall short of their recruitment goals. This article reports the results of formative research conducted in two populations, the public and primary care physicians, to identify messages that may raise awareness and increase interest in clinical trials and be used in a national communication campaign. Results suggested that participants were primarily motivated to participate in clinical trials out of a self-interest to help themselves first. Messages illustrated that current treatments were tested via clinical trials, helped normalize trials as routine practices, and reduced concerns over trying something new first. Participants wanted messages that portray trials as state-of-the-art choices that offer some hope, show people like themselves, and are described in a clear, concise manner with actionable steps for them to take. The study revealed some differences in message salience, with healthy audiences exhibiting lower levels of interest. Our results suggest that targeted messages are needed, and that communication with primary health-care providers is an important and necessary component in raising patient awareness of the importance of clinical trials.

Clinical implementation of integrated whole-genome copy number and mutation profiling for glioblastoma

PubMed Central

Ramkissoon, Shakti H.; Bi, Wenya Linda; Schumacher, Steven E.; Ramkissoon, Lori A.; Haidar, Sam; Knoff, David; Dubuc, Adrian; Brown, Loreal; Burns, Margot; Cryan, Jane B.; Abedalthagafi, Malak; Kang, Yun Jee; Schultz, Nikolaus; Reardon, David A.; Lee, Eudocia Q.; Rinne, Mikael L.; Norden, Andrew D.; Nayak, Lakshmi; Ruland, Sandra; Doherty, Lisa M.; LaFrankie, Debra C.; Horvath, Margaret; Aizer, Ayal A.; Russo, Andrea; Arvold, Nils D.; Claus, Elizabeth B.; Al-Mefty, Ossama; Johnson, Mark D.; Golby, Alexandra J.; Dunn, Ian F.; Chiocca, E. Antonio; Trippa, Lorenzo; Santagata, Sandro; Folkerth, Rebecca D.; Kantoff, Philip; Rollins, Barrett J.; Lindeman, Neal I.; Wen, Patrick Y.; Ligon, Azra H.; Beroukhim, Rameen; Alexander, Brian M.; Ligon, Keith L.

2015-01-01

Background Multidimensional genotyping of formalin-fixed paraffin-embedded (FFPE) samples has the potential to improve diagnostics and clinical trials for brain tumors, but prospective use in the clinical setting is not yet routine. We report our experience with implementing a multiplexed copy number and mutation-testing program in a diagnostic laboratory certified by the Clinical Laboratory Improvement Amendments. Methods We collected and analyzed clinical testing results from whole-genome array comparative genomic hybridization (OncoCopy) of 420 brain tumors, including 148 glioblastomas. Mass spectrometry–based mutation genotyping (OncoMap, 471 mutations) was performed on 86 glioblastomas. Results OncoCopy was successful in 99% of samples for which sufficient DNA was obtained (n = 415). All clinically relevant loci for glioblastomas were detected, including amplifications (EGFR, PDGFRA, MET) and deletions (EGFRvIII, PTEN, 1p/19q). Glioblastoma patients ≤40 years old had distinct profiles compared with patients >40 years. OncoMap testing reliably identified mutations in IDH1, TP53, and PTEN. Seventy-seven glioblastoma patients enrolled on trials, of whom 51% participated in targeted therapeutic trials where multiplex data informed eligibility or outcomes. Data integration identified patients with complete tumor suppressor inactivation, albeit rarely (5% of patients) due to lack of whole-gene coverage in OncoMap. Conclusions Combined use of multiplexed copy number and mutation detection from FFPE samples in the clinical setting can efficiently replace singleton tests for clinical diagnosis and prognosis in most settings. Our results support incorporation of these assays into clinical trials as integral biomarkers and their potential to impact interpretation of results. Limited tumor suppressor variant capture by targeted genotyping highlights the need for whole-gene sequencing in glioblastoma. PMID:25754088

A cluster randomized clinical trial comparing fit‐tested and non‐fit‐tested N95 respirators to medical masks to prevent respiratory virus infection in health care workers

PubMed Central

MacIntyre, Chandini Raina; Wang, Quanyi; Cauchemez, Simon; Seale, Holly; Dwyer, Dominic E.; Yang, Peng; Shi, Weixian; Gao, Zhanhai; Pang, Xinghuo; Zhang, Yi; Wang, Xiaoli; Duan, Wei; Rahman, Bayzidur; Ferguson, Neil

2011-01-01

Please cite this paper as: MacIntyre et al. (2011) A cluster randomized clinical trial comparing fit‐tested and non‐fit‐tested N95 respirators to medical masks to prevent respiratory virus infection in health care workers. Influenza and Other Respiratory Viruses DOI: 10.1111/j.1750‐2659.2010.00198.x. Background  We compared the efficacy of medical masks, N95 respirators (fit tested and non fit tested), in health care workers (HCWs). Methods  A cluster randomized clinical trial (RCT) of 1441 HCWs in 15 Beijing hospitals was performed during the 2008/2009 winter. Participants wore masks or respirators during the entire work shift for 4 weeks. Outcomes included clinical respiratory illness (CRI), influenza‐like illness (ILI), laboratory‐confirmed respiratory virus infection and influenza. A convenience no‐mask/respirator group of 481 health workers from nine hospitals was compared. Findings  The rates of CRI (3·9% versus 6·7%), ILI (0·3% versus 0·6%), laboratory‐confirmed respiratory virus (1·4% versus 2·6%) and influenza (0·3% versus 1%) infection were consistently lower for the N95 group compared to medical masks. By intention‐to‐treat analysis, when P values were adjusted for clustering, non‐fit‐tested N95 respirators were significantly more protective than medical masks against CRI, but no other outcomes were significant. The rates of all outcomes were higher in the convenience no‐mask group compared to the intervention arms. There was no significant difference in outcomes between the N95 arms with and without fit testing. Rates of fit test failure were low. In a post hoc analysis adjusted for potential confounders, N95 masks and hospital level were significant, but medical masks, vaccination, handwashing and high‐risk procedures were not. Interpretation  Rates of infection in the medical mask group were double that in the N95 group. A benefit of respirators is suggested but would need to be confirmed by a larger trial, as this study may have been underpowered. The finding on fit testing is specific to the type of respirator used in the study and cannot be generalized to other respirators. Trial registration  Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN: ACTRN12609000257268 (http://www.anzctr.org.au). PMID:21477136

Summary and Recommendations from the National Cancer Institute’s Clinical Trials Planning Meeting on Novel Therapeutics for Non-Muscle Invasive Bladder Cancer

PubMed Central

Lerner, Seth P.; Bajorin, Dean F.; Dinney, Colin P.; Efstathiou, Jason A.; Groshen, Susan; Hahn, Noah M.; Hansel, Donna; Kwiatkowski, David; O’Donnell, Michael; Rosenberg, Jonathan; Svatek, Robert; Abrams, Jeffrey S.; Al-Ahmadie, Hikmat; Apolo, Andrea B.; Bellmunt, Joaquim; Callahan, Margaret; Cha, Eugene K.; Drake, Charles; Jarow, Jonathan; Kamat, Ashish; Kim, William; Knowles, Margaret; Mann, Bhupinder; Marchionni, Luigi; McConkey, David; McShane, Lisa; Ramirez, Nilsa; Sharabi, Andrew; Sharpe, Arlene H.; Solit, David; Tangen, Catherine M.; Amiri, Abdul Tawab; Van Allen, Eliezer; West, Pamela J.; Witjes, J. A.; Quale, Diane Zipursky

2016-01-01

The NCI Bladder Cancer Task Force convened a Clinical Trials Planning Meeting (CTPM) Workshop focused on Novel Therapeutics for Non-Muscle Invasive Bladder Cancer (NMIBC). Meeting attendees included a broad and multi-disciplinary group of clinical and research stakeholders and included leaders from NCI, FDA, National Clinical Trials Network (NCTN), advocacy and the pharmaceutical and biotech industry. The meeting goals and objectives were to: 1) create a collaborative environment in which the greater bladder research community can pursue future optimally designed novel clinical trials focused on the theme of molecular targeted and immune-based therapies in NMIBC; 2) frame the clinical and translational questions that are of highest priority; and 3) develop two clinical trial designs focusing on immunotherapy and molecular targeted therapy. Despite successful development and implementation of large Phase II and Phase III trials in bladder and upper urinary tract cancers, there are no active and accruing trials in the NMIBC space within the NCTN. Disappointingly, there has been only one new FDA approved drug (Valrubicin) in any bladder cancer disease state since 1998. Although genomic-based data for bladder cancer are increasingly available, translating these discoveries into practice changing treatment is still to come. Recently, major efforts in defining the genomic characteristics of NMIBC have been achieved. Aligned with these data is the growing number of targeted therapy agents approved and/or in development in other organ site cancers and the multiple similarities of bladder cancer with molecular subtypes in these other cancers. Additionally, although bladder cancer is one of the more immunogenic tumors, some tumors have the ability to attenuate or eliminate host immune responses. Two trial concepts emerged from the meeting including a window of opportunity trial (Phase 0) testing an FGFR3 inhibitor and a second multi-arm multi-stage trial testing combinations of BCG or radiotherapy and immunomodulatory agents in patients who recur after induction BCG (BCG failure). PMID:27376138

Introduction to a Special Issue of the Journal of Immunological Methods: Building global resource programs to support HIV/AIDS clinical trial studies.

PubMed

Sanchez, Ana M; Denny, Thomas N; O'Gorman, Maurice

2014-07-01

This Special Issue of the Journal of Immunological Methods includes 16 manuscripts describing quality assurance activities related to virologic and immunologic monitoring of six global laboratory resource programs that support international HIV/AIDS clinical trial studies: Collaboration for AIDS Vaccine Discovery (CAVD); Center for HIV/AIDS Vaccine Immunology (CHAVI); External Quality Assurance Program Oversight Laboratory (EQAPOL); HIV Vaccine Trial Network (HVTN); International AIDS Vaccine Initiative (IAVI); and Immunology Quality Assessment (IQA). The reports from these programs address the many components required to develop comprehensive quality control activities and subsequent quality assurance programs for immune monitoring in global clinical trials including: all aspects of processing, storing, and quality assessment of PBMC preparations used ubiquitously in HIV clinical trials, the development and optimization of assays for CD8 HIV responses and HIV neutralization, a comprehensive global HIV virus repository, and reports on the development and execution of novel external proficiency testing programs for immunophenotyping, intracellular cytokine staining, ELISPOT and luminex based cytokine measurements. In addition, there are articles describing the implementation of Good Clinical Laboratory Practices (GCLP) in a large quality assurance laboratory, the development of statistical methods specific for external proficiency testing assessment, a discussion on the ability to set objective thresholds for measuring rare events by flow cytometry, and finally, a manuscript which addresses a framework for the structured reporting of T cell immune function based assays. It is anticipated that this series of manuscripts covering a wide range of quality assurance activities associated with the conduct of global clinical trials will provide a resource for individuals and programs involved in improving the harmonization, standardization, accuracy, and sensitivity of virologic and immunologic testing. Copyright © 2014 Elsevier B.V. All rights reserved.

Four-way-leaning test shows larger limits of stability than a circular-leaning test.

PubMed

Thomsen, Mikkel Højgaard; Støttrup, Nicolai; Larsen, Frederik Greve; Pedersen, Ann-Marie Sydow Krogh; Poulsen, Anne Grove; Hirata, Rogerio Pessoto

2017-01-01

Limits of stability (LOS) have extensive clinical and rehabilitational value yet no standard consensus on measuring LOS exists. LOS measured using a leaning or a circling protocol is commonly used in research and clinical settings, however differences in protocols and reliability problems exist. This study measured LOS using a four-way-leaning test and a circular-leaning test to test which showed larger LOS measurements. Furthermore, number of adaptation trials needed for consistent results was assessed. Limits of stability were measured using a force plate (Metitur Good Balance System ® ) sampling at 50Hz. Thirty healthy subjects completed 30 trials assessing LOS alternating between four-way-leaning test and circular-leaning test. A main effect of methods (ANOVA:F(1,28)=45.86, P<0.01) with the four-way-leaning test showing larger values than the circular-leaning test (NK, P<0.01). An interaction between method×directions was found (ANOVA:F(3, 84)=24.87, P<0.01). The four-way-leaning test showed larger LOS in anterior (NK, P<0.05), right (NK, P<0.01) and left direction (NK, P<0.01). Analysis of LOS for the four-way-leaning test showed a difference between trials (ANOVA:F(14,392)=7.81, P<0.01). Differences were found between trial 1 and 7 (NK, P<0.03), trial 6 and 8 (NK, P<0.02) and trial 7 and 15 (NK, P<0.02). Four-way-leaning test showed high correlation (ICC>0.87) between first and second trial for all directions. Four-way-leaning test yields larger LOS in anterior, right and left direction making it more reliable when measuring LOS. A learning effect was found up to the 8th trial, which suggests using 8 adaptation trials before reliable LOS is measured. Copyright © 2016 Elsevier B.V. All rights reserved.

Regulating trust in pediatric clinical trials.

PubMed

Pinxten, Wim; Nys, Herman; Dierickx, Kris

2008-12-01

The participation of minors in clinical trials is essential to provide safe and effective medical care to children. Because few drugs have been tested in children, pediatricians are forced to prescribe medications off-label with uncertain efficacy and safety. In this article, we analyze how the enrollment of minors in clinical trials is negotiated within relationships of mutual trust between clinicians, minors, and their parents. After a brief description of the problems associated with involving minors in clinical research, we consider how existing "relationships of trust" can be used as a place where the concerns of research subjects can be more fully discussed and addressed. Building on the tacit recognition of trust found in The European Clinical Trials Directive we make policy recommendations that allow for clearer, more ethically informed guidelines for enrolling minors in clinical research.

Use of outcome measures in pulmonary hypertension clinical trials.

PubMed

Parikh, Kishan S; Rajagopal, Sudarshan; Arges, Kristine; Ahmad, Tariq; Sivak, Joseph; Kaul, Prashant; Shah, Svati H; Tapson, Victor; Velazquez, Eric J; Douglas, Pamela S; Samad, Zainab

2015-09-01

To evaluate the use of surrogate measures in pulmonary hypertension (PH) clinical trials and how it relates to clinical practice. Studies of pulmonary arterial hypertension (PAH) employ a variety of surrogate measures in addition to clinical events because of a small patient population, participant burden, and costs. The use of these measures in PH drug trials is poorly defined. We searched PubMed/MEDLINE/Embase for randomized or prospective cohort PAH clinical treatment trials from 1985 to 2013. Extracted data included intervention, trial duration, study design, patient characteristics, and primary and secondary outcome measures. To compare with clinical practice, we assessed the use of surrogate measures in a clinical sample of patients on PH medications at Duke University Medical Center between 2003 and 2014. Between 1985 and 2013, 126 PAH trials were identified and analyzed. Surrogate measures served as primary endpoints in 119 trials (94.0%). Inclusion of invasive hemodynamics decreased over time (78.6%, 75.0%, 52.2%; P for trend = .02), while functional testing (7.1%, 60.0%, 81.5%; P for trend < .0001) and functional status or quality of life (0%, 47.6%, 62.8%; P for trend < .0001) increased in PAH trials over the same time periods. Echocardiography data were reported as a primary or secondary outcome in 32 trials (25.4%) with increased use from 1985-1994 to 1995-2004 (7.1% vs 35.0%, P = .04), but the trend did not continue to 2005-2013 (25.0%). In comparison, among 450 patients on PAH therapies at our institution between 2003 and 2013, clinical assessments regularly incorporated serial echocardiography and 6-minute walk distance tests (92% and 95% of patients, respectively) and repeat measurement of invasive hemodynamics (46% of patients). The majority of PAH trials have utilized surrogate measures as primary endpoints. The use of these surrogate endpoints has evolved significantly over time with increasing use of patient-centered endpoints and decreasing or stable use of imaging and invasive measures. In contrast, imaging and invasive measures are commonly used in contemporary clinical practice. Further research is needed to validate and standardize currently used measures. Copyright © 2015 Elsevier Inc. All rights reserved.

Development and Application of Direct Data Capture for Monitoring Medication Compliance in Clinical Trials.

PubMed

Kim, Eun-Young

2017-10-01

The monitoring of medication compliance in clinical trials is important but labor intensive. To check medication compliance in clinical trials, a system was developed, and its technical feasibility evaluated. The system consisted of three parts: a management part (clinical trial center database and a developed program), clinical trial investigator part (monitoring), and clinical trial participant part (personal digital assistant [PDA] with a barcode scanner). The system was tested with 20 participants for 2 weeks, and compliance was evaluated. This study developed a medication compliance monitoring system that used a PDA with a barcode scanner, which sent reminder/warning messages, logged medication barcode data, and provided compliance information to investigators. Registered participants received short message service (SMS) reminder/warning messages on their PDA and sent barcode data at the dosing time. The age range of the participants was 29 to 73 years. Five participants were <50 years old and 8 were ≥65 years old. The total mean compliance rate was 82.3%. The mean compliance rate was 83.1% in participants <65 years old and 81.1% in those ≥65 years old. The system was feasible, usable, and effective, even with elderly participants, for monitoring medication compliance in clinical trials using a PDA with a barcode scanner, and may improve the quality of clinical trials.

Improving the Reporting of Clinical Trials of Infertility Treatments (IMPRINT): modifying the CONSORT statement.

PubMed

2014-10-01

Clinical trials testing infertility treatments often do not report on the major outcomes of interest to patients and clinicians and the public (such as live birth) nor on the harms, including maternal risks during pregnancy and fetal anomalies. This is complicated by the multiple participants in infertility trials which may include a woman (mother), a man (father), and a third individual if successful, their offspring (child), who is also the desired outcome of treatment. The primary outcome of interest and many adverse events occur after cessation of infertility treatment and during pregnancy and the puerperium, which creates a unique burden of follow-up for clinical trial investigators and participants. In 2013, because of the inconsistencies in trial reporting and the unique aspects of infertility trials not adequately addressed by existing Consolidated Standards of Reporting Trials (CONSORT) statements, we convened a consensus conference in Harbin, China, with the aim of planning modifications to the CONSORT checklist to improve the quality of reporting of clinical trials testing infertility treatment. The consensus group recommended that the preferred primary outcome of all infertility trials is live birth (defined as any delivery of a live infant after ≥20 weeks' gestation) or cumulative live birth, defined as the live birth per women over a defined time period (or number of treatment cycles). In addition, harms to all participants should be systematically collected and reported, including during the intervention, any resulting pregnancy, and the neonatal period. Routine information should be collected and reported on both male and female participants in the trial. We propose to track the change in quality that these guidelines may produce in published trials testing infertility treatments. Our ultimate goal is to increase the transparency of benefits and risks of infertility treatments to provide better medical care to affected individuals and couples. Copyright © 2014 The Author. Published by Elsevier Inc. All rights reserved.

A guide to clinical trials for cancer

MedlinePlus

... experience side effects. The new treatment may not work for you. The new treatment may not be as good as standard treatment. You may need more office visits and more tests. Your insurance may not pay for all of your costs in a clinical trial.

Comparative Approaches to Understanding the Relation Between Aging and Physical Function

PubMed Central

Cesari, Matteo; Seals, Douglas R.; Shively, Carol A.; Carter, Christy S.

2016-01-01

Despite dedicated efforts to identify interventions to delay aging, most promising interventions yielding dramatic life-span extension in animal models of aging are often ineffective when translated to clinical trials. This may be due to differences in primary outcomes between species and difficulties in determining the optimal clinical trial paradigms for translation. Measures of physical function, including brief standardized testing batteries, are currently being proposed as biomarkers of aging in humans, are predictive of adverse health events, disability, and mortality, and are commonly used as functional outcomes for clinical trials. Motor outcomes are now being incorporated into preclinical testing, a positive step toward enhancing our ability to translate aging interventions to clinical trials. To further these efforts, we begin a discussion of physical function and disability assessment across species, with special emphasis on mice, rats, monkeys, and man. By understanding how physical function is assessed in humans, we can tailor measurements in animals to better model those outcomes to establish effective, standardized translational functional assessments with aging. PMID:25910845

Asian Americans and Cancer Clinical Trials: A Mixed-Methods Approach to Understanding Awareness and Experience

PubMed Central

Paterniti, Debora A.; Chen, Moon S.; Chiechi, Christine; Beckett, Laurel A.; Horan, Nora; Turrell, Corinne; Smith, Ligaya; Morain, Claudia; Montell, Lisa; Gonzalez, Jose Luis; Davis, Sharon; Lara, Primo N.

2006-01-01

Cancer clinical trials have been based on low accrual rates. Barriers to recruitment of minority populations affect the generalizability and impact of trial findings for those populations. The authors undertook a mixed-methods approach to understanding levels of awareness and experiences with cancer clinical trials. A survey was administered to new cancer patients and their caretakers (family, close friends, or other social support) at outpatient oncology clinics. Field observations of the trial accrual process also were conducted by employing the grounded theory approach in qualitative methods. Comparison of survey results for Asian-American respondents and non-Asian respondents indicated that Asians were less likely to have heard the term “clinical trial” and were more likely to define a clinical trial as “an experiment” or “a test procedure in a clinic” than non-Asians. Asians were more likely to have employer-based insurance and to report understanding issues related to cost reimbursement. Asians were less likely to have been involved in or to know someone in a trial and reported less willingness than white respondents to consider trial participation. Qualitative observations suggested that Asians who presented for a potential trial were interested in the availability of a novel cancer therapy but were not eligible for available trials. Multiple strategies will be necessary to enhance awareness of and experience with accrual to cancer clinical trials for Asians, including richer understanding and increased involvement of Asians in cancer clinical trials and greater attention to the location and diversity of the Asian population in structuring study centers and evaluating trial results. PMID:16247795

A European multi-language initiative to make the general population aware of independent clinical research: the European Communication on Research Awareness Need project.

PubMed

Mosconi, Paola; Antes, Gerd; Barbareschi, Giorgio; Burls, Amanda; Demotes-Mainard, Jacques; Chalmers, Iain; Colombo, Cinzia; Garattini, Silvio; Gluud, Christian; Gyte, Gill; Mcllwain, Catherine; Penfold, Matt; Post, Nils; Satolli, Roberto; Valetto, Maria Rosa; West, Brian; Wolff, Stephanie

2016-01-12

The ECRAN (European Communication on Research Awareness Needs) project was initiated in 2012, with support from the European Commission, to improve public knowledge about the importance of independent, multinational, clinical trials in Europe. Participants in the ECRAN consortium included clinicians and methodologists directly involved in clinical trials; researchers working in partnership with the public and patients; representatives of patients; and experts in science communication. We searched for, and evaluated, relevant existing materials and developed additional materials and tools, making them freely available under a Creative Commons licence. The principal communication materials developed were: 1. A website ( http://ecranproject.eu ) in six languages, including a Media centre section to help journalists to disseminate information about the ECRAN project 2. An animated film about clinical trials, dubbed in the 23 official languages of the European Community, and an interactive tutorial 3. An inventory of resources, available in 23 languages, searchable by topic, author, and media type 4. Two educational games for young people, developed in six languages 5. Testing Treatments interactive in a dozen languages, including five official European Community languages 6. An interactive tutorial slide presentation testing viewers' knowledge about clinical trials Over a 2-year project, our multidisciplinary and multinational consortium was able to produce, and make freely available in many languages, new materials to promote public knowledge about the importance of independent and international clinical trials. Sustained funding for the ECRAN information platform could help to promote successful recruitment to independent clinical trials supported through the European Clinical Research Infrastructure Network.

Comparing the effect of a decision aid plus patient navigation with usual care on colorectal cancer screening completion in vulnerable populations: study protocol for a randomized controlled trial

PubMed Central

2014-01-01

Background Screening can reduce colorectal cancer (CRC) incidence and mortality. However, screening is underutilized in vulnerable patient populations, particularly among Latinos. Patient-directed decision aids can increase CRC screening knowledge, self-efficacy, and intent; however, their effect on actual screening test completion tends to be modest. This is probably because decision aids do not address some of the patient-specific barriers that prevent successful completion of CRC screening in these populations. These individual barriers might be addressed though patient navigation interventions. This study will test a combined decision aid and patient navigator intervention on screening completion in diverse populations of vulnerable primary care patients. Methods/Design We will conduct a multisite, randomized controlled trial with patient-level randomization. Planned enrollment is 300 patients aged 50 to 75 years at average CRC risk presenting for appointments at two primary clinics in North Carolina and New Mexico. Intervention participants will view a video decision aid immediately before the clinic visit. The 14 to 16 minute video presents information about fecal occult blood tests and colonoscopy and will be viewed on a portable computer tablet in English or Spanish. Clinic-based patient navigators are bilingual and bicultural and will provide both face-to-face and telephone-based navigation. Control participants will view an unrelated food safety video and receive usual care. The primary outcome is completion of a CRC screening test at six months. Planned subgroup analyses include examining intervention effectiveness in Latinos, who will be oversampled. Secondarily, the trial will evaluate the intervention effects on knowledge of CRC screening, self-efficacy, intent, and patient-provider communication. The study will also examine whether patient ethnicity, acculturation, language preference, or health insurance status moderate the intervention effect on CRC screening. Discussion This pragmatic randomized controlled trial will test a combined decision aid and patient navigator intervention targeting CRC screening completion. Findings from this trial may inform future interventions and implementation policies designed to promote CRC screening in vulnerable patient populations and to reduce screening disparities. Clinical trial registration ClinicalTrials.gov NCT02054598. PMID:25004983

Methodological considerations in the design and implementation of clinical trials.

PubMed

Cirrincione, Constance T; Lavoie Smith, Ellen M; Pang, Herbert

2014-02-01

To review study design issues related to clinical trials led by oncology nurses, with special attention to those conducted within the cooperative group setting; to emphasize the importance of the statistician's role in the process of clinical trials. Studies available at clinicaltrials.gov using experimental designs that have been published in peer-reviewed journals; cooperative group trials are highlighted. The clinical trial is a primary means to test intervention efficacy. A properly designed and powered study with clear and measurable objectives is as important as the intervention itself. Collaboration among the study team, including the statistician, is central in developing and conducting appropriately designed studies. For optimal results, collaboration is an ongoing process that should begin early on. Copyright © 2014 Elsevier Inc. All rights reserved.

Global issues in drug development for Alzheimer's disease.

PubMed

Doody, Rachelle S; Cole, Patricia E; Miller, David S; Siemers, Eric; Black, Ronald; Feldman, Howard; Schindler, Rachel; Graham, Stephen; Heath, Theresa; Khachaturian, Ara S; Evans, Rebecca; Carrillo, Maria C

2011-03-01

The number of clinical trials for Alzheimer's disease conducted outside the United States in a broad array of countries is increasing. As the number of compounds ready for clinical testing increases, and as trials become longer and more complex, this trend is expected to grow. The cultural and ethical context of global clinical trials, potential benefits for those involved, and practical approaches to obstacles generated by these global trials were discussed at a meeting of the Alzheimer's Association Research Roundtable. Regulatory issues, including regional differences in study registration procedures, rules for collecting and reporting serious adverse events, requirements for national identity of study populations, and regulatory audits were also discussed by individuals who are knowledgeable about global clinical trials for Alzheimer's disease. Copyright © 2011 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

South Asian patients' views and experiences of clinical trial participation.

PubMed

Hussain-Gambles, Mah

2004-12-01

This paper explores South Asian patients' views and experiences of clinical trial participation, as part of a larger study which sought to assess British South Asian under-representation in clinical trials. The study was based on semi-structured interviews with South Asian trial participants in primary care and specialist treatment centres in the north of England. Fifteen South Asian patients who had participated in one of six different clinical trials to test pharmaceutical products comprised the study cohort. South Asian motivations to participate in clinical trials are similar to those of the majority 'White' population. Clear and concise trial information (provided by caring and understanding trial staff) was considered an important aspect of the respondents' experiences. Appealing to South Asian peoples' altruistic nature by making them aware of South Asian under-representation (especially in clinical trials that investigate illnesses prevalent in their community) was also identified as a strong motivational factor. Potential barriers to their participation included: trial burden (which bears heavily on the poor), language, and discriminatory practices in the NHS, which can lead to mistrust of health professionals. In addition, female modesty and preference for female trial staff was recognized as a 'cultural' barrier to participation. There are more similarities than differences between the experiences of British South Asians and 'White' trial participants. Present findings suggest that ethnicity operates at different levels. In addition to South Asian trial participants' culture, social class and gender are also as likely to affect their participation in clinical trials. To improve South Asian accrual rates, strategies should be designed to take into consideration linguistic differences and improving overall trust in the clinical trial team.

NIH-Supported Trials Test Hormonal Therapy in Older Men with Low Testosterone Levels

MedlinePlus

... February 18, 2016 NIH-supported trials test hormonal therapy in older men with low testosterone levels Testosterone ... Hadley, M.D., director of NIA’s Division of Geriatrics and Clinical Gerontology. “In contrast, though, the results ...

Clinical trials of homoeopathy.

PubMed Central

Kleijnen, J; Knipschild, P; ter Riet, G

1991-01-01

OBJECTIVE--To establish whether there is evidence of the efficacy of homoeopathy from controlled trials in humans. DESIGN--Criteria based meta-analysis. Assessment of the methodological quality of 107 controlled trials in 96 published reports found after an extensive search. Trials were scored using a list of predefined criteria of good methodology, and the outcome of the trials was interpreted in relation to their quality. SETTING--Controlled trials published world wide. MAIN OUTCOME MEASURES--Results of the trials with the best methodological quality. Trials of classical homoeopathy and several modern varieties were considered separately. RESULTS--In 14 trials some form of classical homoeopathy was tested and in 58 trials the same single homoeopathic treatment was given to patients with comparable conventional diagnosis. Combinations of several homoeopathic treatments were tested in 26 trials; isopathy was tested in nine trials. Most trials seemed to be of very low quality, but there were many exceptions. The results showed a positive trend regardless of the quality of the trial or the variety of homeopathy used. Overall, of the 105 trials with interpretable results, 81 trials indicated positive results whereas in 24 trials no positive effects of homoeopathy were found. The results of the review may be complicated by publication bias, especially in such a controversial subject as homoeopathy. CONCLUSIONS--At the moment the evidence of clinical trials is positive but not sufficient to draw definitive conclusions because most trials are of low methodological quality and because of the unknown role of publication bias. This indicates that there is a legitimate case for further evaluation of homoeopathy, but only by means of well performed trials. PMID:1825800

Enhancing decision making about participation in cancer clinical trials: development of a question prompt list

PubMed Central

Brown, Richard F.; Shuk, Elyse; Leighl, Natasha; Butow, Phyllis; Ostroff, Jamie; Edgerson, Shawna; Tattersall, Martin

2016-01-01

Purpose Slow accrual to cancer clinical trials impedes the progress of effective new cancer treatments. Poor physician–patient communication has been identified as a key contributor to low trial accrual. Question prompt lists (QPLs) have demonstrated a significant promise in facilitating communication in general, surgical, and palliative oncology settings. These simple patient interventions have not been tested in the oncology clinical trial setting. We aimed to develop a targeted QPL for clinical trials (QPL-CT). Method Lung, breast, and prostate cancer patients who either had (trial experienced) or had not (trial naive) participated in a clinical trial were invited to join focus groups to help develop and explore the acceptability of a QPL-CT. Focus groups were audio-recorded and transcribed. A research team, including a qualitative data expert, analyzed these data to explore patients’ decision-making processes and views about the utility of the QPL-CT prompt to aid in trial decision making. Results Decision making was influenced by the outcome of patients’ comparative assessment of perceived risks versus benefits of a trial, and the level of trust patients had in their doctors’ recommendation about the trial. Severity of a patient’s disease influenced trial decision making only for trial-naive patients. Conclusion Although patients were likely to prefer a paternalistic decision-making style, they expressed valuation of the QPL as an aid to decision making. QPL-CT utility extended beyond the actual consultation to include roles both before and after the clinical trial discussion. PMID:20593202

Leidos Biomed Supports Clinical Trials for Vaccine Against Mosquito-borne Chikungunya | FNLCR Staging

Cancer.gov

An experimental vaccine for mosquito-borne chikungunya is being tested at sites in the Caribbean as part of a phase II clinical trial being managed by the Frederick National Lab. No vaccine or treatment currently exists for the viral disease, which c

Magnetic resonance imaging and transient elastography in the management of Nonalcoholic Fatty Liver Disease (NAFLD).

PubMed

Han, Ma Ai Thanda; Saouaf, Rola; Ayoub, Walid; Todo, Tsuyoshi; Mena, Edward; Noureddin, Mazen

2017-04-01

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and cirrhosis worldwide and the second most common cause of liver transplantation in major medical centers. Because liver steatosis and fibrosis severity are related to disease morbidity and mortality, the extent of disease, and disease progression, they need to be assessed and monitored. In addition, innovation with new drug developments requires disease staging and monitoring in both phase 2 and 3 clinical trials. Currently, disease assessment in both clinical practice and research is mostly performed by liver biopsy, an invasive, procedure with risks. Noninvasive, highly accurate tests are needed that could be used in clinical trials as surrogate endpoints and in clinical practice for monitoring patients. Area Covered: We discuss noninvasive tests, transient elastography (TE) with controlled attenuation parameter (CAP), magnetic resonance imaging (MRI), and MR elastography (MRE), summarize the available evidence of their usefulness for assessing steatosis and fibrosis. Therefore they could be used as clinical trials outcomes and in disease monitoring in clinical practice. Expert Commentary: TE with CAP, MRI and MRE are highly accurate noninvasive diagnostic tools for quantifying hepatic steatosis and fibrosis. Therefore they could be used as clinical trials outcomes and in disease monitoring in clinical practice.

Adjusted regression trend test for a multicenter clinical trial.

PubMed

Quan, H; Capizzi, T

1999-06-01

Studies using a series of increasing doses of a compound, including a zero dose control, are often conducted to study the effect of the compound on the response of interest. For a one-way design, Tukey et al. (1985, Biometrics 41, 295-301) suggested assessing trend by examining the slopes of regression lines under arithmetic, ordinal, and arithmetic-logarithmic dose scalings. They reported the smallest p-value for the three significance tests on the three slopes for safety assessments. Capizzi et al. (1992, Biometrical Journal 34, 275-289) suggested an adjusted trend test, which adjusts the p-value using a trivariate t-distribution, the joint distribution of the three slope estimators. In this paper, we propose an adjusted regression trend test suitable for two-way designs, particularly for multicenter clinical trials. In a step-down fashion, the proposed trend test can be applied to a multicenter clinical trial to compare each dose with the control. This sequential procedure is a closed testing procedure for a trend alternative. Therefore, it adjusts p-values and maintains experimentwise error rate. Simulation results show that the step-down trend test is overall more powerful than a step-down least significant difference test.

The ASCUS/LSIL Triage Study for Cervical Cancer (ALTS) | Division of Cancer Prevention

Cancer.gov

ALTS was a clinical trial to find the best way to help women and their doctors decide what to do about the mildly abnormal and very common Pap test results known as ASCUS and LSIL. | ALTS was a clinical trial to find the best way to help women and their doctors decide what to do about the mildly abnormal and very common Pap test results known as ASCUS and LSIL.

Should academic medical centers conduct clinical trials of the efficacy of intercessory prayer?

PubMed

Halperin, E C

2001-08-01

Intercessory prayers for health or healing are requests to an object of worship for the preservation or restoration of health. There has been a recent proliferation of clinical trials that compare the health outcome of a group of prayed-for patients with that of controls, to test the efficacy of intercessory prayer. In this essay, the author defines the concept of intercessory prayer, contrasts it with other forms of prayer, and reviews the literature concerning clinical trials of its efficacy. The arguments put forward in favor of conducting such trials and those against are described and the reader is invited to consider their relative merits. The author concludes by discussing the potential power of faith in healing, reviewing the philosophical basis and pitfalls of clinical trials of intercessory prayer, and urging readers to weigh the arguments for and against such trials in academic medicine.

Cost-Effectiveness of Early Versus Standard Antiretroviral Therapy in HIV-Infected Adults in Haiti

PubMed Central

Koenig, Serena P.; Bang, Heejung; Severe, Patrice; Jean Juste, Marc Antoine; Ambroise, Alex; Edwards, Alison; Hippolyte, Jessica; Fitzgerald, Daniel W.; McGreevy, Jolion; Riviere, Cynthia; Marcelin, Serge; Secours, Rode; Johnson, Warren D.; Pape, Jean W.; Schackman, Bruce R.

2011-01-01

Background In a randomized clinical trial of early versus standard antiretroviral therapy (ART) in HIV-infected adults with a CD4 cell count between 200 and 350 cells/mm3 in Haiti, early ART decreased mortality by 75%. We assessed the cost-effectiveness of early versus standard ART in this trial. Methods and Findings Trial data included use of ART and other medications, laboratory tests, outpatient visits, radiographic studies, procedures, and hospital services. Medication, laboratory, radiograph, labor, and overhead costs were from the study clinic, and hospital and procedure costs were from local providers. We evaluated cost per year of life saved (YLS), including patient and caregiver costs, with a median of 21 months and maximum of 36 months of follow-up, and with costs and life expectancy discounted at 3% per annum. Between 2005 and 2008, 816 participants were enrolled and followed for a median of 21 months. Mean total costs per patient during the trial were US$1,381 for early ART and US$1,033 for standard ART. After excluding research-related laboratory tests without clinical benefit, costs were US$1,158 (early ART) and US$979 (standard ART). Early ART patients had higher mean costs for ART (US$398 versus US$81) but lower costs for non-ART medications, CD4 cell counts, clinically indicated tests, and radiographs (US$275 versus US$384). The cost-effectiveness ratio after a maximum of 3 years for early versus standard ART was US$3,975/YLS (95% CI US$2,129/YLS–US$9,979/YLS) including research-related tests, and US$2,050/YLS excluding research-related tests (95% CI US$722/YLS–US$5,537/YLS). Conclusions Initiating ART in HIV-infected adults with a CD4 cell count between 200 and 350 cells/mm3 in Haiti, consistent with World Health Organization advice, was cost-effective (US$/YLS <3 times gross domestic product per capita) after a maximum of 3 years, after excluding research-related laboratory tests. Trial registration ClinicalTrials.gov NCT00120510 Please see later in the article for the Editors' Summary PMID:21949643

An educational video to increase clinical trials enrollment among breast cancer patients.

PubMed

Du, Wei; Mood, Darlene; Gadgeel, Shirish; Simon, Michael S

2009-09-01

Only 3% of women with breast cancer participate in cancer clinical trials nationwide. The lack of awareness about clinical trials is a significant barrier towards clinical trials participation. A study was conducted at a large urban Comprehensive Cancer Center to test (1) the effectiveness of an 18-min educational video on improving attitudes toward clinical trials and trials enrollment among new breast cancer patients seen at the Karmanos Cancer Institute, and (2) to assess racial differences in attitudes regarding clinical trials. Participants were randomized to either the educational intervention prior to their first oncology clinic appointment or to standard care. A baseline and 2-week post-intervention survey to assess attitudes toward clinical trials participation was completed by participants. Of 218 subjects recruited, 196 (55% white vs. 45% African American (AA)) eligible patients were included in the analysis. A small increase in therapeutic clinical trial enrollment was observed in the intervention arm but was not statistically significant (10.4% vs. 6.1%; P = 0.277). The intervention also did not result in a clear improvement in patients' attitudes toward clinical trials at posttest. However, a lower enrollment rate for the AA women was noted after adjusting for stage (OR = 0.282, P = 0.049). Significantly more negative scores were noted in 3 out of the 5 baseline attitudinal scales for AA women. The educational video did not significantly increase enrollment in breast cancer clinical trials. The findings that AA women had significantly more negative attitudes toward clinical trials than white women may partially explain the racial disparity in enrollment. An educational video remains a simple and cost-effective way to educate patients. Future studies should focus on designing a new educational video to specifically target cultural and attitudinal barriers in the AA population to more effectively change attitudes and increase trial enrollment.

An educational video to increase clinical trials enrollment among breast cancer patients

PubMed Central

Du, Wei; Mood, Darlene; Gadgeel, Shirish; Simon, Michael S.

2013-01-01

Only 3% of women with breast cancer participate in cancer clinical trials nationwide. The lack of awareness about clinical trials is a significant barrier towards clinical trials participation. A study was conducted at a large urban Comprehensive Cancer Center to test (1) the effectiveness of an 18-min educational video on improving attitudes toward clinical trials and trials enrollment among new breast cancer patients seen at the Karmanos Cancer Institute, and (2) to assess racial differences in attitudes regarding clinical trials. Participants were randomized to either the educational intervention prior to their first oncology clinic appointment or to standard care. A baseline and 2-week post-intervention survey to assess attitudes toward clinical trials participation was completed by participants. Of 218 subjects recruited, 196 (55% white vs. 45% African American (AA)) eligible patients were included in the analysis. A small increase in therapeutic clinical trial enrollment was observed in the intervention arm but was not statistically significant (10.4% vs. 6.1%; P = 0.277). The intervention also did not result in a clear improvement in patients’ attitudes toward clinical trials at posttest. However, a lower enrollment rate for the AA women was noted after adjusting for stage (OR = 0.282, P = 0.049). Significantly more negative scores were noted in 3 out of the 5 baseline attitudinal scales for AA women. The educational video did not significantly increase enrollment in breast cancer clinical trials. The findings that AA women had significantly more negative attitudes toward clinical trials than white women may partially explain the racial disparity in enrollment. An educational video remains a simple and cost-effective way to educate patients. Future studies should focus on designing a new educational video to specifically target cultural and attitudinal barriers in the AA population to more effectively change attitudes and increase trial enrollment. PMID:19152024

78 FR 65338 - Agency Information Collection Activities; Submission for Office of Management and Budget Review...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-31

..., other clinical studies, or in vitro testing. Reports from animal testing are not included. \\3\\ Includes... serious risks from clinical trials within 15 calendar days for findings from in vitro testing that suggest...

Clinical Utility of Epstein-Barr Virus DNA Testing in the Treatment of Nasopharyngeal Carcinoma Patients.

PubMed

Kim, Kelly Y; Le, Quynh-Thu; Yom, Sue S; Ng, Raymond H W; Chan, K C Allen; Bratman, Scott V; Welch, John J; Divi, Rao L; Petryshyn, Raymond A; Conley, Barbara A

2017-08-01

Epstein-Barr virus (EBV) DNA analysis has been shown to be useful for early detection, prognostication, and monitoring of treatment response of nasopharyngeal carcinoma (NPC), and the recent literature provides growing evidence of the clinical utility of EBV DNA testing, particularly to inform treatment decisions for NPC patients. Despite the fact that NPC is a rare disease, the NRG Oncology cooperative group has successfully activated a phase 2/3 randomized clinical trial for NPC with international partners and in that process has discovered that the development of a harmonized EBV DNA test is absolutely critical for integration into clinical trials and for future deployment in clinical and central laboratories. In November 2015, the National Cancer Institute (NCI) convened a workshop of international experts in the treatment of NPC and EBV testing to provide a forum for discussing the state of EBV DNA testing and its clinical utility, and to stimulate consideration of future studies and clinical practice guidelines for EBV DNA. This review provides a summary of that discussion. Published by Elsevier Inc.

Lost in translation: neuropsychiatric drug development.

PubMed

Becker, Robert E; Greig, Nigel H

2010-12-08

Recent studies have identified troubling method and practice lapses in neuropsychiatric drug developments. These problems have resulted in errors that are of sufficient magnitude to invalidate clinical trial data and interpretations. We identify two potential sources for these difficulties: investigators selectively choosing scientific practices for demonstrations of efficacy in human-testing phases of drug development and investigators failing to anticipate the needs of practitioners who must optimize treatment for the individual patient. When clinical investigators neglect to use clinical trials as opportunities to test hypotheses of disease mechanisms in humans, the neuropsychiatric knowledge base loses both credibility and scope. When clinical investigators do not anticipate the need to translate discoveries into applications, the practitioner cannot provide optimal care for the patient. We conclude from this evidence that clinical trials, and other aspects of neuropsychiatric drug development, must adopt more practices from basic science and show greater responsiveness to conditions of clinical practice. We feel that these changes are necessary to overcome current threats to the validity and utility of studies of neurological and psychiatric drugs.

HIV Vaccines

MedlinePlus

... an NIH-supported clinical trial was launched to test a modified HIV vaccine. This current vaccine trial, called HVTN 702, is testing whether an experimental vaccine regimen safely prevents HIV infection among South African adults. Learn more in this blog post and in the video below. /* // ** // */ Why Do We ...

Rapid testing for malaria in settings where microscopy is available and peripheral clinics where only presumptive treatment is available: a randomised controlled trial in Ghana.

PubMed

Ansah, Evelyn K; Narh-Bana, Solomon; Epokor, Michael; Akanpigbiam, Samson; Quartey, Alberta Amu; Gyapong, John; Whitty, Christopher J M

2010-03-05

To test in West Africa the impact of rapid diagnostic tests on the prescription of antimalarials and antibiotics both where microscopy is used for the diagnosis of malaria and in clinical (peripheral) settings that rely on clinical diagnosis. Randomised, controlled, open label clinical trial. Four clinics in the rural Dangme West district of southern Ghana, one in which microscopy is used for diagnosis of malaria ("microscopy setting") and three where microscopy is not available and diagnosis of malaria is made on the basis of clinical symptoms ("clinical setting"). Patients with suspected malaria. Interventions Patients were randomly assigned to either a rapid diagnostic test or the current diagnostic method at the clinic (microscopy or clinical diagnosis). A blood sample for a research microscopy slide was taken for all patients. The primary outcome was the prescription of antimalarials to patients of any age whose double read research slide was negative for malaria. The major secondary outcomes were the correct prescription of antimalarials, the impact of test results on antibiotic prescription, and the correct prescription of antimalarials in children under 5 years. Of the 9236 patients screened, 3452 were randomised in the clinical setting and 3811 in the microscopy setting. Follow-up to 28 days was 97.6% (7088/7263). In the microscopy setting, 722 (51.6%) of the 1400 patients with negative research slides in the rapid diagnostic test arm were treated for malaria compared with 764 (55.0%) of the 1389 patients in the microscopy arm (adjusted odds ratio 0.87, 95% CI 0.71 to 1.1; P=0.16). In the clinical setting, 578 (53.9%) of the 1072 patients in the rapid diagnostic test arm with negative research slides were treated for malaria compared with 982 (90.1%) of the 1090 patients with negative slides in the clinical diagnosis arm (odds ratio 0.12, 95% CI 0.04 to 0.38; P=0.001). The use of rapid diagnostic tests led to better targeting of antimalarials and antibiotics in the clinical but not the microscopy setting, in both children and adults. There were no deaths in children under 5 years at 28 days follow-up in either arm. Where microscopy already exists, introducing rapid diagnostic tests had limited impact on prescriber behaviour. In settings where microscopy was not available, however, using rapid diagnostic tests led to a significant reduction in the overprescription of antimalarials, without any evidence of clinical harm, and to better targeting of antibiotics. Trial registration ClinicalTrials.gov NCT00493922.

In vivo procedures for assessment of hair greasiness.

PubMed

Knott, C A; Daykin, K; Ryan, J

1983-06-01

Synopsis Greasy hair is a common problem in Europe. The first step in developing anti-grease hair products must be to establish a sensitive protocol for measuring any changes in perceived hair greasiness. Sensitive clinical trials and in vivo evaluation methods of determining hair greasiness have been developed that show significant differences in the perceived hair greasiness following the use of different shampoos. Products tested in two clinical trials for efficacy as anti-grease shampoos were an anti-grease shampoo containing 2% 3,4-thiolanediol as the active ingredient, and a baby shampoo based on mild surfactants. The same placebo shampoo based on ether sulphates used in typical European shampoo formulations was used in both tests. A shampoo containing 2% zinc pyrithione was included in the trials as a control, since there were indications that this would increase the amount of hair greasiness. Neither of the test products were shown to be effective anti-grease shampoos. The shampoo containing 2% zinc pyrithione was shown to produce significantly more greasiness than both the placebo and the test shampoos. Since significant differences could be shown between the different shampoos, the protocol and in vivo evaluation techniques used in these clinical trials are considered to be validated.

Evaluating real-time internet therapy and online self-help for problematic alcohol consumers: a three-arm RCT protocol.

PubMed

Blankers, Matthijs; Koeter, Maarten; Schippers, Gerard M

2009-01-14

Only a minority of all alcohol- and drug abusers is receiving professional care. In an attempt to narrow this treatment gap, treatment facilities experiment with online healthcare. Therefore, it is important to test the (cost-)effectiveness of online health interventions in a randomized clinical trial. This paper presents the protocol of a three-arm randomized clinical trial to test the (cost-) effectiveness of online treatment for problem drinkers. Self-help online, therapy online and a waiting list are tested against each other. Primary outcome is change in alcohol consumption. Secondary outcome measures include quality of life and working ability. Incremental cost-effectiveness ratios for self-help online alcohol and therapy online alcohol will be calculated. The predictive validity of participant characteristics on treatment adherence and outcome will be explored. To our best knowledge, this randomized clinical trial will be the first to test the effectiveness of therapy online against both self-help online and a waiting-list. It will provide evidence on (cost-) effectiveness of online treatment for problem drinkers and investigate outcome predictors. This trial is registered in the Dutch Trialregister (Cochrane Collaboration) and traceable as NTR-TC1155.

A lay patient navigation training curriculum targeting disparities in cancer clinical trials.

PubMed

Bryant, Debbie Chatman; Williamson, Deborah; Cartmell, Kathleen; Jefferson, Melanie

2011-12-01

African-Americans experience a disproportionate share of thoracic cancer burden compared to Whites. Low socioeconomic status (SES) and race are factors in low clinical trial enrollment, accounting for the disparities between African-Americans and Whites. Less than 3% of newly diagnosed cancer patients enroll in clinical trials, and of that number, only 10% represent ethnic minorities. The value of clinical trials research is not generalizable without sufficient representation by ethnic minorities. Patient navigation, an intervention designed to ensure timely and efficient access to healthcare, may improve clinical trial enrollment among African-Americans in lung and esophageal trials by influencing a patient's perception of clinical trials. The lack of navigation programs and training may negatively influence standardization of navigation techniques. The purpose of this project was to deliver and evaluate an evidence-based navigation-training curriculum for "lay" navigators. The primary outcomes measured were confidence in the role as navigator, understanding a navigator's role, and knowledge and perception of clinical trials. The results revealed overall confidence in the role as lay navigators increased from pre-to-post test. Lessons learned included the need for preparatory classes to build the navigator's confidence, and additional training components in death and dying. A larger study is warranted to confirm the findings.

Regulation (EC) No 1901/2006 on medicinal products for paediatric use & clinical research in vulnerable populations.

PubMed

Lehmann, Birka

2008-12-08

Before any medicinal product is authorised for use in adults, it must undergo extensive pharmaceutical consistency and stability tests, toxicological tests and clinical trials to ensure that it is of high quality, safe and effective.The same approach may not always be applied to medicinal products used to treat children.Studies showed that over 50% of the medicinal products used in children may not have been tested for use in this age group. The absence of suitable authorised medicinal products to treat conditions in children results from the fact that pharmaceutical companies do not adapt medicinal products to the needs of the paediatric population. This leaves health care professionals with no alternative other than to use medicinal products "off-label" and to use unauthorised products with the associated risks of inefficacy and/or adverse reactions.The Regulation (EC) No 1901/2006 sets up a system of requirements, rewards and incentives, together with horizontal measures, to ensure that medicinal products are researched, developed and authorised to meet the therapeutic needs of children.The Regulation is addressed to: 1. The pharmaceutical industry by setting out the legal framework for receiving rewards and incentives by conducting clinical trials in the paediatric population. 2. The Member States to set out to support research into, and the development and availability of, medicinal products for paediatric use. 3. The Community as funds for research into medicinal products for the paediatric population shall be provided for in the Community budget in order to support studies relating to medicinal products or active substances not covered by a patent or a supplementary protection certificate. The legal framework for conducting clinical trials, including children/minors, is set up in Directive 2001/20/EC, the Clinical Trials Directive (CTD), for the European Union (EU). The CTD establishes specific provisions regarding conduct of clinical trials, including multi-centre trials, on human subjects involving medicinal products and in particular relating to the implementation of good clinical practice. Compliance with this good practice provides assurance that the rights, safety and well-being of trial subjects are protected, and that the results of the clinical trials are credible. The CTD is addressed to all investigators conducting clinical trials including clinical trials in the paediatric population and had to be applied accordingly.In the framework of the authorisation of medicinal products regulated by the Regulation (EC) No 726/2004 and Directive 2001/83/EC as amended and the CTD, and additional implementing Directives and guidelines, the new Regulation (EC) No 1901/2006 is an important new piece of legislation focusing on the requirements to improve the situation for the paediatric population. All Regulations/Directives to be found: http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol1_en.htm.

Regulation (EC) No 1901/2006 on medicinal products for paediatric use & clinical research in vulnerable populations

PubMed Central

Lehmann, Birka

2008-01-01

Before any medicinal product is authorised for use in adults, it must undergo extensive pharmaceutical consistency and stability tests, toxicological tests and clinical trials to ensure that it is of high quality, safe and effective. The same approach may not always be applied to medicinal products used to treat children. Studies showed that over 50% of the medicinal products used in children may not have been tested for use in this age group. The absence of suitable authorised medicinal products to treat conditions in children results from the fact that pharmaceutical companies do not adapt medicinal products to the needs of the paediatric population. This leaves health care professionals with no alternative other than to use medicinal products "off-label" and to use unauthorised products with the associated risks of inefficacy and/or adverse reactions. The Regulation (EC) No 1901/2006 sets up a system of requirements, rewards and incentives, together with horizontal measures, to ensure that medicinal products are researched, developed and authorised to meet the therapeutic needs of children. The Regulation is addressed to: 1. The pharmaceutical industry by setting out the legal framework for receiving rewards and incentives by conducting clinical trials in the paediatric population. 2. The Member States to set out to support research into, and the development and availability of, medicinal products for paediatric use. 3. The Community as funds for research into medicinal products for the paediatric population shall be provided for in the Community budget in order to support studies relating to medicinal products or active substances not covered by a patent or a supplementary protection certificate. The legal framework for conducting clinical trials, including children/minors, is set up in Directive 2001/20/EC, the Clinical Trials Directive (CTD), for the European Union (EU). The CTD establishes specific provisions regarding conduct of clinical trials, including multi-centre trials, on human subjects involving medicinal products and in particular relating to the implementation of good clinical practice. Compliance with this good practice provides assurance that the rights, safety and well-being of trial subjects are protected, and that the results of the clinical trials are credible. The CTD is addressed to all investigators conducting clinical trials including clinical trials in the paediatric population and had to be applied accordingly. In the framework of the authorisation of medicinal products regulated by the Regulation (EC) No 726/2004 and Directive 2001/83/EC as amended and the CTD, and additional implementing Directives and guidelines, the new Regulation (EC) No 1901/2006 is an important new piece of legislation focusing on the requirements to improve the situation for the paediatric population. All Regulations/Directives to be found: PMID:19063722

Two-sample statistics for testing the equality of survival functions against improper semi-parametric accelerated failure time alternatives: an application to the analysis of a breast cancer clinical trial.

PubMed

Broët, Philippe; Tsodikov, Alexander; De Rycke, Yann; Moreau, Thierry

2004-06-01

This paper presents two-sample statistics suited for testing equality of survival functions against improper semi-parametric accelerated failure time alternatives. These tests are designed for comparing either the short- or the long-term effect of a prognostic factor, or both. These statistics are obtained as partial likelihood score statistics from a time-dependent Cox model. As a consequence, the proposed tests can be very easily implemented using widely available software. A breast cancer clinical trial is presented as an example to demonstrate the utility of the proposed tests.

Measuring continuous baseline covariate imbalances in clinical trial data

PubMed Central

Ciolino, Jody D.; Martin, Renee’ H.; Zhao, Wenle; Hill, Michael D.; Jauch, Edward C.; Palesch, Yuko Y.

2014-01-01

This paper presents and compares several methods of measuring continuous baseline covariate imbalance in clinical trial data. Simulations illustrate that though the t-test is an inappropriate method of assessing continuous baseline covariate imbalance, the test statistic itself is a robust measure in capturing imbalance in continuous covariate distributions. Guidelines to assess effects of imbalance on bias, type I error rate, and power for hypothesis test for treatment effect on continuous outcomes are presented, and the benefit of covariate-adjusted analysis (ANCOVA) is also illustrated. PMID:21865270

Behavioral and cognitive outcomes for clinical trials in children with neurofibromatosis type 1.

PubMed

van der Vaart, Thijs; Rietman, André B; Plasschaert, Ellen; Legius, Eric; Elgersma, Ype; Moll, Henriëtte A

2016-01-12

To evaluate the appropriateness of cognitive and behavioral outcome measures in clinical trials in neurofibromatosis type 1 (NF1) by analyzing the degree of deficits compared to reference groups, test-retest reliability, and how scores correlate between outcome measures. Data were analyzed from the Simvastatin for cognitive deficits and behavioral problems in patients with neurofibromatosis type 1 (NF1-SIMCODA) trial, a randomized placebo-controlled trial of simvastatin for cognitive deficits and behavioral problems in children with NF1. Outcome measures were compared with age-specific reference groups to identify domains of dysfunction. Pearson r was computed for before and after measurements within the placebo group to assess test-retest reliability. Principal component analysis was used to identify the internal structure in the outcome data. Strongest mean score deviations from the reference groups were observed for full-scale intelligence (-1.1 SD), Rey Complex Figure Test delayed recall (-2.0 SD), attention problems (-1.2 SD), and social problems (-1.1 SD). Long-term test-retest reliability were excellent for Wechsler scales (r > 0.88), but poor to moderate for other neuropsychological tests (r range 0.52-0.81) and Child Behavioral Checklist subscales (r range 0.40-0.79). The correlation structure revealed 2 strong components in the outcome measures behavior and cognition, with no correlation between these components. Scores on psychosocial quality of life correlate strongly with behavioral problems and less with cognitive deficits. Children with NF1 show distinct deficits in multiple domains. Many outcome measures showed weak test-retest correlations over the 1-year trial period. Cognitive and behavioral outcomes are complementary. This analysis demonstrates the need to include reliable outcome measures on a variety of cognitive and behavioral domains in clinical trials for NF1. © 2015 American Academy of Neurology.

Undisclosed antiretroviral drug use in a multinational clinical trial (HIV Prevention Trials Network 052).

PubMed

Fogel, Jessica M; Wang, Lei; Parsons, Teresa L; Ou, San-San; Piwowar-Manning, Estelle; Chen, Ying; Mudhune, Victor O; Hosseinipour, Mina C; Kumwenda, Johnstone; Hakim, James G; Chariyalertsak, Suwat; Panchia, Ravindre; Sanne, Ian; Kumarasamy, Nagalingeswaran; Grinsztejn, Beatriz; Makhema, Joseph; Pilotto, Jose; Santos, Breno R; Mayer, Kenneth H; McCauley, Marybeth; Gamble, Theresa; Bumpus, Namandjé N; Hendrix, Craig W; Cohen, Myron S; Eshleman, Susan H

2013-11-15

The HIV Prevention Trials Network 052 study enrolled serodiscordant couples. Index participants infected with human immunodeficiency virus reported no prior antiretroviral (ARV) treatment at enrollment. ARV drug testing was performed retrospectively using enrollment samples from a subset of index participants. ARV drugs were detected in 45 of 96 participants (46.9%) with an undetectable viral load, 2 of 48 (4.2%) with a low viral load, and 1 of 65 (1.5%) with a high viral load (P < .0001); they were also detected in follow-up samples from participants who were not receiving study-administered treatment. ARV drug testing may be useful in addition to self-report of ARV drug use in some clinical trial settings.

Pediatric clinical trial studies antibody treatment for various types of solid tumors | Center for Cancer Research

Cancer.gov

A clinical trial for pediatric patients will test the safety and efficacy of enoblituzumab in solid tumors that express a specific protein, including neuroblastoma, rhabdomyosarcoma, osteosarcoma, Ewing sarcoma, Wilms tumor, or desmoplastic small round cell tumor. Read more... 

Clinical trial explores new glioblastoma treatment regimen | Center for Cancer Research

Cancer.gov

On average, a patient with glioblastoma lives for only about a year after diagnosis. In a new clinical trial, CCR researchers will test whether a combination of a vaccine made from the patient’s tumor with another immunotherapy treatment can increase survival rates. Read more...  

New clinical trial aims to prevent breast cancer from recurring in the brain | Center for Cancer Research

Cancer.gov

In some types of breast cancer, the tumor cells spread more frequently to the brain. A new clinical trial run by CCR investigators will test whether a drug called temozolomide can prevent these deadly lesions from recurring. Read more... 

Evidence-Based Youth Psychotherapy in the Mental Health Ecosystem

ERIC Educational Resources Information Center

Weisz, John R.; Ugueto, Ana M.; Cheron, Daniel M.; Herren, Jenny

2013-01-01

Five decades of randomized trials research have produced dozens of evidence-based psychotherapies (EBPs) for youths. The EBPs produce respectable effects in traditional efficacy trials, but the effects shrink markedly when EBPs are tested in practice contexts with clinically referred youths and compared to usual clinical care. We considered why…

Improving outcomes in adults with epilepsy and intellectual disability (EpAID) using a nurse-led intervention: study protocol for a cluster randomised controlled trial.

PubMed

Ring, Howard; Gilbert, Nakita; Hook, Roxanne; Platt, Adam; Smith, Christopher; Irvine, Fiona; Donaldson, Cam; Jones, Elizabeth; Kelly, Joanna; Mander, Adrian; Murphy, Caroline; Pennington, Mark; Pullen, Angela; Redley, Marcus; Rowe, Simon; Wason, James

2016-06-24

In adults with intellectual disability (ID) and epilepsy there are suggestions that improvements in management may follow introduction of epilepsy nurse-led care. However, this has not been tested in a definitive clinical trial and results cannot be generalised from general population studies as epilepsy tends to be more severe and to involve additional clinical comorbidities in adults with ID. This trial investigates whether nurses with expertise in epilepsy and ID, working proactively to a clinically defined role, can improve clinical and quality of life outcomes in the management of epilepsy within this population, compared to treatment as usual. The trial also aims to establish whether any perceived benefits represent good value for money. The EpAID clinical trial is a two-arm cluster randomised controlled trial of nurse-led epilepsy management versus treatment as usual. This trial aims to obtain follow-up data from 320 participants with ID and drug-resistant epilepsy. Participants are randomly assigned either to a 'treatment as usual' control or a 'defined epilepsy nurse role' active arm, according to the cluster site at which they are treated. The active intervention utilises the recently developed Learning Disability Epilepsy Specialist Nurse Competency Framework for adults with ID. Participants undergo 4 weeks of baseline data collection, followed by a minimum of 20 weeks intervention (novel treatment or treatment as usual), followed by 4 weeks of follow-up data collection. The primary outcome is seizure severity, including associated injuries and the level of distress manifest by the patient in the preceding 4 weeks. Secondary outcomes include cost-utility analysis, carer strain, seizure frequency and side effects. Descriptive measures include demographic and clinical descriptors of participants and clinical services in which they receive their epilepsy management. Qualitative study of clinical interactions and semi-structured interviews with clinicians and participants' carers are also undertaken. The EpAID clinical trial is the first cluster randomised controlled trial to test possible benefits of a nurse-led intervention in adults with epilepsy and ID. This research will have important implications for ID and epilepsy services. The challenges of undertaking such a trial in this population, and the approaches to meeting these are discussed. International Standard Randomised Controlled Trial Number: ISRCTN96895428 version 1.1. Registered on 26 March 2013.

Using digital multimedia to improve parents' and children's understanding of clinical trials.

PubMed

Tait, Alan R; Voepel-Lewis, Terri; Levine, Robert

2015-06-01

Data show that many research subjects have difficulty understanding study information using traditional paper consent documents. This study, therefore, was designed to evaluate the effect of an interactive multimedia program on improving parents' and children's understanding of clinical trial concepts and participation. Parents (n=148) and children (n=135) were each randomised to receive information regarding clinical trials using either a traditional paper format (TF) or an interactive iPad program (IP) with inline exercises. Participants' understanding of the information was assessed using semistructured interviews prior to (pretest) and after (post-test) receiving the information. Participants also completed a short survey to assess their perceptions of information delivery and satisfaction with the process. Regardless of the mode of information delivery, all participants demonstrated improved pretest to post-test understanding. While there were no statistical differences in parents' post-test understanding between the TF and IP groups, children in the IP group had significantly greater post-test understanding compared with children in the TF group (11.65 (4.1) vs 8.85 (4.1) (2.8, 1.4, 4.2) 0-18 scale where 18=complete understanding). Furthermore, the IP was found to be significantly 'easier to follow' and 'more effective' in presenting information compared with the TF. Results demonstrated the importance of providing information regarding clinical trial concepts to parents and children. Importantly, the ability of interactive multimedia to improve understanding of clinical trial concepts and satisfaction with information delivery, particularly among children, supports this approach as a novel and effective vehicle for enhancing the informed consent process. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Update on Clinical Trials in Dry Age-related Macular Degeneration

PubMed Central

Taskintuna, Ibrahim; Elsayed, M. E. A. Abdalla; Schatz, Patrik

2016-01-01

This review article summarizes the most recent clinical trials for dry age-related macular degeneration (AMD), the most common cause of vision loss in the elderly in developed countries. A literature search through websites https://www.pubmed.org and https://www.clinicaltrials.gov/, both accessed no later than November 04, 2015, was performed. We identified three Phase III clinical trials that were completed over the recent 5 years Age-Related Eye Disease Study 2 (AREDS2), implantable miniature telescope and tandospirone, and several other trials targeting a variety of mechanisms including, oxidative stress, complement inhibition, visual cycle inhibition, retinal and choroidal blood flow, stem cells, gene therapy, and visual rehabilitation. To date, none of the biologically oriented therapies have resulted in improved vision. Vision improvement was reported with an implantable mini telescope. Stem cells therapy holds a potential for vision improvement. The AREDS2 formulas did not add any further reduced risk of progression to advanced AMD, compared to the original AREDS formula. Several recently discovered pathogenetic mechanisms in dry AMD have enabled development of new treatment strategies, and several of these have been tested in recent clinical trials and are currently being tested in ongoing trials. The rapid development and understanding of pathogenesis holds promise for the future. PMID:26957835

Outcomes research in cancer clinical trial cooperative groups: the RTOG model.

PubMed

Bruner, D W; Movsas, B; Konski, A; Roach, M; Bondy, M; Scarintino, C; Scott, C; Curran, W

2004-08-01

The Radiation Therapy Oncology Group (RTOG), a National Cancer Institute sponsored cancer clinical trials research cooperative, has recently formed an Outcomes Committee to assess a comprehensive array of clinical trial endpoints and factors impacting the net effect of therapy. To study outcomes in a consistent, comprehensive and coordinated manner, the RTOG Outcomes Committee developed a model to assess clinical, humanistic, and economic outcomes important in clinical trials. This paper reviews how the RTOG incorporates outcomes research into cancer clinical trials, and demonstrates utilization of the RTOG Outcomes Model to test hypotheses related to non-small-cell lung cancer (NSCLC). In this example, the clinical component of the model indicates that the addition of chemotherapy to radiotherapy (RT) improves survival but increases the risk of toxicity. The humanistic component indicates that esophagitis is the symptom impacting quality of life the greatest and may outweigh the benefits in elderly (> or =70 years) patients. The economic component of the model indicates that accounting for quality-adjusted survival, concurrent chemoRT for the treatment of NSCLC is within the range of economically acceptable recommendations. The RTOG Outcomes Model guides a comprehensive program of research that systematically measures a triad of endpoints considered important to clinical trials research.

The cost of implementing rapid HIV testing in sexually transmitted disease clinics in the United States.

PubMed

Eggman, Ashley A; Feaster, Daniel J; Leff, Jared A; Golden, Matthew R; Castellon, Pedro C; Gooden, Lauren; Matheson, Tim; Colfax, Grant N; Metsch, Lisa R; Schackman, Bruce R

2014-09-01

Rapid HIV testing in high-risk populations can increase the number of persons who learn their HIV status and avoid spending clinic resources to locate persons identified as HIV infected. We determined the cost to sexually transmitted disease (STD) clinics of point-of-care rapid HIV testing using data from 7 public clinics that participated in a randomized trial of rapid testing with and without brief patient-centered risk reduction counseling in 2010. Costs included counselor and trainer time, supplies, and clinic overhead. We applied national labor rates and test costs. We calculated median clinic start-up costs and mean cost per patient tested, and projected incremental annual costs of implementing universal rapid HIV testing compared with current testing practices. Criteria for offering rapid HIV testing and methods for delivering nonrapid test results varied among clinics before the trial. Rapid HIV testing cost an average of US $22/patient without brief risk reduction counseling and US $46/patient with counseling in these 7 clinics. Median start-up costs per clinic were US $1100 and US $16,100 without and with counseling, respectively. Estimated incremental annual costs per clinic of implementing universal rapid HIV testing varied by whether or not brief counseling is conducted and by current clinic testing practices, ranging from a savings of US $19,500 to a cost of US $40,700 without counseling and a cost of US $98,000 to US $153,900 with counseling. Universal rapid HIV testing in STD clinics with same-day results can be implemented at relatively low cost to STD clinics, if brief risk reduction counseling is not offered.

“Entering a Clinical Trial: Is it Right For You?"-- A Randomized Study of The Clinical Trials Video and Its Impact on the Informed Consent Process

PubMed Central

Hoffner, Brianna; Bauer-Wu, Susan; Hitchcock-Bryan, Suzanne; Powell, Mark; Wolanski, Andrew; Joffe, Steven

2011-01-01

PURPOSE This randomized study was designed to assess the utility of an educational video in preparing cancer patients for decisions about clinical trial participation. The study assessed the effect of the video on patients’ understanding and perceptions of clinical trials, its impact on decision making and patient-provider communication, and patients’ satisfaction with the video. METHODS Ninety adults considering cancer clinical trials were randomized to receive (n=45) or not receive (n=45) the video. Using the validated Quality of Informed Consent (QuIC), respondents’ knowledge about clinical trial participation was assessed. All subjects completed additional questions about satisfaction with the video, decision making, and patient-provider communication. Data were analyzed using the Wilcoxon rank-sum test, regression model and descriptive statistics. RESULTS Although intent-to-treat analysis found no significant group differences in objective understanding between those randomized to view or not view the video, the majority of participants reported favorable experiences with regard to watching the video: 85% found the video was an important source of information about clinical trials; 81% felt better prepared to discuss the trial with their physician; 89% of those who watched the video with family indicated that it helped family better understand clinical trials; and 73% indicated it helped family accept their decision about participation. CONCLUSIONS Although the video did not measurably improve patients’ knowledge about clinical trials, it was an important source of information, helped educate families, and enhanced patient communication with their oncology providers. PMID:22009665

Testing homogeneity of proportion ratios for stratified correlated bilateral data in two-arm randomized clinical trials.

PubMed

Pei, Yanbo; Tian, Guo-Liang; Tang, Man-Lai

2014-11-10

Stratified data analysis is an important research topic in many biomedical studies and clinical trials. In this article, we develop five test statistics for testing the homogeneity of proportion ratios for stratified correlated bilateral binary data based on an equal correlation model assumption. Bootstrap procedures based on these test statistics are also considered. To evaluate the performance of these statistics and procedures, we conduct Monte Carlo simulations to study their empirical sizes and powers under various scenarios. Our results suggest that the procedure based on score statistic performs well generally and is highly recommended. When the sample size is large, procedures based on the commonly used weighted least square estimate and logarithmic transformation with Mantel-Haenszel estimate are recommended as they do not involve any computation of maximum likelihood estimates requiring iterative algorithms. We also derive approximate sample size formulas based on the recommended test procedures. Finally, we apply the proposed methods to analyze a multi-center randomized clinical trial for scleroderma patients. Copyright © 2014 John Wiley & Sons, Ltd.

Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples.

PubMed Central

Peto, R.; Pike, M. C.; Armitage, P.; Breslow, N. E.; Cox, D. R.; Howard, S. V.; Mantel, N.; McPherson, K.; Peto, J.; Smith, P. G.

1977-01-01

Part I of this report appeared in the previous issue (Br. J. Cancer (1976) 34,585), and discussed the design of randomized clinical trials. Part II now describes efficient methods of analysis of randomized clinical trials in which we wish to compare the duration of survival (or the time until some other untoward event first occurs) among different groups of patients. It is intended to enable physicians without statistical training either to analyse such data themselves using life tables, the logrank test and retrospective stratification, or, when such analyses are presented, to appreciate them more critically, but the discussion may also be of interest to statisticians who have not yet specialized in clinical trial analyses. PMID:831755

Interim analysis: A rational approach of decision making in clinical trial.

PubMed

Kumar, Amal; Chakraborty, Bhaswat S

2016-01-01

Interim analysis of especially sizeable trials keeps the decision process free of conflict of interest while considering cost, resources, and meaningfulness of the project. Whenever necessary, such interim analysis can also call for potential termination or appropriate modification in sample size, study design, and even an early declaration of success. Given the extraordinary size and complexity today, this rational approach helps to analyze and predict the outcomes of a clinical trial that incorporate what is learned during the course of a study or a clinical development program. Such approach can also fill the gap by directing the resources toward relevant and optimized clinical trials between unmet medical needs and interventions being tested currently rather than fulfilling only business and profit goals.

Analysis of repeated measurement data in the clinical trials

PubMed Central

Singh, Vineeta; Rana, Rakesh Kumar; Singhal, Richa

2013-01-01

Statistics is an integral part of Clinical Trials. Elements of statistics span Clinical Trial design, data monitoring, analyses and reporting. A solid understanding of statistical concepts by clinicians improves the comprehension and the resulting quality of Clinical Trials. In biomedical research it has been seen that researcher frequently use t-test and ANOVA to compare means between the groups of interest irrespective of the nature of the data. In Clinical Trials we record the data on the patients more than two times. In such a situation using the standard ANOVA procedures is not appropriate as it does not consider dependencies between observations within subjects in the analysis. To deal with such types of study data Repeated Measure ANOVA should be used. In this article the application of One-way Repeated Measure ANOVA has been demonstrated by using the software SPSS (Statistical Package for Social Sciences) Version 15.0 on the data collected at four time points 0 day, 15th day, 30th day, and 45th day of multicentre clinical trial conducted on Pandu Roga (~Iron Deficiency Anemia) with an Ayurvedic formulation Dhatrilauha. PMID:23930038

In Vivo Measurement of Drug Efficacy in Breast Cancer

DTIC Science & Technology

2016-10-01

analysis. At the clinical level, this study will result in pertinent data regarding several agents currently in clinical trials. At the basic science ...clinical level, this study will result in pertinent data regarding several agents currently in clinical trials. At the basic science level, we will...mg/kg BLZ-945 or encapsulated drug were tested in BALB/C mice expressing tumors in mammary fat pads, showing limited additional efficacy as seen

Protocol investigating the clinical utility of an objective measure of activity and attention (QbTest) on diagnostic and treatment decision-making in children and young people with ADHD—‘Assessing QbTest Utility in ADHD’ (AQUA): a randomised controlled trial

PubMed Central

Hall, Charlotte L; Walker, Gemma M; Valentine, Althea Z; Guo, Boliang; Kaylor-Hughes, Catherine; James, Marilyn; Daley, David; Sayal, Kapil; Hollis, Chris

2014-01-01

Introduction The National Institute for Health and Care Excellence (NICE) guidelines for attention deficit/hyperactivity disorder (ADHD) state that young people need to have access to the best evidence-based care to improve outcome. The current ‘gold standard’ ADHD diagnostic assessment combines clinical observation with subjective parent, teacher and self-reports. In routine practice, reports from multiple informants may be unavailable or contradictory, leading to diagnostic uncertainty and delay. The addition of objective tests of attention and activity may help reduce diagnostic uncertainty and delays in initiating treatment leading to improved outcomes. This trial investigates whether providing clinicians with an objective report of levels of attention, impulsivity and activity can lead to an earlier, and more accurate, clinical diagnosis and improved patient outcome. Methods and analysis This multisite randomised controlled trial will recruit young people (aged 6–17 years old) who have been referred for an ADHD diagnostic assessment at Child and Adolescent Mental Health Services (CAMHS) and Community Paediatric clinics across England. Routine clinical assessment will be augmented by the QbTest, incorporating a continuous performance test (CPT) and infrared motion tracking of activity. The participant will be randomised into one of two study arms: QbOpen (clinician has immediate access to a QbTest report): QbBlind (report is withheld until the study end). Primary outcomes are time to diagnosis and diagnostic accuracy. Secondary outcomes include clinician's diagnostic confidence and routine clinical outcome measures. Cost-effective analysis will be conducted, alongside a qualitative assessment of the feasibility and acceptability of incorporating QbTest in routine practice. Ethics and dissemination The findings from the study will inform commissioners, clinicians and managers about the feasibility, acceptability, clinical utility and cost-effectiveness of incorporating QbTest into routine diagnostic assessment of young people with ADHD. The results will be submitted for publication in peer-reviewed journals. The study has received ethical approval. Trial registration number NCT02209116. PMID:25448628

Using "clinical trial diaries" to track patterns of participation for serial healthy volunteers in U.S. phase I studies.

PubMed

Edelblute, Heather B; Fisher, Jill A

2015-02-01

Phase I testing of investigational drugs relies on healthy volunteers as research participants. Many U.S. healthy volunteers enroll repeatedly in clinical trials for the financial compensation. Serial participants are incentivized to ignore restrictions on their participation, and no centralized clinical trial registry prevents dual enrollment. Little is currently known about how healthy volunteers participate in studies over time, hampering the development of policies to protect this group. We detail a methodology developed as part of a longitudinal study to track in real-time healthy volunteers' Phase I participation. Illustrating these data through three case studies, we document how healthy volunteers use strategies, such as qualifying for studies at more than one clinic and traveling significant distances, to maximize their participation. Our findings suggest that "clinical trial diaries" can generate critical information about serial research participation and point to ethical issues unique to healthy volunteers' involvement in Phase I clinical trials. © The Author(s) 2015.

Relative and absolute reliability of the clinical version of the Narrow Path Walking Test (NPWT) under single and dual task conditions.

PubMed

Gimmon, Yoav; Jacob, Grinshpon; Lenoble-Hoskovec, Constanze; Büla, Christophe; Melzer, Itshak

2013-01-01

Decline in gait stability has been associated with increased fall risk in older adults. Reliable and clinically feasible methods of gait instability assessment are needed. This study evaluated the relative and absolute reliability and concurrent validity of the testing procedure of the clinical version of the Narrow Path Walking Test (NPWT) under single task (ST) and dual task (DT) conditions. Thirty independent community-dwelling older adults (65-87 years) were tested twice. Participants were instructed to walk within the 6-m narrow path without stepping out. Trial time, number of steps, trial velocity, number of step errors, and number of cognitive task errors were determined. Intraclass correlation coefficients (ICCs) were calculated as indices of agreement, and a graphic approach called "mountain plot" was applied to help interpret the direction and magnitude of disagreements between testing procedures. Smallest detectable change and smallest real difference (SRD) were computed to determine clinically relevant improvement at group and individual levels, respectively. Concurrent validity was assessed using Performance Oriented Mobility Assessment Tool (POMA) and the Short Physical Performance Battery (SPPB). Test-retest agreement (ICC1,2) varied from 0.77 to 0.92 in ST and from 0.78 to 0.92 in DT conditions, with no apparent systematic differences between testing procedures demonstrated by the mountain plot graphs. Smallest detectable change and smallest real change were small for motor task performance and larger for cognitive errors. Significant correlations were observed for trial velocity and trial time with POMA and SPPB. The present results indicate that the NPWT testing procedure is highly reliable and reproducible. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Rationale and design of REACT: a randomised controlled trial assessing the effectiveness of home-collection to increase chlamydia retesting and detect repeat positive tests.

PubMed

Smith, Kirsty S; Hocking, Jane S; Chen, Marcus; Fairley, Christopher K; McNulty, Anna; Read, Phillip; Bradshaw, Catriona S; Tabrizi, Sepehr N; Wand, Handan; Saville, Marion; Rawlinson, William; Garland, Suzanne M; Donovan, Basil; Kaldor, John M; Guy, Rebecca

2014-04-24

Repeat infection with Chlamydia trachomatis is common and increases the risk of sequelae in women and HIV seroconversion in men who have sex with men (MSM). Despite guidelines recommending chlamydia retesting three months after treatment, retesting rates are low. We are conducting the first randomised controlled trial to assess the effectiveness of home collection combined with short message service (SMS) reminders on chlamydia retesting and reinfection rates in three risk groups. The REACT (retest after Chlamydia trachomatis) trial involves 600 patients diagnosed with chlamydia: 200 MSM, 200 women and 200 heterosexual men recruited from two Australian sexual health clinics where SMS reminders for retesting are routine practice. Participants will be randomised to the home group (3-month SMS reminder and home-collection) or the clinic group (3-month SMS reminder to return to the clinic). Participants in the home group will be given the choice of attending the clinic if they prefer. The mailed home-collection kit includes a self-collected vaginal swab (women), UriSWAB (Copan) for urine collection (heterosexual men), and UriSWAB plus rectal swab (MSM). The primary outcome is the retest rate at 1-4 months after a chlamydia diagnosis, and the secondary outcomes are: the repeat positive test rate; the reinfection rate; the acceptability of home testing with SMS reminders; and the cost effectiveness of home testing. Sexual behaviour data collected via an online survey at 4-5 months, and genotyping of repeat infections, will be used to discriminate reinfections from treatment failures. The trial will be conducted over two years. An intention to treat analysis will be conducted. This study will provide evidence about the effectiveness of home-collection combined with SMS reminders on chlamydia retesting, repeat infection and reinfection rates in three risk groups. The trial will determine client acceptability and cost effectiveness of this strategy. Australian and New Zealand Clinical Trials Registry ACTRN12611000968976.

Landscape review of current HIV 'kick and kill' cure research - some kicking, not enough killing.

PubMed

Thorlund, Kristian; Horwitz, Marc S; Fife, Brian T; Lester, Richard; Cameron, D William

2017-08-29

Current antiretroviral therapy (ART) used to treat human immunodeficiency virus (HIV) patients is life-long because it only suppresses de novo infections. Recent efforts to eliminate HIV have tested the ability of a number of agents to reactivate ('Kick') the well-known latent reservoir. This approach is rooted in the assumption that once these cells are reactivated the host's immune system itself will eliminate ('Kill') the virus. While many agents have been shown to reactivate large quantities of the latent reservoir, the impact on the size of the latent reservoir has been negligible. This suggests that the immune system is not sufficient to eliminate reactivated reservoirs. Thus, there is a need for more emphasis on 'kill' strategies in HIV cure research, and how these might work in combination with current or future kick strategies. We conducted a landscape review of HIV 'cure' clinical trials using 'kick and kill' approaches. We identified and reviewed current available clinical trial results in human participants as well as ongoing and planned clinical trials. We dichotomized trials by whether they did not include or include a 'kill' agent. We extracted potential reasons why the 'kill' is missing from current 'kick and kill' strategies. We subsequently summarized and reviewed current 'kill' strategies have entered the phase of clinical trial testing in human participants and highlighted those with the greatest promise. The identified 'kick' trials only showed promise on surrogate measures activating latent T-cells, but did not show any positive effects on clinical 'cure' measures. Of the 'kill' agents currently being tested in clinical trials, early results have shown small but meaningful proportions of participants remaining off ART for several months with broadly neutralizing antibodies, as well as agents for regulating immune cell responses. A similar result was also recently observed in a trial combining a conventional 'kick' with a vaccine immune booster ('kill'). While an understanding of the efficacy of each individual component is crucial, no single 'kick' or 'kill' agent is likely to be a fully effective cure. Rather, the solution is likely found in a combination of multiple 'kick and kill' interventions.

A Pilot Study to Determine the Effect of an Educational DVD in Philippine Languages on Cancer Clinical Trial Participation among Filipinos in Hawai'i.

PubMed

Felicitas-Perkins, Jamie Q; Palalay, Melvin Paul; Cuaresma, Charlene; Ho, Reginald Cs; Chen, Moon S; Dang, Julie; Loui, William S

2017-07-01

We conducted an experimental pilot study in an oncology clinic in Honolulu, Hawai'i to determine the effect of a culturally-tailored educational DVD on cancer clinical trial participation among Filipino cancer patients. Thirty-seven patients participated in the study, with 17 randomized into the control group (ie, usual education) and 20 into the intervention group (ie, usual education plus educational DVD). Participants completed pre- and post-educational questionnaires with items asking about understanding of several cancer topics, behavioral outcomes, and attitudes regarding several treatment and physician related topics. A Fisher's exact test was conducted to explore the association between enrollment into a clinical trial and group assignment. General linear models were created to determine significant differences between study groups in post-education response scores for each questionnaire item after controlling for age, gender, education, and pre-education response scores. Two participants from the control group and three participants from the intervention group enrolled into clinical trials. Results showed no significant association between clinical trial enrollment and study group assignment ( P > .99). A significant difference was found between study groups on surety of joining the clinical trial suggested to them ( P = .013). A multilingual educational DVD to supplement clinical trial education may positively influence Filipino cancer patients to move forward with the decision to join a cancer clinical trial. However, health literacy may serve as a major barrier to actual enrollment into the particular clinical trial available to a patient.

Geographic Proximity and Racial Disparities in Cancer Clinical Trial Participation

PubMed Central

Kanarek, Norma F.; Tsai, Hua-Ling; Metzger-Gaud, Sharon; Damron, Dorothy; Guseynova, Alla; Klamerus, Justin F.; Rudin, Charles M.

2011-01-01

This study assessed the effects of race and place of residence on clinical trial participation by patients seen at a designated NCI comprehensive cancer center. Clinical trial accrual to cancer case ratios were evaluated using a database of residents at the continental United States seen at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins from 2005 to 2007. Place of residence was categorized into 3 nonoverlapping geographic areas: Baltimore City, non–Baltimore City catchment area, and non–catchment area. Controlling for age, sex, county poverty level, and cancer site, significant race and place of residence differences were seen in therapeutic or nontherapeutic clinical trials participation. White non–Baltimore City catchment area residents, the designated reference group, achieved the highest participation rate. Although the test of interaction (control group compared with all others) was not significant, some race–geographic area group differences were detected. In therapeutic trials, most race–place of residence group levels were statistically lower and different from reference; in nontherapeutic trials, race-specific Baltimore City groups participated at levels similar to reference. Baltimore City residents had lower participation rates only in therapeutic trials, irrespective of race. County poverty level was not significant but was retained as a confounder. Place of residence and race were found to be significant predictors of participation in therapeutic and nontherapeutic clinical trials, although patterns differed somewhat between therapeutic and nontherapeutic trials. Clinical trial accruals are not uniform across age, sex, race, place of residence, cancer site, or trial type, underscoring that cancer centers must better understand their source patients to enhance clinical trial participation. PMID:21147901

Missing data frequency and correlates in two randomized surgical trials for urinary incontinence in women.

PubMed

Brubaker, Linda; Litman, Heather J; Kim, Hae-Young; Zimmern, Philippe; Dyer, Keisha; Kusek, John W; Richter, Holly E; Stoddard, Anne

2015-08-01

Missing data is frequently observed in clinical trials; high rates of missing data may jeopardize trial outcome validity. We determined the rates of missing data over time, by type of data collected and compared demographic and clinical factors associated with missing data among women who participated in two large randomized clinical trials of surgery for stress urinary incontinence, the Stress Incontinence Surgical Treatment Efficacy Trial (SISTEr) and the Trial of Midurethral Sling (TOMUS). The proportions of subjects who attended and missed each follow-up visit were calculated. The chi-squared test, Fisher's exact test and t test were used to compare women with and without missing data, as well as the completeness of the data for each component of the composite primary outcome. Data completeness for the primary outcome computation in the TOMUS trial (62.3%) was nearly double that in the SISTEr trial (35.7%). The follow-up visit attendance rate decreased over time. A higher proportion of subjects attended all follow-up visits in the TOMUS trial and overall there were fewer missing data for the period that included the primary outcome assessment at 12 months. The highest levels of complete data for the composite outcome variables were for the symptoms questionnaire (SISTEr 100 %, TOMUS 99.8%) and the urinary stress test (SISTEr 96.1%, TOMUS 96.7%). In both studies, the pad test was associated with the lowest levels of complete data (SISTEr 85.1%, TOMUS 88.3%) and approximately one in ten subjects had incomplete voiding diaries at the time of primary outcome assessment. Generally, in both studies, a higher proportion of younger subjects had missing data. This analysis lacked a patient perspective as to the reasons for missing data that could have provided additional information on subject burden, motivations for adherence and study design. In addition, we were unable to compare the effects of the different primary outcome assessment time-points in an identically designed trial. Missing visits and data increased with time. Questionnaire data and physical outcome data (urinary stress test) that could be assessed during a visit were least prone to missing data, whereas data for variables that required subject effort while away from the research team (pad test, voiding diary) were more likely to be missing. Older subjects were more likely to provide complete data.

Trial Readiness in Cavernous Angiomas With Symptomatic Hemorrhage (CASH).

PubMed

Polster, Sean P; Cao, Ying; Carroll, Timothy; Flemming, Kelly; Girard, Romuald; Hanley, Daniel; Hobson, Nicholas; Kim, Helen; Koenig, James; Koskimäki, Janne; Lane, Karen; Majersik, Jennifer J; McBee, Nichol; Morrison, Leslie; Shenkar, Robert; Stadnik, Agnieszka; Thompson, Richard E; Zabramski, Joseph; Zeineddine, Hussein A; Awad, Issam A

2018-04-11

Brain cavernous angiomas with symptomatic hemorrhage (CASH) are uncommon but exact a heavy burden of neurological disability from recurrent bleeding, for which there is no proven therapy. Candidate drugs to stabilize the CASH lesion and prevent rebleeding will ultimately require testing of safety and efficacy in multisite clinical trials. Much progress has been made in understanding the epidemiology of CASH, and novel biomarkers have been linked to the biological mechanisms and clinical activity in lesions. Yet, the ability to enroll and risk-stratify CASH subjects has never been assessed prospectively at multiple sites. Biomarkers and other outcomes have not been evaluated for their sensitivity and reliability, nor have they been harmonized across sites. To address knowledge gaps and establish a research network as infrastructure for future clinical trials, through the Trial Readiness grant mechanism, funded by National Institute of Neurological Disorders and Stroke/National Institutes of Health. This project includes an observational cohort study to assess (1) the feasibility of screening, enrollment rates, baseline disease categorization, and follow-up of CASH using common data elements at multiple sites, (2) the reliability of imaging biomarkers including quantitative susceptibility mapping and permeability measures that have been shown to correlate with lesion activity, and (3) the rates of recurrent hemorrhage and change in functional status and biomarker measurements during prospective follow-up. We propose a harmonized multisite assessment of enrollment rates of CASH, baseline features relevant to stratification in clinical trials, and follow-up assessments of functional outcomes in relation to clinical bleeds. We introduce novel biomarkers of vascular leak and hemorrhage, with firm mechanistic foundations, which have been linked to clinical disease activity. We shall test their reliability and validity at multiple sites, and assess their changes over time, with and without clinical rebleeds, hence their fitness as outcome instruments in clinical trials. The timing cannot be more opportune, with therapeutic targets identified, exceptional collaboration among researchers and the patient community, along with several drugs ready to benefit from development of a path to clinical testing using this network in the next 5 years.

Why Current Statistics of Complementary Alternative Medicine Clinical Trials is Invalid.

PubMed

Pandolfi, Maurizio; Carreras, Giulia

2018-06-07

It is not sufficiently known that frequentist statistics cannot provide direct information on the probability that the research hypothesis tested is correct. The error resulting from this misunderstanding is compounded when the hypotheses under scrutiny have precarious scientific bases, which, generally, those of complementary alternative medicine (CAM) are. In such cases, it is mandatory to use inferential statistics, considering the prior probability that the hypothesis tested is true, such as the Bayesian statistics. The authors show that, under such circumstances, no real statistical significance can be achieved in CAM clinical trials. In this respect, CAM trials involving human material are also hardly defensible from an ethical viewpoint.

Pharmacogenetics in Cardiovascular Medicine

PubMed Central

Tuteja, Sony; Limdi, Nita

2017-01-01

Purpose of review Pharmacogenetics is an important component of precision medicine. Even within the genomic era, several challenges lie ahead in the road towards clinical implementation of pharmacogenetics in the clinic. This review will summarize the current state of knowledge regarding pharmacogenetics of cardiovascular drugs, focusing on those with the most evidence supporting clinical implementation- clopidogrel, warfarin and simvastatin. Recent findings There is limited translation of pharmacogenetics into clinical practice primarily due to the absence of outcomes data from prospective, randomized, genotype-directed clinical trials. There are several ongoing randomized controlled trials that will provide some answers as to the clinical utility of genotype-directed strategies. Several academic medical centers have pushed towards clinical implementation where the clinical validity data are strong. Their experiences will inform operational requirements of a clinical pharmacogenetics testing including the timing of testing, incorporation of test results into the electronic health record, reimbursement and ethical issues. Summary Pharmacogenetics of clopidogrel, warfarin and simvastatin are three examples where pharmacogenetics testing may provide added clinical value. Continued accumulation of evidence surrounding clinical utility of pharmacogenetics markers is imperative as this will inform reimbursement policy and drive adoption of pharamcogenetics into routine care. PMID:29057167

A novel hypothesis on the sensitivity of the fecal occult blood test: Results of a joint analysis of 3 randomized controlled trials.

PubMed

Lansdorp-Vogelaar, Iris; van Ballegooijen, Marjolein; Boer, Rob; Zauber, Ann; Habbema, J Dik F

2009-06-01

Estimates of the fecal occult blood test (FOBT) (Hemoccult II) sensitivity differed widely between screening trials and led to divergent conclusions on the effects of FOBT screening. We used microsimulation modeling to estimate a preclinical colorectal cancer (CRC) duration and sensitivity for unrehydrated FOBT from the data of 3 randomized controlled trials of Minnesota, Nottingham, and Funen. In addition to 2 usual hypotheses on the sensitivity of FOBT, we tested a novel hypothesis where sensitivity is linked to the stage of clinical diagnosis in the situation without screening. We used the MISCAN-Colon microsimulation model to estimate sensitivity and duration, accounting for differences between the trials in demography, background incidence, and trial design. We tested 3 hypotheses for FOBT sensitivity: sensitivity is the same for all preclinical CRC stages, sensitivity increases with each stage, and sensitivity is higher for the stage in which the cancer would have been diagnosed in the absence of screening than for earlier stages. Goodness-of-fit was evaluated by comparing expected and observed rates of screen-detected and interval CRC. The hypothesis with a higher sensitivity in the stage of clinical diagnosis gave the best fit. Under this hypothesis, sensitivity of FOBT was 51% in the stage of clinical diagnosis and 19% in earlier stages. The average duration of preclinical CRC was estimated at 6.7 years. Our analysis corroborated a long duration of preclinical CRC, with FOBT most sensitive in the stage of clinical diagnosis. (c) 2009 American Cancer Society.

PROspective Multicenter Imaging Study for Evaluation of Chest Pain: Rationale and Design of the PROMISE Trial

PubMed Central

Douglas, Pamela S.; Hoffmann, Udo; Lee, Kerry L.; Mark, Daniel B.; Al-Khalidi, Hussein R.; Anstrom, Kevin; Dolor, Rowena J.; Kosinski, Andrzej; Krucoff, Mitchell W.; Mudrick, Daniel W.; Patel, Manesh R.; Picard, Michael H.; Udelson, James E.; Velazquez, Eric J.; Cooper, Lawton

2014-01-01

Background Suspected coronary artery disease (CAD) is one of the most common, potentially life threatening diagnostic problems clinicians encounter. However, no large outcome-based randomized trials have been performed to guide the selection of diagnostic strategies for these patients. Methods The PROMISE study is a prospective, randomized trial comparing the effectiveness of two initial diagnostic strategies in patients with symptoms suspicious for CAD. Patients are randomized to either: 1) functional testing (exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram); or 2) anatomic testing with >=64 slice multidetector coronary computed tomographic angiography. Tests are interpreted locally in real time by subspecialty certified physicians and all subsequent care decisions are made by the clinical care team. Sites are provided results of central core lab quality and completeness assessment. All subjects are followed for ≥1 year. The primary end-point is the time to occurrence of the composite of death, myocardial infarction, major procedural complications (stroke, major bleeding, anaphylaxis and renal failure) or hospitalization for unstable angina. Results Over 10,000 symptomatic subjects were randomized in 3.2 years at 193 US and Canadian cardiology, radiology, primary care, urgent care and anesthesiology sites. Conclusion Multi-specialty community practice enrollment into a large pragmatic trial of diagnostic testing strategies is both feasible and efficient. PROMISE will compare the clinical effectiveness of an initial strategy of functional testing against an initial strategy of anatomic testing in symptomatic patients with suspected CAD. Quality of life, resource use, cost effectiveness and radiation exposure will be assessed. Clinical trials.gov identifier NCT01174550 PMID:24890527

Rapid diagnostic tests versus clinical diagnosis for managing people with fever in malaria endemic settings

PubMed Central

Odaga, John; Sinclair, David; Lokong, Joseph A; Donegan, Sarah; Hopkins, Heidi; Garner, Paul

2014-01-01

Background In 2010, the World Health Organization recommended that all patients with suspected malaria are tested for malaria before treatment. In rural African settings light microscopy is often unavailable. Diagnosis has relied on detecting fever, and most people were given antimalarial drugs presumptively. Rapid diagnostic tests (RDTs) provide a point-of-care test that may improve management, particularly of people for whom the RDT excludes the diagnosis of malaria. Objectives To evaluate whether introducing RDTs into algorithms for diagnosing and treating people with fever improves health outcomes, reduces antimalarial prescribing, and is safe, compared to algorithms using clinical diagnosis. Search methods We searched the Cochrane Infectious Disease Group Specialized Register; CENTRAL (The Cochrane Library); MEDLINE; EMBASE; CINAHL; LILACS; and the metaRegister of Controlled Trials for eligible trials up to 10 January 2014. We contacted researchers in the field and reviewed the reference lists of all included trials to identify any additional trials. Selection criteria Individual or cluster randomized trials (RCTs) comparing RDT-supported algorithms and algorithms using clinical diagnosis alone for diagnosing and treating people with fever living in malaria-endemic settings. Data collection and analysis Two authors independently applied the inclusion criteria and extracted data. We combined data from individually and cluster RCTs using the generic inverse variance method. We presented all outcomes as risk ratios (RR) with 95% confidence intervals (CIs), and assessed the quality of evidence using the GRADE approach. Main results We included seven trials, enrolling 17,505 people with fever or reported history of fever in this review; two individually randomized trials and five cluster randomized trials. All trials were conducted in rural African settings. In most trials the health workers diagnosing and treating malaria were nurses or clinical officers with less than one week of training in RDT supported diagnosis. Health worker prescribing adherence to RDT results was highly variable: the number of participants with a negative RDT result who received antimalarials ranged from 0% to 81%. Overall, RDT supported diagnosis had little or no effect on the number of participants remaining unwell at four to seven days after treatment (6990 participants, five trials, low quality evidence); but using RDTs reduced prescribing of antimalarials by up to three-quarters (17,287 participants, seven trials, moderate quality evidence). As would be expected, the reduction in antimalarial prescriptions was highest where health workers adherence to the RDT result was high, and where the true prevalence of malaria was lower. Using RDTs to support diagnosis did not have a consistent effect on the prescription of antibiotics, with some trials showing higher antibiotic prescribing and some showing lower prescribing in the RDT group (13,573 participants, five trials, very low quality evidence). One trial reported malaria microscopy on all enrolled patients in an area of moderate endemicity, so we could compare the number of patients in the RDT and clinical diagnosis groups that actually had microscopy confirmed malaria infection but did not receive antimalarials. No difference was detected between the two diagnostic strategies (1280 participants, one trial, low quality evidence). Authors' conclusions Algorithms incorporating RDTs can substantially reduce antimalarial prescribing if health workers adhere to the test results. Introducing RDTs has not been shown to improve health outcomes for patients, but adherence to the test result does not seem to result in worse clinical outcomes than presumptive treatment. Concentrating on improving the care of RDT negative patients could improve health outcomes in febrile children. PLAIN LANGUAGE SUMMARY Rapid diagnostic tests versus clinical diagnosis for managing fever in settings where malaria is common Cochrane Collaboration researchers conducted a review of the effects of introducing rapid diagnostic tests (RDTs) for diagnosing malaria in areas where diagnosis has traditionally been based on clinical symptoms alone. After searching for relevant trials, they included seven randomized controlled trials, which enrolled 17,505 people with fever. What are RDTs and how might they improve patient care RDTs are simple to use diagnostic kits which can detect the parasites that cause malaria from one drop of the patient's blood. They do not require laboratory facilities or extensive training, and can provide a simple positive or negative result within 20 minutes, making them suitable for use in rural areas of Africa where most malaria cases occur. Improving malaria diagnosis by introducing RDTs is unlikely to improve the health outcomes of people with true malaria as they would probably have received antimalarials even if the health worker was relying on clinical symptoms alone. However, for patients with fever not due to malaria, RDTs could improve health outcomes by prompting the health worker to look for and treat the true cause of their fever earlier. What the research says In these trials, diagnosis using RDTs had little or no effect on the number of people remaining unwell four to seven days after treatment (low quality evidence). However, using RDTs reduced the prescription of antimalarials by up to three-quarters (moderate quality evidence), and this reduction was highest where health workers only prescribed antimalarials following a positive test, and where malaria was less common. Using RDTs to support diagnosis did not have a consistent effect on the prescription of antibiotics, with some trials showing an increase in antibiotic prescription and some showing a decrease (very low quality evidence). Use of RDTs did not result in more patients with malaria being incorrectly diagnosed as not having malaria and being sent home without treatment (low quality evidence). PMID:24740584

The making of indigenous vascular prosthesis

PubMed Central

Unnikrishnan, Madathipat; Viswanathan, Sidharth; Balasubramaniam, K.; Muraleedharan, C.V.; Lal, Arthur Vijayan; Mohanan, P.V.; Mohanty, Meera; Kapilamoorthy, Tirur Raman

2016-01-01

Background & objectives: Vascular illnesses are on the rise in India, due to increase in lifestyle diseases and demographic transition, requiring intervention to save life, organ or limbs using vascular prosthesis. The aim of this study was to develop indigenous large diameter vascular graft for treatment of patients with vascular pathologies. Methods: The South India Textile Research Association, at Coimbatore, Tamil Nadu, India, developed seamless woven polyester (Polyethylene terephthalate) graft at its research wing. Further characterization and testing followed by clinical trials were conducted at Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India. Fifteen in vivo experiments were carried out in 1992-1994 in pigs as animal model. Controlled (phase I) clinical trial in ten patients was performed along with control graft. Thereafter, phase II trial involved 22 patients who underwent multi-centre clinical trial in four centres across India. Results: Laboratory testing showed that polyester graft was non-toxic, non-leeching and non-haemolytic with preserved long-term quality, further confirming in pigs by implanting in thoracic aorta, comparable to control Dacron grafts. Perigraft incorporation and smooth neointima formation which are prime features of excellent healing characteristics, were noted at explantation at planned intervals. Subsequently in the phase I and II clinical trials, all patients had excellent recovery without mortality or device-related adverse events. Patients receiving the test graft were followed up for 10 and 5 years, respectively. Serial clinical, duplex scans and CT angiograms performed periodically confirmed excellent graft performance. Interpretation & conclusions: Indigenously developed Chitra vascular graft was comparable to commercially available Dacron graft, ready for clinical use at affordable cost to patients as against costly imported grafts. PMID:27748302

Novel fluorescence in situ hybridization-based definition of bacille Calmette-Guérin (BCG) failure for use in enhancing recruitment into clinical trials of intravesical therapies.

PubMed

Kamat, Ashish M; Willis, Daniel L; Dickstein, Rian J; Anderson, Rooselvelt; Nogueras-González, Graciela; Katz, Ruth L; Wu, Xifeng; Barton Grossman, H; Dinney, Colin P

2016-05-01

To present a molecular definition of bacille Calmette-Guérin (BCG) failure that incorporates fluorescence in situ hybridization (FISH) testing to predict BCG failure before it becomes clinically evident, which can be used to enhance trial designs for patients with non-muscle-invasive bladder cancer. We used data from 143 patients who were followed prospectively for 2 years during intravesical BCG therapy, during which time FISH assays were collected and correlated to clinical outcomes. Of the 95 patients with no evidence of tumour at 3-month cystoscopy, 23 developed tumour recurrence and 17 developed disease progression by 2 years. Patients with a positive FISH test at both 6 weeks and 3 months were more likely to develop tumour recurrence (17/37 patients [46%] and 16/28 patients [57%], respectively) than patients with a negative FISH test (6/58 patients [10%] and 3/39 patients [8%], respectively; both P < 0.001). Using hazard ratios for recurrence with positive 6-week and 3-month FISH results, we constructed clinical trial scenarios whereby patients with a negative 3-month cystoscopy and positive FISH result could be considered to have 'molecular BCG failure' and could be enrolled in prospective, randomized clinical trials comparing BCG therapy (control) with an experimental intravesical therapy. Patients with positive early FISH and negative 3-month cystoscopy results can be considered to have molecular BCG failure based on their high rates of recurrence and progression. This definition is intended for use in designing clinical trials, thus potentially allowing continued use of BCG as an ethical comparator arm. © 2015 The Authors BJU International © 2015 BJU International Published by John Wiley & Sons Ltd.

Frederick National Lab Supports Clinical Trials for Vaccine Against Mosquito-borne Chikungunya | Frederick National Laboratory for Cancer Research

Cancer.gov

An experimental vaccine for mosquito-borne chikungunya is being tested at sites in the Caribbean as part of a phase II clinical trial being managed by the Frederick National Lab. No vaccine or treatment currently exists for the viral disease, which c

Inference of median difference based on the Box-Cox model in randomized clinical trials.

PubMed

Maruo, K; Isogawa, N; Gosho, M

2015-05-10

In randomized clinical trials, many medical and biological measurements are not normally distributed and are often skewed. The Box-Cox transformation is a powerful procedure for comparing two treatment groups for skewed continuous variables in terms of a statistical test. However, it is difficult to directly estimate and interpret the location difference between the two groups on the original scale of the measurement. We propose a helpful method that infers the difference of the treatment effect on the original scale in a more easily interpretable form. We also provide statistical analysis packages that consistently include an estimate of the treatment effect, covariance adjustments, standard errors, and statistical hypothesis tests. The simulation study that focuses on randomized parallel group clinical trials with two treatment groups indicates that the performance of the proposed method is equivalent to or better than that of the existing non-parametric approaches in terms of the type-I error rate and power. We illustrate our method with cluster of differentiation 4 data in an acquired immune deficiency syndrome clinical trial. Copyright © 2015 John Wiley & Sons, Ltd.

Progress in defining clinically meaningful changes for clinical trials in nonrenal manifestations of SLE disease activity.

PubMed

Choi, Chan-Bum; Liang, Matthew H; Bae, Sang-Cheol

2016-01-06

Since the 2002 Dusseldorf meeting, one new agent, Benlysta, has been approved by the US Food and Drug Administration for systemic lupus erythematosus. Experiences from the field in conducting trials of all the agents tested during this period have provided valuable practical insights. There has been incremental progress in defining the minimal clinically important difference (MCID) of key disease manifestations and the view is largely that of the health care providers and not that of the person suffering the disease. This basic methodological work on the MCID should improve the efficiency and the clinical relevance of future trials and their design.

Narrowing beam-walking is a clinically feasible approach for assessing balance ability in lower-limb prosthesis users.

PubMed

Sawers, Andrew; Hafner, Brian J

2018-05-08

Challenging clinical balance tests are needed to expose balance deficits in lower-limb prost-hesis users. This study examined whether narrowing beam-walking could overcome conceptual and practical limitations identified in fixed-width beam-walking. Cross-sectional. Unilateral lower-limb prosthesis users. Participants walked 10 times along a low, narrowing beam. Performance was quantified using the normalized distance walked. Heuristic rules were applied to determine whether the narrowing beam task was "too easy," "too hard," or "appropriately challenging" for each participant. Linear regression and Bland-Altman plots were used to determine whether combinations of the first 5 trials could predict participants' stable beam-walking performance. Forty unilateral lower-limb prosthesis users participated. Narrowing beam-walking was appropriately challenging for 98% of participants. Performance stabilized for 93% of participants within 5 trials, while 62% were stable across all trials. The mean of trials 3-5 accurately predicted stable performance. A clinical narrowing beam-walking test is likely to challenge a range of lower-limb prosthesis users, have minimal administrative burden, and exhibit no floor or ceiling effects. Narrowing beam-walking is therefore a clinically viable method to evaluate lower-limb prosthesis users' balance ability, but requires psychometric testing before it is used to assess fall risk.

Gene therapy for Parkinson's disease: Disease modification by GDNF family of ligands.

PubMed

Kirik, Deniz; Cederfjäll, Erik; Halliday, Glenda; Petersén, Åsa

2017-01-01

Gene transfer is a promising drug delivery method of advanced therapeutic entities for Parkinson's disease. One advantage over conventional therapies, such as peripheral delivery of the dopamine pre-cursor l-DOPA, is site-specific expression of proteins with regenerative, disease-modifying and potentially neuroprotective capacity. Several clinical trials have been performed to test the capacity of glial-cell line derived neurotrophic factor and neurturin to rescue degenerating dopaminergic neurons in the substantia nigra and their axon terminals in the striatum by delivery of these neurotrophic factors either as purified protein or by means of viral vector mediated gene delivery to the brain. Although gene therapy approaches tested so far have been shown to be safe, none met their primary endpoints in phase II clinical trials designed and powered to test the efficacy of the intervention. Within the scope of this review we aim to describe the state-of-the-art in the field, how different technical parameters were translated from pre-clinical studies in non-human primates to clinical trials, and what these trials taught us regarding important factors that may pave the way to the success of gene therapy for the treatment of Parkinson's disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Operationalizing hippocampal volume as an enrichment biomarker for amnestic MCI trials: effect of algorithm, test-retest variability and cut-point on trial cost, duration and sample size

PubMed Central

Yu, P.; Sun, J.; Wolz, R.; Stephenson, D.; Brewer, J.; Fox, N.C.; Cole, P.E.; Jack, C.R.; Hill, D.L.G.; Schwarz, A.J.

2014-01-01

Objective To evaluate the effect of computational algorithm, measurement variability and cut-point on hippocampal volume (HCV)-based patient selection for clinical trials in mild cognitive impairment (MCI). Methods We used normal control and amnestic MCI subjects from ADNI-1 as normative reference and screening cohorts. We evaluated the enrichment performance of four widely-used hippocampal segmentation algorithms (FreeSurfer, HMAPS, LEAP and NeuroQuant) in terms of two-year changes in MMSE, ADAS-Cog and CDR-SB. We modeled the effect of algorithm, test-retest variability and cut-point on sample size, screen fail rates and trial cost and duration. Results HCV-based patient selection yielded not only reduced sample sizes (by ~40–60%) but also lower trial costs (by ~30–40%) across a wide range of cut-points. Overall, the dependence on the cut-point value was similar for the three clinical instruments considered. Conclusion These results provide a guide to the choice of HCV cut-point for aMCI clinical trials, allowing an informed trade-off between statistical and practical considerations. PMID:24211008

Participant verification: prevention of co-enrolment in clinical trials in South Africa.

PubMed

Harichund, C; Haripersad, K; Ramjee, R

2013-05-15

As KwaZulu-Natal Province is the epicentre of the HIV epidemic in both South Africa (SA) and globally, it is an ideal location to conduct HIV prevention and therapeutic trials. Numerous prevention trials are currently being conducted here; the potential for participant co-enrolment may compromise the validity of these studies and is therefore of great concern. To report the development and feasibility of a digital, fingerprint-based participant identification method to prevent co-enrolment at multiple clinical trial sites. The Medical Research Council (MRC) HIV Prevention Research Unit (HPRU) developed the Biometric Co-enrolment Prevention System (BCEPS), which uses fingerprint-based biometric technology to identify participants. A trial website was used to determine the robustness and usability of the system. After successful testing, the BCEPS was piloted in July 2010 across 7 HPRU clinical research sites. The BCEPS was pre-loaded with study names and clinical trial sites, with new participant information loaded at first visit to a trial site. We successfully implemented the BCEPS at the 7 HPRU sites. Using the BCEPS, we performed real-time 'flagging' of women who were already enrolled in another study as they entered a trial at an HPRU site and, where necessary, excluded them from participation on site. This system has promise in reducing co-enrolment in clinical trials and represents a valuable tool for future implementation by all groups conducting trials. The MRC is currently co-ordinating this effort with clinical trial sites nationally.

Blood and Marrow Transplant Clinical Trials Network Report on the Development of Novel Endpoints and Selection of Promising Approaches for Graft-versus-Host Disease Prevention Trials.

PubMed

Pasquini, Marcelo C; Logan, Brent; Jones, Richard J; Alousi, Amin M; Appelbaum, Frederick R; Bolaños-Meade, Javier; Flowers, Mary E D; Giralt, Sergio; Horowitz, Mary M; Jacobsohn, David; Koreth, John; Levine, John E; Luznik, Leo; Maziarz, Richard; Mendizabal, Adam; Pavletic, Steven; Perales, Miguel-Angel; Porter, David; Reshef, Ran; Weisdorf, Daniel; Antin, Joseph H

2018-06-01

Graft-versus-host disease (GVHD) is a common complication after hematopoietic cell transplantation (HCT) and associated with significant morbidity and mortality. Preventing GVHD without chronic therapy or increasing relapse is a desired goal. Here we report a benchmark analysis to evaluate the performance of 6 GVHD prevention strategies tested at single institutions compared with a large multicenter outcomes database as a control. Each intervention was compared with the control for the incidence of acute and chronic GVHD and overall survival and against novel composite endpoints: acute and chronic GVHD, relapse-free survival (GRFS), and chronic GVHD, relapse-free survival (CRFS). Modeling GRFS and CRFS using the benchmark analysis further informed the design of 2 clinical trials testing GVHD prophylaxis interventions. This study demonstrates the potential benefit of using an outcomes database to select promising interventions for multicenter clinical trials and proposes novel composite endpoints for use in GVHD prevention trials. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Development and feasibility of the misuse, abuse, and diversion drug event reporting system (MADDERS®).

PubMed

Treister, Roi; Trudeau, Jeremiah J; Van Inwegen, Richard; Jones, Judith K; Katz, Nathaniel P

2016-12-01

Inappropriate use of analgesic drugs has become increasingly pervasive over the past decade. Currently, drug abuse potential is primarily assessed post-marketing; no validated tools are available to assess this potential in phase II and III clinical trials. This paper describes the development and feasibility testing of a Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS), which aims to identify potentially abuse-related events and classify them according to a recently developed classification scheme, allowing the quantification of these events in clinical trials. The system was initially conceived and designed with input from experts and patients, followed by field-testing to assess its feasibility and content validity in both completed and ongoing clinical trials. The results suggest that MADDERS is a feasible system with initial validity. It showed higher rates of the triggering events in subjects taking medications with known abuse potential than in patients taking medications without abuse potential. Additionally, experts agreed on the classification of most abuse-related events in MADDERS. MADDERS is a new systematic approach to collect information on potentially abuse-related events in clinical trials and classify them. The system has demonstrated feasibility for implementation. Additional research is ongoing to further evaluate its validity. Currently, there are no validated tools to assess drug abuse potential during clinical trials. Because of its ease of implementation, its systematic approach, and its preliminary validation results, MADDERS could provide such a tool for clinical trials. (Am J Addict 2016;25:641-651). © 2016 American Academy of Addiction Psychiatry.

Investigations of botanicals on food intake, satiety, weight loss, and oxidative stress: a study protocol of a double-blind, placebo-controlled, crossover study

PubMed Central

Anton, Stephen D.; Shuster, Jonathan; Leeuwenburgh, Christiaan

2013-01-01

Background Botanicals represent an important and underexplored source of potential new therapies that may facilitate caloric restriction and thereby produce long-term weight loss. In particular, one promising botanical that may reduce food intake and body weight by affecting neuroendocrine pathways related to satiety is Garcinia cambogia (Garcinia cambogia Desr.)-derived (−)-hydroxycitric acid (HCA). Methods and Design The objective of this article is to describe the protocol of a clinical trial designed to directly test the effect that Garcinia cambogia-derived HCA has on food intake, satiety, weight loss, and oxidative stress levels, and to serve as a model for similar trials. A total of 48 healthy, overweight and obese individuals (body mass index; BMI range = 25.0 – 39.9) between the ages of 50 to 70 will participate in this double-blind, placebo-controlled, crossover study designed to examine the effects of two doses of Garcinia cambogia-derived HCA on food intake, satiety, weight loss, and oxidative stress levels. This trial will take place at the University of Florida (UF)’s Aging and Rehabilitation Research Center (ARRC) and UF Clinical Research Center (CRC). Food intake represents the primary outcome measure and is calculated based on the total calories consumed at breakfast, lunch, and dinner meals during each test meal day at the CRC. This study can be completed with far fewer subjects than a parallel design. Discussion Of the numerous botanical compounds, the compound Garcinia cambogia-derived HCA was selected for testing in the present study because of its potential to safely reduce food intake, body weight, and oxidative stress levels. We will review potential mechanisms of action and safety parameters throughout this clinical trial, which is registered at ClinicalTrials.gov under NCT01238887. Trial registration ClinicalTrials.gov (Identifier: NCT01238887). PMID:22088584

Rationale and design of a randomised clinical trial comparing vascular closure device and manual compression to achieve haemostasis after diagnostic coronary angiography: the Instrumental Sealing of ARterial puncture site - CLOSURE device versus manual compression (ISAR-CLOSURE) trial.

PubMed

Xhepa, Erion; Byrne, Robert A; Schulz, Stefanie; Helde, Sandra; Gewalt, Senta; Cassese, Salvatore; Linhardt, Maryam; Ibrahim, Tareq; Mehilli, Julinda; Hoppe, Katharina; Grupp, Katharina; Kufner, Sebastian; Böttiger, Corinna; Hoppmann, Petra; Burgdorf, Christof; Fusaro, Massimiliano; Ott, Ilka; Schneider, Simon; Hengstenberg, Christian; Schunkert, Heribert; Laugwitz, Karl-Ludwig; Kastrati, Adnan

2014-06-01

Vascular closure devices (VCD) have been introduced into clinical practice with the aim of increasing the procedural efficiency and clinical safety of coronary angiography. However, clinical studies comparing VCD and manual compression have yielded mixed results, and large randomised clinical trials comparing the two strategies are missing. Moreover, comparative efficacy studies between different VCD in routine clinical use are lacking. The Instrumental Sealing of ARterial puncture site - CLOSURE device versus manual compression (ISAR-CLOSURE) trial is a prospective, randomised clinical trial designed to compare the outcomes associated with the use of VCD or manual compression to achieve femoral haemostasis. The test hypothesis is that femoral haemostasis after coronary angiography achieved using VCD is not inferior to manual compression in terms of access-site-related vascular complications. Patients undergoing coronary angiography via the common femoral artery will be randomised in a 1:1:1 fashion to receive FemoSeal VCD, EXOSEAL VCD or manual compression. The primary endpoint is the incidence of the composite of arterial access-related complications (haematoma ≥5 cm, pseudoaneurysm, arteriovenous fistula, access-site-related bleeding, acute ipsilateral leg ischaemia, the need for vascular surgical/interventional treatment or documented local infection) at 30 days after randomisation. According to power calculations based on non-inferiority hypothesis testing, enrolment of 4,500 patients is planned. The trial is registered at www.clinicaltrials.gov (study identifier: NCT01389375). The safety of VCD as compared to manual compression in patients undergoing transfemoral coronary angiography remains an issue of clinical equipoise. The aim of the ISAR-CLOSURE trial is to assess whether femoral haemostasis achieved through the use of VCD is non-inferior to manual compression in terms of access-site-related vascular complications.

The effect of bronchodilators on forced vital capacity measurement in patients with idiopathic pulmonary fibrosis

PubMed Central

Assayag, Deborah; Vittinghoff, Eric; Ryerson, Christopher J.; Cocconcelli, Elisabetta; Tonelli, Roberto; Hu, Xiaowen; Elicker, Brett M.; Golden, Jeffrey A.; Jones, Kirk D.; King, Talmadge E.; Koth, Laura L.; Lee, Joyce S.; Ley, Brett; Shum, Anthony K.; Wolters, Paul J.; Ryu, Jay H.; Collard, Harold R.

2015-01-01

Background Forced vital capacity (FVC) is a key measure of disease severity in patients with idiopathic pulmonary fibrosis (IPF) and is an important clinical trial endpoint. We hypothesize that reversible airflow limitation co-exists in a subgroup of patients with IPF, and that bronchodilator use will improve the performance characteristics of FVC. Methods IPF patients with pre and post-bronchodilator spirometry testing performed were identified from two tertiary referral cohorts. The difference between pre and post-bronchodilator FVC (intra-test difference) was calculated. The test characteristics of pre and post-bronchodilator FVC change over time (inter-test difference) were assessed in patients with sequential spirometry, and were used to generate sample size estimates for hypothetical clinical trials using change in FVC as the primary endpoint. Results There were 551 patients, contributing 967 unique spirometry tests. The mean intra-test increase in FVC with bronchodilator use was 0.04 liters (2.71 vs. 2.75 liters, p <0.001). Reversible airflow limitation (increase in FEV1 or FVC of ≥12% and ≥200 milliliters) occurred in 9.1% of patients. The inter-test difference in change in FVC over time were equivalent for pre and post-bronchodilator (p = 0.65), leading to similar sample size estimates in a hypothetical clinical trial using change in FVC as the primary endpoint. Conclusion Approximately one in ten patients with IPF has physiological evidence of reversible airflow limitation, and bronchodilator use in these patients may improve the assessment of disease progression based on FVC change over time. Bronchodilator use does not appear to meaningfully impact the precision of FVC as an endpoint in clinical trials. PMID:26140806

Parkinson's Disease Gene Therapy: Success by Design Meets Failure by Efficacy

PubMed Central

Bartus, Raymond T; Weinberg, Marc S; Samulski, R. Jude

2014-01-01

Over the past decade, nine gene therapy clinical trials for Parkinson's disease (PD) have been initiated and completed. Starting with considerable optimism at the initiation of each trial, none of the programs has yet borne sufficiently robust clinical efficacy or found a clear path toward regulatory approval. Despite the immediately disappointing nature of the efficacy outcomes in these trials, the clinical data garnered from the individual studies nonetheless represent tangible and significant progress for the gene therapy field. Collectively, the clinical trials demonstrate that we have overcome the major safety hurdles previously suppressing central nervous system (CNS) gene therapy, for none produced any evidence of untoward risk or harm after administration of various vector-delivery systems. More importantly, these studies also demonstrated controlled, highly persistent generation of biologically active proteins targeted to structures deep in the human brain. Therefore, a renewed, focused emphasis must be placed on advancing clinical efficacy by improving clinical trial design, patient selection and outcome measures, developing more predictive animal models to support clinical testing, carefully performing retrospective analyses, and most importantly moving forward—beyond our past limits. PMID:24356252

Testing non-inferiority of a new treatment in three-arm clinical trials with binary endpoints.

PubMed

Tang, Nian-Sheng; Yu, Bin; Tang, Man-Lai

2014-12-18

A two-arm non-inferiority trial without a placebo is usually adopted to demonstrate that an experimental treatment is not worse than a reference treatment by a small pre-specified non-inferiority margin due to ethical concerns. Selection of the non-inferiority margin and establishment of assay sensitivity are two major issues in the design, analysis and interpretation for two-arm non-inferiority trials. Alternatively, a three-arm non-inferiority clinical trial including a placebo is usually conducted to assess the assay sensitivity and internal validity of a trial. Recently, some large-sample approaches have been developed to assess the non-inferiority of a new treatment based on the three-arm trial design. However, these methods behave badly with small sample sizes in the three arms. This manuscript aims to develop some reliable small-sample methods to test three-arm non-inferiority. Saddlepoint approximation, exact and approximate unconditional, and bootstrap-resampling methods are developed to calculate p-values of the Wald-type, score and likelihood ratio tests. Simulation studies are conducted to evaluate their performance in terms of type I error rate and power. Our empirical results show that the saddlepoint approximation method generally behaves better than the asymptotic method based on the Wald-type test statistic. For small sample sizes, approximate unconditional and bootstrap-resampling methods based on the score test statistic perform better in the sense that their corresponding type I error rates are generally closer to the prespecified nominal level than those of other test procedures. Both approximate unconditional and bootstrap-resampling test procedures based on the score test statistic are generally recommended for three-arm non-inferiority trials with binary outcomes.

Two-Sample Statistics for Testing the Equality of Survival Functions Against Improper Semi-parametric Accelerated Failure Time Alternatives: An Application to the Analysis of a Breast Cancer Clinical Trial

PubMed Central

BROËT, PHILIPPE; TSODIKOV, ALEXANDER; DE RYCKE, YANN; MOREAU, THIERRY

2010-01-01

This paper presents two-sample statistics suited for testing equality of survival functions against improper semi-parametric accelerated failure time alternatives. These tests are designed for comparing either the short- or the long-term effect of a prognostic factor, or both. These statistics are obtained as partial likelihood score statistics from a time-dependent Cox model. As a consequence, the proposed tests can be very easily implemented using widely available software. A breast cancer clinical trial is presented as an example to demonstrate the utility of the proposed tests. PMID:15293627

Randomized clinical trials in orthodontics are rarely registered a priori and often published late or not at all.

PubMed

Papageorgiou, Spyridon N; Antonoglou, Georgios N; Sándor, George K; Eliades, Theodore

2017-01-01

A priori registration of randomized clinical trials is crucial to the transparency and credibility of their findings. Aim of this study was to assess the frequency with which registered and completed randomized trials in orthodontics are published. We searched ClinicalTrials.gov and ISRCTN for registered randomized clinical trials in orthodontics that had been completed up to January 2017 and judged the publication status and date of registered trials using a systematic protocol. Statistical analysis included descriptive statistics, chi-square or Fisher exact tests, and Kaplan-Meier survival estimates. From the 266 orthodontic trials registered up to January 2017, 80 trials had been completed and included in the present study. Among these 80 included trials, the majority (76%) were registered retrospectively, while only 33 (41%) were published at the time. The median time from completion to publication was 20.1 months (interquartile range: 9.1 to 31.6 months), while survival analysis indicated that less than 10% of the trials were published after 5 years from their completion. Finally, 22 (28%) of completed trials remain unpublished even after 5 years from their completion. Publication rates of registered randomized trials in orthodontics remained low, even 5 years after their completion date.

Randomized clinical trials in orthodontics are rarely registered a priori and often published late or not at all

PubMed Central

Antonoglou, Georgios N.; Sándor, George K.; Eliades, Theodore

2017-01-01

A priori registration of randomized clinical trials is crucial to the transparency and credibility of their findings. Aim of this study was to assess the frequency with which registered and completed randomized trials in orthodontics are published. We searched ClinicalTrials.gov and ISRCTN for registered randomized clinical trials in orthodontics that had been completed up to January 2017 and judged the publication status and date of registered trials using a systematic protocol. Statistical analysis included descriptive statistics, chi-square or Fisher exact tests, and Kaplan-Meier survival estimates. From the 266 orthodontic trials registered up to January 2017, 80 trials had been completed and included in the present study. Among these 80 included trials, the majority (76%) were registered retrospectively, while only 33 (41%) were published at the time. The median time from completion to publication was 20.1 months (interquartile range: 9.1 to 31.6 months), while survival analysis indicated that less than 10% of the trials were published after 5 years from their completion. Finally, 22 (28%) of completed trials remain unpublished even after 5 years from their completion. Publication rates of registered randomized trials in orthodontics remained low, even 5 years after their completion date. PMID:28777820

Phase I clinical trial will test multi-targeted immunotherapy in common childhood cancer | Center for Cancer Research

Cancer.gov

Chimeric antigen receptor (CAR) T-cell immunotherapy targeting the protein CD19 has shown promise in treating acute lymphoblastic leukemia (ALL). CD22-CAR T-cell therapy has yielded similarly encouraging results, but many patients relapse after either therapy. In an upcoming phase I clinical trial, Center for Cancer Research investigators will test a new strategy—treating patients with a CAR T-cell therapy that targets CD19 and CD22 simultaneously.

Clinical Neuropathology practice news 1-2014: Pyrosequencing meets clinical and analytical performance criteria for routine testing of MGMT promoter methylation status in glioblastoma

PubMed Central

Preusser, Matthias; Berghoff, Anna S.; Manzl, Claudia; Filipits, Martin; Weinhäusel, Andreas; Pulverer, Walter; Dieckmann, Karin; Widhalm, Georg; Wöhrer, Adelheid; Knosp, Engelbert; Marosi, Christine; Hainfellner, Johannes A.

2014-01-01

Testing of the MGMT promoter methylation status in glioblastoma is relevant for clinical decision making and research applications. Two recent and independent phase III therapy trials confirmed a prognostic and predictive value of the MGMT promoter methylation status in elderly glioblastoma patients. Several methods for MGMT promoter methylation testing have been proposed, but seem to be of limited test reliability. Therefore, and also due to feasibility reasons, translation of MGMT methylation testing into routine use has been protracted so far. Pyrosequencing after prior DNA bisulfite modification has emerged as a reliable, accurate, fast and easy-to-use method for MGMT promoter methylation testing in tumor tissues (including formalin-fixed and paraffin-embedded samples). We performed an intra- and inter-laboratory ring trial which demonstrates a high analytical performance of this technique. Thus, pyrosequencing-based assessment of MGMT promoter methylation status in glioblastoma meets the criteria of high analytical test performance and can be recommended for clinical application, provided that strict quality control is performed. Our article summarizes clinical indications, practical instructions and open issues for MGMT promoter methylation testing in glioblastoma using pyrosequencing. PMID:24359605

Improving the reporting of clinical trials of infertility treatments (IMPRINT): modifying the CONSORT statement†‡.

PubMed

Legro, Richard S; Wu, Xiaoke; Barnhart, Kurt T; Farquhar, Cynthia; Fauser, Bart C J M; Mol, Ben

2014-10-10

Clinical trials testing infertility treatments often do not report on the major outcomes of interest to patients and clinicians and the public (such as live birth) nor on the harms, including maternal risks during pregnancy and fetal anomalies. This is complicated by the multiple participants in infertility trials which may include a woman (mother), a man (father), and result in a third individual if successful, their offspring (child), who is also the desired outcome of treatment. The primary outcome of interest and many adverse events occur after cessation of infertility treatment and during pregnancy and the puerperium, which create a unique burden of follow-up for clinical trial investigators and participants. In 2013, because of the inconsistencies in trial reporting and the unique aspects of infertility trials not adequately addressed by existing Consolidated Standards of Reporting Trials (CONSORT) statements, we convened a consensus conference in Harbin, China, with the aim of planning modifications to the CONSORT checklist to improve the quality of reporting of clinical trials testing infertility treatment. The consensus group recommended that the preferred primary outcome of all infertility trials is live birth (defined as any delivery of a live infant ≥20 weeks gestations) or cumulative live birth, defined as the live birth per women over a defined time period (or number of treatment cycles). In addition, harms to all participants should be systematically collected and reported, including during the intervention, any resulting pregnancy, and during the neonatal period. Routine information should be collected and reported on both male and female participants in the trial. We propose to track the change in quality that these guidelines may produce in published trials testing infertility treatments. Our ultimate goal is to increase the transparency of benefits and risks of infertility treatments to provide better medical care to affected individuals and couples. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C?*.

PubMed

Opal, Steven M; Dellinger, R Phillip; Vincent, Jean-Louis; Masur, Henry; Angus, Derek C

2014-07-01

The developmental pipeline for novel therapeutics to treat sepsis has diminished to a trickle compared to previous years of sepsis research. While enormous strides have been made in understanding the basic molecular mechanisms that underlie the pathophysiology of sepsis, a long list of novel agents have now been tested in clinical trials without a single immunomodulating therapy showing consistent benefit. The only antisepsis agent to successfully complete a phase III clinical trial was human recumbent activated protein C. This drug was taken off the market after a follow-up placebo-controlled trial (human recombinant activated Protein C Worldwide Evaluation of Severe Sepsis and septic Shock [PROWESS SHOCK]) failed to replicate the favorable results of the initial registration trial performed ten years earlier. We must critically reevaluate our basic approach to the preclinical and clinical evaluation of new sepsis therapies. We selected the major clinical studies that investigated interventional trials with novel therapies to treat sepsis over the last 30 years. Phase II and phase III trials investigating new treatments for sepsis and editorials and critiques of these studies. Selected manuscripts and clinical study reports were analyzed from sepsis trials. Specific shortcomings and potential pit falls in preclinical evaluation and clinical study design and analysis were reviewed and synthesized. After review and discussion, a series of 12 recommendations were generated with suggestions to guide future studies with new treatments for sepsis. We need to improve our ability to define appropriate molecular targets for preclinical development and develop better methods to determine the clinical value of novel sepsis agents. Clinical trials must have realistic sample sizes and meaningful endpoints. Biomarker-driven studies should be considered to categorize specific "at risk" populations most likely to benefit from a new treatment. Innovations in clinical trial design such as parallel crossover design, alternative endpoints, or adaptive trials should be pursued to improve the outlook for future interventional trials in sepsis.

Parallel multicentre randomised trial of a clinical trial question prompt list in patients considering participation in phase 3 cancer treatment trials.

PubMed

Tattersall, Martin H N; Jefford, Michael; Martin, Andrew; Olver, Ian; Thompson, John F; Brown, Richard F; Butow, Phyllis N

2017-03-01

To evaluate the effect of a clinical trial question prompt list in patients considering enrolment in cancer treatment trials. Tertiary cancer referral hospitals in three state capital cities in Australia. 88 patients with cancer attending three cancer centres in Australia, who were considering enrolment in phase 3 treatment trials, were invited to enrol in an unblinded randomised trial of provision of a clinical trial question prompt list (QPL) before consenting to enrol in the treatment trial. We developed and pilot tested a targeted QPL for patients with cancer considering clinical trial participation (the clinical trial QPL). Consenting patients were randomised to receive the clinical trial QPL or not before further discussion with their oncologist and/or trial nurse about the treatment trial. Questionnaires were completed at baseline and within 3 weeks of deciding on treatment trial participation. scores on the Quality of Informed Consent questionnaire (QuIC). 88 patients of 130 sought for the study were enrolled (43 males), and 45 received the clinical trial QPL. 49% of trials were chemotherapy interventions for patients with advanced disease, 35% and 16% were surgical adjuvant and radiation adjuvant trials respectively. 70 patients completed all relevant questionnaires. 28 of 43 patients in the control arm compared with 39 of 45 patients receiving the clinical trial QPL completed the QuIC (p=0.0124). There were no significant differences in the QuIC scores between the randomised groups (QuIC part A p=0.08 and QuIC part B p=0.92). There were no differences in patient satisfaction with decisions or in anxiety levels between the randomised groups. Use of a question prompt list did not significantly change the QuIC scores in this randomised trial. ANZCTR 12606000214538 prospectively registered 31/5/2006. Results, ACTRN12606000214538. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Operation Brain Trauma Therapy

DTIC Science & Technology

2016-12-01

either clinical trials in TBI if shown to be highly effective across OBTT, or tested in a precision medicine TBI phenotype (such as contusion) based...clinical trial if shown to be potently effective in one of the models in OBTT (i.e., a model that mimicked a specific clinical TBI phenotype). In... effective drug seen thus far in primary screening albeit with benefit highly model dependent, largely restricted to the CCI model. This suggests

Clinical Trials in a Dish: A Perspective on the Coming Revolution in Drug Development.

PubMed

Fermini, Bernard; Coyne, Shawn T; Coyne, Kevin P

2018-05-01

The pharmaceutical industry is facing unprecedented challenges as the cost of developing new drugs has reached unsustainable levels, fueled in large parts by a high attrition rate in clinical development. Strategies to bridge studies between preclinical testing and clinical trials are needed to reduce the knowledge gap and allow earlier decisions to be made on the continuation or discontinuation of further development of drugs. The discovery and development of human induced pluripotent stem cells (hiPSCs) have opened up new avenues that support the concept of screening for cell-based safety and toxicity at the level of a population. This approach, termed "Clinical Trials in a Dish" (CTiD), allows testing medical therapies for safety or efficacy on cells collected from a representative sample of human patients, before moving into actual clinical trials. It can be applied to the development of drugs for specific populations, and it allows predicting not only the magnitude of effects but also the incidence of patients in a population who will benefit or be harmed by these drugs. This, in turn, can lead to the selection of safer drugs to move into clinical development, resulting in a reduction in attrition. The current article offers a perspective of this new model for "humanized" preclinical drug development.

FDA's perspectives on cardiovascular devices.

PubMed

Chen, Eric A; Patel-Raman, Sonna M; O'Callaghan, Kathryn; Hillebrenner, Matthew G

2009-06-01

The Food and Drug Administration (FDA) decision process for approving or clearing medical devices is often determined by a review of robust clinical data and extensive preclinical testing of the device. The mission statement for the Center for Devices and Radiological Health (CDRH) is to review the information provided by manufacturers so that it can promote and protect the health of the public by ensuring the safety and effectiveness of medical devices deemed appropriate for human use (Food, Drug & Cosmetic Act, Section 903(b)(1, 2(C)), December 31, 2004; accessed December 17, 2008 http://www.fda.gov/opacom/laws/fdcact/fdctoc.htm). For high-risk devices, such as ventricular assist devices (VADs), mechanical heart valves, stents, cardiac resynchronization therapy (CRT) devices, pacemakers, and defibrillators, the determination is based on FDA's review of extensive preclinical bench and animal testing followed by use of the device in a clinical trial in humans. These clinical trials allow the manufacturer to evaluate a device in the intended use population. FDA reviews the data from the clinical trial to determine if the device performed as predicted and the clinical benefits outweigh the risks. This article reviews the regulatory framework for different marketing applications related to cardiovascular devices and describes the process of obtaining approval to study a cardiovascular device in a U.S. clinical trial.

Standardizing in vitro diagnostics tasks in clinical trials: a call for action.

PubMed

Lippi, Giuseppe; Simundic, Ana-Maria; Rodriguez-Manas, Leocadio; Bossuyt, Patrick; Banfi, Giuseppe

2016-05-01

Translational research is defined as the process of applying ideas, insights and discoveries generated through basic scientific inquiry to treatment or prevention of human diseases. Although precise information is lacking, several lines of evidence attest that up to 95% early-phase studies may not translate into tangible outcomes for improving clinical management. Major theoretical hurdles exist in the translational process, but is it also undeniable that many studies may have failed for practical reasons, such as the use of inappropriate diagnostic testing for evaluating efficacy, effectiveness or safety of a given medical intervention, or poor quality in laboratory testing. This can generate biased test results and result in misconceptions during data interpretation, eventually leading to no clinical benefit, possible harm, and a waste of valuable resources. From a genuine economic perspective, it can be estimated that over 10 million euros of funding may be lost each year in clinical trials in the European Union due to preanalytical and analytical problems. These are mostly attributions to the heterogeneity of current guidelines and recommendations for the testing process, to the poor evidence base for basic pre-analytical, analytical and post-analytical requirements in clinical trials, and to the failure to thoughtfully integrate the perspectives of clinicians, patients, nurses and diagnostic companies in laboratory best practices. The most rational means for filling the gap between what we know and what we practice in clinical trials cannot discount the development of multidisciplinary teams including research scientists, clinicians, nurses, patients associations and representative of in vitro diagnostic (IVD) companies, who should actively interplay and collaborate with laboratory professionals to adapt and disseminate evidence-based recommendations about biospecimen collection and management into the research settings, from preclinical to phase III studies.

Trials with errors--preserving the integrity of clinical trials.

PubMed

Guyer, R L

2000-01-01

The crucial final test of medical research is the clinical trial, which determines whether a drug or discovery really is an effective therapy. All people who participate in clinical trials--researchers, sponsors, volunteers, analysts, reviewers, overseers, others--have opportunities to strengthen or weaken the integrity of the trial system by their behavior. Medical research is now officially married to business, and "profitable" connotes something different to each partner. Only if research and business can profit in parallel will the alliance succeed. Every person who is involved in the medical research business faces temptations and must choose how to react. Each has power and must choose how to wield it. Several centuries before this marriage, the Englishman Izaak Walton noted that "Health is...a blessing that money cannot buy."

Microbicide safety/efficacy studies in animals: macaques and small animal models.

PubMed

Veazey, Ronald S

2008-09-01

A number of microbicide candidates have failed to prevent HIV transmission in human clinical trials, and there is uncertainty as to how many additional trials can be supported by the field. Regardless, there are far too many microbicide candidates in development, and a logical and consistent method for screening and selecting candidates for human clinical trials is desperately needed. The unique host and cell specificity of HIV, however, provides challenges for microbicide safety and efficacy screening, that can only be addressed by rigorous testing in relevant laboratory animal models. A number of laboratory animal model systems ranging from rodents to nonhuman primates, and single versus multiple dose challenges have recently been developed to test microbicide candidates. These models have shed light on both the safety and efficacy of candidate microbicides as well as the early mechanisms involved in transmission. This article summarizes the major advantages and disadvantages of the relevant animal models for microbicide safety and efficacy testing. Currently, nonhuman primates are the only relevant and effective laboratory model for screening microbicide candidates. Given the consistent failures of prior strategies, it is now clear that rigorous safety and efficacy testing in nonhuman primates should be a prerequisite for advancing additional microbicide candidates to human clinical trials.

Microbicide Safety/Efficacy studies in animals -macaques and small animal models

PubMed Central

Veazey, Ronald S.

2009-01-01

Purpose of review A number of microbicide candidates have failed to prevent HIV transmission in human clinical trials, and there is uncertainty as to how many additional trials can be supported by the field. Regardless, there are far too many microbicide candidates in development, and a logical and consistent method for screening and selecting candidates for human clinical trials is desperately needed. However, the unique host and cell specificity of HIV provides challenges for microbicide safety and efficacy screening, that can only be addressed by rigorous testing in relevant laboratory animal models. Recent findings A number of laboratory animal model systems ranging from rodents to nonhuman primates, and single versus multiple dose challenges have recently been developed to test microbicide candidates. These models have shed light on both the safety and efficacy of candidate microbicides as well as the early mechanisms involved in transmission. This article summarizes the major advantages and disadvantages of the relevant animal models for microbicide safety and efficacy testing. Summary Currently, nonhuman primates are the only relevant and effective laboratory model for screening microbicide candidates. Given the consistent failures of prior strategies, it is now clear that rigorous safety and efficacy testing in nonhuman primates should be a pre-requisite for advancing additional microbicide candidates to human clinical trials. PMID:19373023

Adaptive clinical trial design.

PubMed

Chow, Shein-Chung

2014-01-01

In recent years, the use of adaptive design methods in clinical trials based on accumulated data at interim has received much attention because of its flexibility and efficiency in pharmaceutical/clinical development. In practice, adaptive design may provide the investigators a second chance to modify or redesign the trial while the study is still ongoing. However, it is a concern that a shift in target patient population may occur after significant adaptations are made. In addition, the overall type I error rate may not be preserved. Moreover, the results may not be reliable and hence are difficult to interpret. As indicated by the US Food and Drug Administration draft guidance on adaptive design clinical trials, the adaptive design has to be a prospectively planned opportunity and should be based on information collected within the study, with or without formal statistical hypothesis testing. This article reviews the relative advantages, limitations, and feasibility of commonly considered adaptive designs in clinical trials. Statistical concerns when implementing adaptive designs are also discussed.

Barriers to Clinical Trial Enrollment in Racial and Ethnic Minority Patients With Cancer

PubMed Central

Hamel, Lauren M.; Penner, Louis A.; Albrecht, Terrance L.; Heath, Elisabeth; Gwede, Clement K.; Eggly, Susan

2016-01-01

Background Clinical trials that study cancer are essential for testing the safety and effectiveness of promising treatments, but most people with cancer never enroll in a clinical trial — a challenge exemplified in racial and ethnic minorities. Underenrollment of racial and ethnic minorities reduces the generalizability of research findings and represents a disparity in access to high-quality health care. Methods Using a multilevel model as a framework, potential barriers to trial enrollment of racial and ethnic minorities were identified at system, individual, and interpersonal levels. Exactly how each level directly or indirectly contributes to doctor–patient communication was also reviewed. Selected examples of implemented interventions are included to help address these barriers. We then propose our own evidence-based intervention addressing barriers at the individual and interpersonal levels. Results Barriers to enrolling a diverse population of patients in clinical trials are complex and multilevel. Interventions focused at each level have been relatively successful, but multilevel interventions have the greatest potential for success. Conclusion To increase the enrollment of racial and ethnic minorities in clinical trials, future interventions should address barriers at multiple levels. PMID:27842322

Engaging diverse communities participating in clinical trials: case examples from across Africa.

PubMed

Nyika, Aceme; Chilengi, Roma; Ishengoma, Deus; Mtenga, Sally; Thera, Mahamadou A; Sissoko, Mahamadou S; Lusingu, John; Tiono, Alfred B; Doumbo, Ogobara; Sirima, Sodiomon B; Lemnge, Martha; Kilama, Wen L

2010-03-26

In the advent of increasing international collaborative research involving participants drawn from populations with diverse cultural backgrounds, community engagement becomes very critical for the smooth conduction of the research. The African Malaria Network Trust (AMANET) is a pan-African non-governmental organization that sponsors and technically supports malaria vaccine trials in various African countries. AMANET sponsored phase Ib or IIb clinical trials of several malaria vaccine candidates in various Africa countries. In Burkina Faso, Mali and Tanzania trials of the merozoite surface protein 3 -- in its Long Synthetic Peptide configuration (MSP3 LSP) -- were conducted. In Mali, the apical membrane antigen 1 (AMA1) was tested, while a hybrid of glutamate rich protein (GLURP) and MSP3 (GMZ2) was tested in Gabon. AMANET recognizes the importance of engaging with the communities from which trial participants are drawn, hence community engagement was given priority in all project activities conducted in the various countries. Existing local social systems were used to engage the communities from which clinical trial participants were drawn. This article focuses on community engagement activities employed at various AMANET-supported clinical trial sites in different countries, highlighting subtle differences in the approaches used. The paper also gives some general pros and cons of community engagement. Community engagement enables two-way sharing of accurate information and ideas between researchers and researched communities, which helps to create an environment conducive to smooth research activities with enhanced sense of research ownership by the communities.

Design of clinical trials involving multiple hypothesis tests with a common control.

PubMed

Schou, I Manjula; Marschner, Ian C

2017-07-01

Randomized clinical trials comparing several treatments to a common control are often reported in the medical literature. For example, multiple experimental treatments may be compared with placebo, or in combination therapy trials, a combination therapy may be compared with each of its constituent monotherapies. Such trials are typically designed using a balanced approach in which equal numbers of individuals are randomized to each arm, however, this can result in an inefficient use of resources. We provide a unified framework and new theoretical results for optimal design of such single-control multiple-comparator studies. We consider variance optimal designs based on D-, A-, and E-optimality criteria, using a general model that allows for heteroscedasticity and a range of effect measures that include both continuous and binary outcomes. We demonstrate the sensitivity of these designs to the type of optimality criterion by showing that the optimal allocation ratios are systematically ordered according to the optimality criterion. Given this sensitivity to the optimality criterion, we argue that power optimality is a more suitable approach when designing clinical trials where testing is the objective. Weighted variance optimal designs are also discussed, which, like power optimal designs, allow the treatment difference to play a major role in determining allocation ratios. We illustrate our methods using two real clinical trial examples taken from the medical literature. Some recommendations on the use of optimal designs in single-control multiple-comparator trials are also provided. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Test-retest reliability and sensitivity of the 20-meter walk test among patients with knee osteoarthritis.

PubMed

Motyl, Jillian M; Driban, Jeffrey B; McAdams, Erica; Price, Lori Lyn; McAlindon, Timothy E

2013-05-10

The 20-meter walk test is a physical function measure commonly used in clinical research studies and rehabilitation clinics to measure gait speed and monitor changes in patients' physical function over time. Unfortunately, the reliability and sensitivity of this walk test are not well defined and, therefore, limit our ability to evaluate real changes in gait speed not attributable to normal variability. The aim of this study was to assess the test-restest reliability and sensitivity of the 20-meter walk test, at a self-selected pace, among patients with mild to moderate knee osteoarthritis (OA) and to suggest a standardized protocol for future test administration. This was a measurement reliability study. Fifteen consecutive people enrolled in a randomized-controlled trial of intra-articular corticosteroid injections for knee OA participated in this study. All participants completed 4 trials on 2 separate days, 7 to 21 days apart (8 trials total). Each day was divided into 2 sessions, which each involved 2 walking trials. We compared walk times between trials with Wilcoxon signed-rank tests. Similar analyses compared average walk times between sessions. To confirm these analyses, we also calculated Spearman correlation coefficients to assess the relationship between sessions. Finally, smallest detectable differences (SDD) were calculated to estimate the sensitivity of the 20-meter walk test. Wilcoxon signed-rank tests between trials within the same session demonstrated that trials in session 1 were significantly different and in the subsequent 3 sessions, the median differences between trials were not significantly different. Therefore, the first session of each day was considered a practice session, and the SDD between the second session of each day were calculated. SDD was -1.59 seconds (walking slower) and 0.15 seconds (walking faster). Practice trials and a standardized protocol should be used in administration of the 20-meter walk test. Changes in walk time between -1.59 seconds (walking slower) and 0.15 seconds (walking faster) should be considered within the range of normal variability of 20-meter walking speed. The primary limitation of our study was a small sample size, which may influence the generalizability of our findings.

Analysis of Factors Affecting Successful Clinical Trial Enrollment in the Context of Three Prospective, Randomized, Controlled Trials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Logan, Jennifer K.; Tang, Chad; Liao, Zhongxing

Purpose: Challenges can arise when attempting to maximize patient enrollment in clinical trials. There have been limited studies focusing on the barriers to enrollment and the efficacy of alternative study design to improve accrual. We analyzed barriers to clinical trial enrollment, particularly the influence of timing, in context of three prospective, randomized oncology trials where one arm was considered more aggressive than the other. Methods and Materials: From June 2011 to March 2015, patients who were enrolled on 3 prospective institutional protocols (an oligometastatic non-small cell lung cancer [NSCLC] trial and 2 proton vs intensity modulated radiation therapy trials inmore » NSCLC and esophageal cancer) were screened for protocol eligibility. Eligible candidates were approached about trial participation, and patient characteristics (age, sex, T/N categorization) were recorded along with details surrounding trial presentation (appointment number). Fisher's exact test, Student's t tests, and multivariate analysis were performed to assess differences between enrolled and refusal patients. Results: A total of 309 eligible patients were approached about trial enrollment. The enrollment success rate during this time span was 52% (n=160 patients). Enrolled patients were more likely to be presented trial information at an earlier appointment (oligometastatic protocol: 5 vs 3 appointments [P<.001]; NSCLC protocol: 4 vs 3 appointments [P=.0018]; esophageal protocol: 3 vs 2 appointments [P=.0086]). No other factors or patient characteristics significantly affected enrollment success rate. Conclusion: Improvement in enrollment rates for randomized control trials is possible, even in difficult accrual settings. Earlier presentation of trial information to patients is the most influential factor for success and may help overcome accrual barriers without compromising trial design.« less

Improving Clinical Trial Efficiency: Thinking outside the Box.

PubMed

Mandrekar, Sumithra J; Dahlberg, Suzanne E; Simon, Richard

2015-01-01

Clinical trial design strategies have evolved over the past few years as a means to accelerate the drug development process so that the right therapies can be delivered to the right patients. Basket, umbrella, and adaptive enrichment strategies represent a class of novel designs for testing targeted therapeutics in oncology. Umbrella trials include a central infrastructure for screening and identification of patients, and focus on a single tumor type or histology with multiple subtrials, each testing a targeted therapy within a molecularly defined subset. Basket trial designs offer the possibility to include multiple molecularly defined subpopulations, often across histology or tumor types, but included in one cohesive design to evaluate the targeted therapy in question. Adaptive enrichment designs offer the potential to enrich for patients with a particular molecular feature that is predictive of benefit for the test treatment based on accumulating evidence from the trial. This review will aim to discuss the fundamentals of these design strategies, the underlying statistical framework, the logistical barriers of implementation, and, ultimately, the interpretation of the trial results. New statistical approaches, extensive multidisciplinary collaboration, and state of the art data capture technologies are needed to implement these strategies in practice. Logistical challenges to implementation arising from centralized assay testing, requirement of multiple specimens, multidisciplinary collaboration, and infrastructure requirements will also be discussed. This review will present these concepts in the context of the National Cancer Institute's precision medicine initiative trials: MATCH, ALCHEMIST, Lung MAP, as well as other trials such as FOCUS4.

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments

PubMed Central

2011-01-01

Background No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes - the "sentinel lesion approach". Methods/design MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. Results Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. Conclusions In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS - the sentinel lesion approach - serving as proof of principle for its future wider applicability. Trial registration ClinicalTrials.gov (NCT00395200). PMID:21366911

Animal testing is still the best way to find new treatments for patients.

PubMed

Garattini, Silvio; Grignaschi, Giuliano

2017-04-01

Experimental research proceeds by hypotheses formulated on the basis of previous or new knowledge and then tested. If they are accepted, they serve as the basis for further hypotheses, and if they are rejected new hypotheses can be developed. In other words, when we are at the frontiers of knowledge the path is forged by "trial and error". When a trial shows a hypothesis is wrong, this is a step toward making fewer errors. This process also applies to drug development. There is no magic formula at present to predict - at the pre-clinical level - the therapeutic value of a drug for people with a disease. However, pre-clinical studies are needed in order to formulate hypotheses that justify clinical trials. Without these preliminary studies in vitro and in vivo in selected animal species it would be unethical to test still unproven chemicals in humans. Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

A cooperative network of trained sites for the conduct of a complex clinical trial: a new concept in multicenter clinical research.

PubMed

Davidson, Robert M; McNeer, J Frederick; Logan, Leanne; Higginbotham, Michael B; Anderson, Jerome; Blackshear, Joseph; Chu, Alan; Hettleman, Bruce; McGrew, Frank; Meesse, Roderick; O'Connor, Christopher; Schneider, Ricky; Wagner, Galen S

2006-02-01

The purpose of this report is to present a model of physicians in full-time clinical practice participating as investigators in multicenter clinical trials, sponsored by a pharmaceutical or medical device company. This gas-exchange substudy was conducted as a pilot study to establish the feasibility of the 10-member EXERcise testing group of the Duke University Cooperative Cardiovascular Society (EXERDUCCS) consortium to perform a complex multicenter trial using cardiopulmonary exercise testing. An active interchange of information was established involving the principal investigator for the substudy, a dedicated full-time project coordinator, a medical director of the overall EXERDUCCS network site, the project coordinator for the sponsor, and all the participating EXERDUCCS investigators and coordinators. The sponsor set as a goal of enrollment of 6 subjects per site, and 8 of the 10 sites met this goal. As a result of the successful enrollment and completion of the study and substudy by the EXERDUCCS sites, the sponsor subsequently increased the payment stipends to the sites to compensate for the extra work and expense incurred. This cooperative experience accomplished several goals: (1) it allowed a complex clinical trial to be successfully completed in a time frame which would not have been possible using only single unconnected sites; (2) it educated the physician-investigators (and their personnel) in exercise cardiopulmonary; and (3) it prepared the sites for future clinical trials involving this methodology.

Unfulfilled translation opportunities in industry sponsored clinical trials.

PubMed

Smed, Marie; Getz, Kenneth A

2013-05-01

Knowledge generated by site representatives through their participation in clinical trials is valuable for testing new products in use and obtaining final market approval. The leverage of this important knowledge is however challenged as the former direct relationships between in-house staff in the industry and site representatives are changing. The process of clinical trials has increased in complexity over the years, resulting in additional management layers. Besides an increase in internal management layers, sponsors often also outsource various tasks related to clinical trials to a CRO (Contract Research Organization) and thereby adding another link in the relationships between site and sponsor. These changes are intended to optimize the time-consuming and costly trial phases; however, there is a need to study whether valuable knowledge and experience is compromised in the process. Limited research exists on the full range of clinical practice insights obtained by investigators during and after clinical trials and how well these insights are transferred to study sponsors. This study explores the important knowledge-transfer processes between sites and sponsors and to what extent sites' knowledge gained in clinical trials is utilized by the industry. Responses from 451 global investigative site representatives are included in the study. The analysis of the extensive dataset reveals that the current processes of collaboration between sites and the industry restrict the leverage of valuable knowledge gained by physicians in the process of clinical trials. These restrictions to knowledge-transfer between site and sponsor are further challenged if CRO partners are integrated in the trial process. Copyright © 2013 Elsevier Inc. All rights reserved.

Parent satisfaction in a multi-site acute trial of risperidone in children with autism: a social validity study.

PubMed

Tierney, Elaine; Aman, Michael; Stout, David; Pappas, Krista; Arnold, L Eugene; Vitiello, Benedetto; Scahill, Lawrence; McDougle, Christopher; McCracken, James; Wheeler, Courtney; Martin, Andres; Posey, David; Shah, Bhavik

2007-03-01

Subjects who view experimental procedures as worthwhile are more likely to participate in clinical trials and comply with study procedures. Designing studies that consider the consumer's perspective will help to forge a better alliance between participants and researchers. Participant satisfaction is seldom assessed in pharmacological research. In this paper, we report on parent satisfaction in a randomized clinical trial in children with autistic disorder and severely disruptive behavior. Parents of 101 children with autism who had participated in a multi-site 8-week double-blind clinical trial of risperidone were given a questionnaire at the end to elicit their perceptions of the appropriateness and acceptability of clinical trial procedures. Ninety-six (95.0%) parents returned the questionnaire. Of these, 80.0 to 96.8%, depending on the question, expressed satisfaction with their child's research participation regardless of treatment outcome or assignment to active drug or placebo. In all, 90.5% of parents indicated that they would "definitely" recommend the clinical trial to other families with similar children. A total of 92.7% indicated that they would rejoin the clinical trial if they had to do it all over again. Ethnic minority subjects were more satisfied than white participants with the use of "learning tests". Parents of children participating in this trial were highly satisfied and supportive of the clinical trial procedures. Random assignment to drug or placebo and the clinical response of their children did not appear to influence their views. Further satisfaction studies of this sort are encouraged.

Virtual colonoscopy, optical colonoscopy, or fecal occult blood testing for colorectal cancer screening: results of a pilot randomized controlled trial.

PubMed

You, John J; Liu, Yudong; Kirby, John; Vora, Parag; Moayyedi, Paul

2015-07-09

No head-to-head randomized controlled trials have demonstrated the superiority of one colorectal screening modality over another in reducing colorectal cancer mortality. We conducted a pilot randomized controlled trial of fecal occult blood testing (FOBT), optical colonoscopy (OC), and virtual colonoscopy (VC), to inform the planning of a larger evaluative trial. Eligible patients (aged 50 to 70) were recruited from five primary care practices in Hamilton, ON, Canada, between March 23, 2010 and August 11, 2010, and randomized 1:1:1 in a parallel design using an automated, centralized telephone service to either FOBT, OC, or VC. To reflect conventional practice, patients received no additional reminders to complete their allocated screening test beyond those received in usual practice. The primary outcome was completion of the assigned screening procedure. Results of the index test and any follow-up investigations were ascertained at 6 months. Participants, caregivers, and outcome assessors were not blinded to group assignment. The trial was stopped early due to lack of ongoing funding. A total of 198 participants were enrolled, of whom 67 were allocated to FOBT, 66 to OC, and 65 to VC. The allocated screening procedure was completed by 43 (64%) subjects allocated to FOBT (95% confidence interval [CI], 52-75%), 53 (80%) subjects allocated to OC (95% CI, 69-88%), and 50 (77%) subjects allocated to VC (95% CI, 65-85%); because the trial stopped early, we had insufficient statistical power to detect clinically relevant differences in completion rates. During 6 months follow-up, colorectal adenomas were detected in 0 (0%) subjects allocated to FOBT, 12 (18%) subjects allocated to OC, and 2 (3%) subjects allocated to VC. One subject in the OC arm had histological evidence of high-grade dysplasia. No subjects were diagnosed with colorectal cancer. In this pilot randomized controlled trial of colorectal cancer screening in a primary care setting, 64-80% of subjects completed their allocated screening test. These findings may be of value to investigators planning clinical trials to evaluate the effectiveness of colorectal cancer screening. ClinicalTrials.gov NCT00865527. https://clinicaltrials.gov/ct2/show/NCT00865527.

Emotion Regulation Enhancement of Cognitive Behavior Therapy for College Student Problem Drinkers: A Pilot Randomized Controlled Trial

ERIC Educational Resources Information Center

Ford, Julian D.; Grasso, Damion J.; Levine, Joan; Tennen, Howard

2018-01-01

This pilot randomized clinical trial tested an emotion regulation enhancement to cognitive behavior therapy (CBT) with 29 college student problem drinkers with histories of complex trauma and current clinically significant traumatic stress symptoms. Participants received eight face-to-face sessions of manualized Internet-supported CBT for problem…

Cognitive-Behavioral Therapy for Intermittent Explosive Disorder: A Pilot Randomized Clinical Trial

ERIC Educational Resources Information Center

McCloskey, Michael S.; Noblett, Kurtis L.; Deffenbacher, Jerry L.; Gollan, Jackie K.; Coccaro, Emil F.

2008-01-01

No randomized clinical trials have evaluated the efficacy of psychotherapy for intermittent explosive disorder (IED). In the present study, the authors tested the efficacy of 12-week group and individual cognitive-behavioral therapies (adapted from J. L. Deffenbacher & M. McKay, 2000) by comparing them with a wait-list control in a randomized…

What do I tell patients about saw palmetto for benign prostatic hyperplasia?

PubMed

Kane, Christopher J; Raheem, Omer A; Bent, Stephen; Avins, Andrew L

2011-08-01

Saw palmetto is widely used to treat lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH). Although there is passionate support for herbal and complementary therapies for LUTS, clinical evidence is mixed. Because there is a well-recognized, profound placebo effect in tests of efficacy for agents treating LUTS, it is imperative that all therapies be tested in placebo-controlled trials. This article reviews evidence of the efficacy and safety of saw palmetto for men with LUTS caused by BPH, with particular emphasis on published randomized clinical trials and the upcoming Complementary and Alternative Medicine for Urologic Symptoms (CAMUS) trial. Copyright © 2011 Elsevier Inc. All rights reserved.

Impact of a Clinical Decision Model for Febrile Children at Risk for Serious Bacterial Infections at the Emergency Department: A Randomized Controlled Trial

PubMed Central

de Vos-Kerkhof, Evelien; Nijman, Ruud G.; Vergouwe, Yvonne; Polinder, Suzanne; Steyerberg, Ewout W.; van der Lei, Johan; Moll, Henriëtte A.; Oostenbrink, Rianne

2015-01-01

Objectives To assess the impact of a clinical decision model for febrile children at risk for serious bacterial infections (SBI) attending the emergency department (ED). Methods Randomized controlled trial with 439 febrile children, aged 1 month-16 years, attending the pediatric ED of a Dutch university hospital during 2010-2012. Febrile children were randomly assigned to the intervention (clinical decision model; n=219) or the control group (usual care; n=220). The clinical decision model included clinical symptoms, vital signs, and C-reactive protein and provided high/low-risks for “pneumonia” and “other SBI”. Nurses were guided by the intervention to initiate additional tests for high-risk children. The clinical decision model was evaluated by 1) area-under-the-receiver-operating-characteristic-curve (AUC) to indicate discriminative ability and 2) feasibility, to measure nurses’ compliance to model recommendations. Primary patient outcome was defined as correct SBI diagnoses. Secondary process outcomes were defined as length of stay; diagnostic tests; antibiotic treatment; hospital admission; revisits and medical costs. Results The decision model had good discriminative ability for both pneumonia (n=33; AUC 0.83 (95% CI 0.75-0.90)) and other SBI (n=22; AUC 0.81 (95% CI 0.72-0.90)). Compliance to model recommendations was high (86%). No differences in correct SBI determination were observed. Application of the clinical decision model resulted in less full-blood-counts (14% vs. 22%, p-value<0.05) and more urine-dipstick testing (71% vs. 61%, p-value<0.05). Conclusions In contrast to our expectations no substantial impact on patient outcome was perceived. The clinical decision model preserved, however, good discriminatory ability to detect SBI, achieved good compliance among nurses and resulted in a more standardized diagnostic approach towards febrile children, with less full blood-counts and more rightfully urine-dipstick testing. Trial Registration Nederlands Trial Register NTR2381 PMID:26024532

An immunologic model for rapid vaccine assessment -- a clinical trial in a test tube.

PubMed

Higbee, Russell G; Byers, Anthony M; Dhir, Vipra; Drake, Donald; Fahlenkamp, Heather G; Gangur, Jyoti; Kachurin, Anatoly; Kachurina, Olga; Leistritz, Del; Ma, Yifan; Mehta, Riyaz; Mishkin, Eric; Moser, Janice; Mosquera, Luis; Nguyen, Mike; Parkhill, Robert; Pawar, Santosh; Poisson, Louis; Sanchez-Schmitz, Guzman; Schanen, Brian; Singh, Inderpal; Song, Haifeng; Tapia, Tenekua; Warren, William; Wittman, Vaughan

2009-09-01

While the duration and size of human clinical trials may be difficult to reduce, there are several parameters in pre-clinical vaccine development that may be possible to further optimise. By increasing the accuracy of the models used for pre-clinical vaccine testing, it should be possible to increase the probability that any particular vaccine candidate will be successful in human trials. In addition, an improved model will allow the collection of increasingly more-informative data in pre-clinical tests, thus aiding the rational design and formulation of candidates entered into clinical evaluation. An acceleration and increase in sophistication of pre-clinical vaccine development will thus require the advent of more physiologically-accurate models of the human immune system, coupled with substantial advances in the mechanistic understanding of vaccine efficacy, achieved by using this model. We believe the best viable option available is to use human cells and/or tissues in a functional in vitro model of human physiology. Not only will this more accurately model human diseases, it will also eliminate any ethical, moral and scientific issues involved with use of live humans and animals. An in vitro model, termed "MIMIC" (Modular IMmune In vitro Construct), was designed and developed to reflect the human immune system in a well-based format. The MIMIC System is a laboratory-based methodology that replicates the human immune system response. It is highly automated, and can be used to simulate a clinical trial for a diverse population, without putting human subjects at risk. The MIMIC System uses the circulating immune cells of individual donors to recapitulate each individual human immune response by maintaining the autonomy of the donor. Thus, an in vitro test system has been created that is functionally equivalent to the donor's own immune system and is designed to respond in a similar manner to the in vivo response. 2009 FRAME.

Changing the Paradigm for the Treatment and Development of New Therapies for FSGS

PubMed Central

Spino, Cathie; Jahnke, Jordan S.; Selewski, David T.; Massengill, Susan; Troost, Jonathan; Gipson, Debbie S.

2016-01-01

Focal segmental glomerulosclerosis (FSGS) is a renal pathology finding that represents a constellation of rare kidney diseases, which manifest as proteinuria, edema nephrotic syndrome, hypertension, and increased risk for kidney failure. Therapeutic options for FSGS are reviewed displaying the expected efficacy from 25 to 69% depending on specific therapy, patient characteristics, cost, and common side effects. This variability in treatment response is likely caused, in part, by the heterogeneity in the etiology and active molecular mechanisms of FSGS. Clinical trials in FSGS have been scant in number and slow to recruit, which may stem, in part, from reliance on classic clinical trial design paradigms. Traditional clinical trial designs based on the “learn and confirm” paradigm may not be appropriate for rare diseases, such as FSGS. Future drug development and testing will require novel approaches to trial designs that have the capacity to enrich study populations and adapt the trial in a planned way to gain efficiencies in trial completion timelines. A clinical trial simulation is provided that compares a classical and more modern design to determine the maximum tolerated dose in FSGS. PMID:27047908

A Randomized Study of How Physicians Interpret Research Funding Disclosures

PubMed Central

Kesselheim, Aaron S.; Robertson, Christopher T.; Myers, Jessica A.; Rose, Susannah L.; Gillet, Victoria; Ross, Kathryn M.; Glynn, Robert J.; Joffe, Steven; Avorn, Jerry

2012-01-01

BACKGROUND The effects of clinical-trial funding on the interpretation of trial results are poorly understood. We examined how such support affects physicians’ reactions to trials with a high, medium, or low level of methodologic rigor. METHODS We presented 503 board-certified internists with abstracts that we designed describing clinical trials of three hypothetical drugs. The trials had high, medium, or low methodologic rigor, and each report included one of three support disclosures: funding from a pharmaceutical company, NIH funding, or none. For both factors studied (rigor and funding), one of the three possible variations was randomly selected for inclusion in the abstracts. Follow-up questions assessed the physicians’ impressions of the trials’ rigor, their confidence in the results, and their willingness to prescribe the drugs. RESULTS The 269 respondents (53.5% response rate) perceived the level of study rigor accurately. Physicians reported that they would be less willing to prescribe drugs tested in low-rigor trials than those tested in medium-rigor trials (odds ratio, 0.64; 95% confidence interval [CI], 0.46 to 0.89; P = 0.008) and would be more willing to prescribe drugs tested in high-rigor trials than those tested in medium-rigor trials (odds ratio, 3.07; 95% CI, 2.18 to 4.32; P<0.001). Disclosure of industry funding, as compared with no disclosure of funding, led physicians to downgrade the rigor of a trial (odds ratio, 0.63; 95% CI, 0.46 to 0.87; P = 0.006), their confidence in the results (odds ratio, 0.71; 95% CI, 0.51 to 0.98; P = 0.04), and their willingness to prescribe the hypothetical drugs (odds ratio, 0.68; 95% CI, 0.49 to 0.94; P = 0.02). Physicians were half as willing to prescribe drugs studied in industry-funded trials as they were to prescribe drugs studied in NIH-funded trials (odds ratio, 0.52; 95% CI, 0.37 to 0.71; P<0.001). These effects were consistent across all levels of methodologic rigor. CONCLUSIONS Physicians discriminate among trials of varying degrees of rigor, but industry sponsorship negatively influences their perception of methodologic quality and reduces their willingness to believe and act on trial findings, independently of the trial’s quality. These effects may influence the translation of clinical research into practice. PMID:22992075

A hybrid method in combining treatment effects from matched and unmatched studies.

PubMed

Byun, Jinyoung; Lai, Dejian; Luo, Sheng; Risser, Jan; Tung, Betty; Hardy, Robert J

2013-12-10

The most common data structures in the biomedical studies have been matched or unmatched designs. Data structures resulting from a hybrid of the two may create challenges for statistical inferences. The question may arise whether to use parametric or nonparametric methods on the hybrid data structure. The Early Treatment for Retinopathy of Prematurity study was a multicenter clinical trial sponsored by the National Eye Institute. The design produced data requiring a statistical method of a hybrid nature. An infant in this multicenter randomized clinical trial had high-risk prethreshold retinopathy of prematurity that was eligible for treatment in one or both eyes at entry into the trial. During follow-up, recognition visual acuity was accessed for both eyes. Data from both eyes (matched) and from only one eye (unmatched) were eligible to be used in the trial. The new hybrid nonparametric method is a meta-analysis based on combining the Hodges-Lehmann estimates of treatment effects from the Wilcoxon signed rank and rank sum tests. To compare the new method, we used the classic meta-analysis with the t-test method to combine estimates of treatment effects from the paired and two sample t-tests. We used simulations to calculate the empirical size and power of the test statistics, as well as the bias, mean square and confidence interval width of the corresponding estimators. The proposed method provides an effective tool to evaluate data from clinical trials and similar comparative studies. Copyright © 2013 John Wiley & Sons, Ltd.

Testing an alternate informed consent process.

PubMed

Yates, Bernice C; Dodendorf, Diane; Lane, Judy; LaFramboise, Louise; Pozehl, Bunny; Duncan, Kathleen; Knodel, Kendra

2009-01-01

One of the main problems in conducting clinical trials is low participation rate due to potential participants' misunderstanding of the rationale for the clinical trial or perceptions of loss of control over treatment decisions. The objective of this study was to test an alternate informed consent process in cardiac rehabilitation participants that involved the use of a multimedia flip chart to describe a future randomized clinical trial and then asked, hypothetically, if they would participate in the future trial. An attractive and inviting visual presentation of the study was created in the form of a 23-page flip chart that included 24 color photographs displaying information about the purpose of the study, similarities and differences between the two treatment groups, and the data collection process. We tested the flip chart in 35 cardiac rehabilitation participants. Participants were asked if they would participate in this future study on two occasions: immediately after the description of the flip chart and 24 hours later, after reading through the informed consent document. Participants were also asked their perceptions of the flip chart and consent process. Of the 35 participants surveyed, 19 (54%) indicated that they would participate in the future study. No participant changed his or her decision 24 hours later after reading the full consent form. The participation rate improved 145% over that of an earlier feasibility study where the recruitment rate was 22%. Most participants stated that the flip chart was helpful and informative and that the photographs were effective in communicating the purpose of the study. Participation rates could be enhanced in future clinical trials by using a visual presentation to explain and describe the study as part of the informed consent process. More research is needed to test alternate methods of obtaining informed consent.

Developing a Cognition Endpoint for Traumatic Brain Injury Clinical Trials

PubMed Central

Crane, Paul K.; Dams-O'Connor, Kristen; Holdnack, James; Ivins, Brian J.; Lange, Rael T.; Manley, Geoffrey T.; McCrea, Michael; Iverson, Grant L.

2017-01-01

Abstract Cognitive impairment is a core clinical feature of traumatic brain injury (TBI). After TBI, cognition is a key determinant of post-injury productivity, outcome, and quality of life. As a final common pathway of diverse molecular and microstructural TBI mechanisms, cognition is an ideal endpoint in clinical trials involving many candidate drugs and nonpharmacological interventions. Cognition can be reliably measured with performance-based neuropsychological tests that have greater granularity than crude rating scales, such as the Glasgow Outcome Scale-Extended, which remain the standard for clinical trials. Remarkably, however, there is no well-defined, widely accepted, and validated cognition endpoint for TBI clinical trials. A single cognition endpoint that has excellent measurement precision across a wide functional range and is sensitive to the detection of small improvements (and declines) in cognitive functioning would enhance the power and precision of TBI clinical trials and accelerate drug development research. We outline methodologies for deriving a cognition composite score and a research program for validation. Finally, we discuss regulatory issues and the limitations of a cognition endpoint. PMID:27188248

Evaluation of a dental floss containing soluble pyrophosphate on calculus formation using a short-term clinical model.

PubMed

Kleber, C J; Putt, M S; Milleman, J L; Harris, M

1998-01-01

This clinical study compared the effect of a dental floss containing 0.25 mg tetrasodium pyrophosphate per cm and a placebo floss on supragingival calculus formation using a 6-week, partial-mouth toothshield model. The six lower anterior teeth were scaled and polished before each 2-week period (i.e., pre-trial, washout, trial). During both the pre-trial and trial periods, subjects brushed twice daily with a non-tartar control dentifrice, while a toothshield protected the six test teeth from brushing. After rinsing with water and removing the shield, they flossed the test teeth. All subjects used placebo floss during the pre-trial period in order to determine the baseline Volpe-Manhold Index (VMI) calculus formation scores, which were used to balance groups for the trial period. During the trial period, one group used the placebo floss, while the second group used the pyrophosphate floss. The final results demonstrated that the pyrophosphate floss significantly inhibited calculus formation between teeth (mesial-distal scores) by 21%, and on labial surfaces by 37% relative to the placebo floss.

Prediction of black box warning by mining patterns of Convergent Focus Shift in clinical trial study populations using linked public data.

PubMed

Ma, Handong; Weng, Chunhua

2016-04-01

To link public data resources for predicting post-marketing drug safety label changes by analyzing the Convergent Focus Shift patterns among drug testing trials. We identified 256 top-selling prescription drugs between 2003 and 2013 and divided them into 83 BBW drugs (drugs with at least one black box warning label) and 173 ROBUST drugs (drugs without any black box warning label) based on their FDA black box warning (BBW) records. We retrieved 7499 clinical trials that each had at least one of these drugs for intervention from the ClinicalTrials.gov. We stratified all the trials by pre-marketing or post-marketing status, study phase, and study start date. For each trial, we retrieved drug and disease concepts from clinical trial summaries to model its study population using medParser and SNOMED-CT. Convergent Focus Shift (CFS) pattern was calculated and used to assess the temporal changes in study populations from pre-marketing to post-marketing trials for each drug. Then we selected 68 candidate drugs, 18 with BBW warning and 50 without, that each had at least nine pre-marketing trials and nine post-marketing trials for predictive modeling. A random forest predictive model was developed to predict BBW acquisition incidents based on CFS patterns among these drugs. Pre- and post-marketing trials of BBW and ROBUST drugs were compared to look for their differences in CFS patterns. Among the 18 BBW drugs, we consistently observed that the post-marketing trials focused more on recruiting patients with medical conditions previously unconsidered in the pre-marketing trials. In contrast, among the 50 ROBUST drugs, the post-marketing trials involved a variety of medications for testing their associations with target intervention(s). We found it feasible to predict BBW acquisitions using different CFS patterns between the two groups of drugs. Our random forest predictor achieved an AUC of 0.77. We also demonstrated the feasibility of the predictor for identifying long-term BBW acquisition events without compromising prediction accuracy. This study contributes a method for post-marketing pharmacovigilance using Convergent Focus Shift (CFS) patterns in clinical trial study populations mined from linked public data resources. These signals are otherwise unavailable from individual data resources. We demonstrated the added value of linked public data and the feasibility of integrating ClinicalTrials.gov summaries and drug safety labels for post-marketing surveillance. Future research is needed to ensure better accessibility and linkage of heterogeneous drug safety data for efficient pharmacovigilance. Copyright © 2016 Elsevier Inc. All rights reserved.

Is one trial enough for repeated testing? Same-day assessments of walking, mobility and fine hand use in people with myotonic dystrophy type 1.

PubMed

Kierkegaard, Marie; Petitclerc, Emilie; Hébert, Luc J; Gagnon, Cynthia

2017-02-01

Performance-based assessments of physical function are essential in people with myotonic dystrophy type 1 (DM1) to monitor disease progression and evaluate interventions. Commonly used are the six-minute walk test, the 10 m-walk test, the timed up-and-go test, the timed-stands test, grip strength tests and the nine-hole peg test. The number of trials needed on a same-day test occasion and whether the first, best or average of trials should be reported as result is unknown. Thus, the aim was to describe and explore differences between trials in these measures of walking, mobility and fine hand use in 70 adults with DM1. Three trials were performed for each test except for the six-minute walk test where two trials were allowed. There were statistical significant differences over trials in all tests except for the 10 m-walk test and grip strength tests. Pair-wise comparisons showed that the second and third trials were in general better than the first, although effect sizes were small. At which trial the individuals performed their best differed between individuals and tests. People with severe muscular impairment had difficulties to perform repeated trials. Intraclass correlation coefficients were all high in analyses exploring how to report results. The conclusion and clinical implication is that, for a same-day test occasion, one trial is sufficient for the 10 m-walk test and grip strength tests, and that repeated trials should be allowed in the timed up-and-go test, timed-stands test and nine-hole peg tests. We recommend that two trials are performed for these latter tests as such a protocol could accommodate people with various levels of impairments and physical limitations. Copyright © 2016 Elsevier B.V. All rights reserved.

Should all acutely ill children in primary care be tested with point-of-care CRP: a cluster randomised trial.

PubMed

Verbakel, Jan Y; Lemiengre, Marieke B; De Burghgraeve, Tine; De Sutter, An; Aertgeerts, Bert; Shinkins, Bethany; Perera, Rafael; Mant, David; Van den Bruel, Ann; Buntinx, Frank

2016-10-06

Point-of-care blood C-reactive protein (CRP) testing has diagnostic value in helping clinicians rule out the possibility of serious infection. We investigated whether it should be offered to all acutely ill children in primary care or restricted to those identified as at risk on clinical assessment. Cluster randomised controlled trial involving acutely ill children presenting to 133 general practitioners (GPs) at 78 GP practices in Belgium. Practices were randomised to undertake point-of-care CRP testing in all children (1730 episodes) or restricted to children identified as at clinical risk (1417 episodes). Clinical risk was assessed by a validated clinical decision rule (presence of one of breathlessness, temperature ≥ 40 °C, diarrhoea and age 12-30 months, or clinician concern). The main trial outcome was hospital admission with serious infection within 5 days. No specific guidance was given to GPs on interpreting CRP levels but diagnostic performance is reported at 5, 20, 80 and 200 mg/L. Restricting CRP testing to those identified as at clinical risk substantially reduced the number of children tested by 79.9 % (95 % CI, 77.8-82.0 %). There was no significant difference between arms in the number of children with serious infection who were referred to hospital immediately (0.16 % vs. 0.14 %, P = 0.88). Only one child with a CRP < 5 mg/L had an illness requiring admission (a child with viral gastroenteritis admitted for rehydration). However, of the 80 children referred to hospital to rule out serious infection, 24 (30.7 %, 95 % CI, 19.6-45.6 %) had a CRP < 5 mg/L. CRP testing should be restricted to children at higher risk after clinical assessment. A CRP < 5 mg/L rules out serious infection and could be used by GPs to avoid unnecessary hospital referrals. ClinicalTrials.gov Identifier: NCT02024282 (registered on 14 th September 2012).

Cartographic Mapping and Travel Burden to Assess and Develop Strategies to Improve Minority Access to National Cancer Clinical Trials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bruner, Deborah Watkins, E-mail: deborah.w.bruner@emory.edu; Pugh, Stephanie L.; Yeager, Katherine A.

Purpose: To assess how accrual to clinical trials is related to US minority population density relative to clinical trial site location and distance traveled to Radiation Therapy Oncology Group (RTOG) clinical trial sites. Methods and Materials: Data included member site address and ZIP codes, patient accrual, and patient race or ethnicity and ZIP code. Geographic Information System maps were developed for overall, Latino, and African American accrual to trials by population density. The Kruskal-Wallis test was used to assess differences in distance traveled by site, type of trial, and race or ethnicity. Results: From 2006 to 2009, 6168 patients enrolledmore » on RTOG trials. The RTOG US site distribution is generally concordant with overall population density. Sites with highest accrual are located throughout the United States and parts of Canada and do not cluster, nor does highest minority accrual cluster in areas of highest US minority population density. Of the 4913 US patients with complete data, patients traveled a median of 11.6 miles to participate in clinical trials. Whites traveled statistically longer distances (12.9 miles; P<.0001) to participate, followed by Latinos (8.22 miles) and African Americans (5.85 miles). Patients were willing to drive longer distances to academic sites than community sites, and there was a trend toward significantly longer median travel for therapeutic versus cancer control or metastatic trials. Conclusions: Location matters, but only to a degree, for minority compared with nonminority participation in clinical trials. Geographic Information System tools help identify gaps in geographic access and travel burden for clinical trials participation. Strategies that emerged using these tools are discussed.« less

Motivation for health information seeking and processing about clinical trial enrollment.

PubMed

Yang, Z Janet; McComas, Katherine; Gay, Geri; Leonard, John P; Dannenberg, Andrew J; Dillon, Hildy

2010-07-01

Low patient accrual in clinical trials poses serious concerns for the advancement of medical science in the United States. Past research has identified health communication as a crucial step in overcoming barriers to enrollment. However, few communication scholars have studied this problem from a sociopsychological perspective to understand what motivates people to look for or pay attention to information about clinical trial enrollment. This study applies the model of Risk Information Seeking and Processing (RISP) to this context of health decision making. By recognizing the uncertainties embedded in clinical trials, we view clinical trial enrollment as a case study of risk. With data from a random-digit-dial telephone survey of 500 adults living in the United States, we used structural equation modeling to test the central part of the RISP model. In particular, we examined the role of optimistic feelings, as a type of positive affect, in motivating information seeking and processing. Our results indicated that rather than exerting an indirect influence on information seeking through motivating a psychological need for more information, optimistic feelings have more direct relationships with information seeking and processing. Similarly, informational subjective norms also exhibit a more direct relationship with information seeking and processing. These results suggest merit in applying the RISP model to study health decision making related to clinical trial enrollment. Our findings also render practical implications on how to improve communication about clinical trial enrollment.

Birth Control in Clinical Trials

PubMed Central

Stewart, J.; Beyer, B. K.; Chadwick, K.; De Schaepdrijver, L.; Desai, M.; Enright, B.; Foster, W.; Hui, J. Y.; Moffat, G. J.; Tornesi, B.; Van Malderen, K.; Wiesner, L.; Chen, C. L.

2015-01-01

The Health and Environmental Sciences Institute (HESI) Developmental and Reproductive Toxicology Technical Committee sponsored a pharmaceutical industry survey on current industry practices for contraception use during clinical trials. The objectives of the survey were to improve our understanding of the current industry practices for contraception requirements in clinical trials, the governance processes set up to promote consistency and/or compliance with contraception requirements, and the effectiveness of current contraception practices in preventing pregnancies during clinical trials. Opportunities for improvements in current practices were also considered. The survey results from 12 pharmaceutical companies identified significant variability among companies with regard to contraception practices and governance during clinical trials. This variability was due primarily to differences in definitions, areas of scientific uncertainty or misunderstanding, and differences in company approaches to enrollment in clinical trials. The survey also revealed that few companies collected data in a manner that would allow a retrospective understanding of the reasons for failure of birth control during clinical trials. In this article, suggestions are made for topics where regulatory guidance or scientific publications could facilitate best practice. These include provisions for a pragmatic definition of women of childbearing potential, guidance on how animal data can influence the requirements for male and female birth control, evidence-based guidance on birth control and pregnancy testing regimes suitable for low- and high-risk situations, plus practical methods to ascertain the risk of drug-drug interactions with hormonal contraceptives. PMID:27042398

A cluster randomized trial of routine HIV-1 viral load monitoring in Zambia: study design, implementation, and baseline cohort characteristics.

PubMed

Koethe, John R; Westfall, Andrew O; Luhanga, Dora K; Clark, Gina M; Goldman, Jason D; Mulenga, Priscilla L; Cantrell, Ronald A; Chi, Benjamin H; Zulu, Isaac; Saag, Michael S; Stringer, Jeffrey S A

2010-03-12

The benefit of routine HIV-1 viral load (VL) monitoring of patients on antiretroviral therapy (ART) in resource-constrained settings is uncertain because of the high costs associated with the test and the limited treatment options. We designed a cluster randomized controlled trial to compare the use of routine VL testing at ART-initiation and at 3, 6, 12, and 18 months, versus our local standard of care (which uses immunological and clinical criteria to diagnose treatment failure, with discretionary VL testing when the two do not agree). Dedicated study personnel were integrated into public-sector ART clinics. We collected participant information in a dedicated research database. Twelve ART clinics in Lusaka, Zambia constituted the units of randomization. Study clinics were stratified into pairs according to matching criteria (historical mortality rate, size, and duration of operation) to limit the effect of clustering, and independently randomized to the intervention and control arms. The study was powered to detect a 36% reduction in mortality at 18 months. From December 2006 to May 2008, we completed enrollment of 1973 participants. Measured baseline characteristics did not differ significantly between the study arms. Enrollment was staggered by clinic pair and truncated at two matched sites. A large clinical trial of routing VL monitoring was successfully implemented in a dynamic and rapidly growing national ART program. Close collaboration with local health authorities and adequate reserve staff were critical to success. Randomized controlled trials such as this will likely prove valuable in determining long-term outcomes in resource-constrained settings. Clinicaltrials.gov NCT00929604.

'PACE-Gate': When clinical trial evidence meets open data access.

PubMed

Geraghty, Keith J

2017-08-01

Science is not always plain sailing and sometimes the voyage is across an angry sea. A recent clinical trial of treatments for chronic fatigue syndrome (the PACE trial) has whipped up a storm of controversy. Patients claim the lead authors overstated the effectiveness of cognitive behavioural therapy and graded exercise therapy by lowering the thresholds they used to determine improvement. In this extraordinary case, patients discovered that the treatments tested had much lower efficacy after an information tribunal ordered the release of data from the PACE trial to a patient who had requested access using a freedom of information request.

A task-specific interactive game-based virtual reality rehabilitation system for patients with stroke: a usability test and two clinical experiments.

PubMed

Shin, Joon-Ho; Ryu, Hokyoung; Jang, Seong Ho

2014-03-06

Virtual reality (VR) is not commonly used in clinical rehabilitation, and commercial VR gaming systems may have mixed effects in patients with stroke. Therefore, we developed RehabMaster™, a task-specific interactive game-based VR system for post-stroke rehabilitation of the upper extremities, and assessed its usability and clinical efficacy. A participatory design and usability tests were carried out for development of RehabMaster with representative user groups. Two clinical trials were then performed. The first was an observational study in which seven patients with chronic stroke received 30 minutes of RehabMaster intervention per day for two weeks. The second was a randomised controlled trial of 16 patients with acute or subacute stroke who received 10 sessions of conventional occupational therapy only (OT-only group) or conventional occupational therapy plus 20 minutes of RehabMaster intervention (RehabMaster + OT group). The Fugl-Meyer Assessment score (FMA), modified Barthel Index (MBI), adverse effects, and drop-out rate were recorded. The requirements of a VR system for stroke rehabilitation were established and incorporated into RehabMaster. The reported advantages from the usability tests were improved attention, the immersive flow experience, and individualised intervention. The first clinical trial showed that the RehabMaster intervention improved the FMA (P = .03) and MBI (P = .04) across evaluation times. The second trial revealed that the addition of RehabMaster intervention tended to enhance the improvement in the FMA (P = .07) but did not affect the improvement in the MBI. One patient with chronic stroke left the trial, and no adverse effects were reported. The RehabMaster is a feasible and safe VR system for enhancing upper extremity function in patients with stroke.

A task-specific interactive game-based virtual reality rehabilitation system for patients with stroke: a usability test and two clinical experiments

PubMed Central

2014-01-01

Background Virtual reality (VR) is not commonly used in clinical rehabilitation, and commercial VR gaming systems may have mixed effects in patients with stroke. Therefore, we developed RehabMaster™, a task-specific interactive game-based VR system for post-stroke rehabilitation of the upper extremities, and assessed its usability and clinical efficacy. Methods A participatory design and usability tests were carried out for development of RehabMaster with representative user groups. Two clinical trials were then performed. The first was an observational study in which seven patients with chronic stroke received 30 minutes of RehabMaster intervention per day for two weeks. The second was a randomised controlled trial of 16 patients with acute or subacute stroke who received 10 sessions of conventional occupational therapy only (OT-only group) or conventional occupational therapy plus 20 minutes of RehabMaster intervention (RehabMaster + OT group). The Fugl-Meyer Assessment score (FMA), modified Barthel Index (MBI), adverse effects, and drop-out rate were recorded. Results The requirements of a VR system for stroke rehabilitation were established and incorporated into RehabMaster. The reported advantages from the usability tests were improved attention, the immersive flow experience, and individualised intervention. The first clinical trial showed that the RehabMaster intervention improved the FMA (P = .03) and MBI (P = .04) across evaluation times. The second trial revealed that the addition of RehabMaster intervention tended to enhance the improvement in the FMA (P = .07) but did not affect the improvement in the MBI. One patient with chronic stroke left the trial, and no adverse effects were reported. Conclusions The RehabMaster is a feasible and safe VR system for enhancing upper extremity function in patients with stroke. PMID:24597650

Safety and immunogenicity of a seasonal trivalent inactivated split influenza vaccine: a phase I randomized clinical trial in healthy Serbian adults

PubMed Central

Stevanovic, Goran; Lavadinovic, Lidija; Filipovic Vignjevic, Svetlana; Holt, Renée; Ilic, Katarina; Berlanda Scorza, Francesco; Sparrow, Erin; Stoiljkovic, Vera; Torelli, Guido; Madenwald, Tamra; Socquet, Muriel; Barac, Aleksandra; Ilieva-Borisova, Yordanka; Pelemis, Mijomir; Flores, Jorge

2018-01-01

ABSTRACT This study was a phase I double-blind, randomized, placebo-controlled trial to evaluate the safety and immunogenicity of a Serbian-produced seasonal trivalent split, inactivated influenza vaccine in healthy adults. The vaccine was manufactured in eggs by the Torlak Institute of Virology, Vaccines and Sera, Belgrade, Serbia and contained A/H1N1, A/H3N2 and B viruses. The clinical trial took place at the Clinical Center of Serbia in Belgrade. Sixty healthy volunteers, aged 18–45 years, were enrolled in the trial. On the day of immunization, volunteers were randomly assigned to receive either a single dose of the trivalent seasonal influenza vaccine (15 μg of hemagglutinin per strain) or placebo (phosphate-buffered saline). Subjects were monitored for adverse events through a clinical history and physical examination, and blood was taken for testing at screening and on day 8 to assess vaccine safety. Serum samples obtained before and 21 days after immunization were tested for influenza antibody titers using hemagglutination-inhibition (HAI) and microneutralization (MN) tests. No serious adverse events were reported. Pain and tenderness at the injection site were the most commonly reported symptoms in both vaccine and placebo groups. Overall, serum HAI responses of fourfold or greater magnitude were observed to H1, H3, and B antigen in 80%, 75%, and 70% of subjects, respectively. Seroprotection rates as measured by HAI were also high (100%, 100% and 86.67%, respectively, for H1, H3 and B). Thus, Torlak's seasonal trivalent influenza vaccine was not associated with adverse events, was well-tolerated and immunogenic. It should be further evaluated in clinical trials to provide sufficient safety and immunogenicity data for licensing in Serbia. PMID:29239682

Institutional mistrust in the organization of pharmaceutical clinical trials

PubMed Central

2010-01-01

In this paper I explore the politics of trust in the clinical testing of pharmaceuticals in the US. Specifically, I analyze trust in terms of its institutional manifestations in the pharmaceutical clinical trials industry. In the process of testing new drugs, pharmaceutical companies must (1) protect their proprietary information from the clinicians who conduct their studies, and (2) find a way to ensure human subjects' compliance to study protocols. Concern with these two critical issues leads drug companies to approach clinicians and research subjects with an attitude of mistrust and the desire to exert control over their activities. This orientation results in an institutionalization of mistrust that structures the relationships and activities required for the clinical development of new pharmaceutical products. PMID:18633728

The Brain Health Registry: An internet-based platform for recruitment, assessment, and longitudinal monitoring of participants for neuroscience studies.

PubMed

Weiner, Michael W; Nosheny, Rachel; Camacho, Monica; Truran-Sacrey, Diana; Mackin, R Scott; Flenniken, Derek; Ulbricht, Aaron; Insel, Philip; Finley, Shannon; Fockler, Juliet; Veitch, Dallas

2018-05-08

Recruitment, assessment, and longitudinal monitoring of participants for neuroscience studies and clinical trials limit the development of new treatments. Widespread Internet use allows data capture from participants in an unsupervised setting. The Brain Health Registry, a website and online registry, collects data from participants and their study partners. The Brain Health Registry obtains self and study partner report questionnaires and neuropsychological data, including the Cogstate Brief Battery, Lumos Labs Neurocognitive Performance Test, and MemTrax Memory Test. Participants provide informed consent before participation. Baseline and longitudinal data were obtained from nearly 57,000 and 28,000 participants, respectively. Over 18,800 participants were referred to, and nearly 1800 were enrolled in, clinical Alzheimer's disease and aging studies, including five observational studies and seven intervention trials. Online assessments of participants and study partners provide useful information at relatively low cost for neuroscience studies and clinical trials and may ultimately be used in routine clinical practice. Copyright © 2018 the Alzheimer's Association. All rights reserved.

Linking quality indicators to clinical trials: an automated approach

PubMed Central

Coiera, Enrico; Choong, Miew Keen; Tsafnat, Guy; Hibbert, Peter; Runciman, William B.

2017-01-01

Abstract Objective Quality improvement of health care requires robust measurable indicators to track performance. However identifying which indicators are supported by strong clinical evidence, typically from clinical trials, is often laborious. This study tests a novel method for automatically linking indicators to clinical trial registrations. Design A set of 522 quality of care indicators for 22 common conditions drawn from the CareTrack study were automatically mapped to outcome measures reported in 13 971 trials from ClinicalTrials.gov. Intervention Text mining methods extracted phrases mentioning indicators and outcome phrases, and these were compared using the Levenshtein edit distance ratio to measure similarity. Main Outcome Measure Number of care indicators that mapped to outcome measures in clinical trials. Results While only 13% of the 522 CareTrack indicators were thought to have Level I or II evidence behind them, 353 (68%) could be directly linked to randomized controlled trials. Within these 522, 50 of 70 (71%) Level I and II evidence-based indicators, and 268 of 370 (72%) Level V (consensus-based) indicators could be linked to evidence. Of the indicators known to have evidence behind them, only 5.7% (4 of 70) were mentioned in the trial reports but were missed by our method. Conclusions We automatically linked indicators to clinical trial registrations with high precision. Whilst the majority of quality indicators studied could be directly linked to research evidence, a small portion could not and these require closer scrutiny. It is feasible to support the process of indicator development using automated methods to identify research evidence. PMID:28651340

Systems pharmacology, pharmacogenetics, and clinical trial design in network medicine.

PubMed

Antman, Elliott; Weiss, Scott; Loscalzo, Joseph

2012-01-01

The rapidly growing disciplines of systems biology and network science are now poised to meet the fields of clinical medicine and pharmacology. Principles of systems pharmacology can be applied to drug design and, ultimately, testing in human clinical trials. Rather than focusing exclusively on single drug targets, systems pharmacology examines the holistic response of a phenotype-dependent pathway or pathways to drug perturbation. Knowledge of individual pharmacogenetic profiles further modulates the responses to these drug perturbations, moving the field toward more individualized ('personalized') drug development. The speed with which the information required to assess these system responses and their genomic underpinnings is changing and the importance of identifying the optimal drug or drug combinations for maximal benefit and minimal risk require that clinical trial design strategies be adaptable. In this paper, we review the tenets of adaptive clinical trial design as they may apply to an era of expanding knowledge of systems pharmacology and pharmacogenomics, and clinical trail design in network medicine. Copyright © 2012 Wiley Periodicals, Inc.

HIV-1 Immunogen: an overview of almost 30 years of clinical testing of a candidate therapeutic vaccine.

PubMed

Graziani, Gina M; Angel, Jonathan B

2016-07-01

Although current antiretroviral therapy (ART) has transformed HIV infection into a chronic, manageable disease, ART does not cure HIV infection. Furthermore, the majority of the world's infected individuals live in resource-limited countries in which access to ART is limited. Thus, the development of an effective therapeutic HIV vaccine would be an invaluable treatment alternative. Developed by the late Dr. Jonas Salk, HIV-1 Immunogen (Remune®) is a candidate therapeutic vaccine that has been studied in thousands of HIV-infected individuals in more than a dozen clinical trials during almost three decades. This Drug Evaluation, which summarizes the results of these trials that have shown the vaccine to be safe and immunogenic, also discusses the contradictory and controversial conclusions drawn from the phases 2, 2/3 and 3 trials that assessed the clinical efficacy of this vaccine. Given the lack of unequivocal clinical benefits of HIV-1 Immunogen despite almost 30 years of extensive testing, it does not appear, in our view, that this vaccine is a clinically effective immunotherapy. However, inclusion of this vaccine in the newly proposed 'Kick/Shock and Kill' strategy for HIV eradication, or use as a prophylactic vaccine, could be considered for future trials.

Preventing Cognitive Decline in Older African Americans with Mild Cognitive Impairment: Design and Methods of a Randomized Clinical Trial

PubMed Central

Rovner, Barry W.; Casten, Robin J.; Hegel, Mark T.; Leiby, Benjamin E.

2012-01-01

Mild Cognitive Impairment (MCI) affects 25% of older African Americans and predicts progression to Alzheimer's disease. An extensive epidemiologic literature suggests that cognitive, physical, and/or social activities may prevent cognitive decline. We describe the methods of a randomized clinical trial to test the efficacy of Behavior Activation to prevent cognitive decline in older African Americans with the amnestic multiple domain subtype of MCI. Community Health Workers deliver 6 initial in-home treatment sessions over 2-3 months and then 6 subsequent in-home booster sessions using language, materials, and concepts that are culturally relevant to older African Americans during this 24 month clinical trial. We are randomizing 200 subjects who are recruited from churches, senior centers, and medical clinics to Behavior Activation or Supportive Therapy, which controls for attention. The primary outcome is episodic memory as measured by the Hopkins Verbal Learning Test-Revised at baseline and at months 3, 12, 18, and 24. The secondary outcomes are general and domain-specific neuropsychological function, activities of daily living, depression, and quality-of-life. The negative results of recent clinical trials of drug treatments for MCI and Alzheimer's disease suggest that behavioral interventions may provide an alternative treatment approach to preserve cognition in an aging society. PMID:22406101

Patient Compliance Is Critical for Equivalent Clinical Outcomes for Breast Cancer Treated by Breast-Conservation Therapy

PubMed Central

Li, Benjamin D. L.; Brown, William A.; Ampil, Frederico L.; Burton, Gary V.; Yu, Herbert; McDonald, John C.

2000-01-01

Objective To determine the compliance with a standard breast-conservation therapy (BCT) program in a predominantly indigent, minority population of patients with early breast cancer (stage I and II) served by a rural state institution in the South; to compare the clinical outcomes of this group with those reported in clinical trials; and to examine the socioeconomic factors that may have contributed to the rate of compliance. Summary Background Data Disease-free survival and overall survival in early breast cancer treated by BCT versus modified radical mastectomy are reported to be equivalent in prospective randomized trials. However, patients enrolled in clinical trials may not be representative of patients living in the various diverse communities that make up the United States. The authors’ hypothesis is that patients enrolled in clinical trials at the national level may not be representative of indigent patients in the rural South and that clinical trial results may not be directly applicable. Methods A retrospective review of 55 women with early-stage breast cancer treated from 1990 to 1995 was performed. Clinical data, compliance with treatment and clinical follow-up, and recurrence rates were examined. Statistical analysis performed include the Fisher exact test, Kaplan-Meier survival analysis, and log-rank test. Results Full compliance (defined as completion of the entire course of radiation therapy and clinical follow-up) with the BCT program was observed in only 36% of patients. Fifteen of the 35 noncompliant patients did not complete radiation therapy. A significantly higher local failure rate was observed: 8 of these 15 patients (53%) have had local failure. In contrast, patients who were either in full compliance with the BCT program or were deficient only in that they missed part of their clinical follow-up had local failure rates of 5% (1/20) and 10% (2/20), respectively. Age, race, stage of cancer, economic status (measured by availability of medical insurance), distance of patient’s residence from the hospital, and education level were evaluated as potential predictors of compliance. None predicted patient compliance, although a trend toward higher compliance was noted in patients with a higher education level, as determined by literacy testing. Conclusions Compliance with the BCT protocol at the authors’ institution was worse than reported in clinical trials, and noncompliance translated into a significant increase in the local failure rate. Factors examined suggest that literacy may play a role in predicting compliance. Although BCT should be discussed with all breast cancer patients, the judicious application of clinical trial data to an institution’s local population is warranted. PMID:10816632

Impact of Prior Cancer on Eligibility for Lung Cancer Clinical Trials

PubMed Central

Laccetti, Andrew L.; Xuan, Lei; Halm, Ethan A.; Pruitt, Sandi L.

2014-01-01

Background In oncology clinical trials, the assumption that a prior cancer diagnosis could interfere with study conduct or outcomes results in frequent exclusion of such patients. We determined the prevalence and characteristics of this practice in lung cancer clinical trials and estimated impact on trial accrual. Methods We reviewed lung cancer clinical trials sponsored or endorsed by the Eastern Oncology Cooperative Group for exclusion criteria related to a prior cancer diagnosis. We estimated prevalence of prior primary cancer diagnoses among lung cancer patients using Surveillance Epidemiology and End Results (SEER)-Medicare linked data. We assessed the association between trial characteristics and prior cancer exclusion using chi-square analysis. All statistical tests were two-sided. Results Fifty-one clinical trials (target enrollment 13072 patients) were included. Forty-one (80%) excluded patients with a prior cancer diagnosis as follows: any prior (14%), within five years (43%), within two or three years (7%), or active cancer (16%). In SEER-Medicare data (n = 210509), 56% of prior cancers were diagnosed within five years before the lung cancer diagnosis. Across trials, the estimated number and proportion of patients excluded because of prior cancer ranged from 0–207 and 0%-18%. Prior cancer was excluded in 94% of trials with survival primary endpoints and 73% of trials with nonsurvival primary endpoints (P = .06). Conclusions A substantial proportion of patients are reflexively excluded from lung cancer clinical trials because of prior cancer. This inclusion criterion is applied widely across studies, including more than two-thirds of trials with nonsurvival endpoints. More research is needed to understand the basis and ramifications of this exclusion policy. PMID:25253615

Comparison among the efficacy of interventions for the return rate to receive the pap test report: randomized controlled clinical trial 1

PubMed Central

Vasconcelos, Camila Teixeira Moreira; Pinheiro, Ana Karina Bezerra; Nicolau, Ana Izabel Oliveira; Lima, Thaís Marques; Barbosa, Denise de Fátima Fernandes

2017-01-01

ABSTRACT Objective: to test the effects of a behavioral, an educative and a comparative intervention on women's adherence to the return appointment to receive the pap test report. Methods: randomized controlled clinical trial at a Primary Health Care Service, involving three groups: EG (educative session and test demonstration), BG (recall ribbon) and standard intervention (card containing the return appointment - graphical reminder), called comparative group here (CG). To select the sample, the following was established: having started sexual activity and undergoing the pap smear during the study, resulting in 775 women. Results: among the 775 women, 585 (75.5%) returned to receive the test result within 65 days. The educative group presented the highest return rate (EG=82%/CG=77%/BG=66%), statistically significant only when compared to the behavioral group (p=0.000). The educative group obtained the smallest interval (p<0.05) concerning the mean number of days of return to receive the test result (EG:M=43days/BG:M=47.5days/CG:M=44.8 days). Conclusion: the educative group reached higher return rates and the women returned earlier, but the behavioral intervention showed to be the least effective. Brazilian Clinical Trial Register: RBR-93ykhs. PMID:28301035

Social Problem Solving and Depressive Symptoms over Time: A Randomized Clinical Trial of Cognitive-Behavioral Analysis System of Psychotherapy, Brief Supportive Psychotherapy, and Pharmacotherapy

ERIC Educational Resources Information Center

Klein, Daniel N.; Leon, Andrew C.; Li, Chunshan; D'Zurilla, Thomas J.; Black, Sarah R.; Vivian, Dina; Dowling, Frank; Arnow, Bruce A.; Manber, Rachel; Markowitz, John C.; Kocsis, James H.

2011-01-01

Objective: Depression is associated with poor social problem solving, and psychotherapies that focus on problem-solving skills are efficacious in treating depression. We examined the associations between treatment, social problem solving, and depression in a randomized clinical trial testing the efficacy of psychotherapy augmentation for…

New clinical trial will test COXEN’s ability to choose best therapy for patients with advanced bladder cancer | Center for Cancer Research

Cancer.gov

The Genitourinary Malignancies Branch is now enrolling participants for a clinical trial that will evaluate whether analyzing a tumor’s genetic profile can identify which approved anticancer drugs are most likely to benefit individual patients whose bladder cancer has stopped responding to standard treatments. Learn more...

Comparative Approaches to Understanding the Relation Between Aging and Physical Function.

PubMed

Justice, Jamie N; Cesari, Matteo; Seals, Douglas R; Shively, Carol A; Carter, Christy S

2016-10-01

Despite dedicated efforts to identify interventions to delay aging, most promising interventions yielding dramatic life-span extension in animal models of aging are often ineffective when translated to clinical trials. This may be due to differences in primary outcomes between species and difficulties in determining the optimal clinical trial paradigms for translation. Measures of physical function, including brief standardized testing batteries, are currently being proposed as biomarkers of aging in humans, are predictive of adverse health events, disability, and mortality, and are commonly used as functional outcomes for clinical trials. Motor outcomes are now being incorporated into preclinical testing, a positive step toward enhancing our ability to translate aging interventions to clinical trials. To further these efforts, we begin a discussion of physical function and disability assessment across species, with special emphasis on mice, rats, monkeys, and man. By understanding how physical function is assessed in humans, we can tailor measurements in animals to better model those outcomes to establish effective, standardized translational functional assessments with aging. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Prostate Cancer Screening Results from PLCO

Cancer.gov

Learn the results of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a large-scale clinical trial to determine whether certain cancer screening tests can help reduce deaths from prostate, lung, colorectal, and ovarian cancer.

Systematic review of the diagnosis of scabies in therapeutic trials.

PubMed

Thompson, M J; Engelman, D; Gholam, K; Fuller, L C; Steer, A C

2017-07-01

Human scabies (infestation with the mite Sarcoptes scabiei var hominis) causes a significant disease burden worldwide, yet there are no agreed diagnostic guidelines. We aimed to determine whether a consistent approach to diagnosing scabies has been used for published scabies therapeutic trials. The data sources used were the MEDLINE, Embase and Cochrane databases, from 1946 to 29 August 2013. Eligible studies were trials of therapeutic interventions against scabies in human subjects, published in English, enrolling patients with scabies, and using various therapeutic interventions. Language was a limitation of this study as some relevant trials published in languages other than English may have been excluded. Each study was reviewed by two independent authors, who assessed the clinical examination and testing approaches used for scabies diagnosis in the included studies. We found that of 71 included trials, 40 (56%) specified which clinical findings were used for diagnosis, which were predominantly rash, rash distribution, pruritus and mite burrows. Parasitological testing was used in 63% of trials (n = 45) and was used more frequently in clinic-based than in field studies. Nearly one-quarter of trials (24%, n = 17) did not define the diagnostic method used. Overall, the diagnostic approaches were poorly described, prohibiting accurate comparison of existing studies. This review further supports the need for consensus diagnostic guidelines for scabies. © 2017 British Association of Dermatologists.

Pretreatment data is highly predictive of liver chemistry signals in clinical trials.

PubMed

Cai, Zhaohui; Bresell, Anders; Steinberg, Mark H; Silberg, Debra G; Furlong, Stephen T

2012-01-01

The goal of this retrospective analysis was to assess how well predictive models could determine which patients would develop liver chemistry signals during clinical trials based on their pretreatment (baseline) information. Based on data from 24 late-stage clinical trials, classification models were developed to predict liver chemistry outcomes using baseline information, which included demographics, medical history, concomitant medications, and baseline laboratory results. Predictive models using baseline data predicted which patients would develop liver signals during the trials with average validation accuracy around 80%. Baseline levels of individual liver chemistry tests were most important for predicting their own elevations during the trials. High bilirubin levels at baseline were not uncommon and were associated with a high risk of developing biochemical Hy's law cases. Baseline γ-glutamyltransferase (GGT) level appeared to have some predictive value, but did not increase predictability beyond using established liver chemistry tests. It is possible to predict which patients are at a higher risk of developing liver chemistry signals using pretreatment (baseline) data. Derived knowledge from such predictions may allow proactive and targeted risk management, and the type of analysis described here could help determine whether new biomarkers offer improved performance over established ones.

Investigational drugs in early development for treating dengue infection.

PubMed

Beesetti, Hemalatha; Khanna, Navin; Swaminathan, Sathyamangalam

2016-09-01

Dengue has emerged as the most significant arboviral disease of the current century. A drug for dengue is an urgent unmet need. As conventional drug discovery efforts have not produced any promising clinical candidates, there is a shift toward re-positioning pre-existing drugs for dengue to fast-track dengue drug development. This article provides an update on the current status of recently completed and ongoing dengue drug trials. All dengue drug trials described in this article were identified from a list of >230 trials that were returned upon searching the World Health Organization's International Clinical Trials Registry Platform web portal using the search term 'dengue' on December 31(st), 2015. None of the handful of drugs tested so far has yielded encouraging results. Early trial experience has served to emphasize the challenge of drug testing in the short therapeutic time window available, the need for tools to predict 'high-risk' patients early on and the limitations of the existing pre-clinical model systems. Significant investment of efforts and resources is a must before the availability of a safe, effective and inexpensive dengue drug becomes a reality. Currently, supportive fluid therapy remains the only option available for dengue treatment.

Case-based reasoning using electronic health records efficiently identifies eligible patients for clinical trials

PubMed Central

Miotto, Riccardo

2015-01-01

Objective To develop a cost-effective, case-based reasoning framework for clinical research eligibility screening by only reusing the electronic health records (EHRs) of minimal enrolled participants to represent the target patient for each trial under consideration. Materials and Methods The EHR data—specifically diagnosis, medications, laboratory results, and clinical notes—of known clinical trial participants were aggregated to profile the “target patient” for a trial, which was used to discover new eligible patients for that trial. The EHR data of unseen patients were matched to this “target patient” to determine their relevance to the trial; the higher the relevance, the more likely the patient was eligible. Relevance scores were a weighted linear combination of cosine similarities computed over individual EHR data types. For evaluation, we identified 262 participants of 13 diversified clinical trials conducted at Columbia University as our gold standard. We ran a 2-fold cross validation with half of the participants used for training and the other half used for testing along with other 30 000 patients selected at random from our clinical database. We performed binary classification and ranking experiments. Results The overall area under the ROC curve for classification was 0.95, enabling the highlight of eligible patients with good precision. Ranking showed satisfactory results especially at the top of the recommended list, with each trial having at least one eligible patient in the top five positions. Conclusions This relevance-based method can potentially be used to identify eligible patients for clinical trials by processing patient EHR data alone without parsing free-text eligibility criteria, and shows promise of efficient “case-based reasoning” modeled only on minimal trial participants. PMID:25769682

Development of Responder Definitions for Fibromyalgia Clinical Trials

PubMed Central

Arnold, Lesley M.; Williams, David A.; Hudson, James I.; Martin, Susan A.; Clauw, Daniel J.; Crofford, Leslie J.; Wang, Fujun; Emir, Birol; Lai, Chinglin; Zablocki, Rong; Mease, Philip J.

2011-01-01

Objective To develop responder definitions for fibromyalgia clinical trials using key symptom and functional domains. Methods 24 candidate responder definitions were developed by expert consensus and evaluated in 12 randomized, placebo-controlled fibromyalgia trials of 4 medications. For each definition, treatment effects of the medication compared with placebo were analyzed using the Cochran-Mantel-Haenszel test or Chi Square test. A meta-analysis of the pooled results for the 4 medications established risk ratios to determine the definitions that best favored medication over placebo. Results Two definitions performed best in the analyses. Both definitions included ≥ 30% reduction in pain and ≥ 10% improvement in physical function. They differed in that one (FM30 short version) included ≥ 30% improvement in sleep or fatigue, and the other (FM30 long version) required ≥ 30% improvement in 2 of the following symptoms: sleep, fatigue, depression, anxiety, or cognition. In the analysis of both versions, the response rate was ≥ 15% for each medication and significantly greater than placebo. The risk ratio favoring drug over placebo (95% CI) in the pooled analysis for the FM30 short version was 1.50 (1.24, 1.82), P ≤ 0.0001; the FM30 long version was 1.60 (1.31, 1.96), P ≤ 0.00001. Conclusion Among the 24 responder definitions tested, 2 were identified as most sensitive in identifying response to treatment. The identification of responder definitions for fibromyalgia clinical trials that include assessments of key symptom and functional domains may improve the sensitivity of clinical trials to identify meaningful improvements, leading to improved management of fibromyalgia. PMID:21953205

Temporal unfolding of declining episodic memory on the Free and Cued Selective Reminding Test in the predementia phase of Alzheimer's disease: Implications for clinical trials.

PubMed

Grober, Ellen; Veroff, Amy E; Lipton, Richard B

2018-01-01

Free and Cued Selective Reminding Test (FCSRT) performance identifies patients with preclinical disease at elevated risk for developing Alzheimer's dementia, predicting diagnosis better than other memory tests. Based on literature mapping FCSRT performance to clinical outcomes and biological markers, and on longitudinal preclinical data from the Baltimore Longitudinal Study of Aging, we developed the Stages of Objective Memory Impairment (SOMI) model. Five sequential stages of episodic memory decline are defined by Free Recall (FR) and Total Recall (TR) score ranges and years prior to dementia diagnosis. We sought to replicate the SOMI model using longitudinal assessments of 142 Einstein Aging Study participants who developed AD over 10 years. Time to diagnosis was at least seven years if FR was intact, at least four years if TR was intact, and two years if TR was impaired, consistent with SOMI model predictions. The SOMI identified incipient dementia with excellent sensitivity and specificity. The SOMI model provides an efficient approach for clinical trial cognitive screening in advance of more costly biomarker studies and ultimately in clinical practice, and provides a vocabulary for understanding AD biomarker patterns and for re-analysis of existing clinical trial data.

RETHINKING THE ROLE OF CLINICAL TRIAL DATA IN INTERNATIONAL INTELLECTUAL PROPERTY LAW: THE CASE FOR A PUBLIC GOODS APPROACH.

PubMed

Reichman, Jerome H

2009-01-01

This article describes the growth and consequences of new intellectual property rights given to pharmaceutical developers, and it advocates treating clinical trials as a public good. Although the soaring cost of clinical trials is well known and discussed, too little attention is given to the underlying rationale for allowing drug developers to recoup their costs through the new intellectual property rights provided in multilateral, regional, and bilateral agreements. Known in the US as "market exclusivity" and in Europe as "data exclusivity," these rights prohibit would-be generic producers from obtaining regulatory approval based on the original producers' undisclosed test data. Market and data exclusivity is codified in US and European domestic law as well as the North American Free Trade Agreement (NAFTA) and, to a lesser degree, the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS). Market and data exclusivity is binding an increasing number of developing countries via Free Trade Agreements (FTAs), which hinder developing countries from manufacturing generic drugs. At a minimum, negotiators should replace the norm of exclusive control over data with a liability rule, or take and pay rule, in which generic manufacturers can use original manufacturers' clinical trial data in exchange for reasonable compensation. A more fundamental solution requires questioning the status quo of proprietary clinical trial data. The conventional wisdom is that market and data exclusivity, and drug developers' consequent ability to limit competition from generics above and beyond patent protection, are a necessary incentive for drug developers to fund ever more expensive clinical trials. Clinical trial data, however, are public goods that will be undersupplied and over protected so long as private actors provide them. Moreover, manufacturers have an incentive to present clinical trial data so that they support regulatory approval at the expense of public health. Although liability rules are better than the status quo, they would not resolve the problem of treating a public good as proprietary. Governments should thus oversee and fund clinical trials as the public good that they are. Clinical tests should be awarded to the most qualified scientists through a competitive process, financed in part with the decrease in drug costs to governmental health care programs and in part with drug developers' contributions, selected to maximize social benefit, and made global via intergovernmental bodies to maximize social return. This would reduce the cost of redundant investigations to the global public health system, lower supply costs to drug consumers, and lower the breakeven point for investment in research to discover new drugs.

A cluster randomized trial of provider-initiated (Opt-out) HIV counseling and testing of tuberculosis patients in South Africa

PubMed Central

Pope, Diana S.; DeLuca, Andrea N.; Kali, Paula; Hausler, Harry; Sheard, Carol; Hoosain, Ebrahim; Chaudhary, Mohammed A.; Celentano, David D.; Chaisson, Richard E.

2008-01-01

Objective To determine whether implementation of provider-initiated HIV counseling would increase the proportion of tuberculosis patients that received HIV counseling and testing. Design Cluster-randomized trial with clinic as unit of randomization Setting Twenty, medium-sized primary care TB clinics in the Nelson Mandela Metropolitan Municipality, Port Elizabeth, Eastern Cape Province, South Africa Subjects A total of 754 adults (≥ 18 years) newly registered as tuberculosis patients the twenty study clinics Intervention Implementation of provider-initiated HIV counseling and testing. Main outcome measures Percentage of TB patients HIV counseled and tested. Secondary Percentage of patients HIV test positive and percentage of those that received cotrimoxazole and who were referred for HIV care. Results A total of 754 adults newly registered as tuberculosis patients were enrolled. In clinics randomly assigned to implement provider-initiated HIV counseling and testing, 20.7% (73/352) patients were counseled versus 7.7% (31/402) in the control clinics (p = 0.011), and 20.2 % (n = 71) versus 6.5% (n = 26) underwent HIV testing (p = 0.009). Of those patients counseled, 97% in the intervention clinics accepted testing versus 79% in control clinics (p =0.12). The proportion of patients identified as HIV-infected in intervention clinics was 8.5% versus 2.5% in control clinics (p=0.044). Fewer than 40% of patients with a positive HIV test were prescribed cotrimoxazole or referred for HIV care in either study arm. Conclusions Provider-initiated HIV counseling significantly increased the proportion of adult TB patients that received HIV counseling and testing, but the magnitude of the effect was small. Additional interventions to optimize HIV testing for TB patients urgently need to be evaluated. PMID:18520677

A cluster-randomized trial of provider-initiated (opt-out) HIV counseling and testing of tuberculosis patients in South Africa.

PubMed

Pope, Diana S; Deluca, Andrea N; Kali, Paula; Hausler, Harry; Sheard, Carol; Hoosain, Ebrahim; Chaudhary, Mohammad A; Celentano, David D; Chaisson, Richard E

2008-06-01

To determine whether implementation of provider-initiated human immunodeficiency virus (HIV) counseling would increase the proportion of tuberculosis (TB) patients who received HIV counseling and testing. Cluster-randomized trial with clinic as the unit of randomization. Twenty, medium-sized primary care TB clinics in the Nelson Mandela Metropolitan Municipality, Port Elizabeth, Eastern Cape Province, South Africa. A total of 754 adults (18 years and older) newly registered as TB patients in the 20 study clinics. Implementation of provider-initiated HIV counseling and testing. Percentage of TB patients HIV counseled and tested. SECONDARY: Percentage of patients with HIV test positive, and percentage of those who received cotrimoxazole and who were referred for HIV care. : A total of 754 adults newly registered as TB patients were enrolled. In clinics randomly assigned to implement provider-initiated HIV counseling and testing, 20.7% (73/352) patients were counseled versus 7.7% (31/402) in the control clinics (P = 0.011), and 20.2% (n = 71) versus 6.5% (n = 26) underwent HIV testing (P = 0.009). Of those patients counseled, 97% in the intervention clinics accepted testing versus 79% in control clinics (P = 0.12). The proportion of patients identified as HIV infected in intervention clinics was 8.5% versus 2.5% in control clinics (P = 0.044). Fewer than 40% of patients with a positive HIV test were prescribed cotrimoxazole or referred for HIV care in either study arm. Provider-initiated HIV counseling significantly increased the proportion of adult TB patients who received HIV counseling and testing, but the magnitude of the effect was small. Additional interventions to optimize HIV testing for TB patients urgently need to be evaluated.

Rapid diagnostic tests compared with malaria microscopy for guiding outpatient treatment of febrile illness in Tanzania: randomised trial.

PubMed

Reyburn, Hugh; Mbakilwa, Hilda; Mwangi, Rose; Mwerinde, Ombeni; Olomi, Raimos; Drakeley, Chris; Whitty, Christopher J M

2007-02-24

To compare rapid diagnostic tests (RDTs) for malaria with routine microscopy in guiding treatment decisions for febrile patients. Randomised trial. Outpatient departments in northeast Tanzania at varying levels of malaria transmission. 2416 patients for whom a malaria test was requested. Staff received training on rapid diagnostic tests; patients sent for malaria tests were randomised to rapid diagnostic test or routine microscopy Proportion of patients with a negative test prescribed an antimalarial drug. Of 7589 outpatient consultations, 2425 (32%) had a malaria test requested. Of 1204 patients randomised to microscopy, 1030 (86%) tested negative for malaria; 523 (51%) of these were treated with an antimalarial drug. Of 1193 patients randomised to rapid diagnostic test, 1005 (84%) tested negative; 540 (54%) of these were treated for malaria (odds ratio 1.13, 95% confidence interval 0.95 to 1.34; P=0.18). Children aged under 5 with negative rapid diagnostic tests were more likely to be prescribed an antimalarial drug than were those with negative slides (P=0.003). Patients with a negative test by any method were more likely to be prescribed an antibiotic (odds ratio 6.42, 4.72 to 8.75; P<0.001). More than 90% of prescriptions for antimalarial drugs in low-moderate transmission settings were for patients for whom a test requested by a clinician was negative for malaria. Although many cases of malaria are missed outside the formal sector, within it malaria is massively over-diagnosed. This threatens the sustainability of deployment of artemisinin combination treatment, and treatable bacterial diseases are likely to be missed. Use of rapid diagnostic tests, with basic training for clinical staff, did not in itself lead to any reduction in over-treatment for malaria. Interventions to improve clinicians' management of febrile illness are essential but will not be easy. Clinical trials NCT00146796 [ClinicalTrials.gov].

Current Treatment and Recent Clinical Research in Alzheimer's Disease

PubMed Central

Neugroschl, Judith; Sano, Mary

2010-01-01

The transition from either epidemiological observation or the bench to rigorously tested clinical trials in patients with Alzheimer's disease is crucial in understanding which treatments are beneficial to patients. The amyloid hypothesis has undergone scrutiny recently, as many trials aimed at reducing amyloid and plaque have been completed or are in the testing phase. Examples include modulation of the secretases involved in beta amyloid formation, anti-aggregation agents, and immunotherapeutic trials. Other therapies targeting hyperphosphorylated tau and novel targets such as enhancement of mitochondrial function, serotonin receptors, receptor for advanced glycation end products, and nerve growth factor, as well as other strategies, are discussed. A brief review of the current Food and Drug Administration–approved treatments is included. PMID:20101716

The role of corruption and unethical behaviour in precluding the placement of industry sponsored clinical trials in sub-Saharan Africa: Stakeholder views.

PubMed

Egharevba, Efe; Atkinson, Jacqueline

2016-08-15

Clinical trials still represent the gold standard in testing the safety and efficacy of new and existing treatments. However, developing regions including sub-Saharan Africa remain underrepresented in pharmaceutical industry sponsored trials for a number of reasons including fear of corruption and unethical behaviour. This fear exists both on the part of pharmaceutical companies, and investigators carrying out research in the region. The objective of this research was to understand the ethical considerations associated with the conduct of pharmaceutical industry sponsored clinical trials in sub-Saharan Africa. Corruption was identified as a significant issue by a number of stakeholders who participated in semi-structured interviews and completed questionnaires. Additionally, fear of being perceived as corrupt or unethical even when conducting ethically sound research was raised as a concern. Thus corruption, whether actual or perceived, is one of a number of issues which have precluded the placement of a greater number of pharmaceutical sponsored clinical trials in this region. More discussion around corruption with all relevant stakeholders is required in order for progress to be made and to enable greater involvement of sub-Saharan African countries in the conduct of industry sponsored clinical trials.

A risk-management approach for effective integration of biomarkers in clinical trials: perspectives of an NCI, NCRI, and EORTC working group.

PubMed

Hall, Jacqueline Anne; Salgado, Roberto; Lively, Tracy; Sweep, Fred; Schuh, Anna

2014-04-01

Clinical cancer research today often includes testing the value of biomarkers to direct treatment and for drug development. However, the practical challenges of integration of molecular information into clinical trial protocols are increasingly appreciated. Inherent difficulties include evidence gaps in available biomarker data, a paucity of robust assay methods, and the design of appropriate studies within the constraints of feasible trial operations, and finite resources. Scalable and proportionate approaches are needed to systematically cope with these challenges. Therefore, we assembled international experts from three clinical trials organisations to identify the common challenges and common solutions. We present a practical risk-assessment framework allowing targeting of scarce resources to crucial issues coupled with a library of useful resources and a simple actionable checklist of recommendations. We hope that these practical methods will be useful for running biomarker-driven trials and ultimately help to develop biomarkers that are ready for integration in routine practice. Copyright © 2014 Elsevier Ltd. All rights reserved.

Robust inference for responder analysis: Innovative clinical trial design using a minimum p-value approach.

PubMed

Lin, Yunzhi

2016-08-15

Responder analysis is in common use in clinical trials, and has been described and endorsed in regulatory guidance documents, especially in trials where "soft" clinical endpoints such as rating scales are used. The procedure is useful, because responder rates can be understood more intuitively than a difference in means of rating scales. However, two major issues arise: 1) such dichotomized outcomes are inefficient in terms of using the information available and can seriously reduce the power of the study; and 2) the results of clinical trials depend considerably on the response cutoff chosen, yet in many disease areas there is no consensus as to what is the most appropriate cutoff. This article addresses these two issues, offering a novel approach for responder analysis that could both improve the power of responder analysis and explore different responder cutoffs if an agreed-upon common cutoff is not present. Specifically, we propose a statistically rigorous clinical trial design that pre-specifies multiple tests of responder rates between treatment groups based on a range of pre-specified responder cutoffs, and uses the minimum of the p-values for formal inference. The critical value for hypothesis testing comes from permutation distributions. Simulation studies are carried out to examine the finite sample performance of the proposed method. We demonstrate that the new method substantially improves the power of responder analysis, and in certain cases, yields power that is approaching the analysis using the original continuous (or ordinal) measure.

Comparing the effect of a decision aid plus patient navigation with usual care on colorectal cancer screening completion in vulnerable populations: study protocol for a randomized controlled trial.

PubMed

Brenner, Alison T; Getrich, Christina M; Pignone, Michael; Rhyne, Robert L; Hoffman, Richard M; McWilliams, Andrew; de Hernandez, Brisa Urquieta; Weaver, Mark A; Tapp, Hazel; Harbi, Khalil; Reuland, Daniel

2014-07-08

Screening can reduce colorectal cancer (CRC) incidence and mortality. However, screening is underutilized in vulnerable patient populations, particularly among Latinos. Patient-directed decision aids can increase CRC screening knowledge, self-efficacy, and intent; however, their effect on actual screening test completion tends to be modest. This is probably because decision aids do not address some of the patient-specific barriers that prevent successful completion of CRC screening in these populations. These individual barriers might be addressed though patient navigation interventions. This study will test a combined decision aid and patient navigator intervention on screening completion in diverse populations of vulnerable primary care patients. We will conduct a multisite, randomized controlled trial with patient-level randomization. Planned enrollment is 300 patients aged 50 to 75 years at average CRC risk presenting for appointments at two primary clinics in North Carolina and New Mexico. Intervention participants will view a video decision aid immediately before the clinic visit. The 14 to 16 minute video presents information about fecal occult blood tests and colonoscopy and will be viewed on a portable computer tablet in English or Spanish. Clinic-based patient navigators are bilingual and bicultural and will provide both face-to-face and telephone-based navigation. Control participants will view an unrelated food safety video and receive usual care. The primary outcome is completion of a CRC screening test at six months. Planned subgroup analyses include examining intervention effectiveness in Latinos, who will be oversampled. Secondarily, the trial will evaluate the intervention effects on knowledge of CRC screening, self-efficacy, intent, and patient-provider communication. The study will also examine whether patient ethnicity, acculturation, language preference, or health insurance status moderate the intervention effect on CRC screening. This pragmatic randomized controlled trial will test a combined decision aid and patient navigator intervention targeting CRC screening completion. Findings from this trial may inform future interventions and implementation policies designed to promote CRC screening in vulnerable patient populations and to reduce screening disparities. ClinicalTrials.gov NCT02054598.

Stakeholders' views on the routine use of n-of-1 trials to improve clinical care and to make resource allocation decisions for drug use.

PubMed

Nikles, Jane; Mitchell, Geoffrey K; Clavarino, Alexandra; Yelland, Michael J; Del Mar, Christopher B

2010-03-01

N-of-1 trials are empirical formal tests using a within-patient randomised, double-blind, cross-over comparison of drug and placebo (or another drug), which we adapted to study individual patients' responses as a clinical tool to guide clinical management. We administered semi-structured interviews to gauge stakeholder perspectives on the possibility of using routine n-of-1 trials for this purpose. Stakeholders included government and non-government health care sector, and patient, clinician and consumer, organisations. Stakeholders supported more widespread implementation of n-of-1 trials, in a targeted fashion, with some caveats. Barriers to their widespread implementation included constraints on doctors' time, doctors' acceptance, drug company acceptance, patient willingness, and cost. Strategies for overcoming barriers included conditional Pharmaceutical Benefits Scheme listing if cost-effective. There was little consensus on which model of n-of-1 trial implementation would be most effective. We discuss different approaches to addressing the several concerns raised to enable widespread introduction of n-of-1 trials into routine clinical practice as a decision tool.

Biomarkers and surrogate endpoints in clinical trials.

PubMed

Fleming, Thomas R; Powers, John H

2012-11-10

One of the most important considerations in designing clinical trials is the choice of outcome measures. These outcome measures could be clinically meaningful endpoints that are direct measures of how patients feel, function, and survive. Alternatively, indirect measures, such as biomarkers that include physical signs of disease, laboratory measures, and radiological tests, often are considered as replacement endpoints or 'surrogates' for clinically meaningful endpoints. We discuss the definitions of clinically meaningful endpoints and surrogate endpoints, and provide examples from recent clinical trials. We provide insight into why indirect measures such as biomarkers may fail to provide reliable evidence about the benefit-to-risk profile of interventions. We also discuss the nature of evidence that is important in assessing whether treatment effects on a biomarker reliably predict effects on a clinically meaningful endpoint, and provide insights into why this reliability is specific to the context of use of the biomarker. Copyright © 2012 John Wiley & Sons, Ltd.

Biomarkers and Surrogate Endpoints In Clinical Trials

PubMed Central

Fleming, Thomas R.; Powers, John H

2012-01-01

One of the most important considerations in designing clinical trials is the choice of outcome measures. These outcome measures could be clinically meaningful endpoints that are direct measures of how patients feel, function and survive. Alternatively, indirect measures, such as biomarkers that include physical signs of disease, laboratory measures and radiological tests, often are considered as replacement endpoints or “surrogates” for clinically meaningful endpoints. We discuss the definitions of clinically meaningful endpoints and surrogate endpoints, and provide examples from recent clinical trials. We provide insight into why indirect measures such as biomarkers may fail to provide reliable evidence about the benefit-to-risk profile of interventions. We also discuss the nature of evidence that is important in assessing whether treatment effects on a biomarker reliably predict effects on a clinically meaningful endpoint, and provide insights into why this reliability is specific to the context of use of the biomarker. . PMID:22711298

Evaluating Intermittent Androgen-Deprivation Therapy Phase III Clinical Trials: The Devil Is in the Details.

PubMed

Hussain, Maha; Tangen, Catherine; Higano, Celestia; Vogelzang, Nicholas; Thompson, Ian

2016-01-20

Intermittent androgen deprivation (IAD) has been widely tested in prostate cancer. However, phase III trials testing continuous androgen deprivation (CAD) versus IAD have reached inconclusive and seemingly contradictory results. Different design and conduct issues must be critically evaluated to better interpret the results. Seven published phase III trials were examined for prespecified design and outcomes. Treatment specifications; primary end point; superiority versus noninferiority design assumptions, including magnitude of assumed versus observed noninferiority margin (NIM); duration of follow-up; and quality-of-life (QOL) outcomes were considered in terms of the results and conclusions reported. Five trials had a superiority and three had a noninferiority primary hypothesis. Only three trials had a uniform population and overall survival (OS) end point. All trials observed better outcomes in terms of OS and progression-free survival (PFS) than assumed at time of study design, translating into prespecified NIMs or hazard ratios that reflected larger absolute differences in OS or PFS between arms. Lower-than-expected event rates also reduced statistical power for the trials. Other factors, including length of follow-up, cause of death, QOL, and primary end point, and their impact on trial interpretation are discussed. No trial to date has demonstrated survival superiority of IAD compared with CAD. Trials concluding IAD is noninferior to CAD were based on wide NIMs that included clinically important survival differences, not likely to be considered comparable by physicians or patients. Interim analyses relying on short follow-up and including a majority of non-prostate cancer deaths will favor a noninferiority conclusion and should be interpreted cautiously. Adequate follow-up is required to ensure capture of prostate cancer deaths in both superiority and noninferiority trials. © 2015 by American Society of Clinical Oncology.

Clinical Trial Design for HIV Prevention Research: Determining Standards of Prevention.

PubMed

Dawson, Liza; Zwerski, Sheryl

2015-06-01

This article seeks to advance ethical dialogue on choosing standards of prevention in clinical trials testing improved biomedical prevention methods for HIV. The stakes in this area of research are high, given the continued high rates of infection in many countries and the budget limitations that have constrained efforts to expand treatment for all who are currently HIV-infected. New prevention methods are still needed; at the same time, some existing prevention and treatment interventions have been proven effective but are not yet widely available in the countries where they most urgently needed. The ethical tensions in this field of clinical research are well known and have been the subject of extensive debate. There is no single clinical trial design that can optimize all the ethically important goals and commitments involved in research. Several recent articles have described the current ethical difficulties in designing HIV prevention trials, especially in resource limited settings; however, there is no consensus on how to handle clinical trial design decisions, and existing international ethical guidelines offer conflicting advice. This article acknowledges these deep ethical dilemmas and moves beyond a simple descriptive approach to advance an organized method for considering what clinical trial designs will be ethically acceptable for HIV prevention trials, balancing the relevant criteria and providing justification for specific design decisions. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Neutropenia as an Adverse Event following Vaccination: Results from Randomized Clinical Trials in Healthy Adults and Systematic Review

PubMed Central

Muturi-Kioi, Vincent; Lewis, David; Launay, Odile; Leroux-Roels, Geert; Anemona, Alessandra; Loulergue, Pierre; Bodinham, Caroline L.; Aerssens, Annelies; Groth, Nicola; Saul, Allan; Podda, Audino

2016-01-01

Background In the context of early vaccine trials aimed at evaluating the safety profile of novel vaccines, abnormal haematological values, such as neutropenia, are often reported. It is therefore important to evaluate how these trials should be planned not to miss potentially important safety signals, but also to understand the implications and the clinical relevance. Methodology We report and discuss the results from five clinical trials (two with a new Shigella vaccine in the early stage of clinical development and three with licensed vaccines) where the absolute neutrophil counts (ANC) were evaluated before and after vaccination. Additionally, we have performed a systematic review of the literature on cases of neutropenia reported during vaccine trials to discuss our results in a more general context. Principal Findings Both in our clinical trials and in the literature review, several cases of neutropenia have been reported, in the first two weeks after vaccination. However, neutropenia was generally transient and had a benign clinical outcome, after vaccination with either multiple novel candidates or well-known licensed vaccines. Additionally, the vaccine recipients with neutropenia frequently had lower baseline ANC than non-neutropenic vaccinees. In many instances neutropenia occurred in subjects of African descent, known to have lower ANC compared to western populations. Conclusions It is important to include ANC and other haematological tests in early vaccine trials to identify potential safety signals. Post-vaccination neutropenia is not uncommon, generally transient and clinically benign, but many vaccine trials do not have a sampling schedule that allows its detection. Given ethnic variability in the level of circulating neutrophils, normal ranges taking into account ethnicity should be used for determination of trial inclusion/exclusion criteria and classification of neutropenia related adverse events. Trial registration ClinicalTrials.gov NCT02017899, NCT02034500, NCT01771367, NCT01765413, NCT02523287 PMID:27490698

Return of the psychedelics: Psilocybin for treatment resistant depression.

PubMed

Patra, Suravi

2016-12-01

Psilocybin, the clinically most researched classic psychedelic has recently been tested for its safety and efficacy in a clinical population of treatment resistant depression. The efficacy of psilocybin in clinical depression previously demonstrated in the elecrophysiologic and neuroimaging findings as also in neuropsychological assessments is further validated by the findings of this rigorously conducted randomized trial. Mechanism of action of psilocybin and efficacy in treatment resistant depression are discussed in this paper. Ethical issues of conducting clinical trials with psychedelics are also discussed with particular emphasis on their relative safety and absence of addiction potential. Implications of these issues for conduct of larger trials for establishing risk benefit ratio in treatment resistant depression are further suggested. Copyright © 2016 Elsevier B.V. All rights reserved.

Leveraging of Open EMR Architecture for Clinical Trial Accrual

PubMed Central

Afrin, Lawrence B.; Oates, James C.; Boyd, Caroline K.; Daniels, Mark S.

2003-01-01

Accrual to clinical trials is a major bottleneck in scientific progress in clinical medicine. Many methods for identifying potential subjects and improving accrual have been pursued; few have succeeded, and none have proven generally reproducible or scalable. We leveraged the open architecture of the core clinical data repository of our electronic medical record system to prototype a solution for this problem in a manner consistent with contemporary regulations and research ethics. We piloted the solution with a local investigator-initiated trial for which candidate identification was expected to be difficult. Key results in the eleven months of experience to date include automated screening of 7,296,708 lab results from 69,288 patients, detection of 1,768 screening tests of interest, identification of 70 potential candidates who met all further automated criteria, and accrual of three candidates to the trial. Hypotheses for this disappointing impact on accrual, and directions for future research, are discussed. PMID:14728125

NITRIC OXIDE FOR THE ADJUNCTIVE TREATMENT OF SEVERE MALARIA: HYPOTHESIS AND RATIONALE

PubMed Central

Hawkes, Michael; Opoka, Robert Opika; Namasopo, Sophie; Miller, Christopher; Conroy, Andrea L.; Serghides, Lena; Kim, Hani; Thampi, Nisha; Liles, W. Conrad; John, Chandy C.; Kain, Kevin C.

2011-01-01

We hypothesize that supplemental inhaled nitric oxide (iNO) will improve outcomes in children with severe malaria receiving standard antimalarial therapy. The rationale for the hypothesized efficacy of iNO rests on: (1) biological plausibility, based on known actions of NO in modulating endothelial activation; (2) pre-clinical efficacy data from animal models of experimental cerebral malaria; and (3) a human trial of the NO precursor L-arginine, which improved endothelial function in adults with severe malaria. iNO is an attractive new candidate for the adjunctive treatment of severe malaria, given its proven therapeutic efficacy in animal studies, track record of safety in clinical practice and numerous clinical trials, inexpensive manufacturing costs, and ease of administration in settings with limited healthcare infrastructure. We plan to test this hypothesis in a randomized controlled trial (ClinicalTrials.gov Identifier: NCT01255215). PMID:21745716

[Differences between clinical trials according to the German law on pharmaceuticals (Arzneimittelgesetz) and trials according to the German law on medical products (Medizinproduktegesetz)].

PubMed

Krummenauer, F

2003-02-01

Similar to the registration process for pharmaceutical agents, medical devices have to undergo standardized clinical evaluation before being marketed and used in routine therapy or diagnostics. However, conduction, submission, and reporting of such clinical evaluations to authorities has to follow the German law on medical products(Medizinproduktegesetz,MPG), which in some central aspects differs remarkably from the German law on pharmaceuticals (Arzneimittelgesetz,AMG). Relevant deviations of MPG requirements from those of the AMG are reviewed with particular emphasis on submission, conduction, and reporting of trials to the authorities in charge. Whereas AMG-based trials focus on the proof of efficacy of pharmaceutical agents, the MPG demands instead proof of functionality of the medical devices; the MPG therefore concentrates more on technically satisfactory results in the context of function and patient safety. The aim of MPG trials is thus CE marking instead of AMG-based registration. However, this focus on functionality implies that medical devices need not necessarily be tested in a clinical trial--in some settings evidence-based evaluation alone will be sufficient. The decision on the necessity of a clinical trial is based mainly on the risk profile and invasive character of the device at hand. The early consideration of differences between AMG and MPG concerning the role and conduction of clinical trials will remarkably increase the (CE) certification process's outcome quality and juridical validity.

Systematic review of the clinical and economic value of gene expression profiles for invasive early breast cancer available in Europe.

PubMed

Blok, E J; Bastiaannet, E; van den Hout, W B; Liefers, G J; Smit, V T H B M; Kroep, J R; van de Velde, C J H

2018-01-01

Gene expression profiles with prognostic capacities have shown good performance in multiple clinical trials. However, with multiple assays available and numerous types of validation studies performed, the added value for daily clinical practice is still unclear. In Europe, the MammaPrint, OncotypeDX, PAM50/Prosigna and Endopredict assays are commercially available. In this systematic review, we aim to assess these assays on four important criteria: Assay development and methodology, clinical validation, clinical utility and economic value. We performed a literature search covering PubMed, Embase, Web of Science and Cochrane, for studies related to one or more of the four selected assays. We identified 147 papers for inclusion in this review. MammaPrint and OncotypeDX both have evidence available, including level IA clinical trial results for both assays. Both assays provide prognostic information. Predictive value has only been shown for OncotypeDX. In the clinical utility studies, a higher reduction in chemotherapy was achieved by OncotypeDX, although the number of available studies differ considerably between tests. On average, economic evaluations estimate that genomic testing results in a moderate increase in total costs, but that these costs are acceptable in relation to the expected improved patient outcome. PAM50/prosigna and EndoPredict showed comparable prognostic capacities, but with less economical and clinical utility studies. Furthermore, for these assays no level IA trial data are available yet. In summary, all assays have shown excellent prognostic capacities. The differences in the quantity and quality of evidence are discussed. Future studies shall focus on the selection of appropriate subgroups for testing and long-term outcome of validation trials, in order to determine the place of these assays in daily clinical practice. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Testing cardiovascular drug safety and efficacy in randomized trials.

PubMed

FitzGerald, Garret A

2014-03-28

Randomized trials provide the gold standard evidence on which rests the decision to approve novel therapeutics for clinical use. They are large and expensive and provide average but unbiased estimates of efficacy and risk. Concern has been expressed about how unrepresentative populations and conditions that pertain in randomized trials might be of the real world, including concerns about the homogeneity of the biomedical and adherence characteristics of volunteers entered into such trials, the dose and constancy of drug administration and the mixture of additional medications that are restricted in such trials but might influence outcome in practice. A distinction has been drawn between trials that establish efficacy and those that demonstrate effectiveness, drugs that patients actually consume in the real world for clinical benefit. However, randomized controlled trials remain the gold standard for establishing efficacy and the testing of effectiveness with less rigorous approaches is a secondary, albeit important consideration. Despite this, there is an appreciation that average results may conceal considerable interindividual variation in drug response, leading to a failure to appreciate clinical value or risk in subsets of patients. Thus, attempts are now being made to individualize risk estimates by modulating those derived from large randomized trials with the individual baseline risk estimates based on demographic and biological criteria-the individual Numbers Needed to Treat to obtain a benefit, such as a life saved. Here, I will consider some reasons why large phase 3 trials-by far the most expensive element of drug development-may fail to address the unmet medical needs, which should justify such effort and investment.

A highly sensitive search strategy for clinical trials in Literatura Latino Americana e do Caribe em Ciências da Saúde (LILACS) was developed.

PubMed

Manríquez, Juan J

2008-04-01

Systematic reviews should include as many articles as possible. However, many systematic reviews use only databases with high English language content as sources of trials. Literatura Latino Americana e do Caribe em Ciências da Saúde (LILACS) is an underused source of trials, and there is not a validated strategy for searching clinical trials to be used in this database. The objective of this study was to develop a sensitive search strategy for clinical trials in LILACS. An analytical survey was performed. Several single and multiple-term search strategies were tested for their ability to retrieve clinical trials in LILACS. Sensitivity, specificity, and accuracy of each single and multiple-term strategy were calculated using the results of a hand-search of 44 Chilean journals as gold standard. After combining the most sensitive, specific, and accurate single and multiple-term search strategy, a strategy with a sensitivity of 97.75% (95% confidence interval [CI]=95.98-99.53) and a specificity of 61.85 (95% CI=61.19-62.51) was obtained. LILACS is a source of trials that could improve systematic reviews. A new highly sensitive search strategy for clinical trials in LILACS has been developed. It is hoped this search strategy will improve and increase the utilization of LILACS in future systematic reviews.

A strategic plan to accelerate development of acute stroke treatments.

PubMed

Marler, John R

2012-09-01

In order to reenergize acute stroke research and accelerate the development of new treatments, we need to transform the usual design and conduct of clinical trials to test for small but significant improvements in effectiveness, and treat patients as soon as possible after stroke onset when treatment effects are most detectable. This requires trials that include thousands of acute stroke patients. A plan to make these trials possible is proposed. There are four components: (1) free access to the electronic medical record; (2) a large stroke emergency network and clinical trial coordinating center connected in real time to hundreds of emergency departments; (3) a clinical trial technology development center; and (4) strategic leadership to raise funds, motivate clinicians to participate, and interact with politicians, insurers, legislators, and other national and international organizations working to advance the quality of stroke care. © 2012 New York Academy of Sciences.

Offering self-administered oral HIV testing to truck drivers in Kenya to increase testing: a randomized controlled trial.

PubMed

Kelvin, Elizabeth A; George, Gavin; Mwai, Eva; Nyaga, Eston; Mantell, Joanne E; Romo, Matthew L; Odhiambo, Jacob O; Starbuck, Lila; Govender, Kaymarlin

2018-01-01

We conducted a randomized controlled trial among 305 truck drivers from two North Star Alliance roadside wellness clinics in Kenya to see if offering HIV testing choices would increase HIV testing uptake. Participants were randomized to be offered (1) a provider-administered rapid blood (finger-prick) HIV test (i.e., standard of care [SOC]) or (2) a Choice between SOC or a self-administered oral rapid HIV test with provider supervision in the clinic. Participants in the Choice arm who refused HIV testing in the clinic were offered a test kit for home use with phone-based posttest counseling. We compared HIV test uptake using the Mantel Haenszel odds ratio (OR) adjusting for clinic. Those in the Choice arm had higher odds of HIV test uptake than those in the SOC arm (OR = 1.5), but the difference was not statistically significant (p = 0.189). When adding the option to take an HIV test kit for home use, the Choice arm had significantly greater odds of testing uptake (OR = 2.8, p = 0.002). Of those in the Choice arm who tested, 26.9% selected the SOC test, 64.6% chose supervised self-testing in the clinic, and 8.5% took a test kit for home use. Participants varied in the HIV test they selected when given choices. Importantly, when participants who refused HIV testing in the clinic were offered a test kit for home use, an additional 8.5% tested. Offering truck drivers a variety of HIV testing choices may increase HIV testing uptake in this key population.

Birth Control in Clinical Trials: Industry Survey of Current Use Practices, Governance, and Monitoring.

PubMed

Stewart, J; Breslin, W J; Beyer, B K; Chadwick, K; De Schaepdrijver, L; Desai, M; Enright, B; Foster, W; Hui, J Y; Moffat, G J; Tornesi, B; Van Malderen, K; Wiesner, L; Chen, C L

2016-03-01

The Health and Environmental Sciences Institute (HESI) Developmental and Reproductive Toxicology Technical Committee sponsored a pharmaceutical industry survey on current industry practices for contraception use during clinical trials. The objectives of the survey were to improve our understanding of the current industry practices for contraception requirements in clinical trials, the governance processes set up to promote consistency and/or compliance with contraception requirements, and the effectiveness of current contraception practices in preventing pregnancies during clinical trials. Opportunities for improvements in current practices were also considered. The survey results from 12 pharmaceutical companies identified significant variability among companies with regard to contraception practices and governance during clinical trials. This variability was due primarily to differences in definitions, areas of scientific uncertainty or misunderstanding, and differences in company approaches to enrollment in clinical trials. The survey also revealed that few companies collected data in a manner that would allow a retrospective understanding of the reasons for failure of birth control during clinical trials. In this article, suggestions are made for topics where regulatory guidance or scientific publications could facilitate best practice. These include provisions for a pragmatic definition of women of childbearing potential, guidance on how animal data can influence the requirements for male and female birth control, evidence-based guidance on birth control and pregnancy testing regimes suitable for low- and high-risk situations, plus practical methods to ascertain the risk of drug-drug interactions with hormonal contraceptives.

Evaluation of DNA Repair Function as a Predictor of Response in a Clinical Trial of PARP Inhibitor Monotherapy for Recurrent Ovarian Carcinoma

DTIC Science & Technology

2016-12-01

no specifi c biomarkers were tested in a trial of a PARP inhibitor in patients with ovarian carcinoma with measurable disease . There is currently no... disease that was measurable with the Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST) and amenable to biopsy at trial entry. Patients...have measurable disease treated with a PARP inhibitor, thereby testing the assay as a biomarker for PARP inhibitor response. Other prospective

Measures of outcome for stimulant trials: ACTTION recommendations and research agenda.

PubMed

Kiluk, Brian D; Carroll, Kathleen M; Duhig, Amy; Falk, Daniel E; Kampman, Kyle; Lai, Shengan; Litten, Raye Z; McCann, David J; Montoya, Ivan D; Preston, Kenzie L; Skolnick, Phil; Weisner, Constance; Woody, George; Chandler, Redonna; Detke, Michael J; Dunn, Kelly; Dworkin, Robert H; Fertig, Joanne; Gewandter, Jennifer; Moeller, F Gerard; Ramey, Tatiana; Ryan, Megan; Silverman, Kenneth; Strain, Eric C

2016-01-01

The development and approval of an efficacious pharmacotherapy for stimulant use disorders has been limited by the lack of a meaningful indicator of treatment success, other than sustained abstinence. In March, 2015, a meeting sponsored by Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) was convened to discuss the current state of the evidence regarding meaningful outcome measures in clinical trials for stimulant use disorders. Attendees included members of academia, funding and regulatory agencies, pharmaceutical companies, and healthcare organizations. The goal was to establish a research agenda for the development of a meaningful outcome measure that may be used as an endpoint in clinical trials for stimulant use disorders. Based on guidelines for the selection of clinical trial endpoints, the lessons learned from prior addiction clinical trials, and the process that led to identification of a meaningful indicator of treatment success for alcohol use disorders, several recommendations for future research were generated. These include a focus on the validation of patient reported outcome measures of functioning, the exploration of patterns of stimulant abstinence that may be associated with physical and/or psychosocial benefits, the role of urine testing for validating self-reported measures of stimulant abstinence, and the operational definitions for reduction-based measures in terms of frequency rather than quantity of stimulant use. These recommendations may be useful for secondary analyses of clinical trial data, and in the design of future clinical trials that may help establish a meaningful indicator of treatment success. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

On the design and analysis of clinical trials with correlated outcomes

PubMed Central

Follmann, Dean; Proschan, Michael

2014-01-01

SUMMARY The convention in clinical trials is to regard outcomes as independently distributed, but in some situations they may be correlated. For example, in infectious diseases, correlation may be induced if participants have contact with a common infectious source, or share hygienic tips that prevent infection. This paper discusses the design and analysis of randomized clinical trials that allow arbitrary correlation among all randomized volunteers. This perspective generalizes the traditional perspective of strata, where patients are exchangeable within strata, and independent across strata. For theoretical work, we focus on the test of no treatment effect μ1 − μ0 = 0 when the n dimensional vector of outcomes follows a Gaussian distribution with known n × n covariance matrix Σ, where the half randomized to treatment (placebo) have mean response μ1 (μ0). We show how the new test corresponds to familiar tests in simple situations for independent, exchangeable, paired, and clustered data. We also discuss the design of trials where Σ is known before or during randomization of patients and evaluate randomization schemes based on such knowledge. We provide two complex examples to illustrate the method, one for a study of 23 family clusters with cardiomyopathy, the other where the malaria attack rates vary within households and clusters of households in a Malian village. PMID:25111420

The NO Regular Defibrillation testing In Cardioverter Defibrillator Implantation (NORDIC ICD) trial: concept and design of a randomized, controlled trial of intra-operative defibrillation testing during de novo defibrillator implantation.

PubMed

Bänsch, Dietmar; Bonnemeier, Hendrik; Brandt, Johan; Bode, Frank; Svendsen, Jesper Hastrup; Felk, Angelika; Hauser, Tino; Wegscheider, Karl

2015-01-01

Although defibrillation (DF) testing is still considered a standard procedure during implantable cardioverter-defibrillator (ICD) insertion and has been an essential element of all trials that demonstrated the survival benefit of ICD therapy, there are no large randomized clinical trials demonstrating that DF testing improves clinical outcome and if the outcome would remain the same by omitting DF testing. Between February 2011 and July 2013, we randomly assigned 1077 patients to ICD implantation with (n = 540) or without (n = 537) DF testing. The intra-operative DF testing was standardized across all participating centres. After inducing a fast ventricular tachycardia (VT) with a heart rate ≥240 b.p.m. or ventricular fibrillation (VF) with a low-energy T-wave shock, DF was attempted with an initial 15 J shock. If the shock reversed the VT or VF, DF testing was considered successful and terminated. If unsuccessful, two effective 24 J shocks were administered. If DF was unsuccessful, the system was reconfigured and another DF testing was performed. An ICD shock energy of 40 J had to be programmed in all patients for treatment of spontaneous VT/VF episodes. The primary endpoint was the average efficacy of the first ICD shock for all true VT/VF episodes in each patient during follow-up. The secondary endpoints included the frequency of system revisions, total fluoroscopy, implantation time, procedural serious adverse events, and all-cause, cardiac, and arrhythmic mortality during follow-up. Home Monitoring was used in all patients to continuously monitor the system integrity, device programming and performance. The NO Regular Defibrillation testing In Cardioverter Defibrillator Implantation (NORDIC ICD) trial is one of two large prospective randomized trials assessing the effect of DF testing omission during ICD implantation. NCT01282918. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments.

PubMed

Connick, Peter; Kolappan, Madhan; Patani, Rickie; Scott, Michael A; Crawley, Charles; He, Xiao-Ling; Richardson, Karen; Barber, Kelly; Webber, Daniel J; Wheeler-Kingshott, Claudia A M; Tozer, Daniel J; Samson, Rebecca S; Thomas, David L; Du, Ming-Qing; Luan, Shi L; Michell, Andrew W; Altmann, Daniel R; Thompson, Alan J; Miller, David H; Compston, Alastair; Chandran, Siddharthan

2011-03-02

No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes--the "sentinel lesion approach". MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS--the sentinel lesion approach--serving as proof of principle for its future wider applicability. ClinicalTrials.gov (NCT00395200).

Transcranial direct current stimulation as a memory enhancer in patients with Alzheimer's disease: a randomized, placebo-controlled trial.

PubMed

Bystad, Martin; Grønli, Ole; Rasmussen, Ingrid Daae; Gundersen, Nina; Nordvang, Lene; Wang-Iversen, Henrik; Aslaksen, Per M

2016-03-23

The purpose of this study was to assess the efficacy of transcranial direct current stimulation (tDCS) on verbal memory function in patients with Alzheimer's disease. We conducted a randomized, placebo-controlled clinical trial in which tDCS was applied in six 30-minute sessions for 10 days. tDCS was delivered to the left temporal cortex with 2-mA intensity. A total of 25 patients with Alzheimer's disease were enrolled in the study. All of the patients were diagnosed according to National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association criteria. Twelve patients received active stimulation, and thirteen patients received placebo stimulation. The primary outcome measure was the change in two parallel versions of the California Verbal Learning Test-Second Edition, a standardized neuropsychological memory test normalized by age and gender. The secondary outcome measures were the Mini Mental State Examination, clock-drawing test, and Trail Making Test A and B. Changes in the California Verbal Learning Test-Second Edition scores were not significantly different between the active and placebo stimulation groups for immediate recall (p = 0.270), delayed recall (p = 0.052), or recognition (p = 0.089). There were nonsignificant differences in score changes on the Mini Mental State Examination (p = 0.799), clock-drawing test (p = 0.378), and Trail Making Test A (p = 0.288) and B (p = 0.093). Adverse effects were not observed. Compared with placebo stimulation, active tDCS stimulation in this clinical trial did not significantly improve verbal memory function in Alzheimer's disease. This study differs from previous studies in terms of the stimulation protocol, trial design, and application of standardized neuropsychological memory assessment. ClinicalTrials.gov identifier NCT02518412 . Registered on 10 August 2015.

Cognitive effects of transcranial direct current stimulation in depression: Results from the SELECT-TDCS trial and insights for further clinical trials.

PubMed

Brunoni, André Russowsky; Tortella, Gabriel; Benseñor, Isabela Martins; Lotufo, Paulo Andrade; Carvalho, André Ferrer; Fregni, Felipe

2016-09-15

Cognitive dysfunction treatment remains an unmet clinical need in major depressive disorder (MDD). Transcranial direct current stimulation (tDCS) may improve cognitive symptoms in MDD. Our aim was to investigate the cognitive effects of tDCS in the Sertraline vs. Electric Current Therapy for Treating Depression Clinical Study (SELECT-TDCS). We also explored whether tDCS could have mood-independent cognitive effects. One hundred twenty MDD patients aged from 18 to 65 years received 12 sessions of active/sham tDCS (2mA for 30min) and real/placebo 50mg/d sertraline over 6 weeks in a factorial trial. We analyzed whether changes in performance of neuropsychological tests (Trail Making, Digit Span, Stroop Task, Mini-Mental Status Exam and Montreal Cognitive Assessment) occurred over time, according to treatment group and depression improvement. Exploratory analyses were carried out to verify the influence of clinical and demographic variables on the outcomes. Cognitive improvement was showed in most tests used, although they occurred regardless of intervention type and depression improvement. Further exploratory analyses revealed that clinical response and education level could have mediated pro-cognitive tDCS effects on some of the tests used. The neuropsychological battery used might not have been sensitive to detect tDCS-induced effects on cognition. Lack of simultaneous cognitive training during application may have also limited its cognitive effects. We found no evidence of beneficial or deleterious cognitive effects of tDCS as a treatment for depression. We discussed clinical trial design considerations for further tDCS studies assessing cognitive effects, including sample and outcomes considerations. Copyright © 2016 Elsevier B.V. All rights reserved.

Natriuretic peptide-guided management in heart failure.

PubMed

Chioncel, Ovidiu; Collins, Sean P; Greene, Stephen J; Ambrosy, Andrew P; Vaduganathan, Muthiah; Macarie, Cezar; Butler, Javed; Gheorghiade, Mihai

2016-08-01

Heart failure is a clinical syndrome that manifests from various cardiac and noncardiac abnormalities. Accordingly, rapid and readily accessible methods for diagnosis and risk stratification are invaluable for providing clinical care, deciding allocation of scare resources, and designing selection criteria for clinical trials. Natriuretic peptides represent one of the most important diagnostic and prognostic tools available for the care of heart failure patients. Natriuretic peptide testing has the distinct advantage of objectivity, reproducibility, and widespread availability.The concept of tailoring heart failure management to achieve a target value of natriuretic peptides has been tested in various clinical trials and may be considered as an effective method for longitudinal biomonitoring and guiding escalation of heart failure therapies with overall favorable results.Although heart failure trials support efficacy and safety of natriuretic peptide-guided therapy as compared with usual care, the relationship between natriuretic peptide trajectory and clinical benefit has not been uniform across the trials, and certain subgroups have not shown robust benefit. Furthermore, the precise natriuretic peptide value ranges and time intervals of testing are still under investigation. If natriuretic peptides fail to decrease following intensification of therapy, further work is needed to clarify the optimal pharmacologic approach. Despite decreasing natriuretic peptide levels, some patients may present with other high-risk features (e.g. elevated troponin). A multimarker panel investigating multiple pathological processes will likely be an optimal alternative, but this will require prospective validation.Future research will be needed to clarify the type and magnitude of the target natriuretic peptide therapeutic response, as well as the duration of natriuretic peptide-guided therapy in heart failure patients.

Dangers of "confirmatory" cancer trials that fail to actually test the original hypothesis.

PubMed

Markman, Maurie

2014-04-01

The concept of "confirmatory" studies is a standard and important component of the overall clinical trials strategy in oncology. However, it is critical that such studies are similar enough in basic design and how they are conducted that they actually have the realistic potential to confirm, or refute, objectively the findings of the original study. In this commentary, two examples of clinical studies in the gynecologic oncology arena suggested by some to serve as "confirmatory" trials for the original reports demonstrate both the dangers and potential inappropriateness of such conclusions.

Bayesian methodology for the design and interpretation of clinical trials in critical care medicine: a primer for clinicians.

PubMed

Kalil, Andre C; Sun, Junfeng

2014-10-01

To review Bayesian methodology and its utility to clinical decision making and research in the critical care field. Clinical, epidemiological, and biostatistical studies on Bayesian methods in PubMed and Embase from their inception to December 2013. Bayesian methods have been extensively used by a wide range of scientific fields, including astronomy, engineering, chemistry, genetics, physics, geology, paleontology, climatology, cryptography, linguistics, ecology, and computational sciences. The application of medical knowledge in clinical research is analogous to the application of medical knowledge in clinical practice. Bedside physicians have to make most diagnostic and treatment decisions on critically ill patients every day without clear-cut evidence-based medicine (more subjective than objective evidence). Similarly, clinical researchers have to make most decisions about trial design with limited available data. Bayesian methodology allows both subjective and objective aspects of knowledge to be formally measured and transparently incorporated into the design, execution, and interpretation of clinical trials. In addition, various degrees of knowledge and several hypotheses can be tested at the same time in a single clinical trial without the risk of multiplicity. Notably, the Bayesian technology is naturally suited for the interpretation of clinical trial findings for the individualized care of critically ill patients and for the optimization of public health policies. We propose that the application of the versatile Bayesian methodology in conjunction with the conventional statistical methods is not only ripe for actual use in critical care clinical research but it is also a necessary step to maximize the performance of clinical trials and its translation to the practice of critical care medicine.

Unexpected individual clinical site variation in eradication rates of group a streptococci by penicillin in multisite clinical trials.

PubMed

Kaplan, Edward L; Oakes, J Michael; Johnson, Dwight R

2007-12-01

Previously, we reported an unexpectedly large percentage of failures by penicillin to eradicate group A streptococci (GAS) from the upper respiratory tract. Because penicillin has been the recommended therapy for the treatment of GAS pharyngitis, our report prompted controversy. Data from clinical trials in which our laboratory has participated demonstrated marked variation in GAS eradication rates among clinical sites. The reasons for such variation have never been adequately examined. We performed statistical analyses of site variation in eradication rates to assess the potential effect on reported reduced penicillin efficacy. Penicillin GAS eradication rates were compared using data from 4 large multisite pharyngitis treatment trials (75 clinical sites; 1158 subjects). Variation in eradication rates among clinical sites was statistically evaluated [chi(2) tests and generalized estimating equation (GEE) regression models]. There was significant site-to-site variation in GAS eradication rates in each of the trials (range, 17-100%; P < 0.005) as well as between separate trials (mean range, 58-69%; P < 0.033). GEE modeling indicated that GAS eradication rates were significantly higher for clinical sites participating in more than one clinical trial. The statistically significant site-to-site variation in penicillin eradication rates was related to factors (dependencies) at individual sites. Such factors may affect assessment of therapeutic efficacy and indicate a necessity for considering clinical site variation before reporting pooled efficacy data from multiple sites; combined data may result in misleading clinical implications. This is the first report documenting significant variation resulting from individual clinical site-related factors and offers a possible explanation for reduced penicillin eradication.

Social Communication is an Emerging Target for Pharmacotherapy in Autism Spectrum Disorder - A Review of the Literature on Potential Agents.

PubMed

Baribeau, Danielle A; Anagnostou, Evdokia

2014-02-01

To review the published literature and registered clinical trials on pharmacologic interventions targeting social communication impairment in Autism Spectrum Disorder (ASD). A comprehensive search of several databases (PubMed, MEDLINE, PsycINFO, Clinical trials.gov) was conducted to identify pharmacologic agents that have been, or will be, tested as treatments for social communication impairment in individuals with ASD. Evidence from basic science research supporting rational drug discovery is surveyed. Data from animal models and early clinical trials suggest that novel and existing compounds, including N-methyl-D-aspartate (NMDA) modulators, γ-aminobutyric acid (GABA) agonists, metabotropic glutamate receptor (mGluR) antagonists and neuropeptides, may enhance social communication/function in ASD. Results from numerous Phase 2 and Phase 3 clinical trials are expected in the near future. Recent evidence suggests that social communication may be an appropriate target for pharmacologic manipulation. It is hoped that, in combination with behavioural interventions, novel therapeutics may soon be clinically available to help improve social outcomes.

Characterization of a whole, inactivated influenza (H5N1) vaccine.

PubMed

Tada, Yoshikazu

2008-11-01

Effective vaccines against the highly pathogenic influenza A/H5N1 virus are being developed worldwide. In Japan, two adjuvanted, inactivated, whole-virion influenza vaccines were recently developed and licensed as mock-up, pre-pandemic vaccine formulations by the Ministry of Health and Labor Welfare of Japan. During the vaccine design and development process, various obstacles were overcome and, in this report, we introduce the non clinical production, immunogenicity data in human and development process that was associated with egg-derived adjuvanted, inactivated, whole-virion influenza A (H5N1) vaccine. Pilot lots of H5N1 vaccine were produced using the avirulent H5N1 reference strain A/Vietnam/1194/2004 (H5N1) NIBRG-14 and administered following adsorption with aluminum hydroxide as an adjuvant. Quality control and formulation stability tests were performed before clinical trials were initiated (phase I-III). The research foundation for microbial diseases of Osaka University (BIKEN) carried out vaccine production, quality control, stability testing and the phase I clinical trial in addition to overseeing the licensing of this vaccine. Mitsubishi Chemical Safety Institute Ltd. carried out the non clinical pharmacological toxicity and safety studies and the Japanese medical association carried out the phase II/III trials. Phase I-III trials took place in 2006. The production processes were well controlled by established tests and validations. Vaccine quality was confirmed by quality control, stability and pre-clinical tests, and the vaccine was approved as a mock-up, pre-pandemic vaccine by the Ministry of Health and Labor Welfare of Japan. Numerous safety and efficacy procedures were carried out prior to the approval of the described vaccine formulation. Some of these procedures were of particular importance e.g., vaccine development, validation, and quality control tests that included strict monitoring of the hemagglutinin (HA) content of the vaccine formulations. Improving vaccine productivity, shortening the production period and improving antigen yield of the avirulent vaccine strains were also considered important vaccine development criteria.

In Silico Evaluation of Pharmacokinetic Optimization for Antimitogram-Based Clinical Trials.

PubMed

Haviari, Skerdi; You, Benoît; Tod, Michel

2018-04-01

Antimitograms are prototype in vitro tests for evaluating chemotherapeutic efficacy using patient-derived primary cancer cells. These tests might help optimize treatment from a pharmacodynamic standpoint by guiding treatment selection. However, they are technically challenging and require refinements and trials to demonstrate benefit to be widely used. In this study, we performed simulations aimed at exploring how to validate antimitograms and how to complement them by pharmacokinetic optimization. A generic model of advanced cancer, including pharmacokinetic-pharmacodynamic monitoring, was used to link dosing schedules with progression-free survival (PFS), as built from previously validated modules. This model was used to explore different possible situations in terms of pharmacokinetic variability, pharmacodynamic variability, and antimitogram performance. The model recapitulated tumor dynamics and standalone therapeutic drug monitoring efficacy consistent with published clinical results. Simulations showed that combining pharmacokinetic and pharmacodynamic optimization should increase PFS in a synergistic fashion. Simulated data were then used to compute required clinical trial sizes, which were 30% to 90% smaller when pharmacokinetic optimization was added to pharmacodynamic optimization. This improvement was observed even when pharmacokinetic optimization alone exhibited only modest benefit. Overall, our work illustrates the synergy derived from combining antimitograms with therapeutic drug monitoring, permitting a disproportionate reduction of the trial size required to prove a benefit on PFS. Accordingly, we suggest that strategies with benefits too small for standalone clinical trials could be validated in combination in a similar manner. Significance: This work offers a method to reduce the number of patients needed for a clinical trial to prove the hypothesized benefit of a drug to progression-free survival, possibly easing opportunities to evaluate combinations. Cancer Res; 78(7); 1873-82. ©2018 AACR . ©2018 American Association for Cancer Research.

[Experiences and recommendations of the German Federal Institute for Drugs and Medical Devices (BfArM) concerning clinical investigation of medical devices and the evaluation of serious adverse events (SAE)].

PubMed

Renisch, B; Lauer, W

2014-12-01

An integral part of the conformity assessment process for medical devices is a clinical evaluation based on clinical data. Particularly in the case of implantable devices and products of risk class III clinical trials must be performed. Since March 2010 applications for the authorization of clinical trials as well as for the waiver of the authorization requirement must be submitted centrally in Germany to the appropriate federal authority, the Federal Institute for Drugs and Medical Devices (BfArM) or the Paul Ehrlich Institute (PEI). In addition to authorization, approval by the responsible ethics committee is also required under law in order to begin clinical testing of medical devices in Germany. In this paper, the legal framework for the clinical testing of medical devices as well as those involved and possible procedures including evaluation criteria for the initial application of a trial and subsequent amendments are presented in detail. In addition, the reporting requirements for serious adverse events (SAEs) are explained and possible consequences of the evaluation are presented. Finally, a summary of application and registration numbers for all areas of extensive experience of the BfArM as well as requests and guidance for applicants are presented.

The National Cancer Institute-American Society of Clinical Oncology Cancer Trial Accrual Symposium: summary and recommendations.

PubMed

Denicoff, Andrea M; McCaskill-Stevens, Worta; Grubbs, Stephen S; Bruinooge, Suanna S; Comis, Robert L; Devine, Peggy; Dilts, David M; Duff, Michelle E; Ford, Jean G; Joffe, Steven; Schapira, Lidia; Weinfurt, Kevin P; Michaels, Margo; Raghavan, Derek; Richmond, Ellen S; Zon, Robin; Albrecht, Terrance L; Bookman, Michael A; Dowlati, Afshin; Enos, Rebecca A; Fouad, Mona N; Good, Marjorie; Hicks, William J; Loehrer, Patrick J; Lyss, Alan P; Wolff, Steven N; Wujcik, Debra M; Meropol, Neal J

2013-11-01

Many challenges to clinical trial accrual exist, resulting in studies with inadequate enrollment and potentially delaying answers to important scientific and clinical questions. The National Cancer Institute (NCI) and the American Society of Clinical Oncology (ASCO) cosponsored the Cancer Trial Accrual Symposium: Science and Solutions on April 29-30, 2010 to examine the state of accrual science related to patient/community, physician/provider, and site/organizational influences, and identify new interventions to facilitate clinical trial enrollment. The symposium featured breakout sessions, plenary sessions, and a poster session including 100 abstracts. Among the 358 attendees were clinical investigators, researchers of accrual strategies, research administrators, nurses, research coordinators, patient advocates, and educators. A bibliography of the accrual literature in these three major areas was provided to participants in advance of the meeting. After the symposium, the literature in these areas was revisited to determine if the symposium recommendations remained relevant within the context of the current literature. Few rigorously conducted studies have tested interventions to address challenges to clinical trials accrual. Attendees developed recommendations for improving accrual and identified priority areas for future accrual research at the patient/community, physician/provider, and site/organizational levels. Current literature continues to support the symposium recommendations. A combination of approaches addressing both the multifactorial nature of accrual challenges and the characteristics of the target population may be needed to improve accrual to cancer clinical trials. Recommendations for best practices and for future research developed from the symposium are provided.

Turning Access into a web-enabled secure information system for clinical trials.

PubMed

Dongquan Chen; Chen, Wei-Bang; Soong, Mayhue; Soong, Seng-Jaw; Orthner, Helmuth F

2009-08-01

Organizations that have limited resources need to conduct clinical studies in a cost-effective, but secure way. Clinical data residing in various individual databases need to be easily accessed and secured. Although widely available, digital certification, encryption, and secure web server, have not been implemented as widely, partly due to a lack of understanding of needs and concerns over issues such as cost and difficulty in implementation. The objective of this study was to test the possibility of centralizing various databases and to demonstrate ways of offering an alternative to a large-scale comprehensive and costly commercial product, especially for simple phase I and II trials, with reasonable convenience and security. We report a working procedure to transform and develop a standalone Access database into a secure Web-based secure information system. For data collection and reporting purposes, we centralized several individual databases; developed, and tested a web-based secure server using self-issued digital certificates. The system lacks audit trails. The cost of development and maintenance may hinder its wide application. The clinical trial databases scattered in various departments of an institution could be centralized into a web-enabled secure information system. The limitations such as the lack of a calendar and audit trail can be partially addressed with additional programming. The centralized Web system may provide an alternative to a comprehensive clinical trial management system.

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; 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

2012-01-01

Abstract 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. Clin Trans Sci 2013; Volume 6: 13–20 PMID:23399084

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. © 2013 Wiley Periodicals, Inc.

Active monitoring, radical prostatectomy, or radiotherapy for localised prostate cancer: study design and diagnostic and baseline results of the ProtecT randomised phase 3 trial.

PubMed

Lane, J Athene; Donovan, Jenny L; Davis, Michael; Walsh, Eleanor; Dedman, Daniel; Down, Liz; Turner, Emma L; Mason, Malcolm D; Metcalfe, Chris; Peters, Tim J; Martin, Richard M; Neal, David E; Hamdy, Freddie C

2014-09-01

Prostate cancer is a major public health problem with considerable uncertainties about the effectiveness of population screening and treatment options. We report the study design, participant sociodemographic and clinical characteristics, and the initial results of the testing and diagnostic phase of the Prostate testing for cancer and Treatment (ProtecT) trial, which aims to investigate the effectiveness of treatments for localised prostate cancer. In this randomised phase 3 trial, men aged 50-69 years registered at 337 primary care centres in nine UK cities were invited to attend a specialist nurse appointment for a serum prostate-specific antigen (PSA) test. Prostate biopsies were offered to men with a PSA concentration of 3·0 μg/L or higher. Consenting participants with clinically localised prostate cancer were randomly assigned to active monitoring (surveillance strategy), radical prostatectomy, or three-dimensional conformal external-beam radiotherapy by a computer-generated allocation system. Randomisation was stratified by site (minimised for differences in participant age, PSA results, and Gleason score). The primary endpoint is prostate cancer mortality at a median 10-year follow-up, ascertained by an independent committee, which will be analysed by intention to treat in 2016. This trial is registered with ClinicalTrials.gov, number NCT02044172, and as an International Standard Randomised Controlled Trial, number ISRCTN20141297. Between Oct 1, 2001, and Jan 20, 2009, 228,966 men were invited to attend an appointment with a specialist nurse. Of the invited men, 100,444 (44%) attended their initial appointment and 82,429 (82%) of attenders had a PSA test. PSA concentration was below the biopsy threshold in 73,538 (89%) men. Of the 8566 men with a PSA concentration of 3·0-19·9 μg/L, 7414 (87%) underwent biopsies. 2896 men were diagnosed with prostate cancer (4% of tested men and 39% of those who had a biopsy), of whom 2417 (83%) had clinically localised disease (mostly T1c, Gleason score 6). With the addition of 247 pilot study participants recruited between 1999 and 2001, 2664 men were eligible for the treatment trial and 1643 (62%) agreed to be randomly assigned (545 to active monitoring, 545 to radiotherapy, and 553 to radical prostatectomy). Clinical and sociodemographic characteristics of randomly assigned participants were balanced across treatment groups. The ProtecT trial randomly assigned 1643 men with localised prostate cancer to active monitoring, radiotherapy, or surgery. Participant clinicopathological features are more consistent with contemporary patient characteristics than in previous prostate cancer treatment trials. UK National Institute for Health Research Health Technology Assessment Programme. Copyright © 2014 Lane et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.

Ensuring Quality in AFRINEST and SATT

PubMed Central

2013-01-01

Background: Three randomized open-label clinical trials [Simplified Antibiotic Therapy Trial (SATT) Bangladesh, SATT Pakistan and African Neonatal Sepsis Trial (AFRINEST)] were developed to test the equivalence of simplified antibiotic regimens compared with the standard regimen of 7 days of parenteral antibiotics. These trials were originally conceived and designed separately; subsequently, significant efforts were made to develop and implement a common protocol and approach. Previous articles in this supplement briefly describe the specific quality control methods used in the individual trials; this article presents additional information about the systematic approaches used to minimize threats to validity and ensure quality across the trials. Methods: A critical component of quality control for AFRINEST and SATT was striving to eliminate variation in clinical assessments and decisions regarding eligibility, enrollment and treatment outcomes. Ensuring appropriate and consistent clinical judgment was accomplished through standardized approaches applied across the trials, including training, assessment of clinical skills and refresher training. Standardized monitoring procedures were also applied across the trials, including routine (day-to-day) internal monitoring of performance and adherence to protocols, systematic external monitoring by funding agencies and external monitoring by experienced, independent trial monitors. A group of independent experts (Technical Steering Committee/Technical Advisory Group) provided regular monitoring and technical oversight for the trials. Conclusions: Harmonization of AFRINEST and SATT have helped to ensure consistency and quality of implementation, both internally and across the trials as a whole, thereby minimizing potential threats to the validity of the trials’ results. PMID:23945575

Credentialing of radiotherapy centres in Australasia for TROG 09.02 (Chisel), a Phase III clinical trial on stereotactic ablative body radiotherapy of early stage lung cancer.

PubMed

Kron, Tomas; Chesson, Brent; Hardcastle, Nicholas; Crain, Melissa; Clements, Natalie; Burns, Mark; Ball, David

2018-05-01

A randomised clinical trial comparing stereotactic ablative body radiotherapy (SABR) with conventional radiotherapy for early stage lung cancer has been conducted in Australia and New Zealand under the auspices of the TransTasman Radiation Oncology Group (NCT01014130). We report on the technical credentialing program as prerequisite for centres joining the trial. Participating centres were asked to develop treatment plans for two test cases to assess their ability to create plans according to protocol. Dose delivery in the presence of inhomogeneity and motion was assessed during a site visit using a phantom with moving inserts. Site visits for the trial were conducted in 16 Australian and 3 New Zealand radiotherapy facilities. The tests with low density inhomogeneities confirmed shortcomings of the AAA algorithm for dose calculation. Dose was assessed for a typical treatment delivery including at least one non-coplanar beam in a stationary and moving phantom. This end-to-end test confirmed that all participating centres were able to deliver stereotactic ablative body radiotherapy with the required accuracy while the planning study demonstrated that they were able to produce acceptable plans for both test cases. The credentialing process documented that participating centres were able to deliver dose as required in the trial protocol. It also gave an opportunity to provide education about the trial and discuss technical issues such as four-dimensional CT, small field dosimetry and patient immobilisation with staff in participating centres. Advances in knowledge: Credentialing is an important quality assurance tool for radiotherapy trials using advanced technology. In addition to confirming technical competence, it provides an opportunity for education and discussion about the trial.

2-D or 3-D Mammography? The Future of Breast Cancer Detection

MedlinePlus

... D or 3-D Mammography?: The Future of Breast Cancer Detection NIH-supported clinical trial tests diagnostic imaging ... new trial may be the answer for finding breast cancer in women who don’t have symptoms. The ...

Modifying the clinical research infrastructure at a dedicated clinical trials unit: assessment of trial development, activation, and participant accrual

PubMed Central

Tang, Chad; Hess, Kenneth R.; Sanders, Dwana; Davis, Suzanne; Buzdar, Aman; Kurzrock, Razelle; Lee, J. Jack; Meric-Bernstam, Funda; Hong, David

2017-01-01

Purpose Information on processes for trials assessing investigational therapeutics is sparse. We assessed the trial development processes within the Department of Investigational Cancer Therapeutics (ICT) at MD Anderson Cancer Center and analyzed their effects on the trial activation timeline and enrollment. Experimental Design Data were from a prospectively maintained registry that tracks all clinical studies at MD Anderson. From this database we identified 2,261 activated phase I-III trials; 221 were done at the ICT. ICT trials were matched to trials from other MD Anderson departments by phase, sponsorship, and submission year. Trial performance metrics were compared with paired Wilcoxon signed rank tests. Results We identified 3 facets of the ICT research infrastructure: parallel processing of trial approval steps; a physician-led research team; and regular weekly meetings to foster research accountability. Separate analyses were conducted stratified by sponsorship (industry [133 ICT and 133 non-ICT trials] or institutional [68 ICT and 68 non-ICT trials]). ICT trial development was faster from IRB approval to activation (median difference of 1.1 months for industry-sponsored trials vs. 2.3 months for institutional) and from activation to first enrollment (median difference of 0.3 months for industry vs. 1.2 months for institutional) (all matched P<0.05). ICT trials also accrued more patients (median difference of 8 participants for industry vs. 33.5 for institutional) quicker (median difference 4.8 participants/year for industry vs. 11.1 for institutional) (all matched P<0.05). Conclusions Use of a clinical research–focused infrastructure within a large academic cancer center was associated with efficient trial development and participant accrual. PMID:27852698

Modifying the Clinical Research Infrastructure at a Dedicated Clinical Trials Unit: Assessment of Trial Development, Activation, and Participant Accrual.

PubMed

Tang, Chad; Hess, Kenneth R; Sanders, Dwana; Davis, Suzanne E; Buzdar, Aman U; Kurzrock, Razelle; Lee, J Jack; Meric-Bernstam, Funda; Hong, David S

2017-03-15

Purpose: Information on processes for trials assessing investigational therapeutics is sparse. We assessed the trial development processes within the Department of Investigational Cancer Therapeutics (ICT) at MD Anderson Cancer Center (Houston, TX) and analyzed their effects on the trial activation timeline and enrolment. Experimental Design: Data were from a prospectively maintained registry that tracks all clinical studies at MD Anderson. From this database, we identified 2,261 activated phase I-III trials; 221 were done at the ICT. ICT trials were matched to trials from other MD Anderson departments by phase, sponsorship, and submission year. Trial performance metrics were compared with paired Wilcoxon signed rank tests. Results: We identified three facets of the ICT research infrastructure: parallel processing of trial approval steps; a physician-led research team; and regular weekly meetings to foster research accountability. Separate analyses were conducted stratified by sponsorship [industry (133 ICT and 133 non-ICT trials) or institutional (68 ICT and 68 non-ICT trials)]. ICT trial development was faster from IRB approval to activation (median difference of 1.1 months for industry-sponsored trials vs. 2.3 months for institutional) and from activation to first enrolment (median difference of 0.3 months for industry vs. 1.2 months for institutional; all matched P < 0.05). ICT trials also accrued more patients (median difference of 8 participants for industry vs. 33.5 for institutional) quicker (median difference 4.8 participants/year for industry vs. 11.1 for institutional; all matched P < 0.05). Conclusions: Use of a clinical research-focused infrastructure within a large academic cancer center was associated with efficient trial development and participant accrual. Clin Cancer Res; 23(6); 1407-13. ©2016 AACR . ©2016 American Association for Cancer Research.

Reasons for Ineligibility in Phase 1 and 2A HIV Vaccine Clinical Trials at Kenya Aids Vaccine Initiative (KAVI), Kenya

PubMed Central

Omosa-Manyonyi, Gloria S.; Jaoko, Walter; Anzala, Omu; Ogutu, Hilda; Wakasiaka, Sabina; Malogo, Roselyn; Nyange, Jacqueline; Njuguna, Pamela; Ndinya-Achola, Jeckoniah; Bhatt, Kirana; Farah, Bashir; Oyaro, Micah; Schmidt, Claudia; Priddy, Frances; Fast, Patricia

2011-01-01

Background With the persistent challenges towards controlling the HIV epidemic, there is an ongoing need for research into HIV vaccines and drugs. Sub-Saharan African countries - worst affected by the HIV pandemic - have participated in the conduct of clinical trials for HIV vaccines. In Kenya, the Kenya AIDS Vaccine Initiative (KAVI) at the University of Nairobi has conducted HIV vaccine clinical trials since 2001. Methodology Participants were recruited after an extensive informed consent process followed by screening to determine eligibility. Screening included an assessment of risk behavior, medical history and physical examination, and if clinically healthy, laboratory testing. In the absence of locally derived laboratory reference ranges, the ranges used in these trials were derived from populations in the West. Principal findings Two hundred eighty-one participants were screened between 2003 and 2006 for two clinical trials. Of these, 167 (59.4%) met the inclusion/exclusion criteria. Overall, laboratory abnormalities based on the non-indigenous laboratory references used were the most frequent reasons (61.4%) for ineligibility. Medical abnormalities contributed 30.7% of the total reasons for ineligibility. Based on the laboratory reference intervals now developed from East and Southern Africa, those ineligible due to laboratory abnormalities would have been 46.3%. Of the eligible participants, 18.6% declined enrolment. Conclusions Participant recruitment for HIV vaccine clinical trials is a rigorous and time-consuming exercise. Over 61% of the screening exclusions in clinically healthy people were due to laboratory abnormalities. It is essential that laboratory reference ranges generated from local populations for laboratory values be used in the conduct of clinical trials to avoid unnecessary exclusion of willing participants and to avoid over-reporting of adverse events for enrolled participants. Trial registration Protocol IAVI VRC V001 [1]. ClinicalTrials.gov NCT00124007 Protocol IAVI 010 [2] (registration with ClincalTrials.gov is in progress) Protocols IAVI 002 and IAVI 004 are Phase 1 trials only mentioned in introductory paragraphs; details will not be reported. Registration was not required when they were conducted. PMID:21283743

Immune Analysis of Brisbane and California H1N1 in Human Sera and the MIMIC System, and Correlating a H1N1 Pandemic Influenza Clinical Trial with a Clinical Trial in a Test Tube

DTIC Science & Technology

2013-02-15

09-C-0119 BAA09-31 & BAA-10-55 Final Report Date of Proposal: Prepared by Sanofi Pasteur VaxDesign Campus...Sciences, seasonal influenza trivalent intramuscular (TIV-IM) or intradermal (TIV-ID) vaccines, and a quadrivalent influenza vaccine (QIV) from Sanofi . We

Implementation of an anonymisation tool for clinical trials using a clinical trial processor integrated with an existing trial patient data information system.

PubMed

Aryanto, Kadek Y E; Broekema, André; Oudkerk, Matthijs; van Ooijen, Peter M A

2012-01-01

To present an adapted Clinical Trial Processor (CTP) test set-up for receiving, anonymising and saving Digital Imaging and Communications in Medicine (DICOM) data using external input from the original database of an existing clinical study information system to guide the anonymisation process. Two methods are presented for an adapted CTP test set-up. In the first method, images are pushed from the Picture Archiving and Communication System (PACS) using the DICOM protocol through a local network. In the second method, images are transferred through the internet using the HTTPS protocol. In total 25,000 images from 50 patients were moved from the PACS, anonymised and stored within roughly 2 h using the first method. In the second method, an average of 10 images per minute were transferred and processed over a residential connection. In both methods, no duplicated images were stored when previous images were retransferred. The anonymised images are stored in appropriate directories. The CTP can transfer and process DICOM images correctly in a very easy set-up providing a fast, secure and stable environment. The adapted CTP allows easy integration into an environment in which patient data are already included in an existing information system.

Concord Grape Juice Polyphenols and Cardiovascular Risk Factors: Dose-Response Relationships

PubMed Central

Blumberg, Jeffrey B.; Vita, Joseph A.; Chen, C. -Y. Oliver

2015-01-01

Pure fruit juices provide nutritional value with evidence suggesting some of their benefits on biomarkers of cardiovascular disease risk may be derived from their constituent polyphenols, particularly flavonoids. However, few data from clinical trials are available on the dose-response relationship of fruit juice flavonoids to these outcomes. Utilizing the results of clinical trials testing single doses, we have analyzed data from studies of 100% Concord grape juice by placing its flavonoid content in the context of results from randomized clinical trials of other polyphenol-rich foods and beverages describing the same outcomes but covering a broader range of intake. We selected established biomarkers determined by similar methods for measuring flow-mediated vasodilation (FMD), blood pressure, platelet aggregation, and the resistance of low density lipoprotein cholesterol (LDL) to oxidation. Despite differences among the clinical trials in the treatment, subjects, and duration, correlations were observed between the dose and FMD. Inverse dose-response relationships, albeit with lower correlation coefficients, were also noted for the other outcomes. These results suggest a clear relationship between consumption of even modest serving sizes of Concord grape juice, flavonoid intake, and effects on risk factors for cardiovascular disease. This approach to dose-response relationships may prove useful for testing other individual foods and beverages. PMID:26633488

Construction of an efficient evaluative instrument for myasthenia gravis: the MG composite.

PubMed

Burns, Ted M; Conaway, Mark R; Cutter, Gary R; Sanders, Donald B

2008-12-01

We assessed the performance of items from the Quantitative Myasthenia Gravis (QMG), MMT (Manual Muscle Test), and MG-ADL (Myasthenia Gravis - Activities of Daily Living) scales, using data from two recently completed treatment trials of generalized MG. Items were selected that were relevant to manifestations of MG, meaningful to both the physician and the patient, and responsive to clinical change. After the 10 items were chosen, they were weighted based on input from MG experts from around the world, considering factors such as quality of life, disease severity, risk, prognosis, validity, and reliability. The MG Composite is easy to administer, takes less than 5 minutes to complete, and requires no equipment. Weighting of the response options of the 10 items should result in ordinal scores that better represent MG status and are more responsive to meaningful clinical change. To better determine its suitability for clinical use and for treatment trials, the MG Composite will be tested prospectively at several academic medical centers and will be used as a secondary measure of efficacy in pending clinical trials of MG.

Medicine, methodology, and values: trade-offs in clinical science and practice.

PubMed

Ho, Vincent K Y

2011-01-01

The current guidelines of evidence-based medicine (EBM) presuppose that clinical research and clinical practice should advance from rigorous scientific tests as they generate reliable, value-free knowledge. Under this presupposition, hypotheses postulated by doctors and patients in the process of their decision making are preferably tested in randomized clinical trials (RCTs), and in systematic reviews and meta-analyses summarizing outcomes from multiple RCTs. Since testing under this scheme is predominantly focused on the criteria of generality and precision achieved through methodological rigor, at the cost of the criterion of realism, translating test results to clinical practice is often problematic. Choices concerning which methodological criteria should have priority are inevitable, however, as clinical trials, and scientific research in general, cannot meet all relevant criteria at the same time. Since these choices may be informed by considerations external to science, we must acknowledge that science cannot be value-free in a strict sense, and this invites a more prominent role for value-laden considerations in evaluating clinical research. The urgency for this becomes even more apparent when we consider the important yet implicit role of scientific theories in EBM, which may also be subjected to methodological evaluation and for which selectiveness in methodological focus is likewise inevitable.

Pretreatment data is highly predictive of liver chemistry signals in clinical trials

PubMed Central

Cai, Zhaohui; Bresell, Anders; Steinberg, Mark H; Silberg, Debra G; Furlong, Stephen T

2012-01-01

Purpose The goal of this retrospective analysis was to assess how well predictive models could determine which patients would develop liver chemistry signals during clinical trials based on their pretreatment (baseline) information. Patients and methods Based on data from 24 late-stage clinical trials, classification models were developed to predict liver chemistry outcomes using baseline information, which included demographics, medical history, concomitant medications, and baseline laboratory results. Results Predictive models using baseline data predicted which patients would develop liver signals during the trials with average validation accuracy around 80%. Baseline levels of individual liver chemistry tests were most important for predicting their own elevations during the trials. High bilirubin levels at baseline were not uncommon and were associated with a high risk of developing biochemical Hy’s law cases. Baseline γ-glutamyltransferase (GGT) level appeared to have some predictive value, but did not increase predictability beyond using established liver chemistry tests. Conclusion It is possible to predict which patients are at a higher risk of developing liver chemistry signals using pretreatment (baseline) data. Derived knowledge from such predictions may allow proactive and targeted risk management, and the type of analysis described here could help determine whether new biomarkers offer improved performance over established ones. PMID:23226004

Commercial broth microdilution panel validation and reproducibility trials for NVP PDF-713 (LBM 415), a novel inhibitor of bacterial peptide deformylase.

PubMed

Fritsche, T R; Moet, G J; Jones, R N

2004-09-01

NVP PDF-713 (LBM 415) is a peptide deformylase inhibitor being progressed into clinical trials. Dry-form broth microdilution panels of NVP PDF-713 were compared to reference MIC panels of 552 recent clinical isolates. Most (99.2%) dry-form MIC results were within +/- 1 log(2) dilution of the reference panel MICs. Of the bacteria tested, Streptococcus pneumoniae and Haemophilus influenzae showed a bias towards higher and lower MICs, respectively. Same-day and between-day reproducibility tests showed that 98.9% and 96.7% of MIC values, respectively, were within +/- 1 log(2) dilution step, thereby demonstrating a high degree of reliability of the dry-form MIC product for clinical studies.

Patent foramen ovale closure with GORE HELEX or CARDIOFORM Septal Occluder vs. antiplatelet therapy for reduction of recurrent stroke or new brain infarct in patients with prior cryptogenic stroke: Design of the randomized Gore REDUCE Clinical Study.

PubMed

Kasner, Scott E; Thomassen, Lars; Søndergaard, Lars; Rhodes, John F; Larsen, Coby C; Jacobson, Joth

2017-12-01

Rationale The utility of patent foramen ovale (PFO) closure for secondary prevention in patients with prior cryptogenic stroke is uncertain despite multiple randomized trials completed to date. Aims The Gore REDUCE Clinical Study (REDUCE) aims to establish superiority of patent foramen ovale closure in conjunction with antiplatelet therapy over antiplatelet therapy alone in reducing the risk of recurrent clinical ischemic stroke or new silent brain infarct in patients who have had a cryptogenic stroke. Methods and design This controlled, open-label trial randomized 664 subjects with cryptogenic stroke at 63 multinational sites in a 2:1 ratio to either antiplatelet therapy plus patent foramen ovale closure (with GORE® HELEX® Septal Occluder or GORE® CARDIOFORM Septal Occluder) or antiplatelet therapy alone. Subjects will be prospectively followed for up to five years. Neuroimaging is required for all subjects at baseline and at two years or study exit. Study outcomes The two co-primary endpoints for the study are freedom from recurrent clinical ischemic stroke through at least 24 months post-randomization and incidence of new brain infarct (defined as clinical ischemic stroke or silent brain infarct) through 24 months. The primary analyses are an unadjusted log-rank test and a binomial test of subject-based proportions, respectively, both on the intent-to-treat population, with adjustment for testing multiplicity. Discussion The REDUCE trial aims to target a patient population with truly cryptogenic strokes. Medical therapy is limited to antiplatelet agents in both arms thereby reducing confounding. The trial should determine whether patent foramen ovale closure with the Gore septal occluders is safe and more effective than medical therapy alone for the prevention of recurrent clinical ischemic stroke or new silent brain infarct; the neuroimaging data will provide an opportunity to further support the proof of concept. The main results are anticipated in 2017. Registration Clinical trial registration-URL: http://clinicaltrials.gov/show/NCT00738894.

Protocol investigating the clinical utility of an objective measure of activity and attention (QbTest) on diagnostic and treatment decision-making in children and young people with ADHD-'Assessing QbTest Utility in ADHD' (AQUA): a randomised controlled trial.

PubMed

Hall, Charlotte L; Walker, Gemma M; Valentine, Althea Z; Guo, Boliang; Kaylor-Hughes, Catherine; James, Marilyn; Daley, David; Sayal, Kapil; Hollis, Chris

2014-12-01

The National Institute for Health and Care Excellence (NICE) guidelines for attention deficit/hyperactivity disorder (ADHD) state that young people need to have access to the best evidence-based care to improve outcome. The current 'gold standard' ADHD diagnostic assessment combines clinical observation with subjective parent, teacher and self-reports. In routine practice, reports from multiple informants may be unavailable or contradictory, leading to diagnostic uncertainty and delay. The addition of objective tests of attention and activity may help reduce diagnostic uncertainty and delays in initiating treatment leading to improved outcomes. This trial investigates whether providing clinicians with an objective report of levels of attention, impulsivity and activity can lead to an earlier, and more accurate, clinical diagnosis and improved patient outcome. This multisite randomised controlled trial will recruit young people (aged 6-17 years old) who have been referred for an ADHD diagnostic assessment at Child and Adolescent Mental Health Services (CAMHS) and Community Paediatric clinics across England. Routine clinical assessment will be augmented by the QbTest, incorporating a continuous performance test (CPT) and infrared motion tracking of activity. The participant will be randomised into one of two study arms: QbOpen (clinician has immediate access to a QbTest report): QbBlind (report is withheld until the study end). Primary outcomes are time to diagnosis and diagnostic accuracy. Secondary outcomes include clinician's diagnostic confidence and routine clinical outcome measures. Cost-effective analysis will be conducted, alongside a qualitative assessment of the feasibility and acceptability of incorporating QbTest in routine practice. The findings from the study will inform commissioners, clinicians and managers about the feasibility, acceptability, clinical utility and cost-effectiveness of incorporating QbTest into routine diagnostic assessment of young people with ADHD. The results will be submitted for publication in peer-reviewed journals. The study has received ethical approval. NCT02209116. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Alzheimer's Prevention Education: If We Build It, Will They Come? www.AlzU.org.

PubMed

Isaacson, R S; Haynes, N; Seifan, A; Larsen, D; Christiansen, S; Berger, J C; Safdieh, J E; Lunde, A M; Luo, A; Kramps, M; McInnis, M; Ochner, C N

2014-01-01

Internet-based educational interventions may be useful for impacting knowledge and behavioral change. However, in AD prevention, little data exists about which educational tools work best in terms of learning and interest in participating in clinical trials. Primary: Assess effectiveness of interactive webinars vs. written blog-posts on AD prevention learning. Secondary: Evaluate the effect of AD prevention education on interest in participating in clinical trials; Assess usability of, and user perceptions about, an online AD education research platform; Classify target populations (demographics, learning needs, interests). Observational. Online. Men/Women, aged 25+, recruited via facebook.com. Alzheimer's Universe (www.AlzU.org) education research platform. Pre/post-test performance, self-reported Likert-scale ratings, completion rates. Over two-weeks, 4268 visits were generated. 503 signed-up for a user account (11.8% join rate), 196 participated in the lessons (39.0%) and 100 completed all beta-testing steps (19.9%). Users randomized to webinar instruction about AD prevention and the stages of AD demonstrated significant increases (p=0.01) in pre vs. post-testing scores compared to blog-post intervention. Upon joining, 42% were interested in participating in a clinical trial in AD prevention. After completing all beta-test activities, interest increased to 86%. Users were primarily women and the largest category was children of AD patients. 66.3% joined to learn more about AD prevention, 65.3% to learn more about AD treatment. Webinar-based education led to significant improvements in learning about AD prevention and the stages of AD. AlzU.org participation more than doubled interest in AD prevention clinical trial participation. Subjects were quickly and cost-effectively recruited, and highly satisfied with the AD education research platform. Based on these data, we will further refine AlzU.org prior to public launch and aim to study the effectiveness of 25 interactive webinar-based vs. blog-post style lessons on learning and patient outcomes, in a randomized, within-subjects design trial.

A computerized handheld decision-support system to improve pulmonary embolism diagnosis: a randomized trial.

PubMed

Roy, Pierre-Marie; Durieux, Pierre; Gillaizeau, Florence; Legall, Catherine; Armand-Perroux, Aurore; Martino, Ludovic; Hachelaf, Mohamed; Dubart, Alain-Eric; Schmidt, Jeannot; Cristiano, Mirko; Chretien, Jean-Marie; Perrier, Arnaud; Meyer, Guy

2009-11-17

Testing for pulmonary embolism often differs from that recommended by evidence-based guidelines. To assess the effectiveness of a handheld clinical decision-support system to improve the diagnostic work-up of suspected pulmonary embolism among patients in the emergency department. Cluster randomized trial. Assignment was by random-number table, providers were not blinded, and outcome assessment was automated. (ClinicalTrials.gov registration number: NCT00188032). 20 emergency departments in France. 1103 and 1768 consecutive outpatients with suspected pulmonary embolism. After a preintervention period involving 20 centers and 1103 patients, in which providers grew accustomed to inputting clinical data into handheld devices and investigators assessed baseline testing, emergency departments were randomly assigned to activation of a decision-support system on the devices (10 centers, 753 patients) or posters and pocket cards that showed validated diagnostic strategies (10 centers, 1015 patients). Appropriateness of diagnostic work-up, defined as any sequence of tests that yielded a posttest probability less than 5% or greater than 85% (primary outcome) or as strict adherence to guideline recommendations (secondary outcome); number of tests per patient (secondary outcome). The proportion of patients who received appropriate diagnostic work-ups was greater during the trial than in the preintervention period in both groups, but the increase was greater in the computer-based guidelines group (adjusted mean difference in increase, 19.3 percentage points favoring computer-based guidelines [95% CI, 2.9 to 35.6 percentage points]; P = 0.023). Among patients with appropriate work-ups, those in the computer-based guidelines group received slightly fewer tests than did patients in the paper guidelines group (mean tests per patient, 1.76 [SD, 0.98] vs. 2.25 [SD, 1.04]; P < 0.001). The study was not designed to show a difference in the clinical outcomes of patients during follow-up. A handheld decision-support system improved diagnostic decision making for patients with suspected pulmonary embolism in the emergency department.

A Biomarker Combining Imaging and Neuropsychological Assessment for Tracking Early Alzheimer's Disease in Clinical Trials.

PubMed

Verma, Nishant; Beretvas, S Natasha; Pascual, Belen; Masdeu, Joseph C; Markey, Mia K

2018-03-14

Combining optimized cognitive (Alzheimer's Disease Assessment Scale- Cognitive subscale, ADAS-Cog) and atrophy markers of Alzheimer's disease for tracking progression in clinical trials may provide greater sensitivity than currently used methods, which have yielded negative results in multiple recent trials. Furthermore, it is critical to clarify the relationship among the subcomponents yielded by cognitive and imaging testing, to address the symptomatic and anatomical variability of Alzheimer's disease. Using latent variable analysis, we thoroughly investigated the relationship between cognitive impairment, as assessed on the ADAS-Cog, and cerebral atrophy. A biomarker was developed for Alzheimer's clinical trials that combines cognitive and atrophy markers. Atrophy within specific brain regions was found to be closely related with impairment in cognitive domains of memory, language, and praxis. The proposed biomarker showed significantly better sensitivity in tracking progression of cognitive impairment than the ADAS-Cog in simulated trials and a real world problem. The biomarker also improved the selection of MCI patients (78.8±4.9% specificity at 80% sensitivity) that will evolve to Alzheimer's disease for clinical trials. The proposed biomarker provides a boost to the efficacy of clinical trials focused in the mild cognitive impairment (MCI) stage by significantly improving the sensitivity to detect treatment effects and improving the selection of MCI patients that will evolve to Alzheimer's disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A Plutocratic Proposal: an ethical way for rich patients to pay for a place on a clinical trial

PubMed Central

Masters, Alexander

2017-01-01

Many potential therapeutic agents are discarded before they are tested in humans. These are not quack medications. They are drugs and other interventions that have been developed by responsible scientists in respectable companies or universities and are often backed up by publications in peer-reviewed journals. These possible treatments might ease suffering and prolong the lives of innumerable patients, yet they have been put aside. In this paper, we outline a novel mechanism—the Plutocratic Proposal—to revive such neglected research and fund early phase clinical trials. The central idea of the Proposal is that any patient who rescues a potential therapeutic agent from neglect by funding early phase clinical trials (either entirely or in large part) should be offered a place on the trial. PMID:28588147

Clopidogrel and warfarin pharmacogenetic tests: what is the evidence for use in clinical practice?

PubMed Central

Shahin, Mohamed H.A.; Johnson, Julie A.

2013-01-01

Purpose of review To review the most promising genetic markers associated with the variability in the safety or efficacy of warfarin and clopidogrel and highlight the verification and validation initiatives for translating clopidogrel and warfarin pharmacogenetic tests to clinical practice. Recent findings Rapid advances in pharmacogenetics, continuous decrease in genotyping cost, development of point-of-care devices and the newly established clinical genotyping programs at several institutions hold the promise of individualizing clopidogrel and warfarin based on genotype. Guidelines have been established to assist clinicians in prescribing clopidogrel or warfarin dose based on genotype. However, the clinical utility of clopidogrel and warfarin is still limited. Accordingly, large randomized clinical trials are underway to define the role of clopidogrel and warfarin pharmacogenetics in clinical practice. Summary Pharmacogenetics has offered compelling evidence toward the individualization of clopidogrel and warfarin therapies. The rapid advances in technology make the clinical implementation of clopidogrel and warfarin pharmacogenetics possible. The clinical genotyping programs and the ongoing clinical trials will help in overcoming some of the barriers facing the clinical implementation of clopidogrel and warfarin pharmacogenetics. PMID:23478884

NCI Pediatric Preclinical Testing Consortium

Cancer.gov

NCI has awarded grants to five research teams to participate in its Pediatric Preclinical Testing Consortium, which is intended to help to prioritize which agents to pursue in pediatric clinical trials.

Current and experimental treatments of Parkinson disease: A guide for neuroscientists.

PubMed

Oertel, Wolfgang; Schulz, Jörg B

2016-10-01

Over a period of more than 50 years, the symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been optimized using pharmacotherapy, deep brain stimulation, and physiotherapy. The arsenal of pharmacotherapies includes L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine. In the later course of the disease, motor complications occur, at which stage different oral formulations of L-Dopa or dopamine agonists with long half-life, a transdermal application or parenteral pumps for continuous drug supply can be subscribed. Alternatively, the patient is offered deep brain stimulation of the subthalamic nucleus (STN) or the internal part of the globus pallidus (GPi). For a more efficacious treatment of motor complications, new formulations of L-Dopa, dopamine agonists, and amantadine as well as new MAO-B and COMT inhibitors are currently tested in clinical trials, and some of them already yielding positive results in phase 3 trials. In addition, non-dopaminergic agents have been tested in the early clinical phase for the treatment of motor fluctuations and dyskinesia, including adenosine A2A antagonists (istradefylline, preladenant, and tozadenant) and modulators of the metabolic glutamate receptor 5 (mGluR5 - mavoglurant) and serotonin (eltoprazine) receptors. Recent clinical trials testing coenzyme Q10, the dopamine agonist pramipexole, creatine monohydrate, pioglitazone, or AAV-mediated gene therapy aimed at increasing expression of neurturin, did not prove efficacious. Treatment with nicotine, caffeine, inosine (a precursor of urate), and isradipine (a dihydropyridine calcium channel blocker), as well as active and passive immunization against α-synuclein and inhibitors or modulators of α-synuclein-aggregation are currently studied in clinical trials. However, to date, no disease-modifying treatment is available. We here review the current status of treatment options for motor and non-motor symptoms, and discuss current investigative strategies for disease modification. This review provides basic insights, mainly addressing basic scientists and non-specialists. It stresses the need to intensify therapeutic PD research and points out reasons why the translation of basic research to disease-modifying therapies has been unsuccessful so far. The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy. For a more efficacious treatment of motor complications, new formulations of L-Dopa, dopamine agonists, and amantadine as well as new MAO-B and COMT inhibitors are currently tested in clinical trials. Non-dopaminergic agents have been tested in the early clinical phase for the treatment of motor fluctuations and dyskinesia. Recent clinical trials testing coenzyme Q10, the dopamine agonist pramipexole, creatine monohydrate, pioglitazone, or AAV-mediated gene therapy aimed at increasing expression of neurturin, did not prove efficacious. Treatment with nicotine, caffeine, and isradipine - a dihydropyridine calcium channel blocker - as well as active and passive immunization against α-synuclein and inhibitors of α-synuclein-aggregation are currently studied in clinical trials. However, to date, no disease-modifying treatment is available for PD. We here review the current status of treatment options and investigative strategies for both motor and non-motor symptoms. This review stresses the need to intensify therapeutic PD research and points out reasons why the translation of basic research to disease-modifying therapies has been unsuccessful so far. This article is part of a special issue on Parkinson disease. © 2016 International Society for Neurochemistry.

RETHINKING THE ROLE OF CLINICAL TRIAL DATA IN INTERNATIONAL INTELLECTUAL PROPERTY LAW: THE CASE FOR A PUBLIC GOODS APPROACH

PubMed Central

REICHMAN, JEROME H.

2009-01-01

This article describes the growth and consequences of new intellectual property rights given to pharmaceutical developers, and it advocates treating clinical trials as a public good. Although the soaring cost of clinical trials is well known and discussed, too little attention is given to the underlying rationale for allowing drug developers to recoup their costs through the new intellectual property rights provided in multilateral, regional, and bilateral agreements. Known in the US as “market exclusivity” and in Europe as “data exclusivity,” these rights prohibit would-be generic producers from obtaining regulatory approval based on the original producers’ undisclosed test data. Market and data exclusivity is codified in US and European domestic law as well as the North American Free Trade Agreement (NAFTA) and, to a lesser degree, the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS). Market and data exclusivity is binding an increasing number of developing countries via Free Trade Agreements (FTAs), which hinder developing countries from manufacturing generic drugs. At a minimum, negotiators should replace the norm of exclusive control over data with a liability rule, or take and pay rule, in which generic manufacturers can use original manufacturers’ clinical trial data in exchange for reasonable compensation. A more fundamental solution requires questioning the status quo of proprietary clinical trial data. The conventional wisdom is that market and data exclusivity, and drug developers’ consequent ability to limit competition from generics above and beyond patent protection, are a necessary incentive for drug developers to fund ever more expensive clinical trials. Clinical trial data, however, are public goods that will be undersupplied and over protected so long as private actors provide them. Moreover, manufacturers have an incentive to present clinical trial data so that they support regulatory approval at the expense of public health. Although liability rules are better than the status quo, they would not resolve the problem of treating a public good as proprietary. Governments should thus oversee and fund clinical trials as the public good that they are. Clinical tests should be awarded to the most qualified scientists through a competitive process, financed in part with the decrease in drug costs to governmental health care programs and in part with drug developers’ contributions, selected to maximize social benefit, and made global via intergovernmental bodies to maximize social return. This would reduce the cost of redundant investigations to the global public health system, lower supply costs to drug consumers, and lower the breakeven point for investment in research to discover new drugs. PMID:20431702

Evaluating Adaptation of a Cancer Clinical Trial Decision Aid for Rural Cancer Patients: A Mixed-Methods Approach.

PubMed

Pathak, Swati; George, Nerissa; Monti, Denise; Robinson, Kathy; Politi, Mary C

2018-06-03

Rural-residing cancer patients often do not participate in clinical trials. Many patients misunderstand cancer clinical trials and their rights as participant. The purpose of this study is to modify a previously developed cancer clinical trials decision aid (DA), incorporating the unique needs of rural populations, and test its impact on knowledge and decision outcomes. The study was conducted in two phases. Phase I recruited 15 rural-residing cancer survivors in a qualitative usability study. Participants navigated the original DA and provided feedback regarding usability and implementation in rural settings. Phase II recruited 31 newly diagnosed rural-residing cancer patients. Patients completed a survey before and after using the revised DA, R-CHOICES. Primary outcomes included decisional conflict, decision self-efficacy, knowledge, communication self-efficacy, and attitudes towards and willingness to consider joining a trial. In phase I, the DA was viewed positively by rural-residing cancer survivors. Participants provided important feedback about factors rural-residing patients consider when thinking about trial participation. In phase II, after using R-CHOICES, participants had higher certainty about their choice (mean post-test = 3.10 vs. pre-test = 2.67; P = 0.025) and higher trial knowledge (mean percentage correct at post-test = 73.58 vs. pre-test = 57.77; P < 0.001). There was no significant change in decision self-efficacy, communication self-efficacy, and attitudes towards or willingness to join trials. The R-CHOICES improved rural-residing patients' knowledge of cancer clinical trials and reduced conflict about making a trial decision. More research is needed on ways to further support decisions about trial participation among this population.

Testing Cardiovascular Drug Safety and Efficacy in Randomized Trials

PubMed Central

FitzGerald, Garret A.

2014-01-01

Randomized trials provide the gold standard evidence on which rests the decision to approve novel therapeutics for clinical use. They are large and expensive and provide average, but unbiased estimates of efficacy and risk. Concern has been expressed about how “unrepresentative” populations and conditions that pertain in randomized trials might be of the “real world”, including concerns about the homogeneity of the biomedical and adherence characteristics of volunteers entered into such trials, the dose and constancy of drug administration and the mixture of additional medications that are restricted in such trials but might influence outcome in practice. A distinction has been drawn between trials which establish “efficacy” and those that demonstrate “effectiveness” - drugs that patients actually consume in the “real world” for clinical benefit1. However, randomized controlled trials remain the gold standard for establishing efficacy and the testing of “effectiveness” with less rigorous approaches is a secondary, albeit important consideration. Despite this, there is an appreciation that “average” results may conceal considerable inter-individual variation in drug response, leading to a failure to appreciate clinical value or risk in subsets of patients2,3Thus, attempts are now being made to individualize risk estimates by modulating those derived from large randomized trials with the individual baseline risk estimates based on demographic and biological criteria - the individual Numbers Needed to Treat to obtain a benefit, such as a life saved4. Here, I will consider some reasons why large phase 3 trials - by far the most expensive element of drug development - may fail to address the “unmet medical needs” which should justify such effort and investment. PMID:24677235

Analysis and design of randomised clinical trials involving competing risks endpoints.

PubMed

Tai, Bee-Choo; Wee, Joseph; Machin, David

2011-05-19

In randomised clinical trials involving time-to-event outcomes, the failures concerned may be events of an entirely different nature and as such define a classical competing risks framework. In designing and analysing clinical trials involving such endpoints, it is important to account for the competing events, and evaluate how each contributes to the overall failure. An appropriate choice of statistical model is important for adequate determination of sample size. We describe how competing events may be summarised in such trials using cumulative incidence functions and Gray's test. The statistical modelling of competing events using proportional cause-specific and subdistribution hazard functions, and the corresponding procedures for sample size estimation are outlined. These are illustrated using data from a randomised clinical trial (SQNP01) of patients with advanced (non-metastatic) nasopharyngeal cancer. In this trial, treatment has no effect on the competing event of loco-regional recurrence. Thus the effects of treatment on the hazard of distant metastasis were similar via both the cause-specific (unadjusted csHR = 0.43, 95% CI 0.25 - 0.72) and subdistribution (unadjusted subHR 0.43; 95% CI 0.25 - 0.76) hazard analyses, in favour of concurrent chemo-radiotherapy followed by adjuvant chemotherapy. Adjusting for nodal status and tumour size did not alter the results. The results of the logrank test (p = 0.002) comparing the cause-specific hazards and the Gray's test (p = 0.003) comparing the cumulative incidences also led to the same conclusion. However, the subdistribution hazard analysis requires many more subjects than the cause-specific hazard analysis to detect the same magnitude of effect. The cause-specific hazard analysis is appropriate for analysing competing risks outcomes when treatment has no effect on the cause-specific hazard of the competing event. It requires fewer subjects than the subdistribution hazard analysis for a similar effect size. However, if the main and competing events are influenced in opposing directions by an intervention, a subdistribution hazard analysis may be warranted.

Reminder systems to improve patient adherence to tuberculosis clinic appointments for diagnosis and treatment

PubMed Central

Liu, Qin; Abba, Katharine; Alejandria, Marissa M; Sinclair, David; Balanag, Vincent M; Lansang, Mary Ann D

2014-01-01

Background People with active tuberculosis (TB) require six months of treatment. Some people find it difficult to complete treatment, and there are several approaches to help ensure completion. One such system relies on reminders, where the health system prompts patients to attend for appointments on time, or re-engages people who have missed or defaulted on a scheduled appointment. Objectives To assess the effects of reminder systems on improving attendance at TB diagnosis, prophylaxis, and treatment clinic appointments, and their effects on TB treatment outcomes. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register, Cochrane Effective Practice andOrganization of Care Group Specialized Register, CENTRAL,MEDLINE, EMBASE, LILACS, CINAHL, SCI-EXPANDED, SSCI, m RCT, and the Indian Journal of Tuberculosis without language restriction up to 29 August 2014. We also checked reference lists and contacted researchers working in the field. Selection criteria Randomized controlled trials (RCTs), including cluster RCTs and quasi-RCTs, and controlled before-and-after studies comparing reminder systems with no reminders or an alternative reminder system for people with scheduled appointments for TB diagnosis, prophylaxis, or treatment. Data collection and analysis Two review authors independently extracted data and assessed the risk of bias in the included trials. We compared the effects of interventions by using risk ratios (RR) and presented RRs with 95% confidence intervals (CIs). Also we assessed the quality of evidence using the GRADE approach. Main results Nine trials, including 4654 participants, met our inclusion criteria. Five trials evaluated appointment reminders for people on treatment for active TB, two for people on prophylaxis for latent TB, and four for people undergoing TB screening using skin tests.We classified the interventions into 'pre-appointment' reminders (telephone calls or letters prior to a scheduled appointment) or'default' reminders (telephone calls, letters, or home visits to people who had missed an appointment). For people being treated for active TB, clinic attendance and TB treatment completion were higher in people receiving pre-appointment reminder phone-calls (clinic attendance: 66% versus 50%; RR 1.32, 95% CI 1.10 to 1.59, one trial (USA), 615 participants, low quality evidence; TB treatment completion: 100% versus 88%; RR 1.14, 95% CI 1.02 to 1.27, one trial (Thailand), 92 participants, low quality evidence). Clinic attendance and TB treatment completion were also higher with default reminders (letters or home visits) (clinic attendance: 52% versus 10%; RR 5.04, 95% CI 1.61 to 15.78, one trial (India), 52 participants, low quality evidence; treatment completion: RR 1.17, 95% CI 1.11 to 1.24, two trials (Iraq and India), 680 participants, moderate quality evidence). For people on TB prophylaxis, clinic attendance was higher with a policy of pre-appointment phone-calls (63% versus 48%; RR 1.30, 95% CI 1.07 to 1.59, one trial (USA), 536 participants); and attendance at the final clinic was higher with regular three-monthly phone-calls or nurse visits (93% versus 65%, one trial (Spain), 318 participants). For people undergoing screening for TB, three trials of pre-appointment phone-calls found little or no effect on the proportion of people returning to clinic for the result of their skin test (three trials, 1189 participants, low quality evidence), and two trials found little or no effect with take home reminder cards (two trials, 711 participants). All four trials were conducted among healthy volunteers in the USA. Authors' conclusions Policies of sending reminders to people pre-appointment, and contacting people who miss appointments, seem sensible additions to any TB programme, and the limited evidence available suggests they have small but potentially important benefits. Future studies of modern technologies such as short message service (SMS) reminders would be useful, particularly in low-resource settings. Plain Language Summary Reminder systems to improve patient attendance at tuberculosis clinics This Cochrane Review summarizes trials evaluating the effects of reminder systems on attendance at tuberculosis (TB) clinics and completion of TB treatment. After searching for relevant trials up to 29 August 2014, we included nine trials, including 4654 people. What are reminder systems and how might they help? Effective treatment for TB requires people to take multiple drugs daily for at least six months. Consequently, once they start to feel well again, some patients stop attending clinics and stop taking theirmedication which can lead to the illness returning and the development of drug resistance. One strategy theWorldHealthOrganization recommends is that an appointed person (a health worker or volunteer) watches the person take their medication everyday (called direct observation). Other strategies include reminder systems to prompt patients to attend for appointments on time, or to re-engage people who have missed or defaulted on a scheduled appointment. These prompts may be in the form of telephone calls or letters before the next scheduled appointment (“pre-appointment reminders”), or phone calls, letters, or home visits after a missed appointment (“default reminders”). What the research says: For people being treated for active TB: - More people attended the clinic and completed TB treatment with pre-appointment reminder phone-calls (low quality evidence). - More people attended the clinic and completed TB treatment with a policy of default reminders (low and moderate quality evidence respectively). For people on TB prophylaxis: - More people attended the clinic with pre-appointment phone-calls, and the number attending the final clinic was higher with threemonthly phone-calls or nurse home visits. For people being treated for active TB: - Similar numbers of people attended clinic for skin test reading with and without pre-appointment phone-calls (low quality evidence). - Similar numbers of people attended clinic for skin test reading with and without take home reminder cards. PMID:25403701

Study design and rationale for Optimal aNtiplatelet pharmacotherapy guided by bedSIDE genetic or functional TESTing in elective percutaneous coronary intervention patients (ONSIDE TEST): a prospective, open-label, randomised parallel-group multicentre trial (NCT01930773).

PubMed

Kołtowski, Łukasz; Aradi, Daniel; Huczek, Zenon; Tomaniak, Mariusz; Sibbing, Dirk; Filipiak, Krzysztof J; Kochman, Janusz; Balsam, Paweł; Opolski, Grzegorz

2016-01-01

High platelet reactivity (HPR) and presence of CYP2C19 loss-of-function alleles are associated with higher risk for periprocedural myocardial infarction in clopidogrel-treated patients undergoing percutaneous coronary intervention (PCI). It is unknown whether personalised treatment based on platelet function testing or genotyping can prevent such complications. The ONSIDE-TEST is a multicentre, prospective, open-label, randomised controlled clinical trial aiming to assess if optimisation of antiplatelet therapy based on either phenotyping or genotyping is superior to conventional care. Patients will be randomised into phenotyping, genotyping, or control arms. In the phenotyping group, patients will be tested with the VerifyNow P2Y12 assay before PCI, and patients with a platelet reactivity unit greater than 208 will be switched over to prasugrel, while others will continue on clopidogrel therapy. In the genotyping group, carriers of the *2 loss-of-function allele will receive prasugrel for PCI, while wild-type subjects will be treated with clopidogrel. Patients in the control arm will be treated with standard-dose clopidogrel. The primary endpoint of the study is the prevalence of periprocedural myocardial injury within 24 h after PCI in the controls as compared to the phenotyping and genotyping group. Secondary endpoints include cardiac death, myocardial infarction, definite or probable stent thrombosis, or urgent repeat revascularisation within 30 days of PCI. Primary safety outcome is Bleeding Academic Research Consortium (BARC) type 3 and 5 bleeding during 30 days of PCI. The ONSIDE TEST trial is expected to verify the clinical utility of an individualised antiplatelet strategy in preventing periprocedural myocardial injury by either phenotyping or genotyping. ClinicalTrials.gov: NCT01930773.

Analysis of Participant Withdrawal in Huntington Disease Clinical Trials.

PubMed

Banno, Haruhiko; Andrzejewski, Kelly L; McDermott, Michael P; Murphy, Alyssa; Majumder, Madhurima; de Blieck, Elisabeth A; Auinger, Peggy; Cudkowicz, Merit E; Atassi, Nazem

2017-01-01

Excellent retention in Huntington disease (HD) clinical trials is essential for testing new therapies. The stage of disease, cognitive status, and availability of a care partner may influence retention in HD clinical trials. We sought to analyze reasons for early withdrawal in three HD clinical trials, and evaluated if either baseline characteristics or follow-up assessments were associated with time to withdrawal. Analyses of participant withdrawal were performed for three randomized, double-blind, placebo-controlled trials including the CARE-HD (coenzyme Q10 and remacemide in HD, n = 347), DOMINO (pilot study of minocycline in HD, n = 114), and 2CARE (coenzyme Q10 in HD, n = 609) trials. Reasons for withdrawal were obtained by review of textual data in the study databases. Participant demographic and clinical characteristics were analyzed as potential predictors of time to withdrawal using Cox-proportional hazards models. Estimated probabilities of withdrawal at 12 months were 2.9% for CARE-HD, 10.5% for DOMINO, and 5.9% for 2CARE. The top reasons for withdrawal (202 in total), expressed as mean percentage across the three trials, were loss to follow-up (23.2%), death (15.9%), and loss of interest/desire to participate (15.2%). Baseline and time-dependent variables associated with time to withdrawal were mainly motor, behavioral, and functional scores. Age, gender, ethnicity, and educational level were not associated with time to withdrawal in any of the three studies. The estimated withdrawal probability at 12 months ranged from 2.9% to 10.5% in the three HD trials considered here. A possible strategy to improve retention of participants in future HD clinical trials is to enroll individuals with higher baseline functional and behavioral status.

Changes in clinical trials methodology over time: a systematic review of six decades of research in psychopharmacology.

PubMed

Brunoni, André R; Tadini, Laura; Fregni, Felipe

2010-03-03

There have been many changes in clinical trials methodology since the introduction of lithium and the beginning of the modern era of psychopharmacology in 1949. The nature and importance of these changes have not been fully addressed to date. As methodological flaws in trials can lead to false-negative or false-positive results, the objective of our study was to evaluate the impact of methodological changes in psychopharmacology clinical research over the past 60 years. We performed a systematic review from 1949 to 2009 on MEDLINE and Web of Science electronic databases, and a hand search of high impact journals on studies of seven major drugs (chlorpromazine, clozapine, risperidone, lithium, fluoxetine and lamotrigine). All controlled studies published 100 months after the first trial were included. Ninety-one studies met our inclusion criteria. We analyzed the major changes in abstract reporting, study design, participants' assessment and enrollment, methodology and statistical analysis. Our results showed that the methodology of psychiatric clinical trials changed substantially, with quality gains in abstract reporting, results reporting, and statistical methodology. Recent trials use more informed consent, periods of washout, intention-to-treat approach and parametric tests. Placebo use remains high and unchanged over time. Clinical trial quality of psychopharmacological studies has changed significantly in most of the aspects we analyzed. There was significant improvement in quality reporting and internal validity. These changes have increased study efficiency; however, there is room for improvement in some aspects such as rating scales, diagnostic criteria and better trial reporting. Therefore, despite the advancements observed, there are still several areas that can be improved in psychopharmacology clinical trials.

Effect of acupuncture on patients with insomnia: study protocol for a randomized controlled trial.

PubMed

Han, Kyung-Hun; Kim, Sang-Young; Chung, Sun-Yong

2014-10-23

Hypnotic drugs tend to be the dominant form of treatment of insomnia, but these come with a number of reported side effects. Acupuncture has been studied as an alternative, resulting in a rising need for methodological research towards verifying its efficacy as insomnia treatment. We describe a proposal for a single-center, patient-assessor-blinded, randomized controlled trial with two parallel arms. A total of 38 patients complete screening tests at the first visit, are registered into the clinical trial, and then randomly assigned to the experimental or sham control groups (19 patients for each group). All subjects are clinical insomnia patients who score a 6 or above on the Pittsburgh Sleep Quality Index (PSQI) and meet all inclusion criteria. All subjects are treated with acupuncture and intradermal acupuncture (IDA) three times during the first week. Five sham acupoints are used in the control group. In the experimental group, five real acupoints (PC6, SP6, HT7, KI6, and BL62) are used unilaterally in turn. Sham acupoints are over 1 cm away from each real acupoint.The primary outcomes are the scores on the Insomnia Severity Index (ISI) and PSQI. Secondary outcomes are the sleep log, the Beck Depression Inventory (BDI), the State-Trait Anxiety Inventory (STAI), the World Health Organization Quality of Life Abbreviated Version (WHOQOL-BREF), the Korean-Auditory Verbal Learning Test (K-AVLT), the Digit Span Test (DS), Event Related Potentials (ERPs) and heart rate variability (HRV) to assess emotional states, sleep quality, cognitive functioning, and electro-physiological changes.Subjects are assessed at three time points: baseline, post-treatment and follow-up. The duration of the clinical trial is 18 days. To study the enhancement of the effectiveness of acupuncture for insomnia, we test the intradermal acupuncture method, which is performed continuously on the subject's skin and stimulated at home by the subject every night. In the trial, objective measurements including ERPs and HRV are used to evaluate states of cognition and autonomic nervous system functioning and subjective self-report questionnaires assess insomnia symptoms.'Sham' acupuncture points provided by STRICTA are used for the control group. ClinicalTrials.gov: NCT01956760, registered 5 September 2013.

Prostate Cancer Screening

MedlinePlus

... decrease the risk of dying from cancer. Scientists study screening tests to find those with the fewest risks and ... or routine screening test for prostate cancer. Screening tests for prostate cancer are under study, and there are screening clinical trials taking place ...

Illustrating idiographic methods for translation research: moderation effects, natural clinical experiments, and complex treatment-by-subgroup interactions.

PubMed

Ridenour, Ty A; Wittenborn, Andrea K; Raiff, Bethany R; Benedict, Neal; Kane-Gill, Sandra

2016-03-01

A critical juncture in translation research involves the preliminary studies of intervention tools, provider training programs, policies, and other mechanisms used to leverage knowledge garnered at one translation stage into another stage. Potentially useful for such studies are rigorous techniques for conducting within-subject clinical trials, which have advanced incrementally over the last decade. However, these methods have largely not been utilized within prevention or translation contexts. The purpose of this manuscript is to demonstrate the flexibility, wide applicability, and rigor of idiographic clinical trials for preliminary testing of intervention mechanisms. Specifically demonstrated are novel uses of state-space modeling for testing intervention mechanisms of short-term outcomes, identifying heterogeneity in and moderation of within-person treatment mechanisms, a horizontal line plot to refine sampling design during the course of a clinic-based experimental study, and the need to test a treatment's efficacy as treatment is administered along with (e.g., traditional 12-month outcomes).

Zika viral polymerase inhibition using anti-HCV drugs both in market and under clinical trials.

PubMed

Elfiky, Abdo A

2016-12-01

In the last few months, a new Zika virus (ZIKV) outbreak evolved in America. In accordance, World Health Organization (WHO) in February 2016 declared it as Public Health Emergency of International Concern (PHEIC). ZIKV infection was reported in more than 60 countries and the disease was spreading since 2007 but with little momentum. Many antiviral drugs are available in market or in laboratories under clinical trials, could affect ZIKV infection. In silico docking study were performed on the ZIKV polymerase to test some of Hepatitis C Virus (HCV) drugs (approved and in clinical trials). The results show potency of almost all of the studied compounds on ZIKV polymerase and hence inhibiting the propagation of the disease. In addition, the study suggested two nucleotide inhibitors (IDX-184 and MK0608) that may be tested as drugs against ZIKV infection. J. Med. Virol. 88:2044-2051, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Comparison of futility monitoring guidelines using completed phase III oncology trials.

PubMed

Zhang, Qiang; Freidlin, Boris; Korn, Edward L; Halabi, Susan; Mandrekar, Sumithra; Dignam, James J

2017-02-01

Futility (inefficacy) interim monitoring is an important component in the conduct of phase III clinical trials, especially in life-threatening diseases. Desirable futility monitoring guidelines allow timely stopping if the new therapy is harmful or if it is unlikely to demonstrate to be sufficiently effective if the trial were to continue to its final analysis. There are a number of analytical approaches that are used to construct futility monitoring boundaries. The most common approaches are based on conditional power, sequential testing of the alternative hypothesis, or sequential confidence intervals. The resulting futility boundaries vary considerably with respect to the level of evidence required for recommending stopping the study. We evaluate the performance of commonly used methods using event histories from completed phase III clinical trials of the Radiation Therapy Oncology Group, Cancer and Leukemia Group B, and North Central Cancer Treatment Group. We considered published superiority phase III trials with survival endpoints initiated after 1990. There are 52 studies available for this analysis from different disease sites. Total sample size and maximum number of events (statistical information) for each study were calculated using protocol-specified effect size, type I and type II error rates. In addition to the common futility approaches, we considered a recently proposed linear inefficacy boundary approach with an early harm look followed by several lack-of-efficacy analyses. For each futility approach, interim test statistics were generated for three schedules with different analysis frequency, and early stopping was recommended if the interim result crossed a futility stopping boundary. For trials not demonstrating superiority, the impact of each rule is summarized as savings on sample size, study duration, and information time scales. For negative studies, our results show that the futility approaches based on testing the alternative hypothesis and repeated confidence interval rules yielded less savings (compared to the other two rules). These boundaries are too conservative, especially during the first half of the study (<50% of information). The conditional power rules are too aggressive during the second half of the study (>50% of information) and may stop a trial even when there is a clinically meaningful treatment effect. The linear inefficacy boundary with three or more interim analyses provided the best results. For positive studies, we demonstrated that none of the futility rules would have stopped the trials. The linear inefficacy boundary futility approach is attractive from statistical, clinical, and logistical standpoints in clinical trials evaluating new anti-cancer agents.

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. Simulations are used to examine small-to-moderate sample properties. Conclusion Innovative clinical trial designs are needed to address the difficulties and issues in the development and validation of biomarker-based personalized therapies. The article shows the advantages of using likelihood inference and interim analysis to meet the challenges in the sample size needed and in the constantly evolving biomarker landscape and genomic and proteomic technologies. PMID:22397801

New male contraceptive entering clinical trials worldwide.

PubMed

1989-10-01

250 men are participating in a clinical trial of a reversible male testosterone contraceptive at the University of Washington in Seattle and at 9 other centers in Europe, Asia, and Australia. Clinicians inject the WHO-developed testosterone enanthate (200 mg) into these men once a week. The testosterone contraceptive instructs the pituitary gland to deactivate 2 hormones which normally maintain the testes' function resulting in a temporary stop of spermatogenesis just like the female oral contraceptive instructs the pituitary gland to suppress ovulation. Tests of 5 ejaculates in preliminary trials have indicated that 50-60% of the men experience azoospermia. Investigators are concerned with the possibility that ejaculates during normal intercourse may contain enough sperm to impregnate the partner. An investigator at the University of Washington believes this clinical trial of 250 men will determine whether this is indeed the case. The concern about contraceptive failure is the main problem with contraceptive testosterone. The minor side effects include weight gain which may be due to increased muscle mass and some sodium retention, acne, and possible reduction of libido but that has not yet occurred in the 250 men in the clinical trial. This contraceptive testosterone does not remain active for long periods of time if administered orally. Researchers are now developing a newer form of the contraceptive which will increase the intervals between administrations from 1 week to 3 months. An investigator from Seattle guesses that this male contraceptive will not be available for marketing in the US until at least 1994.

Remarks spoken before the audience at the final conference plenary session, entitled: "Future directions," at the International Conference on Advances in AIDS Vaccine Development. Fourth annual meeting of the National Cooperative Vaccine Development Groups for AIDS.

PubMed

Nzila, N

1992-08-01

Nzilambi Nzila, Visiting Scientist at the Johns Hopkins University Center for Immunization Research, responds to frequently asked questions about AIDS vaccine clinical trials in Africa. Conference attendees had asked him if the thinks the time is right to begin AIDS vaccine clinical trials in Africa; if African populations and decision makers want to be involved in the trials; and if he thinks that Africans will be used as guinea pigs. Given the magnitude of the AIDS pandemic in Africa and the general population desire for effective responses, Nzila feels that clinical trials could commence. Yes, Africans want to be involved in the early phases of clinical trials to both share their experiences and reap the benefits of an effective and safe vaccine should one be developed. Large IEC campaigns will simply not suffice to stem the spread of HIV. Further, decision makers in Africa should be involved as early as possible to allow then time to recruit HIV-negative volunteers for trials. Finally, Nzila does not equate involvement in vaccine trials with laboratory test animal status, especially since the target population is aware of its participation.

A generic minimization random allocation and blinding system on web.

PubMed

Cai, Hongwei; Xia, Jielai; Xu, Dezhong; Gao, Donghuai; Yan, Yongping

2006-12-01

Minimization is a dynamic randomization method for clinical trials. Although recommended by many researchers, the utilization of minimization has been seldom reported in randomized trials mainly because of the controversy surrounding the validity of conventional analyses and its complexity in implementation. However, both the statistical and clinical validity of minimization were demonstrated in recent studies. Minimization random allocation system integrated with blinding function that could facilitate the implementation of this method in general clinical trials has not been reported. SYSTEM OVERVIEW: The system is a web-based random allocation system using Pocock and Simon minimization method. It also supports multiple treatment arms within a trial, multiple simultaneous trials, and blinding without further programming. This system was constructed with generic database schema design method, Pocock and Simon minimization method and blinding method. It was coded with Microsoft Visual Basic and Active Server Pages (ASP) programming languages. And all dataset were managed with a Microsoft SQL Server database. Some critical programming codes were also provided. SIMULATIONS AND RESULTS: Two clinical trials were simulated simultaneously to test the system's applicability. Not only balanced groups but also blinded allocation results were achieved in both trials. Practical considerations for minimization method, the benefits, general applicability and drawbacks of the technique implemented in this system are discussed. Promising features of the proposed system are also summarized.

Drug-device trials for infectious diseases: CDRH perspective.

PubMed

Meier, Kristen L; Gitterman, Steven

2011-05-01

Assessing the performance of new diagnostic tests for infectious diseases has traditionally focused on comparing the new assay against a reference standard such as culture. In this paper, we suggest that clinical trial designs with both a diagnostic and therapeutic component may be necessary to evaluate the safety and effectiveness of nonmicrobiologically based assays, with a specific emphasis on the test/marker-stratified design. General design challenges for trials of infectious diseases that simultaneously study both diagnostic and therapeutic components (eg, both devices and drugs) are also discussed.

PROspective Multicenter Imaging Study for Evaluation of chest pain: rationale and design of the PROMISE trial.

PubMed

Douglas, Pamela S; Hoffmann, Udo; Lee, Kerry L; Mark, Daniel B; Al-Khalidi, Hussein R; Anstrom, Kevin; Dolor, Rowena J; Kosinski, Andrzej; Krucoff, Mitchell W; Mudrick, Daniel W; Patel, Manesh R; Picard, Michael H; Udelson, James E; Velazquez, Eric J; Cooper, Lawton

2014-06-01

Suspected coronary artery disease (CAD) is one of the most common, potentially life-threatening diagnostic problems clinicians encounter. However, no large outcome-based randomized trials have been performed to guide the selection of diagnostic strategies for these patients. The PROMISE study is a prospective, randomized trial comparing the effectiveness of 2 initial diagnostic strategies in patients with symptoms suspicious for CAD. Patients are randomized to either (1) functional testing (exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram) or (2) anatomical testing with ≥64-slice multidetector coronary computed tomographic angiography. Tests are interpreted locally in real time by subspecialty certified physicians, and all subsequent care decisions are made by the clinical care team. Sites are provided results of central core laboratory quality and completeness assessment. All subjects are followed up for ≥1 year. The primary end point is the time to occurrence of the composite of death, myocardial infarction, major procedural complications (stroke, major bleeding, anaphylaxis, and renal failure), or hospitalization for unstable angina. More than 10,000 symptomatic subjects were randomized in 3.2 years at 193 US and Canadian cardiology, radiology, primary care, urgent care, and anesthesiology sites. Multispecialty community practice enrollment into a large pragmatic trial of diagnostic testing strategies is both feasible and efficient. The PROMISE trial will compare the clinical effectiveness of an initial strategy of functional testing against an initial strategy of anatomical testing in symptomatic patients with suspected CAD. Quality of life, resource use, cost-effectiveness, and radiation exposure will be assessed. Copyright © 2014 Mosby, Inc. All rights reserved.

Improved design of prodromal Alzheimer's disease trials through cohort enrichment and surrogate endpoints.

PubMed

Macklin, Eric A; Blacker, Deborah; Hyman, Bradley T; Betensky, Rebecca A

2013-01-01

Alzheimer's disease (AD) trials initiated during or before the prodrome are costly and lengthy because patients are enrolled long before clinical symptoms are apparent, when disease progression is slow. We hypothesized that design of such trials could be improved by: 1) selecting individuals at moderate near-term risk of progression to AD dementia (the current clinical standard) and 2) by using short-term surrogate endpoints that predict progression to AD dementia. We used a longitudinal cohort of older, initially non-demented, community-dwelling participants (n = 358) to derive selection criteria and surrogate endpoints and tested them in an independent national data set (n = 6,243). To identify a "mid-risk" subgroup, we applied conditional tree-based survival models to Clinical Dementia Rating (CDR) scale scores and common neuropsychological tests. In the validation cohort, a time-to-AD dementia trial applying these mid-risk selection criteria to a pool of all non-demented individuals could achieve equivalent power with 47% fewer participants than enrolling at random from that pool. We evaluated surrogate endpoints measureable over two years of follow-up based on cross-validated concordance between predictions from Cox models and observed time to AD dementia. The best performing surrogate, rate of change in CDR sum-of-boxes, did not reduce the trial duration required for equivalent power using estimates from the validation cohort, but alternative surrogates with better ability to predict time to AD dementia should be able to do so. The approach tested here might improve efficiency of prodromal AD trials using other potential measures and could be generalized to other diseases with long prodromal phases.

Improved design of prodromal Alzheimer’s disease trials through cohort enrichment and surrogate endpoints

PubMed Central

Macklin, Eric A.; Blacker, Deborah; Hyman, Bradley T.; Betensky, Rebecca A.

2013-01-01

Summary Alzheimer’s disease (AD) trials initiated during or before the prodrome are costly and lengthy because patients are enrolled long before clinical symptoms are apparent, when disease progression is slow. We hypothesized that design of such trials could be improved by: (1) selecting individuals at moderate near-term risk of progression to AD dementia (the current clinical standard) and (2) by using short-term surrogate endpoints that predict progression to AD dementia. We used a longitudinal cohort of older, initially non-demented, community-dwelling participants (n=358) to derive selection criteria and surrogate endpoints and tested them in an independent national data set (n=6,243). To identify a “mid-risk” subgroup, we applied conditional tree-based survival models to Clinical Dementia Rating (CDR) scale scores and common neuropsychological tests. In the validation cohort, a time-to-AD dementia trial applying these mid-risk selection criteria to a pool of all non-demented individuals could achieve equivalent power with 47% fewer participants than enrolling at random from that pool. We evaluated surrogate endpoints measureable over two years of follow-up based on cross-validated concordance between predictions from Cox models and observed time to AD dementia. The best performing surrogate, rate of change in CDR sum-of-boxes, did not reduce the trial duration required for equivalent power using estimates from the validation cohort, but alternative surrogates with better ability to predict time to AD dementia should be able to do so. The approach tested here might improve efficiency of prodromal AD trials using other potential measures and could be generalized to other diseases with long prodromal phases. PMID:23629586

Randomised clinical trials with clinician-preferred treatment.

PubMed

Korn, E L; Baumrind, S

1991-01-19

The standard design for randomised clinical trials may be inappropriate when the clinician believes that one of the treatments being tested is superior for the patient, or when the clinician has a preference for one of the treatments. For such instances the suggestion is that the patient is randomly allocated to treatment only when there is clinical disagreement about treatment of choice for that patient, and then the patient is assigned to a clinician who had thought that the regimen allocated is the one most appropriate for that patient.

Sample size calculations for comparative clinical trials with over-dispersed Poisson process data.

PubMed

Matsui, Shigeyuki

2005-05-15

This paper develops a new formula for sample size calculations for comparative clinical trials with Poisson or over-dispersed Poisson process data. The criteria for sample size calculations is developed on the basis of asymptotic approximations for a two-sample non-parametric test to compare the empirical event rate function between treatment groups. This formula can accommodate time heterogeneity, inter-patient heterogeneity in event rate, and also, time-varying treatment effects. An application of the formula to a trial for chronic granulomatous disease is provided. Copyright 2004 John Wiley & Sons, Ltd.

Warfarin Pharmacogenetics

PubMed Central

Johnson, Julie A.; Cavallari, Larisa H.

2014-01-01

The cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase complex 1 (VKORC1) genotypes have been strongly and consistently associated with warfarin dose requirements, and dosing algorithms incorporating genetic and clinical information have been shown to be predictive of stable warfarin dose. However, clinical trials evaluating genotype-guided warfarin dosing produced mixed results, calling into question the utility of this approach. Recent trials used surrogate markers as endpoints rather than clinical endpoints, further complicating translation of the data to clinical practice. The present data do not support genetic testing to guide warfarin dosing, but in the setting where genotype data are available, use of such data in those of European ancestry is reasonable. Outcomes data are expected from an on-going trial, observational studies continue, and more work is needed to define dosing algorithms that incorporate appropriate variants in minority populations; all these will further shape guidelines and recommendations on the clinical utility of genotype-guided warfarin dosing. PMID:25282448

Role of preliminary registry data in development of a clinical trial for an innovative device: a small but integral piece of a health policy initiative

PubMed Central

Ricci, Donald R.; de Vries, Joost; Blanc, Raphael

2017-01-01

ABSTRACT Establishing a national health policy at a macro level involves the integration of a series of health initiatives across a spectrum of activities, including clinical care. Evaluation of the safety and efficacy of a new medical device ultimately evolves to testing in humans. The pathway to a formal prospective clinical trial includes a stepwise appreciation of pre-clinical data and detailed analysis of data obtained from preliminary registries, where information about appropriate patient selection and use of the device is obtained. Evaluation of procedural and follow-up efficacy and safety data in a preliminary series of cases, chosen to simulate published data, allows the design and conduct of clinical trials that are required to verify preliminary observations, closing the loop on one aspect of modifying health policy decisions. PMID:28321285

HIV-1 tropism testing and clinical management of CCR5 antagonists: Quebec review and recommendations.

PubMed

Tremblay, Cécile; Hardy, Isabelle; Lalonde, Richard; Trottier, Benoit; Tsarevsky, Irina; Vézina, Louis-Philippe; Roger, Michel; Wainberg, Mark; Baril, Jean-Guy

2013-01-01

HIV-1 tropism assays play a crucial role in determining the response to CCR5 receptor antagonists. Initially, phenotypic tests were used, but limited access to these tests prompted the development of alternative strategies. Recently, genotyping tropism has been validated using a Canadian technology in clinical trials investigating the use of maraviroc in both experienced and treatment-naive patients. The present guidelines review the evidence supporting the use of genotypic assays and provide recommendations regarding tropism testing in daily clinical management.

Adaptive graph-based multiple testing procedures

PubMed Central

Klinglmueller, Florian; Posch, Martin; Koenig, Franz

2016-01-01

Multiple testing procedures defined by directed, weighted graphs have recently been proposed as an intuitive visual tool for constructing multiple testing strategies that reflect the often complex contextual relations between hypotheses in clinical trials. Many well-known sequentially rejective tests, such as (parallel) gatekeeping tests or hierarchical testing procedures are special cases of the graph based tests. We generalize these graph-based multiple testing procedures to adaptive trial designs with an interim analysis. These designs permit mid-trial design modifications based on unblinded interim data as well as external information, while providing strong family wise error rate control. To maintain the familywise error rate, it is not required to prespecify the adaption rule in detail. Because the adaptive test does not require knowledge of the multivariate distribution of test statistics, it is applicable in a wide range of scenarios including trials with multiple treatment comparisons, endpoints or subgroups, or combinations thereof. Examples of adaptations are dropping of treatment arms, selection of subpopulations, and sample size reassessment. If, in the interim analysis, it is decided to continue the trial as planned, the adaptive test reduces to the originally planned multiple testing procedure. Only if adaptations are actually implemented, an adjusted test needs to be applied. The procedure is illustrated with a case study and its operating characteristics are investigated by simulations. PMID:25319733

Reliability and equivalence of alternate forms for the Symbol Digit Modalities Test: implications for multiple sclerosis clinical trials.

PubMed

Benedict, Ralph H B; Smerbeck, Audrey; Parikh, Rajavi; Rodgers, Jonathan; Cadavid, Diego; Erlanger, David

2012-09-01

Cognitive impairment is common in multiple sclerosis (MS), but is seldom assessed in clinical trials investigating the effects of disease-modifying therapies. The Symbol Digit Modalities Test (SDMT) is a particularly promising tool due to its sensitivity and robust correlation with brain magnetic resonance imaging (MRI) and vocational disability. Unfortunately, there are no validated alternate SDMT forms, which are needed to mitigate practice effects. The aim of the study was to assess the reliability and equivalence of SDMT alternate forms. Twenty-five healthy participants completed each of five alternate versions of the SDMT - the standard form, two versions from the Rao Brief Repeatable Battery, and two forms specifically designed for this study. Order effects were controlled using a Latin-square research design. All five versions of the SDMT produced mean values within 3 raw score points of one another. Three forms were very consistent, and not different by conservative statistical tests. The SDMT test-retest reliability using these forms was good to excellent, with all r values exceeding 0.80. For the first time, we find good evidence that at least three alternate versions of the SDMT are of equivalent difficulty in healthy adults. The forms are reliable, and can be implemented in clinical trials emphasizing cognitive outcomes.

Construction of a database for published phase II/III drug intervention clinical trials for the period 2009-2014 comprising 2,326 records, 90 disease categories, and 939 drug entities.

PubMed

Jeong, Sohyun; Han, Nayoung; Choi, Boyoon; Sohn, Minji; Song, Yun-Kyoung; Chung, Myeon-Woo; Na, Han-Sung; Ji, Eunhee; Kim, Hyunah; Rhew, Ki Yon; Kim, Therasa; Kim, In-Wha; Oh, Jung Mi

2016-06-01

To construct a database of published clinical drug trials suitable for use 1) as a research tool in accessing clinical trial information and 2) in evidence-based decision-making by regulatory professionals, clinical research investigators, and medical practitioners. Comprehensive information obtained from a search of design elements and results of clinical trials in peer reviewed journals using PubMed (http://www.ncbi.nlm.ih.gov/pubmed). The methodology to develop a structured database was devised by a panel composed of experts in medical, pharmaceutical, information technology, and members of Ministry of Food and Drug Safety (MFDS) using a step by step approach. A double-sided system consisting of user mode and manager mode served as the framework for the database; elements of interest from each trial were entered via secure manager mode enabling the input information to be accessed in a user-friendly manner (user mode). Information regarding methodology used and results of drug treatment were extracted as detail elements of each data set and then inputted into the web-based database system. Comprehensive information comprising 2,326 clinical trial records, 90 disease states, and 939 drugs entities and concerning study objectives, background, methods used, results, and conclusion could be extracted from published information on phase II/III drug intervention clinical trials appearing in SCI journals within the last 10 years. The extracted data was successfully assembled into a clinical drug trial database with easy access suitable for use as a research tool. The clinically most important therapeutic categories, i.e., cancer, cardiovascular, respiratory, neurological, metabolic, urogenital, gastrointestinal, psychological, and infectious diseases were covered by the database. Names of test and control drugs, details on primary and secondary outcomes and indexed keywords could also be retrieved and built into the database. The construction used in the database enables the user to sort and download targeted information as a Microsoft Excel spreadsheet. Because of the comprehensive and standardized nature of the clinical drug trial database and its ease of access it should serve as valuable information repository and research tool for accessing clinical trial information and making evidence-based decisions by regulatory professionals, clinical research investigators, and medical practitioners.

Adolescent knowledge and attitudes related to clinical trials.

PubMed

Brown, Devin L; Cowdery, Joan E; Jones, Toni Stokes; Langford, Aisha; Gammage, Catherine; Jacobs, Teresa L

2015-06-01

Poor enrollment plagues most clinical trials. Furthermore, despite mandates to improve minority representation in clinical trial participation, little progress has been made. We investigated the knowledge and attitudes of adolescents related to clinical trials and made race/ethnicity comparisons in an attempt to identify a possible educational intervention target. Students aged 13-18 years in southeast Michigan were offered participation through a class at one high school or two academic summer enrichment programs that drew from multiple high schools (73% response). Questionnaires previously validated in adults were administered. Non-Hispanic whites were compared with minorities using Wilcoxon rank-sum tests. Of the 82 respondents, the median age was 16 years (interquartile range: 15-17 years); 22 (28%) were white, 41 (51%) were African American, 11 (14%) were multiracial, 2 (2%) were American Indian or Alaska Native, 1 (1%) was Asian, 3 (4%) were Native Hawaiian or other Pacific Islander, and 2 respondents did not report a race (but did report Hispanic ethnicity). Nine (12%) were Hispanic. Only 27 (33%) had ever heard of a clinical trial. On a scale from 1 (most receptive) to 5 (least receptive) for learning more about a clinical trial for a relevant medical condition, the median score was 2 (interquartile range: 1-3) and for participating in a clinical trial for a relevant medical condition was 2 (interquartile range: 2-3). Overall knowledge was poor, with a median of 46% (interquartile range: 23%-62%) of knowledge answers correct. Knowledge was reduced (p = 0.0006) and attitudes were more negative (p = 0.05) in minorities than non-Hispanic whites, while minorities also endorsed more substantial barriers to trial participation (p = 0.0002). Distrust was similar between minority students and non-Hispanic whites (p = 0.15), and self-efficacy was greater in non-Hispanic whites (p = 0.05). Educational interventions directed toward adolescents that address knowledge, attitudes, and distrust in order to improve clinical trial awareness and receptivity overall are needed and may represent a tool to address disparities in minority enrollment in clinical trials. © The Author(s) 2015.

Optical treatment of amblyopia in older children and adults is essential prior to enrolment in a clinical trial.

PubMed

Gao, Tina Y; Anstice, Nicola; Babu, Raiju J; Black, Joanna M; Bobier, William R; Dai, Shuan; Guo, Cindy X; Hess, Robert F; Jenkins, Michelle; Jiang, Yannan; Kearns, Lisa; Kowal, Lionel; Lam, Carly S Y; Pang, Peter C K; Parag, Varsha; South, Jayshree; Staffieri, Sandra Elfride; Wadham, Angela; Walker, Natalie; Thompson, Benjamin

2018-03-01

Optical treatment alone can improve visual acuity (VA) in children with amblyopia, thus clinical trials investigating additional amblyopia therapies (such as patching or videogames) for children require a preceding optical treatment phase. Emerging therapies for adult patients are entering clinical trials. It is unknown whether optical treatment is effective for adults with amblyopia and whether an optical correction phase is required for trials involving adults. We examined participants who underwent optical treatment in the Binocular Treatment for Amblyopia using Videogames (BRAVO) clinical trial (ANZCTR ID: ACTRN12613001004752). Participants were recruited in three age groups (7 to 12, 13 to 17, or ≥18 years), and had unilateral amblyopia due to anisometropia and/or strabismus, with amblyopic eye VA of 0.30-1.00 logMAR (6/12 to 6/60, 20/40 to 20/200). Corrective lenses were prescribed based on cycloplegic refraction to fully correct any anisometropia. VA was assessed using the electronic visual acuity testing algorithm (e-ETDRS) test and near stereoacuity was assessed using the Randot Preschool Test. Participants were assessed every four weeks up to 16 weeks, until either VA was stable or until amblyopic eye VA improved to better than 0.30 logMAR, rendering the participant ineligible for the trial. Eighty participants (mean age 24.6 years, range 7.6-55.5 years) completed four to 16 weeks of optical treatment. A small but statistically significant mean improvement in amblyopic eye VA of 0.05 logMAR was observed (S.D. 0.08 logMAR; paired t-test p < 0.0001). Twenty-five participants (31%) improved by ≥1 logMAR line and of these, seven (9%) improved by ≥2 logMAR lines. Stereoacuity improved in 15 participants (19%). Visual improvements were not associated with age, presence of strabismus, or prior occlusion treatment. Two adult participants withdrew due to intolerance to anisometropic correction. Sixteen out of 80 participants (20%) achieved better than 0.30 logMAR VA in the amblyopic eye after optical treatment. Nine of these participants attended additional follow-up and four (44%) showed further VA improvements. Improvements from optical treatment resulted in one-fifth of participants becoming ineligible for the main clinical trial. Studies investigating additional amblyopia therapies must include an appropriate optical treatment only phase and/or parallel treatment group regardless of patient age. Optical treatment of amblyopia in adult patients warrants further investigation. © 2018 The Authors Ophthalmic & Physiological Optics © 2018 The College of Optometrists.

THE 6-MINUTE WALK TEST AND OTHER CLINICAL ENDPOINTS IN DUCHENNE MUSCULAR DYSTROPHY: RELIABILITY, CONCURRENT VALIDITY, AND MINIMAL CLINICALLY IMPORTANT DIFFERENCES FROM A MULTICENTER STUDY

PubMed Central

McDonald, Craig M; Henricson, Erik K; Abresch, R Ted; Florence, Julaine; Eagle, Michelle; Gappmaier, Eduard; Glanzman, Allan M; Spiegel, Robert; Barth, Jay; Elfring, Gary; Reha, Allen; Peltz, Stuart W

2013-01-01

Introduction: An international clinical trial enrolled 174 ambulatory males ≥5 years old with nonsense mutation Duchenne muscular dystrophy (nmDMD). Pretreatment data provide insight into reliability, concurrent validity, and minimal clinically important differences (MCIDs) of the 6-minute walk test (6MWT) and other endpoints. Methods: Screening and baseline evaluations included the 6-minute walk distance (6MWD), timed function tests (TFTs), quantitative strength by myometry, the PedsQL, heart rate–determined energy expenditure index, and other exploratory endpoints. Results: The 6MWT proved feasible and reliable in a multicenter context. Concurrent validity with other endpoints was excellent. The MCID for 6MWD was 28.5 and 31.7 meters based on 2 statistical distribution methods. Conclusions: The ratio of MCID to baseline mean is lower for 6MWD than for other endpoints. The 6MWD is an optimal primary endpoint for Duchenne muscular dystrophy (DMD) clinical trials that are focused therapeutically on preservation of ambulation and slowing of disease progression. Muscle Nerve 48: 357–368, 2013 PMID:23674289

Checklist for clinical readiness published

Cancer.gov

Scientists from NCI, together with collaborators from outside academic centers, have developed a checklist of criteria to evaluate the readiness of complex molecular tests that will guide decisions made during clinical trials. The checklist focuses on tes

Study Identifies New Lymphoma Treatment Target

Cancer.gov

NCI researchers have identified new therapeutic targets for diffuse large B-cell lymphoma. Drugs that hit these targets are under clinical development and the researchers hope to begin testing them in clinical trials of patients with DLBCL.

Ethics and eplerenone.

PubMed

Gupta, Shruti; Fugh-Berman, Adriane J; Scialli, Anthony

2013-02-01

The use of a placebo arm in clinical trials is unethical if there is an active comparator that is acceptably safe and effective. We argue that reasonable evidence of effectiveness and safety of an inexpensive alternative to an expensive therapy is sufficient to require that the inexpensive therapy be included as a comparator when the expensive therapy is tested, and that use of an inactive placebo comparator only is not ethical. For example, studies of the expensive drug eplerenone for congestive heart failure have not included a spironolactone arm, although there is reasonable evidence that spironolactone would be safe and effective, and spironolactone is inexpensive. The requirement to study inexpensive therapies is based on avoidance of unnecessary cost in medical care as an example of non-maleficence. Several ethical actors in the design, conduct, and publication of clinical trials and their results bear responsibility for the appropriate conduct of clinical trials. That responsibility includes protecting study subjects from being asked to participate in clinical trials that serve primarily to promote the use of new and expensive therapies.

Editorial--Avoiding Unethical Helicobacter pylori Clinical Trials: Susceptibility-Based Studies and Probiotics as Adjuvants.

PubMed

Graham, David Y

2015-10-01

As a general rule, any clinical study where the result is already known or when the investigator(s) compares an assigned treatment against another assigned treatment known to be ineffective in the study population (e.g., in a population with known clarithromycin resistance) is unethical. As susceptibility-based therapy will always be superior to empiric therapy in any population with a prevalence of antimicrobial resistance >0%, any trial that randomizes susceptibility-based therapy with empiric therapy would be unethical. The journal Helicobacter welcomes susceptibility or culture-guided studies, studies of new therapies, and studies of adjuvants and probiotics. However, the journal will not accept for review any study we judge to be lacking clinical equipoise or which assign subjects to a treatment known to be ineffective, such as a susceptibility-based clinical trial with an empiric therapy comparator. To assist authors, we provide examples and suggestions regarding trial design for comparative studies, for susceptibility-based studies, and for studies testing adjuvants or probiotics. © 2015 John Wiley & Sons Ltd.

Editorial - Avoiding unethical Helicobacter pylori clinical trials: Susceptibility-based studies and probiotics as adjuvants

PubMed Central

Graham, David Y.

2016-01-01

As a general rule, any clinical study where the result is already known or when the investigator(s) compares an assigned treatment against another assigned treatment known to be ineffective in the study population (e.g. in a population with known clarithromycin resistance) is unethical. Since susceptibility-based therapy will always be superior to empiric therapy in any population with a prevalence of antimicrobial resistance greater than 0%, any trial that randomizes susceptibility-based therapy with empiric therapy would be unethical. The journal Helicobacter welcomes susceptibility or culture-guided studies, studies of new therapies and of adjuvants and probiotics. However, the Journal will not accept for review any study we judge to be lacking clinical equipoise or which assign subjects to a treatment known to be ineffective, such as a susceptibility-based clinical trial with an empiric therapy comparator. To assist authors we provide examples and suggestion regarding trial design for comparative studies, for susceptibility-based studies, and for studies testing adjuvants or probiotics. PMID:26123529

Use of nonintrusive sensor-based information and communication technology for real-world evidence for clinical trials in dementia.

PubMed

Teipel, Stefan; König, Alexandra; Hoey, Jesse; Kaye, Jeff; Krüger, Frank; Robillard, Julie M; Kirste, Thomas; Babiloni, Claudio

2018-06-21

Cognitive function is an important end point of treatments in dementia clinical trials. Measuring cognitive function by standardized tests, however, is biased toward highly constrained environments (such as hospitals) in selected samples. Patient-powered real-world evidence using information and communication technology devices, including environmental and wearable sensors, may help to overcome these limitations. This position paper describes current and novel information and communication technology devices and algorithms to monitor behavior and function in people with prodromal and manifest stages of dementia continuously, and discusses clinical, technological, ethical, regulatory, and user-centered requirements for collecting real-world evidence in future randomized controlled trials. Challenges of data safety, quality, and privacy and regulatory requirements need to be addressed by future smart sensor technologies. When these requirements are satisfied, these technologies will provide access to truly user relevant outcomes and broader cohorts of participants than currently sampled in clinical trials. Copyright © 2018. Published by Elsevier Inc.

How should we discuss genetic testing with women newly diagnosed with breast cancer? Design and implementation of a randomized controlled trial of two models of delivering education about treatment-focused genetic testing to younger women newly diagnosed with breast cancer

PubMed Central

2012-01-01

Background Germline BRCA1 and BRCA2 mutation testing offered shortly after a breast cancer diagnosis to inform women’s treatment choices - treatment-focused genetic testing ‘TFGT’ - has entered clinical practice in specialist centers and is likely to be soon commonplace in acute breast cancer management, especially for younger women. Yet the optimal way to deliver information about TFGT to younger women newly diagnosed with breast cancer is not known, particularly for those who were not suspected of having a hereditary breast cancer syndrome prior to their cancer diagnosis. Also, little is known about the behavioral and psychosocial impact or cost effectiveness of educating patients about TFGT. This trial aims to examine the impact and efficiency of two models of educating younger women newly diagnosed with breast cancer about genetic testing in order to provide evidence for a safe and effective future clinical pathway for this service. Design/methods In this non-inferiority randomized controlled trial, 140 women newly diagnosed with breast cancer (aged less than 50 years) are being recruited from nine cancer centers in Australia. Eligible women with either a significant family history of breast and/or ovarian cancer or with other high risk features suggestive of a mutation detection rate of > 10% are invited by their surgeon prior to mastectomy or radiotherapy. After completing the first questionnaire, participants are randomized to receive either: (a) an educational pamphlet about genetic testing (intervention) or (b) a genetic counseling appointment at a family cancer center (standard care). Each participant is offered genetic testing for germline BRCA mutations. Decision-related and psychosocial outcomes are assessed over 12 months and include decisional conflict (primary outcome);uptake of bilateral mastectomy and/or risk-reducing salpingo-oophorectomy; cancer-specific- and general distress; family involvement in decision making; and decision regret. A process-oriented retrospective online survey will examine health professionals’ attitudes toward TFGT; a health economic analysis will determine the cost effectiveness of the intervention. Discussion This trial will provide crucial information about the impact, efficiency and cost effectiveness of an educational pamphlet designed to inform younger women newly diagnosed with breast cancer about genetic testing. Issues regarding implementation of the trial are discussed. Trial registration The study is registered with the Australian and New Zealand Clinical Trials Group (Registration no: ACTRN12610000502033) PMID:22838957

Brain and Spinal Tumors: Hope through Research

MedlinePlus

... remember that all potential therapies must stand the tests of well-designed, carefully controlled clinical trials and long-term follow-up of treated patients before any conclusions can be drawn about their safety or effectiveness. New trial designs are also being developed to more quickly evaluate ...

Risks of Prostate Cancer Screening

MedlinePlus

... decrease the risk of dying from cancer. Scientists study screening tests to find those with the fewest risks and ... or routine screening test for prostate cancer. Screening tests for prostate cancer are under study, and there are screening clinical trials taking place ...

Methodological Issues in Trials of Complementary and Alternative Medicine Interventions

PubMed Central

Sikorskii, Alla; Wyatt, Gwen; Victorson, David; Faulkner, Gwen; Rahbar, Mohammad Hossein

2010-01-01

Background Complementary and alternative medicine (CAM) use is widespread among cancer patients. Information on safety and efficacy of CAM therapies is needed for both patients and health care providers. Well-designed randomized clinical trials (RCTs) of CAM therapy interventions can inform both clinical research and practice. Objectives To review important issues that affect the design of RCTs for CAM interventions. Methods Using the methods component of the Consolidated Standards for Reporting Trials (CONSORT) as a guiding framework, and a National Cancer Institute-funded reflexology study as an exemplar, methodological issues related to participants, intervention, objectives, outcomes, sample size, randomization, blinding, and statistical methods were reviewed. Discussion Trials of CAM interventions designed and implemented according to appropriate methodological standards will facilitate the needed scientific rigor in CAM research. Interventions in CAM can be tested using proposed methodology, and the results of testing will inform nursing practice in providing safe and effective supportive care and improving the well-being of patients. PMID:19918155

Aromatherapy for treatment of hypertension: a systematic review.

PubMed

Hur, Myung-Haeng; Lee, Myeong Soo; Kim, Chan; Ernst, Edzard

2012-02-01

The objective of this review is to systematically review the evidence for the effectiveness of aromatherapy in the treatment of high blood pressure. Twelve databases were searched from their inception through December 2009. Controlled trials testing aromatherapy in patients with hypertension of any origin that assessed blood pressure were considered. The selection of studies, data extraction and validations were performed independently by two reviewers. One randomized clinical trial (RCT) and four non-randomized controlled clinical trials (CCTs) met our inclusion criteria. The one RCT included tested the effects of aromatherapy as compared with placebo and showed significant reduction of systolic blood pressure and diastolic blood pressure. All of the four CCTs showed favourable effects of aromatherapy. However, all of the CCTs also had a high risk of bias. The existing trial evidence does not show convincingly that aromatherapy is effective for hypertension. Future studies should be of high quality with a particular emphasis on designing an adequate control intervention. © 2010 Blackwell Publishing Ltd.

Preventing ARDS

PubMed Central

Beitler, Jeremy R.; Schoenfeld, David A.

2014-01-01

Advances in critical care practice have led to a substantial decline in the incidence of ARDS over the past several years. Low tidal volume ventilation, timely resuscitation and antimicrobial administration, restrictive transfusion practices, and primary prevention of aspiration and nosocomial pneumonia have likely contributed to this reduction. Despite decades of research, there is no proven pharmacologic treatment of ARDS, and mortality from ARDS remains high. Consequently, recent initiatives have broadened the scope of lung injury research to include targeted prevention of ARDS. Prediction scores have been developed to identify patients at risk for ARDS, and clinical trials testing aspirin and inhaled budesonide/formoterol for ARDS prevention are ongoing. Future trials aimed at preventing ARDS face several key challenges. ARDS has not been validated as an end point for pivotal clinical trials, and caution is needed when testing toxic therapies that may prevent ARDS yet potentially increase mortality. PMID:25288000

SMART: self-management of anticoagulation, a randomised trial [ISRCTN19313375].

PubMed

McCahon, Deborah; Fitzmaurice, David A; Murray, Ellen T; Fuller, Christopher J; Hobbs, Richard F D; Allan, Teresa F; Raftery, James P

2003-09-18

Oral anticoagulation monitoring has traditionally taken place in secondary care because of the need for a laboratory blood test, the international normalised ratio (INR). The development of reliable near patient testing (NPT) systems for INR estimation has facilitated devolution of testing to primary care. Patient self-management is a logical progression from the primary care model. This study will be the first to randomise non-selected patients in primary care, to either self-management or standard care. The study was a multi-centred randomised controlled trial with patients from 49 general practices recruited. Those suitable for inclusion were aged 18 or over, with a long term indication for oral anticoagulation, who had taken warfarin for at least six months. Patients randomised to the intervention arm attended at least two training sessions which were practice-based, 1 week apart. Each patient was assessed on their capability to undertake self management. If considered capable, they were given a near patient INR testing monitor, test strips and quality control material for home testing. Patients managed their own anticoagulation for a period of 12 months and performed their INR test every 2 weeks. Control patients continued with their pre-study care either attending hospital or practice based anticoagulant clinics. The methodology used in this trial will overcome concerns from previous trials of selection bias and relevance to the UK health service. The study will give a clearer understanding of the benefits of self-management in terms of clinical and cost effectiveness and patient preference.

Clinical Trial Results Summary for Laypersons: A User Testing Study.

PubMed

Raynor, D K; Myers, L; Blackwell, K; Kress, B; Dubost, A; Joos, A

2018-01-01

To apply "user testing" to maximize readability and acceptability of a Clinical Trial Results Laypersons Summary-a new European requirement. "User testing" (using questionnaire and semistructured interview) assessed whether people could find and understand key points. Findings were used to improve content and design, prior to retesting. Participants had a range of levels of health literacy and there was a higher education group. Participants accessed the summary on screen. In round 1 we tested 12 points of information. In round 2 a revised summary addressing round 1 findings was tested, leading to a third final version. In round 1, 2 of 12 points of information did not reach the target and interviews raised further format and content issues (some distracting technical explanations and inability to find or understand the 2 main study purposes). These findings informed revisions for the version tested in round 2, with 2 different points not reaching the target (inclusion criteria relating to duration of seasonal allergies and how researchers found out about participants' symptoms). Identified problems in both rounds were addressed and reflected in the final version. Despite improvements, participants did not consistently understand that summaries were intended for the public, or to only interpret results of single trials in the context of additional trials. All readers, including those with higher education, found the clear and straightforward language acceptable. Applying "user testing" resulted in a largely health-literate summary suitable for people across a range of backgrounds.

The National Cancer Institute–American Society of Clinical Oncology Cancer Trial Accrual Symposium: Summary and Recommendations

PubMed Central

Denicoff, Andrea M.; McCaskill-Stevens, Worta; Grubbs, Stephen S.; Bruinooge, Suanna S.; Comis, Robert L.; Devine, Peggy; Dilts, David M.; Duff, Michelle E.; Ford, Jean G.; Joffe, Steven; Schapira, Lidia; Weinfurt, Kevin P.; Michaels, Margo; Raghavan, Derek; Richmond, Ellen S.; Zon, Robin; Albrecht, Terrance L.; Bookman, Michael A.; Dowlati, Afshin; Enos, Rebecca A.; Fouad, Mona N.; Good, Marjorie; Hicks, William J.; Loehrer, Patrick J.; Lyss, Alan P.; Wolff, Steven N.; Wujcik, Debra M.; Meropol, Neal J.

2013-01-01

Introduction: Many challenges to clinical trial accrual exist, resulting in studies with inadequate enrollment and potentially delaying answers to important scientific and clinical questions. Methods: The National Cancer Institute (NCI) and the American Society of Clinical Oncology (ASCO) cosponsored the Cancer Trial Accrual Symposium: Science and Solutions on April 29-30, 2010 to examine the state of accrual science related to patient/community, physician/provider, and site/organizational influences, and identify new interventions to facilitate clinical trial enrollment. The symposium featured breakout sessions, plenary sessions, and a poster session including 100 abstracts. Among the 358 attendees were clinical investigators, researchers of accrual strategies, research administrators, nurses, research coordinators, patient advocates, and educators. A bibliography of the accrual literature in these three major areas was provided to participants in advance of the meeting. After the symposium, the literature in these areas was revisited to determine if the symposium recommendations remained relevant within the context of the current literature. Results: Few rigorously conducted studies have tested interventions to address challenges to clinical trials accrual. Attendees developed recommendations for improving accrual and identified priority areas for future accrual research at the patient/community, physician/provider, and site/organizational levels. Current literature continues to support the symposium recommendations. Conclusions: A combination of approaches addressing both the multifactorial nature of accrual challenges and the characteristics of the target population may be needed to improve accrual to cancer clinical trials. Recommendations for best practices and for future research developed from the symposium are provided. PMID:24130252

Computerized patient identification for the EMBRACA clinical trial using real-time data from the PRAEGNANT network for metastatic breast cancer patients.

PubMed

Hein, Alexander; Gass, Paul; Walter, Christina Barbara; Taran, Florin-Andrei; Hartkopf, Andreas; Overkamp, Friedrich; Kolberg, Hans-Christian; Hadji, Peyman; Tesch, Hans; Ettl, Johannes; Wuerstlein, Rachel; Lounsbury, Debra; Lux, Michael P; Lüftner, Diana; Wallwiener, Markus; Müller, Volkmar; Belleville, Erik; Janni, Wolfgang; Fehm, Tanja N; Wallwiener, Diethelm; Ganslandt, Thomas; Ruebner, Matthias; Beckmann, Matthias W; Schneeweiss, Andreas; Fasching, Peter A; Brucker, Sara Y

2016-07-01

As breast cancer is a diverse disease, clinical trials are becoming increasingly diversified and are consequently being conducted in very small subgroups of patients, making study recruitment increasingly difficult. The aim of this study was to assess the use of data from a remote data entry system that serves a large national registry for metastatic breast cancer. The PRAEGNANT network is a real-time registry with an integrated biomaterials bank that was designed as a scientific study and as a means of identifying patients who are eligible for clinical trials, based on clinical and molecular information. Here, we report on the automated use of the clinical data documented to identify patients for a clinical trial (EMBRACA) for patients with metastatic breast cancer. The patients' charts were assessed by two independent physicians involved in the clinical trial and also by a computer program that tested patients for eligibility using a structured query language script. In all, 326 patients from two study sites in the PRAEGNANT network were included in the analysis. Using expert assessment, 120 of the 326 patients (37 %) appeared to be eligible for inclusion in the EMBRACA study; with the computer algorithm assessment, a total of 129 appeared to be eligible. The sensitivity of the computer algorithm was 0.87 and its specificity was 0.88. Using computer-based identification of patients for clinical trials appears feasible. With the instrument's high specificity, its application in a large cohort of patients appears to be feasible, and the workload for reassessing the patients is limited.

Vitamin K for upper gastrointestinal bleeding in people with acute or chronic liver diseases.

PubMed

Martí-Carvajal, Arturo J; Solà, Ivan

2015-06-09

Upper gastrointestinal bleeding is one of the most frequent causes of morbidity and mortality in the course of liver cirrhosis. Several treatments are used for upper gastrointestinal bleeding in people with liver diseases. One of them is vitamin K administration, but it is not known whether it benefits or harms people with acute or chronic liver disease and upper gastrointestinal bleeding. This is an update of this Cochrane review. To assess the beneficial and harmful effects of vitamin K for people with acute or chronic liver disease and upper gastrointestinal bleeding. We searched The Cochrane Hepato-Biliary Controlled Trials Register (February 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2 of 12, 2015), MEDLINE (Ovid SP) (1946 to February 2015), EMBASE (Ovid SP) (1974 to February 2015), Science Citation Index EXPANDED (1900 to February 2015), and LILACS (1982 to 25 February 2015). We sought additional randomised trials from two registries of clinical trials: the World Health Organization Clinical Trials Search Portal and the metaRegister of Controlled Trials. We looked through the reference lists of the retrieved publications and review articles. Randomised clinical trials irrespective of blinding, language, or publication status for assessment of benefits and harms. We considered observational studies for assessment of harms only. \\We aimed to summarise data from randomised clinical trials using Standard Cochrane methodology and assess them according to the GRADE approach. We found no randomised trials on vitamin K for upper gastrointestinal bleeding in people with liver diseases assessing benefits and harms of the intervention. We identified no quasi-randomised studies, historically controlled studies, or observational studies assessing harms. This updated review found no randomised clinical trials of vitamin K for upper gastrointestinal bleeding in people with liver diseases. The benefits and harms of vitamin K need to be tested in randomised clinical trials. Until randomised clinical trials are conducted to assess the trade-off between benefits and harms, we cannot recommend or refute the use of vitamin K for upper gastrointestinal bleeding in people with liver diseases.

The use of a battery of tracking tests in the quantitative evaluation of neurological function

NASA Technical Reports Server (NTRS)

Repa, B. S.; Albers, J. W.; Potvin, A. R.; Tourtellotte, W. W.

1972-01-01

A tracking test battery has been applied in a drug trail designed to compare the efficacy of L-DOPA and amantadine to that of L-DOPA and placebo in the treatment of 28 patients with Parkinson's disease. The drug trial provided an ideal opportunity for objectively evaluating the usefulness of tracking tests in assessing changes in neurologic function. Evaluating changes in patient performance resulting from disease progression and controlled clinical trials is of great importance in establishing effective treatment programs.

Development of an objective gene expression panel as an alternative to self-reported symptom scores in human influenza challenge trials.

PubMed

Muller, Julius; Parizotto, Eneida; Antrobus, Richard; Francis, James; Bunce, Campbell; Stranks, Amanda; Nichols, Marshall; McClain, Micah; Hill, Adrian V S; Ramasamy, Adaikalavan; Gilbert, Sarah C

2017-06-08

Influenza challenge trials are important for vaccine efficacy testing. Currently, disease severity is determined by self-reported scores to a list of symptoms which can be highly subjective. A more objective measure would allow for improved data analysis. Twenty-one volunteers participated in an influenza challenge trial. We calculated the daily sum of scores (DSS) for a list of 16 influenza symptoms. Whole blood collected at baseline and 24, 48, 72 and 96 h post challenge was profiled on Illumina HT12v4 microarrays. Changes in gene expression most strongly correlated with DSS were selected to train a Random Forest model and tested on two independent test sets consisting of 41 individuals profiled on a different microarray platform and 33 volunteers assayed by qRT-PCR. 1456 probes are significantly associated with DSS at 1% false discovery rate. We selected 19 genes with the largest fold change to train a random forest model. We observed good concordance between predicted and actual scores in the first test set (r = 0.57; RMSE = -16.1%) with the greatest agreement achieved on samples collected approximately 72 h post challenge. Therefore, we assayed samples collected at baseline and 72 h post challenge in the second test set by qRT-PCR and observed good concordance (r = 0.81; RMSE = -36.1%). We developed a 19-gene qRT-PCR panel to predict DSS, validated on two independent datasets. A transcriptomics based panel could provide a more objective measure of symptom scoring in future influenza challenge studies. Trial registration Samples were obtained from a clinical trial with the ClinicalTrials.gov Identifier: NCT02014870, first registered on December 5, 2013.

Liver Function Tests

MedlinePlus

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

A preliminary placebo-controlled crossover trial of fludrocortisone for chronic fatigue syndrome.

PubMed

Peterson, P K; Pheley, A; Schroeppel, J; Schenck, C; Marshall, P; Kind, A; Haugland, J M; Lambrecht, L J; Swan, S; Goldsmith, S

1998-04-27

To provide a preliminary assessment of the efficacy and safety of fludrocortisone acetate treatment of chronic fatigue syndrome. A placebo-controlled, double-blind, random-allocation crossover trial of 6 weeks of fludrocortisone. An outpatient clinical trials unit. Twenty-five participants with chronic fatigue syndrome (mean age, 40 years; 19 [76%] women; mean duration of illness, 7.0 years) were recruited from a research and clinic registry. Five patients withdrew from the trial. All participants were scheduled to receive fludrocortisone acetate (0.1-0.2 mg) or a placebo for 6 weeks in each treatment. Self-administered questionnaires were completed at the beginning and end of each treatment arm that asked patients to rate the severity of their symptoms on a visual analogue scale. The Medical Outcomes Study 36-Item Short-Form Health Survey, a reaction time test, and a treadmill exercise test were used to assess functional status. Blood pressure, heart rate, and plasma norepinephrine levels were obtained at baseline. Blood pressure and heart rate were recorded at the end of the exercise test and monitored at all subsequent visits. At baseline, the study participants reported symptom severity greater than 5 for most symptoms, and all had evidence of marked functional impairments. No improvement was observed in the severity of any symptom or in any test of function for the 20 participants who completed both arms of the trial. Blood pressure and heart rate readings were unaffected by treatment, and plasma norepinephrine levels did not differ from those of a healthy control group. The incidence of adverse experiences was similar in the fludrocortisone and placebo arms of the trial. Low-dose fludrocortisone does not provide sufficient benefit to be evident in a preliminary blinded trial of unselected patients with chronic fatigue syndrome.

[Adequate application of quantitative and qualitative statistic analytic methods in acupuncture clinical trials].

PubMed

Tan, Ming T; Liu, Jian-ping; Lao, Lixing

2012-08-01

Recently, proper use of the statistical methods in traditional Chinese medicine (TCM) randomized controlled trials (RCTs) has received increased attention. Statistical inference based on hypothesis testing is the foundation of clinical trials and evidence-based medicine. In this article, the authors described the methodological differences between literature published in Chinese and Western journals in the design and analysis of acupuncture RCTs and the application of basic statistical principles. In China, qualitative analysis method has been widely used in acupuncture and TCM clinical trials, while the between-group quantitative analysis methods on clinical symptom scores are commonly used in the West. The evidence for and against these analytical differences were discussed based on the data of RCTs assessing acupuncture for pain relief. The authors concluded that although both methods have their unique advantages, quantitative analysis should be used as the primary analysis while qualitative analysis can be a secondary criterion for analysis. The purpose of this paper is to inspire further discussion of such special issues in clinical research design and thus contribute to the increased scientific rigor of TCM research.

Clinical score and rapid antigen detection test to guide antibiotic use for sore throats: randomised controlled trial of PRISM (primary care streptococcal management).

PubMed

Little, Paul; Hobbs, F D Richard; Moore, Michael; Mant, David; Williamson, Ian; McNulty, Cliodna; Cheng, Ying Edith; Leydon, Geraldine; McManus, Richard; Kelly, Joanne; Barnett, Jane; Glasziou, Paul; Mullee, Mark

2013-10-10

To determine the effect of clinical scores that predict streptococcal infection or rapid streptococcal antigen detection tests compared with delayed antibiotic prescribing. Open adaptive pragmatic parallel group randomised controlled trial. Primary care in United Kingdom. Patients aged ≥ 3 with acute sore throat. An internet programme randomised patients to targeted antibiotic use according to: delayed antibiotics (the comparator group for analyses), clinical score, or antigen test used according to clinical score. During the trial a preliminary streptococcal score (score 1, n=1129) was replaced by a more consistent score (score 2, n=631; features: fever during previous 24 hours; purulence; attends rapidly (within three days after onset of symptoms); inflamed tonsils; no cough/coryza (acronym FeverPAIN). Symptom severity reported by patients on a 7 point Likert scale (mean severity of sore throat/difficulty swallowing for days two to four after the consultation (primary outcome)), duration of symptoms, use of antibiotics. For score 1 there were no significant differences between groups. For score 2, symptom severity was documented in 80% (168/207 (81%) in delayed antibiotics group; 168/211 (80%) in clinical score group; 166/213 (78%) in antigen test group). Reported severity of symptoms was lower in the clinical score group (-0.33, 95% confidence interval -0.64 to -0.02; P=0.04), equivalent to one in three rating sore throat a slight versus moderate problem, with a similar reduction for the antigen test group (-0.30, -0.61 to -0.00; P=0.05). Symptoms rated moderately bad or worse resolved significantly faster in the clinical score group (hazard ratio 1.30, 95% confidence interval 1.03 to 1.63) but not the antigen test group (1.11, 0.88 to 1.40). In the delayed antibiotics group, 75/164 (46%) used antibiotics. Use of antibiotics in the clinical score group (60/161) was 29% lower (adjusted risk ratio 0.71, 95% confidence interval 0.50 to 0.95; P=0.02) and in the antigen test group (58/164) was 27% lower (0.73, 0.52 to 0.98; P=0.03). There were no significant differences in complications or reconsultations. Targeted use of antibiotics for acute sore throat with a clinical score improves reported symptoms and reduces antibiotic use. Antigen tests used according to a clinical score provide similar benefits but with no clear advantages over a clinical score alone. ISRCTN32027234.

An analysis of adaptive design variations on the sequential parallel comparison design for clinical trials.

PubMed

Mi, Michael Y; Betensky, Rebecca A

2013-04-01

Currently, a growing placebo response rate has been observed in clinical trials for antidepressant drugs, a phenomenon that has made it increasingly difficult to demonstrate efficacy. The sequential parallel comparison design (SPCD) is a clinical trial design that was proposed to address this issue. The SPCD theoretically has the potential to reduce the sample-size requirement for a clinical trial and to simultaneously enrich the study population to be less responsive to the placebo. Because the basic SPCD already reduces the placebo response by removing placebo responders between the first and second phases of a trial, the purpose of this study was to examine whether we can further improve the efficiency of the basic SPCD and whether we can do so when the projected underlying drug and placebo response rates differ considerably from the actual ones. Three adaptive designs that used interim analyses to readjust the length of study duration for individual patients were tested to reduce the sample-size requirement or increase the statistical power of the SPCD. Various simulations of clinical trials using the SPCD with interim analyses were conducted to test these designs through calculations of empirical power. From the simulations, we found that the adaptive designs can recover unnecessary resources spent in the traditional SPCD trial format with overestimated initial sample sizes and provide moderate gains in power. Under the first design, results showed up to a 25% reduction in person-days, with most power losses below 5%. In the second design, results showed up to a 8% reduction in person-days with negligible loss of power. In the third design using sample-size re-estimation, up to 25% power was recovered from underestimated sample-size scenarios. Given the numerous possible test parameters that could have been chosen for the simulations, the study's results are limited to situations described by the parameters that were used and may not generalize to all possible scenarios. Furthermore, dropout of patients is not considered in this study. It is possible to make an already complex design such as the SPCD adaptive, and thus more efficient, potentially overcoming the problem of placebo response at lower cost. Ultimately, such a design may expedite the approval of future effective treatments.

An analysis of adaptive design variations on the sequential parallel comparison design for clinical trials

PubMed Central

Mi, Michael Y.; Betensky, Rebecca A.

2013-01-01

Background Currently, a growing placebo response rate has been observed in clinical trials for antidepressant drugs, a phenomenon that has made it increasingly difficult to demonstrate efficacy. The sequential parallel comparison design (SPCD) is a clinical trial design that was proposed to address this issue. The SPCD theoretically has the potential to reduce the sample size requirement for a clinical trial and to simultaneously enrich the study population to be less responsive to the placebo. Purpose Because the basic SPCD design already reduces the placebo response by removing placebo responders between the first and second phases of a trial, the purpose of this study was to examine whether we can further improve the efficiency of the basic SPCD and if we can do so when the projected underlying drug and placebo response rates differ considerably from the actual ones. Methods Three adaptive designs that used interim analyses to readjust the length of study duration for individual patients were tested to reduce the sample size requirement or increase the statistical power of the SPCD. Various simulations of clinical trials using the SPCD with interim analyses were conducted to test these designs through calculations of empirical power. Results From the simulations, we found that the adaptive designs can recover unnecessary resources spent in the traditional SPCD trial format with overestimated initial sample sizes and provide moderate gains in power. Under the first design, results showed up to a 25% reduction in person-days, with most power losses below 5%. In the second design, results showed up to a 8% reduction in person-days with negligible loss of power. In the third design using sample size re-estimation, up to 25% power was recovered from underestimated sample size scenarios. Limitations Given the numerous possible test parameters that could have been chosen for the simulations, the study’s results are limited to situations described by the parameters that were used, and may not generalize to all possible scenarios. Furthermore, drop-out of patients is not considered in this study. Conclusions It is possible to make an already complex design such as the SPCD adaptive, and thus more efficient, potentially overcoming the problem of placebo response at lower cost. Ultimately, such a design may expedite the approval of future effective treatments. PMID:23283576

A data-driven approach to quality risk management.

PubMed

Alemayehu, Demissie; Alvir, Jose; Levenstein, Marcia; Nickerson, David

2013-10-01

An effective clinical trial strategy to ensure patient safety as well as trial quality and efficiency involves an integrated approach, including prospective identification of risk factors, mitigation of the risks through proper study design and execution, and assessment of quality metrics in real-time. Such an integrated quality management plan may also be enhanced by using data-driven techniques to identify risk factors that are most relevant in predicting quality issues associated with a trial. In this paper, we illustrate such an approach using data collected from actual clinical trials. Several statistical methods were employed, including the Wilcoxon rank-sum test and logistic regression, to identify the presence of association between risk factors and the occurrence of quality issues, applied to data on quality of clinical trials sponsored by Pfizer. ONLY A SUBSET OF THE RISK FACTORS HAD A SIGNIFICANT ASSOCIATION WITH QUALITY ISSUES, AND INCLUDED: Whether study used Placebo, whether an agent was a biologic, unusual packaging label, complex dosing, and over 25 planned procedures. Proper implementation of the strategy can help to optimize resource utilization without compromising trial integrity and patient safety.

From Laboratory Research to a Clinical Trial

PubMed Central

Michels, Harold T.; Keevil, C. William; Salgado, Cassandra D.; Schmidt, Michael G.

2015-01-01

Objective: This is a translational science article that discusses copper alloys as antimicrobial environmental surfaces. Bacteria die when they come in contact with copper alloys in laboratory tests. Components made of copper alloys were also found to be efficacious in a clinical trial. Background: There are indications that bacteria found on frequently touched environmental surfaces play a role in infection transmission. Methods: In laboratory testing, copper alloy samples were inoculated with bacteria. In clinical trials, the amount of live bacteria on the surfaces of hospital components made of copper alloys, as well as those made from standard materials, was measured. Finally, infection rates were tracked in the hospital rooms with the copper components and compared to those found in the rooms containing the standard components. Results: Greater than a 99.9% reduction in live bacteria was realized in laboratory tests. In the clinical trials, an 83% reduction in bacteria was seen on the copper alloy components, when compared to the surfaces made from standard materials in the control rooms. Finally, the infection rates were found to be reduced by 58% in patient rooms with components made of copper, when compared to patients' rooms with components made of standard materials. Conclusions: Bacteria die on copper alloy surfaces in both the laboratory and the hospital rooms. Infection rates were lowered in those hospital rooms containing copper components. Thus, based on the presented information, the placement of copper alloy components, in the built environment, may have the potential to reduce not only hospital-acquired infections but also patient treatment costs. PMID:26163568

Availability and affordability of new medicines in Latin American countries where pivotal clinical trials were conducted.

PubMed

Homedes, Núria; Ugalde, Antonio

2015-10-01

To assess whether new pharmaceutical products approved by the United States Food and Drug Administration (FDA) in 2011 and 2012 were registered, commercialized and sold at affordable prices in the Latin American countries where they were tested. We obtained a list of new molecular entities (new pharmaceutical products) approved by the FDA in 2011 and 2012. FDA medical reviews indicated the countries where pivotal clinical trials had been conducted. The registration status of the products was obtained from pharmaceutical registers; pharmaceutical companies confirmed their availability in national markets and local pricing observatories provided the price of medicines in retail pharmacies. Affordability was assessed as the cost of a course of treatment as a proportion of monthly income. Information on safety and efficacy was gathered from independent drug bulletins. Of an expected 114 registrations, if the 33 products had been registered in all the countries where tested, only 68 (60%) were completed. Eight products were registered and commercialized in all countries but 10 had not been registered in any of the countries. With one exception, products for which we obtained pricing information ( n  = 18) cost more than the monthly minimum wage in all countries and 12 products cost at least five times the monthly minimum wage. Many pharmaceutical products tested in Latin America are unavailable and/or unaffordable to most of the population. Ethical review committees should consider the local affordability and therapeutic relevance of new products as additional criteria for the approval of clinical trials. Finally, clinical trials have opportunity costs that need to be assessed.

Report of a consultation on the optimization of clinical challenge trials for evaluation of candidate blood stage malaria vaccines, 18-19 March 2009, Bethesda, MD, USA.

PubMed

Moorthy, V S; Diggs, C; Ferro, S; Good, M F; Herrera, S; Hill, A V; Imoukhuede, E B; Kumar, S; Loucq, C; Marsh, K; Ockenhouse, C F; Richie, T L; Sauerwein, R W

2009-09-25

Development and optimization of first generation malaria vaccine candidates has been facilitated by the existence of a well-established Plasmodium falciparum clinical challenge model in which infectious sporozoites are administered to human subjects via mosquito bite. While ideal for testing pre-erythrocytic stage vaccines, some researchers believe that the sporozoite challenge model is less appropriate for testing blood stage vaccines. Here we report a consultation, co-sponsored by PATH MVI, USAID, EMVI and WHO, where scientists from all institutions globally that have conducted such clinical challenges in recent years and representatives from regulatory agencies and funding agencies met to discuss clinical malaria challenge models. Participants discussed strengthening and harmonizing the sporozoite challenge model and considered the pros and cons of further developing a blood stage challenge possibly better suited for evaluating the efficacy of blood stage vaccines. This report summarizes major findings and recommendations, including an update on the Plasmodium vivax clinical challenge model, the prospects for performing experimental challenge trials in malaria endemic countries and an update on clinical safety data. While the focus of the meeting was on the optimization of clinical challenge models for evaluation of blood stage candidate malaria vaccines, many of the considerations are relevant for the application of challenge trials to other purposes.

Where have all the pilot studies gone? A follow-up on 30 years of pilot studies in Clinical Rehabilitation

PubMed Central

Kaur, Navaldeep; Figueiredo, Sabrina; Bouchard, Vanessa; Moriello, Carolina; Mayo, Nancy

2017-01-01

Introduction: Pilot studies are meritorious for determining the feasibility of a definitive clinical trial in terms of conduct and potential for efficacy, but their possible applications for planning a future trial are not always fully realized. The purpose of this review was to estimate the extent to which pilot/feasibility studies: (i) addressed needed objectives; (ii) led to definitive trials; and (iii) whether the subsequent undertaking of a definitive trial was influenced by the strength of the evidence of outcome improvement. Methods: Trials published in the journal Clinical Rehabilitation, since its inception, were eligible if the word ‘pilot’ or ‘feasibility’ was specified somewhere in the article. A total of 191 studies were reviewed, results were summarized descriptively, and between-group effect sizes were computed. Results: The specific purposes of piloting were stated in only 58% (n = 110) of the studies. The most frequent purpose was to estimate the potential for efficacy (85%), followed by testing the feasibility of the intervention (60%). Only 12% of the studies were followed by a definitive trial; <4% of studies had a main study underway or a published study protocol. There was no relationship between observed effect size and follow-up of pilot studies, although the confidence intervals were very wide owing to small number of trials that followed on. Discussion: Labelling and reporting of pilot studies needs to be improved to be concordant with the recently issued CONSORT guidelines. Feasibility needs to be fully tested and demonstrated prior to committing considerable human and monetary resources. PMID:28786333

Role of technology in supporting quality control and treatment fidelity in a family caregiver clinical trial.

PubMed

Farran, Carol J; Etkin, Caryn D; McCann, Judith J; Paun, Olimpia; Eisenstein, Amy R; Wilbur, Joellen

2011-11-01

This article describes how a family caregiver lifestyle physical activity clinical trial uses research technology to enhance quality control and treatment fidelity. This trial uses a range of Internet, Blaise(®) Windows-based software and Echo Server technologies to support quality control issues, such as data collection, data entry, and study management advocated by the clinical trials literature, and to ensure treatment fidelity concerning intervention implementation (i.e., design, training, delivery, receipt, and enactment) as proposed by the National Institutes of Health Behavior Change Consortium. All research staff are trained to use these technologies. Strengths of this technological approach to support quality control and treatment fidelity include the comprehensive plan, involvement of all staff, and ability to maintain accurate and timely data. Limitations include the upfront time and costs for developing and testing these technological methods, and having support staff readily available to address technological issues if they occur.

The first decade of the National Drug Abuse Treatment Clinical Trials Network: bridging the gap between research and practice to improve drug abuse treatment.

PubMed

Tai, Betty; Straus, Michele M; Liu, David; Sparenborg, Steven; Jackson, Ron; McCarty, Dennis

2010-06-01

The National Institute on Drug Abuse established the National Drug Abuse Treatment Clinical Trials Network (CTN) in 1999 to improve the quality of addiction treatment using science as the vehicle. The network brings providers from community-based drug abuse treatment programs and scientists from university-based research centers together in an alliance that fosters bidirectional communication and collaboration. Collaboration enhanced the relevance of research to practice and facilitated the development and implementation of evidence-based treatments in community practice settings. The CTN's 20 completed trials tested pharmacological, behavioral, and integrated treatment interventions for adolescents and adults; more than 11,000 individuals participated in the trials. This article reviews the rationale for the CTN, describes the translation of its guiding principles into research endeavors, and anticipates the future evolution of clinical research within the Network.

The First Decade of the National Drug Abuse Treatment Clinical Trials Network: Bridging the Gap Between Research and Practice to Improve Drug Abuse Treatment

PubMed Central

Tai, Betty; Straus, Michele M.; Liu, David; Sparenborg, Steven; Jackson, Ron; McCarty, Dennis

2010-01-01

The National Institute on Drug Abuse established the National Drug Abuse Treatment Clinical Trials Network (CTN) in 1999 to improve the quality of addiction treatment using science as the vehicle. The network brings providers from community-based drug abuse treatment programs and scientists from university-based research centers together in an alliance that fosters bi-directional communication and collaboration. Collaboration enhanced the relevance of research to practice and facilitated the development and implementation of evidence-based treatments in community practice settings. The CTN’s 20 completed trials tested pharmacological, behavioral, and integrated treatment interventions for adolescents and adults; more than 11,000 individuals participated in the trials. This paper reviews the rationale for the CTN, describes the translation of its guiding principles into research endeavors, and anticipates the future evolution of clinical research within the Network. PMID:20307794

Clinical development of mTOR inhibitors in breast cancer

PubMed Central

2014-01-01

The mammalian target of rapamycin (mTOR) pathway is a central pathway that regulates mRNA translation, protein synthesis, glucose metabolism, lipid synthesis and autophagy, and is involved in malignant transformation. Several randomized trials have shown that the use of mTOR inhibitors could improve patient outcome with hormone receptor-positive or human epidermal growth factor receptor-2-positive breast cancer. This review analyzes new perspectives from these trials. Preclinical studies have suggested that the mTOR pathway may play a role in the resistance to hormone therapy, trastuzumab and chemotherapy for breast cancer. This concept has been tested in clinical trials for neoadjuvant treatment and for metastatic breast cancer patients. Also, much effort has gone into the identification of biomarkers that will allow for more precise stratification of patients. Findings from these studies will provide indispensable tools for the design of future clinical trials and identify new perspectives and challenges for researchers and clinicians. PMID:25189767

Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014

PubMed Central

Schneider, Lon S.; Mangialasche, Francesca; Andreasen, Niels; Feldman, Howard; Giacobini, Ezio; Jones, Roy; Mantua, Valentina; Mecocci, Patrizia; Pani, Luca; Winblad, Bengt; Kivipelto, Miia

2014-01-01

The modern era of drug development for Alzheimer’s disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer’s disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here we review the development of treatments for Alzheimer’s disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer’s disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild to moderate Alzheimer’s disease criteria, recently extending to early or prodromal Alzheimer disease or ‘mild cognitive impairment due to Alzheimer’s disease’, for drugs considered to be disease modifying. The duration of trials has remained at 6 to 12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early-stage Alzheimer’s disease trial samples by using biomarkers and phase-specific outcomes. In conclusion, validated drug targets for Alzheimer’s disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late-phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods. PMID:24605808

The Paradox of Equipoise: The Principle That Drives and Limits Therapeutic Discoveries in Clinical Research

PubMed Central

Djulbegovic, Benjamin

2009-01-01

Background Progress in clinical medicine relies on the willingness of patients to take part in experimental clinical trials, particularly randomized controlled trials (RCTs). Before agreeing to enroll in clinical trials, patients require guarantees that they will not knowingly be harmed and will have the best possible chances of receiving the most favorable treatments. This guarantee is provided by the acknowledgment of uncertainty (equipoise), which removes ethical dilemmas and makes it easier for patients to enroll in clinical trials. Methods Since the design of clinical trials is mostly affected by clinical equipoise, the “clinical equipoise hypothesis” has been postulated. If the uncertainty requirement holds, this means that investigators cannot predict what they are going to discover in any individual trial that they undertake. In some instances, new treatments will be superior to standard treatments, while in others, standard treatments will be superior to experimental treatments, and in still others, no difference will be detected between new and standard treatments. It is hypothesized that there must be a relationship between the overall pattern of treatment successes and the uncertainties that RCTs are designed to address. Results An analysis of published trials shows that the results cannot be predicted at the level of individual trials. However, the results also indicate that the overall pattern of discovery of treatment success across a series of trials is predictable and is consistent with clinical equipoise hypothesis. The analysis shows that we can discover no more than 25% to 50% of successful treatments when they are tested in RCTs. The analysis also indicates that this discovery rate is optimal in helping to preserve the clinical trial system; a high discovery rate (eg, a 90% to 100% probability of success) is neither feasible nor desirable since under these circumstances, neither the patient nor the researcher has an interest in randomization. This in turn would halt the RCT system as we know it. Conclusions The “principle or law of clinical discovery” described herein predicts the efficiency of the current system of RCTs at generating discoveries of new treatments. The principle is derived from the requirement for uncertainty or equipoise as a precondition for RCTs, the precept that paradoxically drives discoveries of new treatments while limiting the proportion and rate of new therapeutic discoveries. PMID:19910921

Efficacy test of a toothpaste in reducing extrinsic dental stain

NASA Astrophysics Data System (ADS)

Agustanti, A.; Ramadhani, S. A.; Adiatman, M.; Rahardjo, A.; Callea, M.; Yavuz, I.; Maharani, D. A.

2017-08-01

This clinical trial compared the external dental stain reduction achieved by tested toothpaste versus placebo in adult patients. In this double-blind, parallel, randomised clinical trial, 45 female volunteers with a mean age of 20 years old were included. All study subjects front teeth were topically applicated with Silver Diamine Fluoride (SDF) to create external dental stains. Subjects were randomized into test (n=22) and control (n=23) groups. Toothpastes were used for two days to analyse the effects of removing external stains on the labial surfaces of all anterior teeth. VITA Easyshade Advance 4.0 was used to measure dental extrinsic stains changes. The analysis showed statistically significant efficacy of the tested toothpaste in reducing external dental stain caused by SDF, comparing to the placebo toothpaste, after one and two days of usage. The tested toothpaste was effective in reducing dental stain.

Rapid Onset of Retinal Toxicity From High-Dose Hydroxychloroquine Given for Cancer Therapy.

PubMed

Leung, Loh-Shan B; Neal, Joel W; Wakelee, Heather A; Sequist, Lecia V; Marmor, Michael F

2015-10-01

To report rapid onset of retinal toxicity in a series of patients followed on high-dose (1000 mg daily) hydroxychloroquine during an oncologic clinical trial studying hydroxychloroquine with erlotinib for non-small cell lung cancer. Retrospective observational case series. Ophthalmic surveillance was performed on patients in a multicenter clinical trial testing high-dose (1000 mg daily) hydroxychloroquine for advanced non-small cell lung cancer. The US Food & Drug Administration-recommended screening protocol included only visual acuity testing, dilated fundus examination, Amsler grid testing, and color vision testing. In patients seen at Stanford, additional sensitive screening procedures were added at the discretion of the retinal physician: high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging, Humphrey visual field (HVF) testing, and multifocal electroretinography (mfERG). Out of the 7 patients having exposure of at least 6 months, 2 developed retinal toxicity (at 11 and 17 months of exposure). Damage was identified by OCT imaging, mfERG testing, and, in 1 case, visual field testing. Fundus autofluorescence imaging remained normal. Neither patient had symptomatic visual acuity loss. These cases show that high doses of hydroxychloroquine can initiate the development of retinal toxicity within 1-2 years. Although synergy with erlotinib is theoretically possible, there are no prior reports of erlotinib-associated retinal toxicity despite over a decade of use in oncology. These results also suggest that sensitive retinal screening tests should be added to ongoing and future clinical trials involving high-dose hydroxychloroquine to improve safety monitoring and preservation of vision. Published by Elsevier Inc.

A Randomized Clinical Trial Comparing Use of Rapid Molecular Testing for Staphylococcus aureus for Patients With Cutaneous Abscesses in the Emergency Department With Standard of Care

PubMed Central

May, Larissa S.; Rothman, Richard E.; Miller, Loren G.; Brooks, Gillian; Zocchi, Mark; Zatorski, Catherine; Dugas, Andrea F.; Ware, Chelsea E.; Jordan, Jeanne A.

2017-01-01

OBJECTIVE To determine whether real-time availability of rapid molecular results of Staphylococcus aureus would impact emergency department clinician antimicrobial selection for adults with cutaneous abscesses. DESIGN We performed a prospective, randomized controlled trial comparing a rapid molecular test with standard of care culture-based testing. Follow-up telephone calls were made at between 2 and 7 days, 1 month, and 3 months after discharge. SETTING Two urban, academic emergency departments. PATIENTS Patients at least 18 years old presenting with a chief complaint of abscess, cellulitis, or insect bite and receiving incision and drainage were eligible. Seven hundred seventy-eight people were assessed for eligibility and 252 met eligibility criteria. METHODS Clinician antibiotic selection and clinical outcomes were evaluated. An ad hoc outcome of test performance was performed. RESULTS We enrolled 252 patients and 126 were randomized to receive the rapid test. Methicillin-susceptible S. aureus–positive patients receiving rapid test results were prescribed beta-lactams more often than controls (absolute difference, 14.5% [95% CI, 1.1%–30.1%]) whereas methicillin-resistant S. aureus–positive patients receiving rapid test results were more often prescribed anti–methicillin-resistant S. aureus antibiotics (absolute difference, 21.5% [95% CI, 10.1%–33.0%]). There were no significant differences between the 2 groups in 1-week or 3-month clinical outcomes. CONCLUSION Availability of rapid molecular test results after incision and drainage was associated with more-targeted antibiotic selection. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01523899 PMID:26306996

Applying novel nutrient drink to clinical trial of functional dyspepsia.

PubMed

Lim, Chul-Hyun; Choi, Myung-Gyu; Baeg, Myong Ki; Moon, Sung Jin; Kim, Jin Su; Cho, Yu Kyung; Park, Jae Myung; Lee, In Seok; Kim, Sang Woo; Choi, Kyu Yong

2014-04-30

The drink test has been regarded as a surrogate marker of gastric accommodation. The aims of this study were to develop a novel nutrient drink test (NDT) protocol and investigate its potential for application to a clinical trial of functional dyspepsia (FD). A novel NDT was designed, involving drinking 125 mL of nutrient 4 times at 5-minute intervals or until maximal tolerability. Healthy volunteers and patients with FD rated their symptoms every 5 minutes for 20 minutes in a developmental study. Patients with FD were enrolled in an open trial of itopride for 4 weeks. NDT was performed before and after treatment. Improvement of integrative symptoms score during NDT after treatment for more than 50% compared with baseline was de-fined as responder. Total aggregate symptom scores, sum of symptom scores measured during NDT, were higher in FD patients (n = 40, 368.1 ± 245.3) than in controls (n = 19, 215.9 ± 171.2) (P = 0.018) in a developmental study. In an open trial of itopride, symp-tom scores measured during NDT decreased significantly at all time points after treatment in responders (n = 49), whereas did not in non-responders (n = 25). Total aggregate symptom score for NDT correlated significantly with integrative dyspeptic symptom score, sum of 8 symptom scores of NDI questionnaire, at baseline (r = 0.374, P = 0.001) and after treatment (r = 0.480, P ＜ 0.001). Our novel NDT can quantify dyspeptic symptoms and reflected therapeutic effects of itopride treatment in a clinical trial of FD patients. This NDT can be used as an effective parameter in clinical trials or drug development programs for assessing effects of novel therapies on postprandial symptoms.

Applying Novel Nutrient Drink to Clinical Trial of Functional Dyspepsia

PubMed Central

Lim, Chul-Hyun; Choi, Myung-Gyu; Baeg, Myong Ki; Moon, Sung Jin; Kim, Jin Su; Cho, Yu Kyung; Park, Jae Myung; Lee, In Seok; Kim, Sang Woo; Choi, Kyu Yong

2014-01-01

Background/Aims The drink test has been regarded as a surrogate marker of gastric accommodation. The aims of this study were to develop a novel nutrient drink test (NDT) protocol and investigate its potential for application to a clinical trial of functional dyspepsia (FD). Methods A novel NDT was designed, involving drinking 125 mL of nutrient 4 times at 5-minute intervals or until maximal tolerability. Healthy volunteers and patients with FD rated their symptoms every 5 minutes for 20 minutes in a developmental study. Patients with FD were enrolled in an open trial of itopride for 4 weeks. NDT was performed before and after treatment. Improvement of integrative symptoms score during NDT after treatment for more than 50% compared with baseline was defined as responder. Results Total aggregate symptom scores, sum of symptom scores measured during NDT, were higher in FD patients (n = 40, 368.1 ± 245.3) than in controls (n = 19, 215.9 ± 171.2) (P = 0.018) in a developmental study. In an open trial of itopride, symptom scores measured during NDT decreased significantly at all time points after treatment in responders (n = 49), whereas did not in non-responders (n = 25). Total aggregate symptom score for NDT correlated significantly with integrative dyspeptic symptom score, sum of 8 symptom scores of NDI questionnaire, at baseline (r = 0.374, P = 0.001) and after treatment (r = 0.480, P < 0.001). Conclusions Our novel NDT can quantify dyspeptic symptoms and reflected therapeutic effects of itopride treatment in a clinical trial of FD patients. This NDT can be used as an effective parameter in clinical trials or drug development programs for assessing effects of novel therapies on postprandial symptoms. PMID:24840374

Successful Outcomes of a Clinical Decision Support System in an HIV Practice: A Randomized Controlled Trial

PubMed Central

Robbins, Gregory K.; Lester, William; Johnson, Kristin L.; Chang, Yuchiao; Estey, Gregory; Surrao, Dominic; Zachary, Kimon; Lammert, Sara M.; Chueh, Henry; Meigs, James B.; Freedberg, Kenneth A.

2013-01-01

Background Data to support improved patient outcomes from clinical decision support systems (CDSS) are lacking in HIV care. Objective To conduct a randomized controlled trial testing the efficacy of a CDSS to improve HIV outcomes in an outpatient clinic. Design We conducted a randomized controlled trial where half of each provider’s patients were randomized to interactive or static computer alerts (ClinicalTrials.gov #NCT00678600). Setting The study was conducted at the Massachusetts General Hospital HIV Clinic. Subjects Participants were HIV providers and their HIV-infected patients. Intervention Computer alerts were generated for virologic failure (HIV RNA >400 c/mL after HIV RNA ≤400 c/mL), evidence of suboptimal follow-up, and 11 abnormal laboratory tests. Providers received interactive computer alerts, facilitating appointment rescheduling and repeat laboratory testing, for half of their patients and static alerts for the other half. Measurements The primary endpoint was change in CD4 count. Other endpoints included time-to-clinical event, 6-month suboptimal follow-up, and severe laboratory toxicity. Results Thirty-three HIV providers followed 1,011 HIV-infected patients. For the intervention arm, the mean CD4 count increase was greater (5.3 versus 3.2 cells/mm3/month; difference = 2.0 cells/mm3/month 95% CI [0.1, 4.0], p=0.040) and the rate of 6-month suboptimal follow-up was lower (20.6 versus 30.1 events per 100 patient-years, p=0.022). Median time-to-next scheduled appointment was shorter in the intervention arm after a suboptimal follow-up alert (1.71 versus 3.48 months; p<0.001) and after a toxicity alert (2.79 versus >6 months for control); p=0.072). Ninety-six percent of providers supported adopting the CDSS as part of standard care. Limitations This was a one-year informatics study conducted at a single hospital sub-specialty clinic. Conclusion A CDSS using interactive provider alerts improved CD4 counts and clinic follow-up for HIV-infected patients. Wider implementation of such systems can provide important clinical benefits. PMID:23208165

Rifaximin: The Revolutionary Antibiotic Approach for Irritable Bowel Syndrome.

PubMed

Triantafyllou, Konstantinos; Sioulas, Athanasios D; Giamarellos-Bourboulis, Evangelos J

2015-01-01

A large number of clinical studies using breath testing and a smaller number of studies using quantitative cultures of the upper small intestine established a link between irritable bowel syndrome (IBS) and small intestinal bacterial overgrowth (SIBO). A series of 12 studies both prospective and retrospective in design in a population of patients with SIBO without IBS showed that the non-absorbable antibiotic rifaximin can eradicate SIBO as proved through decrease of the exhaled hydrogen and methane in breath tests. The efficacy of rifaximin was superior over the comparator treatment in most of these studies. Based on these findings, short course rifaximin was tested in various concentrations in eight open-label trials in patients with IBS and proven SIBO by breath test. Similar efficacy of rifaximin was shown in SIBO eradication; this was accompanied by improvement of the global score for IBS symptoms. Finally, five double-blind randomized clinical trials were conducted in patients with IBS; four were placebo-controlled. The larger trials were TARGET 1 and TARGET 2 studies testing rifaximin at a regimen of 550 mg tid for 14 days. All trials showed a significant superiority of rifaximin over comparator for the improvement of global symptoms of IBS and bloating. Although the aforementioned results render rifaximin a revolutionary therapeutic approach for IBS, several concerns on induction of antimicrobial resistant flora remain.

Protocol for a prospective interventional trial to develop a diagnostic index test for stroke as a cause of vertigo, dizziness and imbalance in the emergency room (EMVERT study)

PubMed Central

Bardins, Stanislavs; Müller, Hans-Helge; Jahn, Klaus; Zwergal, Andreas

2017-01-01

Introduction Identifying stroke as a cause of acute vertigo, dizziness and imbalance in the emergency room is still a clinical challenge. Many patients are admitted to stroke units, but only a minority will have strokes. This imposes a heavy financial burden on the healthcare system. The aim of this study is to develop a diagnostic index test to identify patients with a high risk of having a stroke as the cause of acute vertigo and imbalance. Methods and analysis Patients with acute onset of vertigo, dizziness, postural imbalance or double vision within the last 24 hours lasting for at least 10 min are eligible to be included in the study. Patients with clinically proven peripheral or central aetiology will be excluded. In the emergency room, all enrolled patients will undergo standardised neuro-ophthalmological/physiological testing (including video-oculography, mobile posturography, measurement of subjective visual vertical) (EMVERT block 1). Within 10 days, standardised MRI will be performed as a reference test to identify stroke (EMVERT block 2). Data from EMVERT block 2 will be compared with results from block 1 in order to devise a diagnostic index test with a high specificity and sensitivity to predict the risk of stroke in the emergency room. Ethics and dissemination The study was approved by the ethics committee of the University of Munich and will be conducted according to the Guideline for Good Clinical Practice, the Federal Data Protecting Act and the Helsinki Declaration of the World Medical Association in its recent version. Study results are expected to be published in international peer-reviewed journals and will be presented at international conferences. Trial registration number German Clinical Trial Register: DRKS00008992; Universal trial number: U1111-1172-8719); pre-results. PMID:29018076

Advice for acute low back pain: a comparison of what research supports and what guidelines recommend.

PubMed

Stevens, Matthew L; Lin, Chung-Wei C; de Carvalho, Flavia A; Phan, Kevin; Koes, Bart; Maher, Chris G

2017-10-01

Advice is widely considered an effective treatment for acute low back pain (LBP); however, details on what and how to deliver this intervention is less clear. We assessed and compared clinical trials that test advice for acute LBP with practice guidelines for their completeness of reporting and concordance on the content, method of delivery, and treatment regimen of advice interventions. Systematic review. Advice randomized controlled trials were identified through a systematic search. Guidelines were taken from recent overviews of guidelines for LBP. Completeness of reporting was assessed using the Template for Intervention Description and Replication checklist. Thematic analysis was used to characterize advice interventions into topics across the aspects of content, method of delivery, and regimen. Concordance between clinical trials and guidelines was assessed by comparing the number of trials that found a statistically significant treatment effect for an intervention that included a specific advice topic with the number of guidelines recommending that topic. The median (interquartile range) completeness of reporting for clinical trials and guidelines was 8 (7-9) and 3 (2-4) out of nine items on the Template for Intervention Description and Replication checklist, respectively. Guideline recommendations were discordant with clinical trials for 50% of the advice topics identified. Completeness of reporting was less than ideal for randomized controlled trials and extremely poor for guidelines. The recommendations made in guidelines of advice for acute LBP were often not concordant with the results of clinical trials. Taken together, these findings mean that the potential clinical value of advice interventions for patients with acute LBP is probably not being realized. Copyright © 2017 Elsevier Inc. All rights reserved.

Suboptimal Dosing Parameters as Possible Factors in the Negative Phase III Clinical Trials of Progesterone for Traumatic Brain Injury.

PubMed

Howard, Randy B; Sayeed, Iqbal; Stein, Donald G

2017-06-01

To date, outcomes for all Phase III clinical trials for traumatic brain injury (TBI) have been negative. The recent disappointing results of the Progesterone for the Treatment of Traumatic Brain Injury (ProTECT) and Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury (SyNAPSe) Phase III trials for progesterone in TBI have triggered considerable speculation about the reasons for the negative outcomes of these two studies in particular and for those of all previous Phase III TBI clinical trials in general. Among the factors proposed to explain the ProTECT III and SyNAPSe results, the investigators themselves and others have cited: 1) the pathophysiological complexity of TBI itself; 2) issues with the quality and clinical relevance of the preclinical animal models; 3) insufficiently sensitive clinical endpoints; and 4) inappropriate clinical trial designs and strategies. This paper highlights three critical trial design factors that may have contributed substantially to the negative outcomes: 1) suboptimal doses and treatment durations in the Phase II studies; 2) the strategic decision not to perform Phase IIB studies to optimize these variables before initiating Phase III; and 3) the lack of incorporation of the preclinical and Chinese Phase II results, as well as allometric scaling principles, into the Phase III designs. Given these circumstances and the exceptional pleiotropic potential of progesterone as a TBI (and stroke) therapeutic, we are advocating a return to Phase IIB testing. We advocate the incorporation of dose and schedule optimization focused on lower doses and a longer duration of treatment, combined with the addressing of other potential trial design problems raised by the authors in the recently published trial results.

Assessment of the clinical relevance of quantitative sensory testing with Von Frey monofilaments in patients with allodynia and neuropathic pain. A pilot study.

PubMed

Keizer, D; van Wijhe, M; Post, W J; Uges, D R A; Wierda, J M K H

2007-08-01

Allodynia is a common and disabling symptom in many patients with neuropathic pain. Whereas quantification of pain mostly depends on subjective pain reports, allodynia can also be measured objectively with quantitative sensory testing. In this pilot study, we investigated the clinical relevance of quantitative sensory testing with Von Frey monofilaments in patients with allodynia as a consequence of a neuropathic pain syndrome, by means of correlating subjective pain scores with pain thresholds obtained with quantitative sensory testing. During a 4-week trial, we administered a cannabis extract to 17 patients with allodynia. We quantified the severity of the allodynia with Von Frey monofilaments before, during and after the patients finished the trial. We also asked the patients to rate their pain on a numeric rating scale at these three moments. We found that most of the effect of the cannabis occurred in the last 2 weeks of the trial. In this phase, we observed that the pain thresholds, as measured with Von Frey monofilaments, were inversely correlated with a decrease of the perceived pain intensity. These preliminary findings indicate clinical relevance of quantitative sensory testing with Von Frey monofilaments in the quantification of allodynia in patients with neuropathic pain, although confirmation of our data is still required in further studies to position this method of quantitative sensory testing as a valuable tool, for example, in the evaluation of therapeutic interventions for neuropathic pain.

Defining precision: The precision medicine initiative trials NCI-MPACT and NCI-MATCH.

PubMed

Coyne, Geraldine O'Sullivan; Takebe, Naoko; Chen, Alice P

"Precision" trials, using rationally incorporated biomarker targets and molecularly selective anticancer agents, have become of great interest to both patients and their physicians. In the endeavor to test the cornerstone premise of precision oncotherapy, that is, determining if modulating a specific molecular aberration in a patient's tumor with a correspondingly specific therapeutic agent improves clinical outcomes, the design of clinical trials with embedded genomic characterization platforms which guide therapy are an increasing challenge. The National Cancer Institute Precision Medicine Initiative is an unprecedented large interdisciplinary collaborative effort to conceptualize and test the feasibility of trials incorporating sequencing platforms and large-scale bioinformatics processing that are not currently uniformly available to patients. National Cancer Institute-Molecular Profiling-based Assignment of Cancer Therapy and National Cancer Institute-Molecular Analysis for Therapy Choice are 2 genomic to phenotypic trials under this National Cancer Institute initiative, where treatment is selected according to predetermined genetic alterations detected using next-generation sequencing technology across a broad range of tumor types. In this article, we discuss the objectives and trial designs that have enabled the public-private partnerships required to complete the scale of both trials, as well as interim trial updates and strategic considerations that have driven data analysis and targeted therapy assignment, with the intent of elucidating further the benefits of this treatment approach for patients. Copyright © 2017. Published by Elsevier Inc.

Interest and Uptake of MC1R Testing for Melanoma Risk in a Diverse Primary Care Population: A Randomized Clinical Trial.

PubMed

Hay, Jennifer L; Zielaskowski, Kate; Meyer White, Kirsten; Kaphingst, Kimberly; Robers, Erika; Guest, Dolores; Sussman, Andrew; Talamantes, Yvonne; Schwartz, Matthew; Rodríguez, Vivian M; Li, Yuelin; Schofield, Elizabeth; Bigney, Jessica; Hunley, Keith; Buller, David; Berwick, Marianne

2018-06-01

Germline variants in the MC1R gene are common and confer moderate melanoma risk in those with varied skin types. Approaches to precision skin cancer prevention that include genetic information may promote risk awareness and risk reduction in the general population, including Hispanics. To examine prevalence of interest in and uptake of MC1R testing in the general population and examine patterns across demographic and skin cancer risk factors. A randomized clinical trial examined interest in and uptake of MC1R testing among patients at University of New Mexico General Internal Medicine clinics. Study participants were randomized to either a usual-care condition (National Cancer Institute skin cancer pamphlet for diverse skin types) or an MC1R test offer. Participants were registered clinic patients (≥6 months) and English or Spanish fluent. Of the 600 participants recruited to the overall trial, the present study included those 499 participants randomized to the MC1R test offer. Participants were presented with the option to log onto the study website to read 3 educational modules presenting the rationale, benefits, and drawbacks of MC1R testing. Main outcomes include website log on (yes vs no), saliva test kit request (yes vs no), and saliva test kit return for MC1R testing (yes vs no). Demographic and skin cancer risk factors were examined as potential predictors of test interest and uptake. Of the 499 participants (220 [44%] non-Hispanic white, 242 [48%] Hispanic, 396 [79%] female; mean [SD] age, 54 [14.3] years), 232 (46%) elected to learn about MC1R testing by logging onto the website; 204 (88%) of those who logged on decided to request testing; and 167 (82%) of those who requested testing returned the kit. The strongest predictors of website log on were race/ethnicity and education (non-Hispanic whites were more likely to log on [odds ratio for Hispanics vs non-Hispanic whites, 0.5; 95% CI, 0.3-0.7], as were more highly educated individuals [odds ratio for more than high school vs high school or less, 2.7; 95% CI, 1.7-4.3]). The strongest predictor of ordering the test was sunburn history (odds ratio, 5.4; 95% CI, 2.3-12.9 vs no sunburn history). There were moderately high levels of MC1R test interest and uptake in this diverse sample. Addressing potential barriers to testing may be warranted as genomic information becomes integrated into general population approaches to the precision prevention of skin cancer. ClinicalTrials.gov identifier: NCT03130569.

Vaccine approaches to malaria control and elimination: Insights from mathematical models.

PubMed

White, Michael T; Verity, Robert; Churcher, Thomas S; Ghani, Azra C

2015-12-22

A licensed malaria vaccine would provide a valuable new tool for malaria control and elimination efforts. Several candidate vaccines targeting different stages of the malaria parasite's lifecycle are currently under development, with one candidate, RTS,S/AS01 for the prevention of Plasmodium falciparum infection, having recently completed Phase III trials. Predicting the public health impact of a candidate malaria vaccine requires using clinical trial data to estimate the vaccine's efficacy profile--the initial efficacy following vaccination and the pattern of waning of efficacy over time. With an estimated vaccine efficacy profile, the effects of vaccination on malaria transmission can be simulated with the aid of mathematical models. Here, we provide an overview of methods for estimating the vaccine efficacy profiles of pre-erythrocytic vaccines and transmission-blocking vaccines from clinical trial data. In the case of RTS,S/AS01, model estimates from Phase II clinical trial data indicate a bi-phasic exponential profile of efficacy against infection, with efficacy waning rapidly in the first 6 months after vaccination followed by a slower rate of waning over the next 4 years. Transmission-blocking vaccines have yet to be tested in large-scale Phase II or Phase III clinical trials so we review ongoing work investigating how a clinical trial might be designed to ensure that vaccine efficacy can be estimated with sufficient statistical power. Finally, we demonstrate how parameters estimated from clinical trials can be used to predict the impact of vaccination campaigns on malaria using a mathematical model of malaria transmission. Copyright © 2015 Elsevier Ltd. All rights reserved.

Primary outcome indices in illicit drug dependence treatment research: systematic approach to selection and measurement of drug use end-points in clinical trials

PubMed Central

Donovan, Dennis M.; Bigelow, George E.; Brigham, Gregory S.; Carroll, Kathleen M.; Cohen, Allan J.; Gardin, John G.; Hamilton, John A.; Huestis, Marilyn A.; Hughes, John R.; Lindblad, Robert; Marlatt, G. Alan; Preston, Kenzie L.; Selzer, Jeffrey A.; Somoza, Eugene C.; Wakim, Paul G.; Wells, Elizabeth A.

2012-01-01

Aims Clinical trials test the safety and efficacy of behavioral and pharmacological interventions in drug-dependent individuals. However, there is no consensus about the most appropriate outcome(s) to consider in determining treatment efficacy or on the most appropriate methods for assessing selected outcome(s). We summarize the discussion and recommendations of treatment and research experts, convened by the US National Institute on Drug Abuse, to select appropriate primary outcomes for drug dependence treatment clinical trials, and in particular the feasibility of selecting a common outcome to be included in all or most trials. Methods A brief history of outcomes employed in prior drug dependence treatment research, incorporating perspectives from tobacco and alcohol research, is included. The relative merits and limitations of focusing on drug-taking behavior, as measured by self-report and qualitative or quantitative biological markers, are evaluated. Results Drug-taking behavior, measured ideally by a combination of self-report and biological indicators, is seen as the most appropriate proximal primary outcome in drug dependence treatment clinical trials. Conclusions We conclude that the most appropriate outcome will vary as a function of salient variables inherent in the clinical trial, such as the type of intervention, its target, treatment goals (e.g. abstinence or reduction of use) and the perspective being taken (e.g. researcher, clinical program, patient, society). It is recommended that a decision process, based on such trial variables, be developed to guide the selection of primary and secondary outcomes as well as the methods to assess them. PMID:21781202

[Challenges in the organization of investigator initiated trials: in transplantation medicine].

PubMed

Schnitzbauer, A A; Lamby, P E; Mutzbauer, I; von Hassel, J; Geissler, E K; Schlitt, H J

2011-03-01

Transplantation medicine offers multiple translational questions which should preferably be transferred to clinical evidence. The current gold standard for testing such questions and hypotheses is by prospective randomized controlled trials (RCT). The trials should be performed independently from the medical industry to avoid conflicts of interests and to guarantee a strict scientific approach. A good model is an investigator initiated trial (IIT) in which academic institutions function as the sponsor and in which normally a scientific idea stands before marketing interests of a certain medical product. We present a model for an IIT which is sponsored and coordinated by Regensburg University Hospital at 45 sites in 13 nations (SiLVER study), highlight special pitfalls of this study and offer alternatives to this approach. Finances: financial support in clinical trials can be obtained from the medical industry. Alternatively in Germany the Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung) offers annual grants. The expansion of financial support through foundations is desirable. Infrastructure: sponsorship within the pharmaceutics act (Arzneimittelgesetz) demands excellent infrastructural conditions and a professional team to accomplish clinical, logistic, regulatory, legal and ethical challenges in a RCT. If a large trial has sufficient financial support certain tasks can be outsourced and delegated to contract research organizations, coordinating centers for clinical trials or partners in the medical industry. Clinical scientific advances to improve evidence are an enormous challenge when performed as an IIT. However, academic sponsors can perform (international) IITs when certain rules are followed and should be defined as the gold standard when scientific findings have to be established clinically.

Targeting targeted agents: open issues for clinical trial design.

PubMed

Bria, Emilio; Di Maio, Massimo; Carlini, Paolo; Cuppone, Federica; Giannarelli, Diana; Cognetti, Francesco; Milella, Michele

2009-05-22

Molecularly targeted agents for the treatment of solid tumors had entered the market in the last 5 years, with a great impact upon both the scientific community and the society. Many randomized phase III trials conducted in recent years with new targeted agents, despite previous data coming from preclinical research and from phase II trials were often promising, have produced disappointingly negative results. Some other trials have actually met their primary endpoint, demonstrating a statistically significant result favouring the experimental treatment. Unfortunately, with a few relevant exceptions, this advantage is often small, if not negligible, in absolute terms. The difference between statistical significance and clinical relevance should always be considered when translating clinical trials' results in the practice. The reason why this 'revolution' did not significantly impact on cancer treatment to displace chemotherapy from the patient' bedside is in part due to complicated, and in many cases, unknown, mechanisms of action of such drugs; indeed, the traditional way the clinical investigators were used to test the efficacy of 'older' chemotherapeutics, has become 'out of date' from the methodological perspective. As these drugs should be theoretically tailored upon featured bio-markers expressed by the patients, the clinical trial design should follow new rules based upon stronger hypotheses than those developed so far. Indeed, the early phases of basic and clinical drug development are crucial in the correct process which is able to correctly identify the target (when present). Targeted trial designs can result in easier studies, with less, better selected, and supported by stronger proofs of response evidences, patients, in order to not waste time and resources.

New trial engineers immune cells to treat solid tumors | Center for Cancer Research

Cancer.gov

No existing systemic treatments can currently eradicate the great majority of metastatic solid cancers. To meet that need, Steve Rosenberg, M.D., Ph.D., is testing a new immunotherapy that targets each tumor’s unique genetic mutations in a clinical trial.

The Recombinant Bacille Calmette-Guérin Vaccine VPM1002: Ready for Clinical Efficacy Testing.

PubMed

Nieuwenhuizen, Natalie E; Kulkarni, Prasad S; Shaligram, Umesh; Cotton, Mark F; Rentsch, Cyrill A; Eisele, Bernd; Grode, Leander; Kaufmann, Stefan H E

2017-01-01

The only licensed vaccine against tuberculosis (TB), bacille Calmette-Guérin (BCG), protects against severe extrapulmonary forms of TB but is virtually ineffective against the most prevalent form of the disease, pulmonary TB. BCG was genetically modified at the Max Planck Institute for Infection Biology to improve its immunogenicity by replacing the urease C encoding gene with the listeriolysin encoding gene from Listeria monocytogenes . Listeriolysin perturbates the phagosomal membrane at acidic pH. Urease C is involved in neutralization of the phagosome harboring BCG. Its depletion allows for rapid phagosome acidification and promotes phagolysosome fusion. As a result, BCGΔ ureC :: hly (VPM1002) promotes apoptosis and autophagy and facilitates release of mycobacterial antigens into the cytosol. In preclinical studies, VPM1002 has been far more efficacious and safer than BCG. The vaccine was licensed to Vakzine Projekt Management and later sublicensed to the Serum Institute of India Pvt. Ltd., the largest vaccine producer in the world. The vaccine has passed phase I clinical trials in Germany and South Africa, demonstrating its safety and immunogenicity in young adults. It was also successfully tested in a phase IIa randomized clinical trial in healthy South African newborns and is currently undergoing a phase IIb study in HIV exposed and unexposed newborns. A phase II/III clinical trial will commence in India in 2017 to assess efficacy against recurrence of TB. The target indications for VPM1002 are newborn immunization to prevent TB as well as post-exposure immunization in adults to prevent TB recurrence. In addition, a Phase I trial in non-muscle invasive bladder cancer patients has been completed, and phase II trials are ongoing. This review describes the development of VPM1002 from the drawing board to its clinical assessment.

Effect of xylitol versus sorbitol: a quantitative systematic review of clinical trials.

PubMed

Mickenautsch, Steffen; Yengopal, Veerasamy

2012-08-01

This study aimed to appraise, within the context of tooth caries, the current clinical evidence and its risk for bias regarding the effects of xylitol in comparison with sorbitol. Databases were searched for clinical trials to 19 March 2011. Inclusion criteria required studies to: test a caries-related primary outcome; compare the effects of xylitol with those of sorbitol; describe a clinical trial with two or more arms, and utilise a prospective study design. Articles were excluded if they did not report computable data or did not follow up test and control groups in the same way. Individual dichotomous and continuous datasets were extracted from accepted articles. Selection and performance/detection bias were assessed. Sensitivity analysis was used to investigate attrition bias. Egger's regression and funnel plotting were used to investigate risk for publication bias. Nine articles were identified. Of these, eight were accepted and one was excluded. Ten continuous and eight dichotomous datasets were extracted. Because of high clinical heterogeneity, no meta-analysis was performed. Most of the datasets favoured xylitol, but this was not consistent. The accepted trials may be limited by selection bias. Results of the sensitivity analysis indicate a high risk for attrition bias. The funnel plot and Egger's regression results suggest a low publication bias risk. External fluoride exposure and stimulated saliva flow may have confounded the measured anticariogenic effect of xylitol. The evidence identified in support of xylitol over sorbitol is contradictory, is at high risk for selection and attrition bias and may be limited by confounder effects. Future high-quality randomised controlled trials are needed to show whether xylitol has a greater anticariogenic effect than sorbitol. © 2012 FDI World Dental Federation.

Advances in Retinal Prosthetic Research: A Systematic Review of Engineering and Clinical Characteristics of Current Prosthetic Initiatives.

PubMed

Cheng, Derrick L; Greenberg, Paul B; Borton, David A

2017-03-01

To date, reviews of retinal prostheses have focused primarily on devices undergoing human trials in the Western Hemisphere and fail to capture significant advances in materials and engineering research in countries such as Japan and Korea, as well as projects in early stages of development. To address these gaps, this systematic review examines worldwide advances in retinal prosthetic research, evaluates engineering characteristics and clinical progress of contemporary device initiatives, and identifies potential directions for future research in the field of retinal prosthetics. A literature search using PubMed, Google Scholar, and IEEExplore was conducted following the PRISMA Guidelines for Systematic Review. Inclusion criteria were peer-reviewed papers demonstrating progress in human or animal trials and papers discussing the prosthetic engineering design. For each initiative, a description of the device, its engineering considerations, and recent clinical results were provided. Ten prosthetic initiatives met our inclusion criteria and were organized by stimulation location. Of these initiatives, four have recently completed human trials, three are undergoing multi- or single-center human trials, and three are undergoing preclinical animal testing. Only the Argus II (FDA 2013, CE 2011) has obtained FDA approval for use in the United States; the Alpha-IMS (CE 2013) has achieved the highest visual acuity using a Landolt-C test to date and is the only device presently undergoing a multicenter clinical trial. Several distinct approaches to retinal stimulation have been successful in eliciting visual precepts in animals and/or humans. However, many clinical needs are still not met and engineering challenges must be addressed before a retinal prosthesis with the capability to fully and safely restore functional vision can be realized.

Current nonclinical testing paradigm enables safe entry to First-In-Human clinical trials: The IQ consortium nonclinical to clinical translational database.

PubMed

Monticello, Thomas M; Jones, Thomas W; Dambach, Donna M; Potter, David M; Bolt, Michael W; Liu, Maggie; Keller, Douglas A; Hart, Timothy K; Kadambi, Vivek J

2017-11-01

The contribution of animal testing in drug development has been widely debated and challenged. An industry-wide nonclinical to clinical translational database was created to determine how safety assessments in animal models translate to First-In-Human clinical risk. The blinded database was composed of 182 molecules and contained animal toxicology data coupled with clinical observations from phase I human studies. Animal and clinical data were categorized by organ system and correlations determined. The 2×2 contingency table (true positive, false positive, true negative, false negative) was used for statistical analysis. Sensitivity was 48% with a 43% positive predictive value (PPV). The nonhuman primate had the strongest performance in predicting adverse effects, especially for gastrointestinal and nervous system categories. When the same target organ was identified in both the rodent and nonrodent, the PPV increased. Specificity was 84% with an 86% negative predictive value (NPV). The beagle dog had the strongest performance in predicting an absence of clinical adverse effects. If no target organ toxicity was observed in either test species, the NPV increased. While nonclinical studies can demonstrate great value in the PPV for certain species and organ categories, the NPV was the stronger predictive performance measure across test species and target organs indicating that an absence of toxicity in animal studies strongly predicts a similar outcome in the clinic. These results support the current regulatory paradigm of animal testing in supporting safe entry to clinical trials and provide context for emerging alternate models. Copyright © 2017 Elsevier Inc. All rights reserved.

Impact of a clinical decision model for febrile children at risk for serious bacterial infections at the emergency department: a randomized controlled trial.

PubMed

de Vos-Kerkhof, Evelien; Nijman, Ruud G; Vergouwe, Yvonne; Polinder, Suzanne; Steyerberg, Ewout W; van der Lei, Johan; Moll, Henriëtte A; Oostenbrink, Rianne

2015-01-01

To assess the impact of a clinical decision model for febrile children at risk for serious bacterial infections (SBI) attending the emergency department (ED). Randomized controlled trial with 439 febrile children, aged 1 month-16 years, attending the pediatric ED of a Dutch university hospital during 2010-2012. Febrile children were randomly assigned to the intervention (clinical decision model; n = 219) or the control group (usual care; n = 220). The clinical decision model included clinical symptoms, vital signs, and C-reactive protein and provided high/low-risks for "pneumonia" and "other SBI". Nurses were guided by the intervention to initiate additional tests for high-risk children. The clinical decision model was evaluated by 1) area-under-the-receiver-operating-characteristic-curve (AUC) to indicate discriminative ability and 2) feasibility, to measure nurses' compliance to model recommendations. Primary patient outcome was defined as correct SBI diagnoses. Secondary process outcomes were defined as length of stay; diagnostic tests; antibiotic treatment; hospital admission; revisits and medical costs. The decision model had good discriminative ability for both pneumonia (n = 33; AUC 0.83 (95% CI 0.75-0.90)) and other SBI (n = 22; AUC 0.81 (95% CI 0.72-0.90)). Compliance to model recommendations was high (86%). No differences in correct SBI determination were observed. Application of the clinical decision model resulted in less full-blood-counts (14% vs. 22%, p-value < 0.05) and more urine-dipstick testing (71% vs. 61%, p-value < 0.05). In contrast to our expectations no substantial impact on patient outcome was perceived. The clinical decision model preserved, however, good discriminatory ability to detect SBI, achieved good compliance among nurses and resulted in a more standardized diagnostic approach towards febrile children, with less full blood-counts and more rightfully urine-dipstick testing. Nederlands Trial Register NTR2381.

Hidden Treasures and Secret Pitfalls: Application of the Capability Approach to ParkinsonNet.

PubMed

Canoy, Marcel; Faber, Marjan J; Munneke, Marten; Oortwijn, Wija; Nijkrake, Maarten J; Bloem, Bastiaan R

2015-01-01

In the Netherlands, the largest health technology assessment (HTA) program funds mainly (cost-)effectiveness studies and implementation research. The cost-effectiveness studies are usually controlled clinical trials which simultaneously collect cost data. The success of a clinical trial typically depends on the effect size for the primary outcome, such as health gains or mortality rates. A drawback is that in case of a negative primary outcome, relevant other (and perhaps more implicit) benefits might be missed. Conversely, positive trials can contain adverse outcomes that may also remain hidden. The capability approach (developed by Nobel Prize winner and philosopher Sen) is an instrument that may reveal such "hidden treasures and secret pitfalls" that lie embedded within clinical trials, beyond the more traditional outcomes. Here, we exemplify the possible merits of the capability approach using a large clinical trial (funded by the HTA program in the Netherlands) that aimed to evaluate the ParkinsonNet concept, an innovative network approach for Parkinson patients. This trial showed no effects for the primary outcome, but the ParkinsonNet concept tested in this study was nevertheless met with great enthusiasm and was rapidly implemented throughout an entire country, and meanwhile also internationally. We applied the capability approach to the ParkinsonNet concept, and this analysis yielded additional benefits within several capability domains. These findings seems to substantiate the claim that richer policy debates may ensue by applying the capability approach to clinical trial data, in addition to traditional outcomes.

Conducting qualitative research within Clinical Trials Units: avoiding potential pitfalls.

PubMed

Cooper, Cindy; O'Cathain, Alicia; Hind, Danny; Adamson, Joy; Lawton, Julia; Baird, Wendy

2014-07-01

The value of using qualitative research within or alongside randomised controlled trials (RCTs) is becoming more widely accepted. Qualitative research may be conducted concurrently with pilot or full RCTs to understand the feasibility and acceptability of the interventions being tested, or to improve trial conduct. Clinical Trials Units (CTUs) in the United Kingdom (UK) manage large numbers of RCTs and, increasingly, manage the qualitative research or collaborate with qualitative researchers external to the CTU. CTUs are beginning to explicitly manage the process, for example, through the use of standard operating procedures for designing and implementing qualitative research with trials. We reviewed the experiences of two UK Clinical Research Collaboration (UKCRC) registered CTUs of conducting qualitative research concurrently with RCTs. Drawing on experiences gained from 15 studies, we identify the potential for the qualitative research to undermine the successful completion or scientific integrity of RCTs. We show that potential problems can arise from feedback of interim or final qualitative findings to members of the trial team or beyond, in particular reporting qualitative findings whilst the trial is on-going. The problems include: We make recommendations for improving the management of qualitative research within CTUs. Copyright © 2014. Published by Elsevier Inc.

The clinical effectiveness and cost-effectiveness of the PROGENSA® prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation.

PubMed

Nicholson, Amanda; Mahon, James; Boland, Angela; Beale, Sophie; Dwan, Kerry; Fleeman, Nigel; Hockenhull, Juliet; Dundar, Yenal

2015-10-01

There is no single definitive test to identify prostate cancer in men. Biopsies are commonly used to obtain samples of prostate tissue for histopathological examination. However, this approach frequently misses cases of cancer, meaning that repeat biopsies may be necessary to obtain a diagnosis. The PROGENSA(®) prostate cancer antigen 3 (PCA3) assay (Hologic Gen-Probe, Marlborough, MA, USA) and the Prostate Health Index (phi; Beckman Coulter Inc., Brea, CA, USA) are two new tests (a urine test and a blood test, respectively) that are designed to be used to help clinicians decide whether or not to recommend a repeat biopsy. To evaluate the clinical effectiveness and cost-effectiveness of the PCA3 assay and the phi in the diagnosis of prostate cancer. Multiple publication databases and trial registers were searched in May 2014 (from 2000 to May 2014), including MEDLINE, EMBASE, The Cochrane Library, ISI Web of Science, Medion, Aggressive Research Intelligence Facility database, ClinicalTrials.gov, International Standard Randomised Controlled Trial Number Register and World Health Organization International Clinical Trials Registry Platform. The assessment of clinical effectiveness involved three separate systematic reviews, namely reviews of the analytical validity, the clinical validity of these tests and the clinical utility of these tests. The assessment of cost-effectiveness comprised a systematic review of full economic evaluations and the development of a de novo economic model. The perspective of the evaluation was the NHS in England and Wales. Men suspected of having prostate cancer for whom the results of an initial prostate biopsy were negative or equivocal. The use of the PCA3 score or phi in combination with existing tests (including histopathology results, prostate-specific antigen level and digital rectal examination), multiparametric magnetic resonance imaging and clinical judgement. In addition to documents published by the manufacturers, six studies were identified for inclusion in the analytical validity review. The review identified issues concerning the precision of the PCA3 assay measurements. It also highlighted issues relating to the storage requirements and stability of samples intended for analysis using the phi assay. Fifteen studies met the inclusion criteria for the clinical validity review. These studies reported results for 10 different clinical comparisons. There was insufficient evidence to enable the identification of appropriate test threshold values for use in a clinical setting. In addition, the implications of adding either the PCA3 assay or the phi to clinical assessment were not clear. Furthermore, the addition of the PCA3 assay or the phi to clinical assessment plus magnetic resonance imaging was not found to improve discrimination. No published papers met the inclusion criteria for either the clinical utility review or the cost-effectiveness review. The results from the cost-effectiveness analyses indicated that using either the PCA3 assay or the phi in the NHS was not cost-effective. The main limitations of the systematic review of clinical validity are that the review conclusions are over-reliant on findings from one study, the descriptions of clinical assessment vary widely within reviewed studies and many of the reported results for the clinical validity outcomes do not include either standard errors or confidence intervals. The clinical benefit of using the PCA3 assay or the phi in combination with existing tests, scans and clinical judgement has not yet been confirmed. The results from the cost-effectiveness analyses indicate that the use of these tests in the NHS would not be cost-effective. This study is registered as PROSPERO CRD42014009595. The National Institute for Health Research Health Technology Assessment programme.

Learning disease relationships from clinical drug trials.

PubMed

Haslam, Bryan; Perez-Breva, Luis

2017-01-01

Our objective is to test the limits of the assumption that better learning from data in medicine requires more granular data. We hypothesize that clinical trial metadata contains latent scientific, clinical, and regulatory expert knowledge that can be accessed to draw conclusions about the underlying biology of diseases. We seek to demonstrate that this latent information can be uncovered from the whole body of clinical trials. We extract free-text metadata from 93 654 clinical drug trials and introduce a representation that allows us to compare different trials. We then construct a network of diseases using only the trial metadata. We view each trial as the summation of expert knowledge of biological mechanisms and medical evidence linking a disease to a drug believed to modulate the pathways of that disease. Our network representation allows us to visualize disease relationships based on this underlying information. Our disease network shows surprising agreement with another disease network based on genetic data and on the Medical Subject Headings (MeSH) taxonomy, yet also contains unique disease similarities. The agreement of our results with other sources indicates that our premise regarding latent expert knowledge holds. The disease relationships unique to our network may be used to generate hypotheses for future biological and clinical research as well as drug repurposing and design. Our results provide an example of using experimental data on humans to generate biologically useful information and point to a set of new and promising strategies to link clinical outcomes data back to biological research. © The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Clinical Trial Assessment of Infrastructure Matrix Tool to Improve the Quality of Research Conduct in the Community.

PubMed

Dimond, Eileen P; Zon, Robin T; Weiner, Bryan J; St Germain, Diane; Denicoff, Andrea M; Dempsey, Kandie; Carrigan, Angela C; Teal, Randall W; Good, Marjorie J; McCaskill-Stevens, Worta; Grubbs, Stephen S; Dimond, Eileen P; Zon, Robin T; Weiner, Bryan J; St Germain, Diane; Denicoff, Andrea M; Dempsey, Kandie; Carrigan, Angela C; Teal, Randall W; Good, Marjorie J; McCaskill-Stevens, Worta; Grubbs, Stephen S

2016-01-01

Several publications have described minimum standards and exemplary attributes for clinical trial sites to improve research quality. The National Cancer Institute (NCI) Community Cancer Centers Program (NCCCP) developed the clinical trial Best Practice Matrix tool to facilitate research program improvements through annual self-assessments and benchmarking. The tool identified nine attributes, each with three progressive levels, to score clinical trial infrastructural elements from less to more exemplary. The NCCCP sites correlated tool use with research program improvements, and the NCI pursued a formative evaluation to refine the interpretability and measurability of the tool. From 2011 to 2013, 21 NCCCP sites self-assessed their programs with the tool annually. During 2013 to 2014, NCI collaborators conducted a five-step formative evaluation of the matrix tool. Sites reported significant increases in level-three scores across the original nine attributes combined (P<.001). Two specific attributes exhibited significant change: clinical trial portfolio diversity and management (P=.0228) and clinical trial communication (P=.0281). The formative evaluation led to revisions, including renaming the Best Practice Matrix as the Clinical Trial Assessment of Infrastructure Matrix (CT AIM), expanding infrastructural attributes from nine to 11, clarifying metrics, and developing a new scoring tool. Broad community input, cognitive interviews, and pilot testing improved the usability and functionality of the tool. Research programs are encouraged to use the CT AIM to assess and improve site infrastructure. Experience within the NCCCP suggests that the CT AIM is useful for improving quality, benchmarking research performance, reporting progress, and communicating program needs with institutional leaders. The tool model may also be useful in disciplines beyond oncology.

Combination therapy for advanced or metastatic non-small cell lung cancer will be tested in new clinical trial | Center for Cancer Research

Cancer.gov

Non-small cell lung cancer (NSCLC) develops when abnormal lung cells begin to grow out of control. These cells can form into a tumor and spread to other areas of the body. David Schrump, M.D., of the Thoracic and Gastrointestinal Oncology Branch is leading a clinical trial of a new combination treatment for patients with advanced or metastatic NSCLC that cannot be treated

Using Minitel Network and New Software Engineering Techniques for Randomized Clinical Trials Management

PubMed Central

Lepage, E.; Tavernier, H.; Bouhaddou, O.; Jais, JP.; Gisselbrecht, C.; Aurengo, A.; Boiron, M.

1989-01-01

The usual Randomized Clinical Trials (RCT) management using an anachronic procedure involving a flowsheet exchange between the remote centers and the coordinating center presents a number of inadequacies. Eligibility criteria are not always verified by the coordinating center before inclusion in the trial and randomization. Laboratory tests and therapeutic adjustments are frequently decided from memory by the clinician which often leads to data oversight and variability of therapeutic decisions. This results in protocol deviations and alteration of the efficiency of the RCT. HICREN is a medical consultation system designed to take into account the different difficulties encountered during RCT driving. The system integrates a clinical database with artificial intelligence technics to manage clinical trial data on non-expensive and widely available Minitel® terminals. Randomization is then possible, after eligibility criteria are satisfied, anytime and anywhere in France through the national telematic network. HICREN also includes an intuitive graphic interface to increase physician's compliance: a user friendly dialogue manager supports on line data entry with multi-windowing facilities and pull down menus. Interactive data validation is achieved through an interface to dedicated C programs. Patient follow up is achieved by an expert system that proposes appropriate dose of treatment according to the rules defined in the trial. At present, HICREN is implemented on the CISARC system for conducting three randomized clinical trials and one epidemiologic study.

Selecting Patients for Intra-arterial Therapy in the Context of a Clinical Trial for Neuroprotection

PubMed Central

Lyden, Patrick; Weymer, Sara; Coffey, Chris; Cudkowicz, Merit; Berg, Samantha; O’Brien, Sarah; Fisher, Marc; Haley, E. Clarke; Khatri, Pooja; Saver, Jeff; Levine, Steven; Levy, Howard; Rymer, Marilyn; Wechsler, Lawrence; Jadhav, Ashutosh; McNeil, Elizabeth; Waddy, Salina; Pryor, Kent

2016-01-01

Background and Purpose The advent of intra-arterial neurothrombectomy (IAT) for acute ischemic stroke opens a potentially transformative opportunity to improve neuroprotection studies. Combining a putative neuroprotectant with recanalization could produce more powerful trials but could introduce heterogeneity and adverse event possibilities. We sought to demonstrate feasibility of IAT in neuroprotectant trials by defining IAT selection criteria for an ongoing neuroprotectant clinical trial. Methods The study drug, 3K3A-APC, is a pleiotropic cytoprotectant and may reduce thrombolysis associated hemorrhage. The NeuroNEXT trial NN104 (RHAPSODY) is designed to establish a maximally tolerated dose of 3K3A-APC. Each trial site provided their IAT selection criteria. An expert panel reviewed site criteria and published evidence. Finally, the trial leadership designed IAT selection criteria. Results Derived selection criteria reflected consistency among the sites and comparability to published IAT trials. A protocol amendment allowing IAT (and relaxed age, NIHSS, and time limits) in the RHAPSODY trial was implemented on June 15, 2015. Recruitment before and after the amendment improved from 8 enrolled patients (601 screened, 1.3%) to 51 patients (821 screened, 6.2%), OR [95%CL] of 4.9 [2.3,10.4], p<0.001). Gross recruitment was 0.11 patients/site/month vs. 0.43 patients/site/month, respectively, before and after the amendment. Conclusions It is feasible to include IAT in a neuroprotectant trial for acute ischemic stroke. Criteria are presented for including such patients in a manner that is consistent with published evidence for IAT while still preserving the ability to test the role of the putative neuroprotectant. Clinical Trial Registration Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714. PMID:27803392

Utility-based designs for randomized comparative trials with categorical outcomes

PubMed Central

Murray, Thomas A.; Thall, Peter F.; Yuan, Ying

2016-01-01

A general utility-based testing methodology for design and conduct of randomized comparative clinical trials with categorical outcomes is presented. Numerical utilities of all elementary events are elicited to quantify their desirabilities. These numerical values are used to map the categorical outcome probability vector of each treatment to a mean utility, which is used as a one-dimensional criterion for constructing comparative tests. Bayesian tests are presented, including fixed sample and group sequential procedures, assuming Dirichlet-multinomial models for the priors and likelihoods. Guidelines are provided for establishing priors, eliciting utilities, and specifying hypotheses. Efficient posterior computation is discussed, and algorithms are provided for jointly calibrating test cutoffs and sample size to control overall type I error and achieve specified power. Asymptotic approximations for the power curve are used to initialize the algorithms. The methodology is applied to re-design a completed trial that compared two chemotherapy regimens for chronic lymphocytic leukemia, in which an ordinal efficacy outcome was dichotomized and toxicity was ignored to construct the trial’s design. The Bayesian tests also are illustrated by several types of categorical outcomes arising in common clinical settings. Freely available computer software for implementation is provided. PMID:27189672

Charting a Roadmap for Heart Failure Biomarker Studies

PubMed Central

Ahmad, Tariq; Fiuzat, Mona; Pencina, Michael J.; Geller, Nancy L.; Zannad, Faiez; Cleland, John G. F.; Snider, James V.; Blankenberg, Stephan; Adams, Kirkwood F.; Redberg, Rita F.; Kim, Jae B.; Mascette, Alice; Mentz, Robert J.; O'Connor, Christopher M.; Felker, G. Michael; Januzzi, James L.

2014-01-01

Heart failure is a syndrome with a pathophysiological basis that can be traced to dysfunction in several interconnected molecular pathways. Identification of biomarkers of heart failure that allow measurement of the disease on a molecular level has resulted in enthusiasm for their use in prognostication and selection of appropriate therapies. However, despite considerable amounts of information available on numerous biomarkers, inconsistent research methodologies and lack of clinical correlations have made bench-to-bedside translations rare and left the literature with countless publications of varied quality. There is a need for a systematic and collaborative approach aimed at definitively studying the clinical benefits of novel biomarkers. In this review, on the basis of input from academia, industry, and governmental agencies, we propose a systematized approach based on adherence to specific quality measures for studies looking to augment current prediction model or use biomarkers to tailor therapeutics. We suggest that study quality, rather than results, should determine publication and propose a system for grading biomarker studies. We outline the need for collaboration between clinical investigators and statisticians to introduce more advanced statistical methodologies into the field of biomarkers that would allow for data from a large number of variables to be distilled into clinically actionable information. Lastly, we propose the creation of a heart failure biomarker consortium that would allow for a comprehensive list of biomarkers to be concomitantly analyzed in a pooled sample of randomized clinical trials and hypotheses to be generated for testing in biomarker-guided trials. Such a consortium could collaborate in sharing samples to identify biomarkers, undertake meta- analyses on completed trials, and spearhead clinical trials to test the clinical utility of new biomarkers. PMID:24929535

A blinded randomised placebo-controlled trial investigating the efficacy of morphine analgesia for procedural pain in infants: Trial protocol.

PubMed

Slater, Rebeccah; Hartley, Caroline; Moultrie, Fiona; Adams, Eleri; Juszczak, Ed; Rogers, Richard; Norman, Jane E; Patel, Chetan; Stanbury, Kayleigh; Hoskin, Amy; Green, Gabrielle

2016-11-15

Infant pain has both immediate and long-term negative consequences, yet in clinical practice it is often undertreated. To date, few pain-relieving drugs have been tested in infants. Morphine is a potent analgesic that provides effective pain relief in adults, but there is inconclusive evidence for its effectiveness in infants. The purpose of this study is to establish whether oral morphine provides effective analgesia for procedural pain in infants. A blinded, placebo-controlled, parallel-group randomized, phase II, clinical trial will be undertaken to determine whether morphine sulphate administered orally prior to clinically-required retinopathy of prematurity (ROP) screening and heel lancing provides effective analgesia. 
156 infants between 34 and 42 weeks' gestational age who require a clinical heel lance and ROP screening on the same test occasion will be included in the trial. Infants will be randomised to receive either a single dose of morphine sulphate (100 μg/kg) or placebo. Each infant will be monitored for 48 hours and safety data will be collected during the 24 hours following drug administration. The primary outcome will be the Premature Infant Pain Profile-revised (PIPP-R) score 30 seconds after ROP screening. The co-primary outcome will be the magnitude of nociceptive-specific brain activity evoked by a clinically-required heel lance. Infant clinical stability will be assessed by comparing the number of episodes of bradycardia, tachycardia, desaturation and apnoea, and changes in respiratory support requirements in the 24-hour periods before and after the clinical intervention. In addition, drug safety will be assessed by considering the occurrence of apnoeic and hypotensive episodes requiring intervention in the 24-hour period following drug administration. This study has been published as an Accepted Protocol Summary by The Lancet .

Lung Carcinoma Predictive Biomarker Testing by Immunoperoxidase Stains in Cytology and Small Biopsy Specimens: Advantages and Limitations.

PubMed

Zhou, Fang; Moreira, Andre L

2016-12-01

- In the burgeoning era of molecular genomics, immunoperoxidase (IPOX) testing grows increasingly relevant as an efficient and effective molecular screening tool. Patients with lung carcinoma may especially benefit from the use of IPOX because most lung carcinomas are inoperable at diagnosis and only diagnosed by small tissue biopsy or fine-needle sampling. When such small specimens are at times inadequate for molecular testing, positive IPOX results still provide actionable information. - To describe the benefits and pitfalls of IPOX in the detection of biomarkers in lung carcinoma cytology specimens and small biopsies by summarizing the currently available commercial antibodies, preanalytic variables, and analytic considerations. - PubMed. - Commercial antibodies exist for IPOX detection of aberrant protein expression due to EGFR L858R mutation, EGFR E746_A750 deletion, ALK rearrangement, ROS1 rearrangement, and BRAF V600E mutation, as well as PD-L1 expression in tumor cells. Automated IPOX protocols for ALK and PD-L1 detection were recently approved by the Food and Drug Administration as companion diagnostics for targeted therapies, but consistent interpretive criteria remain to be elucidated, and such protocols do not yet exist for other biomarkers. The inclusion of cytology specimens in clinical trials would expand patients' access to testing and treatment, yet there is a scarcity of clinical trial data regarding the application of IPOX to cytology, which can be attributed to trial designers' lack of familiarity with the advantages and limitations of cytology. The content of this review may be used to inform clinical trial design and advance IPOX validation studies.

Relevance and acceptability of using the Quantiferon gold test (QGIT) to screen CD4 blood draws for latent TB infection among PLHIV in South Africa: formative qualitative research findings from the TEKO trial.

PubMed

Kerrigan, Deanna; Tudor, Carrie; Motlhaoleng, Katlego; Lebina, Limakatso; Qomfu, Cokiswa; Variava, Ebrahim; Chon, Sandy; Martinson, Neil; Golub, Jonathan E

2018-04-16

Tuberculosis (TB) is the leading cause of mortality among people living with HIV (PLHIV), despite the availability of effective preventive therapy. The TEKO trial is assessing the impact of using a blood test, Quantiferon-TB Gold In-Tube Test (QGIT), to screen for latent TB compared to the Tuberculin Screening Test (TST) among PLHIV in South Africa. Fifty-six qualitative interviews were conducted with PLHIV and clinical providers participating in the TEKO trial. We explored TB screening, diagnosis, and treatment guidelines and processes and the use of the QGIT to screen for latent TB infection at the time of CD4 blood draw. Thematic content analysis was conducted. Considerable variability in TB screening procedures was documented due to lack of personnel and clarity regarding current national TB guidelines for PLHIV. Few clinics had started using the TST per national guidelines and many patients had never heard of isoniazid preventive therapy (IPT). Nearly all participants supported the idea of latent TB screening using routine blood drawn for CD4 counts. Findings indicate that screening for latent TB infection using QGIT from blood drawn for CD4 counts among PLHIV is an acceptable approach to increase latent TB detection given the challenges associated with ensuring systematic latent TB screening in overburdened public clinics. The results presented here were from formative research related to the TEKO trial (Identifier NCT02119130 , registered 10 April 2014).

Ten-year NEDO BVAD development program: moving forward to the clinical arena.

PubMed

Motomura, Tadashi; Okubo, Hisashi; Oda, Takeshi; Ogawa, Daisuke; Okahisa, Toshiya; Igo, Stephen; Shinohara, Toshiyuki; Yamamoto, Yoshiro; Noguchi, Chikaya; Ishizuka, Tsukasa; Okamoto, Eiji; Nosé, Yukihiko

2006-01-01

Since 1995, the Baylor Group has been developing a totally implantable NEDO BVAD system. This 10-year program was completed in March 2005, and preparation for clinical trials is underway. This article summarizes the entire 10-year NEDO program and describes the strategy for clinical trials. The project aimed to achieve: (1) dual centrifugal pumps with the ability of full biventricular support, (2) a compact system implantable into small adults, (3) a totally implantable system with transcutaneous energy transmission system (TETS), (4) a durable system with a lifetime of over 5 years, and (5) a system free of thrombus and with minimal hemolysis. The final goals are to complete preclinical system evaluations and commence the clinical trials in the near future. In vitro studies have demonstrated a pump capacity of over 8.5 l/min and an Index of Hemolysis of <0.004 g/100 l. The pump-bearing life expectancy was over 5 years. To date, eight pumps endured in vivo studies of over 3 months without complications, including thromboembolic events. The in vitro endurance studies of eight pumps are longer than 1 year. There were no mechanical malfunctions or pump failure. A stepwise clinical trial is being planned: Step1, a wearable BVAD/VAD will be clinically studied; Step 2, the BVAD/VAD will be implanted intracorporeally without TETS; and, Step 3, a totally implantable system will be clinically evaluated. The NEDO BVAD system has completed preclinical testing. Clinical trial preparation is underway.

Prioritization in comparative effectiveness research: the CANCERGEN Experience.

PubMed

Thariani, Rahber; Wong, William; Carlson, Josh J; Garrison, Louis; Ramsey, Scott; Deverka, Patricia A; Esmail, Laura; Rangarao, Sneha; Hoban, Carolyn J; Baker, Laurence H; Veenstra, David L

2012-05-01

Systematic approaches to stakeholder-informed research prioritization are a central focus of comparative effectiveness research. Genomic testing in cancer is an ideal area to refine such approaches given rapid innovation and potentially significant impacts on patient outcomes. To develop and pilot test a stakeholder-informed approach to prioritizing genomic tests for future study in collaboration with the cancer clinical trials consortium SWOG. We conducted a landscape analysis to identify genomic tests in oncology using a systematic search of published and unpublished studies, and expert consultation. Clinically valid tests suitable for evaluation in a comparative study were presented to an external stakeholder group. Domains to guide the prioritization process were identified with stakeholder input, and stakeholders ranked tests using multiple voting rounds. A stakeholder group was created including representatives from patient-advocacy groups, payers, test developers, regulators, policy makers, and community-based oncologists. We identified 9 domains for research prioritization with stakeholder feedback: population impact; current standard of care, strength of association; potential clinical benefits, potential clinical harms, economic impacts, evidence of need, trial feasibility, and market factors. The landscape analysis identified 635 studies; of 9 tests deemed to have sufficient clinical validity, 6 were presented to stakeholders. Two tests in lung cancer (ERCC1 and EGFR) and 1 test in breast cancer (CEA/CA15-3/CA27.29) were identified as top research priorities. Use of a diverse stakeholder group to inform research prioritization is feasible in a pragmatic and timely manner. Additional research is needed to optimize search strategies, stakeholder group composition, and integration with existing prioritization mechanisms.

Prioritization in Comparative Effectiveness Research: The CANCERGEN Experience in Cancer Genomics

PubMed Central

Thariani, Rahber; Wong, William; Carlson, Josh J; Garrison, Louis; Ramsey, Scott; Deverka, Patricia A; Esmail, Laura; Rangarao, Sneha; Hoban, Carolyn J; Baker, Laurence H; Veenstra, David L

2012-01-01

Background Systematic approaches to stakeholder-informed research prioritization are a central focus of comparative effectiveness research. Genomic testing in cancer is an ideal area to refine such approaches given rapid innovation and potentially significant impacts on patient outcomes. Objective To develop and pilot-test a stakeholder-informed approach to prioritizing genomic tests for future study in collaboration with the cancer clinical trials consortium SWOG. Methods We conducted a landscape-analysis to identify genomic tests in oncology using a systematic search of published and unpublished studies, and expert consultation. Clinically valid tests suitable for evaluation in a comparative study were presented to an external stakeholder group. Domains to guide the prioritization process were identified with stakeholder input, and stakeholders ranked tests using multiple voting rounds. Results A stakeholder group was created including representatives from patient-advocacy groups, payers, test developers, regulators, policy-makers, and community-based oncologists. We identified nine domains for research prioritization with stakeholder feedback: population impact; current standard of care, strength of association; potential clinical benefits, potential clinical harms, economic impacts, evidence of need, trial feasibility, and market factors. The landscape-analysis identified 635 studies; of 9 tests deemed to have sufficient clinical validity, 6 were presented to stakeholders. Two tests in lung cancer (ERCC1 and EGFR) and one test in breast cancer (CEA/CA15-3/CA27.29) were identified as top research priorities. Conclusions Use of a diverse stakeholder group to inform research prioritization is feasible in a pragmatic and timely manner. Additional research is needed to optimize search strategies, stakeholder group composition and integration with existing prioritization mechanisms. PMID:22274803

Lupus community panel proposals for optimising clinical trials: 2018

PubMed Central

Merrill, Joan T; Manzi, Susan; Aranow, Cynthia; Askenase, Anca; Bruce, Ian; Chakravarty, Eliza; Chong, Ben; Costenbader, Karen; Dall’Era, Maria; Ginzler, Ellen; Hanrahan, Leslie; Kalunian, Ken; Merola, Joseph; Raymond, Sandra; Rovin, Brad; Saxena, Amit; Werth, Victoria P

2018-01-01

Formidable impediments stand in the way of treatment development for lupus. These include the unwieldy size of current trials, international competition for scarce patients, complex outcome measures and a poor understanding of these outcomes in the world at large. The heterogeneity of the disease itself coupled to superimposition of variegated background polypharmacy has created enough immunological noise to virtually ensure the failure of lupus treatment trials, leaving an understandable suspicion that at least some of the results in testing failed drugs over the years may not have been negative, but merely uninterpretable. The authors have consulted with many clinical trial investigators, biopharmaceutical developers and stakeholders from government and voluntary sectors. This paper examines the available evidence that supports workable trial designs and proposes approaches to improve the odds of completing interpretable treatment development programs for lupus. PMID:29657738

Power of automated algorithms for combining time-line follow-back and urine drug screening test results in stimulant-abuse clinical trials.

PubMed

Oden, Neal L; VanVeldhuisen, Paul C; Wakim, Paul G; Trivedi, Madhukar H; Somoza, Eugene; Lewis, Daniel

2011-09-01

In clinical trials of treatment for stimulant abuse, researchers commonly record both Time-Line Follow-Back (TLFB) self-reports and urine drug screen (UDS) results. To compare the power of self-report, qualitative (use vs. no use) UDS assessment, and various algorithms to generate self-report-UDS composite measures to detect treatment differences via t-test in simulated clinical trial data. We performed Monte Carlo simulations patterned in part on real data to model self-report reliability, UDS errors, dropout, informatively missing UDS reports, incomplete adherence to a urine donation schedule, temporal correlation of drug use, number of days in the study period, number of patients per arm, and distribution of drug-use probabilities. Investigated algorithms include maximum likelihood and Bayesian estimates, self-report alone, UDS alone, and several simple modifications of self-report (referred to here as ELCON algorithms) which eliminate perceived contradictions between it and UDS. Among the algorithms investigated, simple ELCON algorithms gave rise to the most powerful t-tests to detect mean group differences in stimulant drug use. Further investigation is needed to determine if simple, naïve procedures such as the ELCON algorithms are optimal for comparing clinical study treatment arms. But researchers who currently require an automated algorithm in scenarios similar to those simulated for combining TLFB and UDS to test group differences in stimulant use should consider one of the ELCON algorithms. This analysis continues a line of inquiry which could determine how best to measure outpatient stimulant use in clinical trials (NIDA. NIDA Monograph-57: Self-Report Methods of Estimating Drug Abuse: Meeting Current Challenges to Validity. NTIS PB 88248083. Bethesda, MD: National Institutes of Health, 1985; NIDA. NIDA Research Monograph 73: Urine Testing for Drugs of Abuse. NTIS PB 89151971. Bethesda, MD: National Institutes of Health, 1987; NIDA. NIDA Research Monograph 167: The Validity of Self-Reported Drug Use: Improving the Accuracy of Survey Estimates. NTIS PB 97175889. GPO 017-024-01607-1. Bethesda, MD: National Institutes of Health, 1997).

A Quantitative Assessment of the Reporting Quality of Herbal Medicine Research: The Road to Improvement.

PubMed

Naumann, Ken

2018-02-01

To quantify different aspects of the quality of reporting of herbal medicine clinical trials, to determine how that quality is affecting the conclusions of meta-analyses, and to target areas for improvement in future herbal medicine research reporting. The Electronic databases PubMed, Academic Search Premier, ScienceDirect, and Alt HealthWatch were searched for meta-analyses of herbal medicines in refereed journals and Cochrane Reviews in the years 2000-2004 and 2010-2014. The search was limited to meta-analyses of randomized controlled trials involving humans and published in English. Judgments and descriptions within the meta-analyses were used to report on risks of bias in the included clinical trials and the meta-analyses themselves. Out of 3264 citations, 9 journal-published meta-analyses were selected from 2000 to 2004, 116 from 2010 to 2014, and 44 Cochrane Reviews from 2010 to 2014. Across both time frames and categories of publication, <42% of the trials included in the meta-analyses described adequate randomization; <19% described concealment methods; <26% described double blinding; <29% described outcome assessment blinding, ≤53% discussed incomplete data, and <36% were nonselective in their reporting. Less than 54% of trials reported on adverse events and 64% of meta-analyses did not include a single trial with a low risk of bias. Taxonomic verification and chemical characterization of test products were infrequent in trials. Only 40% of meta-analyses considered publication bias and, of those that did, 90% found evidence for it. Cochrane Reviews were more likely than other sources to make negative conclusions of efficacy or to defer conclusions because of the absence of high quality trials. Meta-analyses of herbal medicines include a significant number of clinical trials that do not meet the recommended standards for clinical trial reporting. This quantitative assessment identified significant publication bias and other bias risks that may be due to inadequate trial design or incomplete reporting of outcomes. Suggested improvements to herbal medicine clinical trial reporting are discussed.

Evaluation of a prototype interactive consent program for pediatric clinical trials: a pilot study

PubMed Central

Voepel-Lewis, Terri; McGonegal, Maureen; Levine, Robert

2011-01-01

Standard written methods of presenting research information may be difficult for many parents and children to understand. This pilot study was designed to examine the use of a novel prototype interactive consent program for describing a hypothetical pediatric asthma trial to parents and children. Parents and children were interviewed to examine their baseline understanding of key elements of a clinical trial, eg, randomization, placebo, and blinding. Subjects then reviewed age-appropriate versions of an interactive computer program describing an asthma trial, and their understanding of key research concepts was again tested along with their understanding of the details of the trial. Parents and children also completed surveys to examine their perceptions and satisfaction with the program. Both parents and children demonstrated improved understanding of key research concepts following administration of the consent program. For example, the percentage of parents and children who could correctly define the terms clinical trials and placebo improved from 60% to 80%, and 80% to 100% among parents and 25% to 50% and 0% to 50% among children, respectively, following review of the interactive programs. Parents and children's overall understanding of the details of the asthma trial were 14.2±0.84 and 9.25±4.9 (0–15 scale, where 15 is complete understanding), respectively. Results also suggest that the interactive programs were easy to use and facilitated understanding of the clinical trial among parents and children. Interactive media may offer an effective means of presenting understandable information to parents and children regarding participation in clinical trials. Further work to examine this novel approach appears warranted. PMID:21803924

Adapting Social Neuroscience Measures for Schizophrenia Clinical Trials, Part 2: Trolling the Depths of Psychometric Properties

PubMed Central

Kern, Robert S.

2013-01-01

The psychometric properties of 4 paradigms adapted from the social neuroscience literature were evaluated to determine their suitability for use in clinical trials of schizophrenia. This 2-site study (University of California, Los Angeles and University of North Carolina) included 173 clinically stable schizophrenia outpatients and 88 healthy controls. The social cognition battery was administered twice to the schizophrenia group (baseline, 4-week retest) and once to the control group. The 4 paradigms included 2 that assess perception of nonverbal social and action cues (basic biological motion and emotion in biological motion) and 2 that involve higher level inferences about self and others’ mental states (self-referential memory and empathic accuracy). Each paradigm was evaluated on (1) patient vs healthy control group differences, (2) test-retest reliability, (3) utility as a repeated measure, and (4) tolerability. Of the 4 paradigms, empathic accuracy demonstrated the strongest characteristics, including large between-group differences, adequate test-retest reliability (.72), negligible practice effects, and good tolerability ratings. The other paradigms showed weaker psychometric characteristics in their current forms. These findings highlight challenges in adapting social neuroscience paradigms for use in clinical trials. PMID:24072805

A novel approach to rater training and certification in multinational trials.

PubMed

Jeglic, Elizabeth; Kobak, Kenneth A; Engelhardt, Nina; Williams, Janet B W; Lipsitz, Joshua D; Salvucci, Donna; Bryson, Heather; Bellew, Kevin

2007-07-01

Clinical trials are becoming increasingly international in scope. Global studies pose unique challenges in training and calibrating raters owing to language and cultural differences. Recent findings that poorly conducted interviews reduce study power, makes attention to raters' clinical skills critical. In this study, 109 raters from 14 countries went through a two-step certification process on the Hamilton Depression and Anxiety Rating Scales: (i) an online didactic tutorial on scoring conventions, and (ii) applied clinical training, consisting of small language-specific groups in which raters took turns interviewing patients while observed by an expert trainer, and observation and evaluation of individual interviews. Translators were used when native-language trainers were unavailable. Those who were unable to attend the startup meeting received the training individually via telephone. Results found a significant improvement in raters' knowledge of scoring conventions, with the mean number of correct answers on the 20-item test improving from 14.59 to 17.83, P<0.0001. In addition, raters' clinical skills improved significantly, with the mean score on the Rater Applied Performance Scale improving from their first to their second testing from 10.25 to 11.31, P=0.003. These results support the efficacy of this applied training model in improving raters' applied clinical skills in multinational trials.

Uptake of Home-Based HIV Testing, Linkage to Care, and Community Attitudes about ART in Rural KwaZulu-Natal, South Africa: Descriptive Results from the First Phase of the ANRS 12249 TasP Cluster-Randomised Trial

PubMed Central

Okesola, Nonhlanhla; Tanser, Frank; Thiebaut, Rodolphe; Rekacewicz, Claire; Newell, Marie-Louise

2016-01-01

Background The 2015 WHO recommendation of antiretroviral therapy (ART) for all immediately following HIV diagnosis is partially based on the anticipated impact on HIV incidence in the surrounding population. We investigated this approach in a cluster-randomised trial in a high HIV prevalence setting in rural KwaZulu-Natal. We present findings from the first phase of the trial and report on uptake of home-based HIV testing, linkage to care, uptake of ART, and community attitudes about ART. Methods and Findings Between 9 March 2012 and 22 May 2014, five clusters in the intervention arm (immediate ART offered to all HIV-positive adults) and five clusters in the control arm (ART offered according to national guidelines, i.e., CD4 count ≤ 350 cells/μl) contributed to the first phase of the trial. Households were visited every 6 mo. Following informed consent and administration of a study questionnaire, each resident adult (≥16 y) was asked for a finger-prick blood sample, which was used to estimate HIV prevalence, and offered a rapid HIV test using a serial HIV testing algorithm. All HIV-positive adults were referred to the trial clinic in their cluster. Those not linked to care 3 mo after identification were contacted by a linkage-to-care team. Study procedures were not blinded. In all, 12,894 adults were registered as eligible for participation (5,790 in intervention arm; 7,104 in control arm), of whom 9,927 (77.0%) were contacted at least once during household visits. HIV status was ever ascertained for a total of 8,233/9,927 (82.9%), including 2,569 ascertained as HIV-positive (942 tested HIV-positive and 1,627 reported a known HIV-positive status). Of the 1,177 HIV-positive individuals not previously in care and followed for at least 6 mo in the trial, 559 (47.5%) visited their cluster trial clinic within 6 mo. In the intervention arm, 89% (194/218) initiated ART within 3 mo of their first clinic visit. In the control arm, 42.3% (83/196) had a CD4 count ≤ 350 cells/μl at first visit, of whom 92.8% initiated ART within 3 mo. Regarding attitudes about ART, 93% (8,802/9,460) of participants agreed with the statement that they would want to start ART as soon as possible if HIV-positive. Estimated baseline HIV prevalence was 30.5% (2,028/6,656) (95% CI 25.0%, 37.0%). HIV prevalence, uptake of home-based HIV testing, linkage to care within 6 mo, and initiation of ART within 3 mo in those with CD4 count ≤ 350 cells/μl did not differ significantly between the intervention and control clusters. Selection bias related to noncontact could not be entirely excluded. Conclusions Home-based HIV testing was well received in this rural population, although men were less easily contactable at home; immediate ART was acceptable, with good viral suppression and retention. However, only about half of HIV-positive people accessed care within 6 mo of being identified, with nearly two-thirds accessing care by 12 mo. The observed delay in linkage to care would limit the individual and public health ART benefits of universal testing and treatment in this population. Trial registration ClinicalTrials.gov NCT01509508 PMID:27504637

Physical performance and clinical outcomes in dialysis patients: a secondary analysis of the EXCITE trial.

PubMed

Torino, Claudia; Manfredini, Fabio; Bolignano, Davide; Aucella, Filippo; Baggetta, Rossella; Barillà, Antonio; Battaglia, Yuri; Bertoli, Silvio; Bonanno, Graziella; Castellino, Pietro; Ciurlino, Daniele; Cupisti, Adamasco; D'Arrigo, Graziella; De Paola, Luciano; Fabrizi, Fabrizio; Fatuzzo, Pasquale; Fuiano, Giorgio; Lombardi, Luigi; Lucisano, Gaetano; Messa, Piergiorgio; Rapanà, Renato; Rapisarda, Francesco; Rastelli, Stefania; Rocca-Rey, Lisa; Summaria, Chiara; Zuccalà, Alessandro; Tripepi, Giovanni; Catizone, Luigi; Zoccali, Carmine; Mallamaci, Francesca

2014-01-01

Scarce physical activity predicts shorter survival in dialysis patients. However, the relationship between physical (motor) fitness and clinical outcomes has never been tested in these patients. We tested the predictive power of an established metric of motor fitness, the Six-Minute Walking Test (6MWT), for death, cardiovascular events and hospitalization in 296 dialysis patients who took part in the trial EXCITE (ClinicalTrials.gov Identifier: NCT01255969). During follow up 69 patients died, 90 had fatal and non-fatal cardiovascular events, 159 were hospitalized and 182 patients had the composite outcome. In multivariate Cox models - including the study allocation arm and classical and non-classical risk factors - an increase of 20 walked metres during the 6MWT was associated to a 6% reduction of the risk for the composite end-point (P=0.001) and a similar relationship existed between the 6MWT, mortality (P<0.001) and hospitalizations (P=0.03). A similar trend was observed for cardiovascular events but this relationship did not reach statistical significance (P=0.09). Poor physical performance predicts a high risk of mortality, cardiovascular events and hospitalizations in dialysis patients. Future studies, including phase-2 EXCITE, will assess whether improving motor fitness may translate into better clinical outcomes in this high risk population. © 2014 S. Karger AG, Basel.

Implementation Quality: Lessons Learned in the Context of the Head Start REDI Trial

ERIC Educational Resources Information Center

Domitrovich, Celene E.; Gest, Scott D.; Jones, Damon; Gill, Sukhdeep; Sanford DeRousie, Rebecca M.

2010-01-01

This study uses data collected in the intervention classrooms (N = 22) of Head Start REDI (Research-based, Developmentally Informed), a randomized clinical trial testing the efficacy of a comprehensive preschool curriculum targeting children's social-emotional competence, language, and emergent literacy skills delivered by teachers who received…

A review of monochromatic light devices for the treatment of alopecia areata.

PubMed

Darwin, Evan; Arora, Harleen; Hirt, Penelope A; Wikramanayake, Tongyu Cao; Jimenez, Joaquin J

2018-02-01

There are many laser technologies that are being tested that claim to support hair regrowth for patients with alopecia areata (AA). In this paper, we will determine whether the body of evidence supports the use of devices using monochromatic light sources to treat AA. Articles were gathered from PubMed, Embase, and the Cochrane database using these keywords: lasers, excimer laser, low-level laser therapy (LLLT), low-level light therapy, alopecia, alopecia areata, and hair loss with a category modifier of English. Ten clinical trials and seven case reports/abstracts were assessed. Eight clinical trials and two case reports demonstrated hair regrowth with the 308-nm excimer laser/light in men, women, and children. One case report demonstrated hair regrowth with the ALBA 355® laser. One clinical trial and two case reports demonstrated hair regrowth with LLLT. While two case reports demonstrated hair regrowth with fractional laser therapy, one clinical trial showed no improvement. The 308-nm excimer laser is a safe and effective treatment for men, women, and children with refractory AA of the scalp and beard. Larger, double-blinded clinical trials should be conducted to compare excimer laser therapy to standard treatments. More data is needed to determine the efficacy of LLLT and fractional laser therapy in the treatment of AA.

The costs associated with adverse event procedures for an international HIV clinical trial determined by activity-based costing.

PubMed

Chou, Victoria B; Omer, Saad B; Hussain, Hamidah; Mugasha, Christine; Musisi, Maria; Mmiro, Francis; Musoke, Philippa; Jackson, J Brooks; Guay, Laura A

2007-12-01

To determine costs for adverse event (AE) procedures for a large HIV perinatal trial by analyzing actual resource consumption using activity-based costing (ABC) in an international research setting. The AE system for an ongoing clinical trial in Uganda was evaluated using ABC techniques to determine costs from the perspective of the study. Resources were organized into cost categories (eg, personnel, patient care expenses, laboratory testing, equipment). Cost drivers were quantified, and unit cost per AE was calculated. A subset of time and motion studies was performed prospectively to observe clinic personnel time required for AE identification. In 18 months, there were 9028 AEs, with 970 (11%) reported as serious adverse events. Unit cost per AE was $101.97. Overall, AE-related costs represented 32% ($920,581 of $2,834,692) of all study expenses. Personnel ($79.30) and patient care ($11.96) contributed the greatest proportion of component costs. Reported AEs were predominantly nonserious (mild or moderate severity) and unrelated to study drug(s) delivery. Intensive identification and management of AEs to conduct clinical trials ethically and protect human subjects require expenditure of substantial human and financial resources. Better understanding of these resource requirements should improve planning and funding of international HIV-related clinical trials.

How might acupuncture work? A systematic review of physiologic rationales from clinical trials.

PubMed

Moffet, Howard H

2006-07-07

Scientific interest in acupuncture has led numerous investigators to conduct clinical trials to test the efficacy of acupuncture for various conditions, but the mechanisms underlying acupuncture are poorly understood. The author conducted a PubMed search to obtain a fair sample of acupuncture clinical trials published in English in 2005. Each article was reviewed for a physiologic rationale, as well as study objectives and outcomes, experimental and control interventions, country of origin, funding sources and journal type. Seventy-nine acupuncture clinical trials were identified. Twenty-six studies (33%) offered no physiologic rationale. Fifty-three studies (67%) posited a physiologic basis for acupuncture: 33 (62% of 53) proposed neurochemical mechanisms, 2 (4%) segmental nervous system effects, 6 (11%) autonomic nervous system regulation, 3 (6%) local effects, 5 (9%) effects on brain function and 5 (9%) other effects. No rationale was proposed for stroke; otherwise having a rationale was not associated with objective, positive or negative findings, means of intervention, country of origin, funding source or journal type. The dominant explanation for how acupuncture might work involves neurochemical responses and is not reported to be dependent on treatment objective, specific points, means or method of stimulation. Many acupuncture trials fail to offer a meaningful rationale, but proposing a rationale can help investigators to develop and test a causal hypothesis, choose an appropriate control and rule out placebo effects. Acupuncture may stimulate self-regulatory processes independent of the treatment objective, points, means or methods used; this would account for acupuncture's reported benefits in so many disparate pathologic conditions.

Whose data set is it anyway? Sharing raw data from randomized trials.

PubMed

Vickers, Andrew J

2006-05-16

Sharing of raw research data is common in many areas of medical research, genomics being perhaps the most well-known example. In the clinical trial community investigators routinely refuse to share raw data from a randomized trial without giving a reason. Data sharing benefits numerous research-related activities: reproducing analyses; testing secondary hypotheses; developing and evaluating novel statistical methods; teaching; aiding design of future trials; meta-analysis; and, possibly, preventing error, fraud and selective reporting. Clinical trialists, however, sometimes appear overly concerned with being scooped and with misrepresentation of their work. Both possibilities can be avoided with simple measures such as inclusion of the original trialists as co-authors on any publication resulting from data sharing. Moreover, if we treat any data set as belonging to the patients who comprise it, rather than the investigators, such concerns fall away. Technological developments, particularly the Internet, have made data sharing generally a trivial logistical problem. Data sharing should come to be seen as an inherent part of conducting a randomized trial, similar to the way in which we consider ethical review and publication of study results. Journals and funding bodies should insist that trialists make raw data available, for example, by publishing data on the Web. If the clinical trial community continues to fail with respect to data sharing, we will only strengthen the public perception that we do clinical trials to benefit ourselves, not our patients.

Older cancer patients in cancer clinical trials are underrepresented. Systematic literature review of almost 5000 meta- and pooled analyses of phase III randomized trials of survival from breast, prostate and lung cancer.

PubMed

Dunn, Cita; Wilson, Andrew; Sitas, Freddy

2017-12-01

Older people represent increasing proportions of the population with cancer. To understand the representivity of cancer treatments in older people, we performed a systematic literature review using PRISMA guidelines of the age distribution of clinical trial participants for three leading cancer types, namely breast, prostate, and lung. We used PubMed to identify articles detailing meta or pooled-analyses of phase III, randomised controlled trials (RCTs) of survival for breast, prostate and lung cancer, published ≤5 years from 2016. We compared the age distribution of participants to that of these cancers for "More developed regions". 4993 potential papers were identified, but only three papers on breast cancer, three on lung cancer, and none on prostate cancer presented the age distribution of their participants. Except for one paper of breast cancer, participants ≥70 years in all other papers were underrepresented. We recommend the age distribution of patients be clearly reported in all clinical trials, as per guidelines. Clinical trials ought to be more representative of the populations most affected by the disease for which treatments are being tested. This should lead to better knowledge of effectiveness of treatments and better translation of trial results to optimal care of older cancer patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

Hypothesis testing in clinical trials.

PubMed

Green, S B

2000-08-01

In designing and analyzing any clinical trial, two issues related to patient heterogeneity must be considered: (1) the effect of chance and (2) the effect of bias. These issues are addressed by enrolling adequate numbers of patients in the study and using randomization for treatment assignment. An "intention-to-treat" analysis of outcome data includes all individuals randomized and counted in the group to which they are randomized. There is an increased risk of spurious results with a greater number of subgroup analyses, particularly when these analyses are data derived. Factorial designs are sometimes appropriate and can lead to efficiencies by addressing more than one comparison of interventions in a single trial.

Potential Psychiatric Uses for MDMA.

PubMed

Yazar-Klosinski, B B; Mithoefer, M C

2017-02-01

Phase II trials of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy have demonstrated initial safety and efficacy for treatment of posttraumatic stress disorder (PTSD), with potential for expansion to depression and anxiety disorders. In these trials, single doses of MDMA are administered in a model of medication-assisted psychotherapy, differing from trials involving daily drug administration without psychotherapy. This model presents an opportunity to utilize accelerated regulatory pathways, such as the US Food and Drug Administration (FDA) Breakthrough Therapy Designation, to most effectively and expeditiously test such novel approaches. © 2016, The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

An Analysis of Factors Affecting Successful Clinical Trial Enrollment in the Context of Three Prospective Randomized Control Trials

PubMed Central

Logan, Jennifer K; Tang, Chad; Liao, Zhongxing; Lee, J. Jack; Heymach, John V.; Swisher, Stephen G.; Welsh, James W.; Zhang, Jianjun; Lin, Steven H.; Gomez, Daniel R.

2018-01-01

Purpose Effective clinical trial enrollment can be difficult in a protocol designs that contain one treatment arm that is perceived as being more “aggressive” or “favorable.” There have been limited studies focusing on the barriers to enrollment and the efficacy of alternative study design to improve accrual. We analyzed barriers to enrollment, particularly the influence of timing, in context of three prospective randomized oncology trials where one arm was considered more aggressive. Methods and materials From June 2011 to March 2015, patients who were enrolled on three prospective institutional protocols (an oligometastatic non-small cell lung cancer (NSCLC) trial, and two proton vs. intensity-modulated radiation therapy (IMRT) trials in NSCLC and esophageal cancer) were screened for protocol eligibility. Eligible candidates were approached about trial participation, and patient characteristics (age, sex, T/N categorization) were recorded along with details surrounding trial presentation (appointment number). Fisher’s exact test, Student’s t tests, and multivariate analysis were performed to assess differences between enrolled and refusal patients. Results 309 eligible patients were approached about trial enrollment. The enrollment success rate (ESR) during this time span was 52% (n=160 patients). Enrolled patients were more likely to be presented trial information at an earlier appointment (oligomet protocol: 5 vs. 3 appointments (P<0.001), NSCLC protocol: 4 vs. 3 appointments (P = 0.0018), esophageal protocol: 3 vs. 2 appointments (P = 0.0086No other factors or patient characteristics significantly affected ESR. Conclusion Improvement in enrollment rates for randomized control trials is possible, even in difficult accrual settings. Earlier presentation of trial information to patients is the most influential factor for success, and may help overcome accrual barriers without compromising trial design. PMID:28244413

Integrating Comparative Effectiveness Design Elements and Endpoints Into a Phase III, Randomized Clinical Trial (SWOG S1007) Evaluating OncotypeDX-Guided Management for Women With Breast Cancer Involving Lymph Nodes

PubMed Central

Ramsey, Scott D.; Barlow, William E.; Gonzalez-Angulo, Ana M.; Tunis, Sean; Baker, Laurence; Crowley, John; Deverka, Patricia; Veenstra, David; Hortobagyi, Gabriel N.

2012-01-01

Women with breast cancer involving the lymph nodes are typically treated with cytotoxic chemotherapy. Retrospective evaluations of prior studies suggest that the 21-gene test (OncotypeDX®), may allow identification of those who can safely avoid chemotherapy. To better understand the performance of the 21-gene test, the RxPONDER (Rx for Positive Node, Endocrine Responsive breast cancer) study was designed, a multicenter Phase III trial randomizing women with hormone receptor-positive and HER2-negative breast cancer involving 1–3 lymph nodes and a 21-gene assay recurrence score (RS) of 25 or less to endocrine therapy alone versus chemotherapy followed by endocrine therapy. As one of the first large-scale comparative-effectiveness studies in oncology, RxPONDER utilized an external stakeholder group to help inform the design of the trial. Stakeholders met with representatives of SWOG over several months through a structured discussion process. The stakeholder engagement process resulted in several changes being made to the trial design. In addition, stakeholder representatives from the health insurance industry provided guidance regarding a mechanism whereby the costs of OncotypeDX® would be paid by the majority of health insurers as part of the trial. The process may serve as a template for future studies evaluating the comparative effectiveness of genomic tests in oncology, particularly those that are conducted within cooperative clinical trials groups. PMID:23000081

Mixed-Meal Tolerance Test Versus Glucagon Stimulation Test for the Assessment of β-Cell Function in Therapeutic Trials in Type 1 Diabetes

PubMed Central

Greenbaum, Carla J.; Mandrup-Poulsen, Thomas; McGee, Paula Friedenberg; Battelino, Tadej; Haastert, Burkhard; Ludvigsson, Johnny; Pozzilli, Paolo; Lachin, John M.; Kolb, Hubert

2008-01-01

OBJECTIVE—β-Cell function in type 1 diabetes clinical trials is commonly measured by C-peptide response to a secretagogue in either a mixed-meal tolerance test (MMTT) or a glucagon stimulation test (GST). The Type 1 Diabetes TrialNet Research Group and the European C-peptide Trial (ECPT) Study Group conducted parallel randomized studies to compare the sensitivity, reproducibility, and tolerability of these procedures. RESEARCH DESIGN AND METHODS—In randomized sequences, 148 TrialNet subjects completed 549 tests with up to 2 MMTT and 2 GST tests on separate days, and 118 ECPT subjects completed 348 tests (up to 3 each) with either two MMTTs or two GSTs. RESULTS—Among individuals with up to 4 years’ duration of type 1 diabetes, >85% had measurable stimulated C-peptide values. The MMTT stimulus produced significantly higher concentrations of C-peptide than the GST. Whereas both tests were highly reproducible, the MMTT was significantly more so (R2 = 0.96 for peak C-peptide response). Overall, the majority of subjects preferred the MMTT, and there were few adverse events. Some older subjects preferred the shorter duration of the GST. Nausea was reported in the majority of GST studies, particularly in the young age-group. CONCLUSIONS—The MMTT is preferred for the assessment of β-cell function in therapeutic trials in type 1 diabetes. PMID:18628574

Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes.

PubMed

Greenbaum, Carla J; Mandrup-Poulsen, Thomas; McGee, Paula Friedenberg; Battelino, Tadej; Haastert, Burkhard; Ludvigsson, Johnny; Pozzilli, Paolo; Lachin, John M; Kolb, Hubert

2008-10-01

Beta-cell function in type 1 diabetes clinical trials is commonly measured by C-peptide response to a secretagogue in either a mixed-meal tolerance test (MMTT) or a glucagon stimulation test (GST). The Type 1 Diabetes TrialNet Research Group and the European C-peptide Trial (ECPT) Study Group conducted parallel randomized studies to compare the sensitivity, reproducibility, and tolerability of these procedures. In randomized sequences, 148 TrialNet subjects completed 549 tests with up to 2 MMTT and 2 GST tests on separate days, and 118 ECPT subjects completed 348 tests (up to 3 each) with either two MMTTs or two GSTs. Among individuals with up to 4 years' duration of type 1 diabetes, >85% had measurable stimulated C-peptide values. The MMTT stimulus produced significantly higher concentrations of C-peptide than the GST. Whereas both tests were highly reproducible, the MMTT was significantly more so (R(2) = 0.96 for peak C-peptide response). Overall, the majority of subjects preferred the MMTT, and there were few adverse events. Some older subjects preferred the shorter duration of the GST. Nausea was reported in the majority of GST studies, particularly in the young age-group. The MMTT is preferred for the assessment of beta-cell function in therapeutic trials in type 1 diabetes.

Low molecular weight heparins in the prevention of deep-vein thrombosis in general surgery.

PubMed

Breddin, H K

1999-01-01

Unfractionated heparin (UFH) was the established treatment in the early 1980s for the prophylaxis of venous thromboembolic disease (VTED) in patients undergoing general surgery. This was one of the earliest indications in which low molecular weight heparins (LMWHs) were tested, and about 40 trials have revealed that these agents are at least as effective and safe as UFH with a tendency of superiority when higher dosages are used. In most trials, the fibrinogen uptake test has been used to assess the frequency of deep vein thrombosis. LMWHs exhibit a number of improved features over UFH, including ease of administration and convenient once daily dosing, facilitating outpatient management. A still open question is the ideal time and dose of the first one or two injections of a LMWH. To determine the clinical relevance of product differentiation further, clinical trials, directly comparing different LMWHs, are required.

Old and new acetylcholinesterase inhibitors for Alzheimer's disease.

PubMed

Galimberti, Daniela; Scarpini, Elio

2016-10-01

To date, pharmacological treatment of Alzheimer's disease (AD) includes Acetylcholinesterase Inhibitors (AChEIs) for mild-to-moderate AD, and memantine for moderate-to-severe AD. AChEIs reversibly inhibit acetylcholinesterase (AChE), thus increasing the availability of acetylcholine in cholinergic synapses, enhancing cholinergic transmission. These drugs provide symptomatic short-term benefits, without clearly counteracting the progression of the disease. On the wake of successful clinical trials which lead to the marketing of AChEIs donepezil, rivastigmine and galantamine, many compounds with AChEI properties have been developed and tested mainly in Phase I-II clinical trials in the last twenty years. Here, we review clinical trials initiated and interrupted, and those ongoing so far. Despite many clinical trials with novel AChEIs have been carried out after the registration of those currently used to treat mild to moderate AD, none so far has been successful in a Phase III trial and marketed. Alzheimer's disease is a complex multifactorial disorder, therefore therapy should likely address not only the cholinergic system but also additional neurotransmitters. Moreover, such treatments should be started in very mild phases of the disease, and preventive strategies addressed in elderly people.

Healthy participants in phase I clinical trials: the quality of their decision to take part.

PubMed

Rabin, Cheryl; Tabak, Nili

2006-08-01

This study was set out to test the quality of the decision-making process of healthy volunteers in clinical trials. Researchers fear that the decision to volunteer for clinical trials is taken inadequately and that the signature on the consent forms, meant to affirm that consent was 'informed', is actually insubstantial. The study design was quasi-experimental, using a convenience quota sample. Over a period of a year, candidates were approached during their screening process for a proposed clinical trial, after concluding the required 'Informed Consent' procedure. In all, 100 participants in phase I trials filled out questionnaires based ultimately on the Janis and Mann model of vigilant information processing, during their stay in the research centre. Only 35% of the participants reached a 'quality decision'. There is a definite correlation between information processing and quality decision-making. However, many of the healthy research volunteers (58%) do not seek out information nor check alternatives before making a decision. Full disclosure is essential to a valid informed consent procedure but not sufficient; emphasis must be put on having the information understood and assimilated. Research nurses play a central role in achieving this objective.

Biosimilars in Inflammatory Bowel Disease: Facts and Fears of Extrapolation.

PubMed

Ben-Horin, Shomron; Vande Casteele, Niels; Schreiber, Stefan; Lakatos, Peter Laszlo

2016-12-01

Biologic drugs such as infliximab and other anti-tumor necrosis factor monoclonal antibodies have transformed the treatment of immune-mediated inflammatory conditions such as Crohn's disease and ulcerative colitis (collectively known as inflammatory bowel disease [IBD]). However, the complex manufacturing processes involved in producing these drugs mean their use in clinical practice is expensive. Recent or impending expiration of patents for several biologics has led to development of biosimilar versions of these drugs, with the aim of providing substantial cost savings and increased accessibility to treatment. Biosimilars undergo an expedited regulatory process. This involves proving structural, functional, and biological biosimilarity to the reference product (RP). It is also expected that clinical equivalency/comparability will be demonstrated in a clinical trial in one (or more) sensitive population. Once these requirements are fulfilled, extrapolation of biosimilar approval to other indications for which the RP is approved is permitted without the need for further clinical trials, as long as this is scientifically justifiable. However, such justification requires that the mechanism(s) of action of the RP in question should be similar across indications and also comparable between the RP and the biosimilar in the clinically tested population(s). Likewise, the pharmacokinetics, immunogenicity, and safety of the RP should be similar across indications and comparable between the RP and biosimilar in the clinically tested population(s). To date, most anti-tumor necrosis factor biosimilars have been tested in trials recruiting patients with rheumatoid arthritis. Concerns have been raised regarding extrapolation of clinical data obtained in rheumatologic populations to IBD indications. In this review, we discuss the issues surrounding indication extrapolation, with a focus on extrapolation to IBD. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Daily electronic self-monitoring of subjective and objective symptoms in bipolar disorder--the MONARCA trial protocol (MONitoring, treAtment and pRediCtion of bipolAr disorder episodes): a randomised controlled single-blind trial.

PubMed

Faurholt-Jepsen, Maria; Vinberg, Maj; Christensen, Ellen Margrethe; Frost, Mads; Bardram, Jakob; Kessing, Lars Vedel

2013-01-01

Electronic self-monitoring of affective symptoms using cell phones is suggested as a practical and inexpensive way to monitor illness activity and identify early signs of affective symptoms. It has never been tested in a randomised clinical trial whether electronic self-monitoring improves outcomes in bipolar disorder. We are conducting a trial testing the effect of using a Smartphone for self-monitoring in bipolar disorder. We developed the MONARCA application for Android-based Smartphones, allowing patients suffering from bipolar disorder to do daily self-monitoring-including an interactive feedback loop between patients and clinicians through a web-based interface. The effect of the application was tested in a parallel-group, single-blind randomised controlled trial so far including 78 patients suffering from bipolar disorder in the age group 18-60 years who were given the use of a Smartphone with the MONARCA application (intervention group) or to the use of a cell phone without the application (placebo group) during a 6-month study period. The study was carried out from September 2011. The outcomes were changes in affective symptoms (primary), social functioning, perceived stress, self-rated depressive and manic symptoms, quality of life, adherence to medication, stress and cognitive functioning (secondary and tertiary). Recruitment is ongoing. Ethical permission has been obtained. Positive, neutral and negative findings of the study will be published. The trial is approved by the Regional Ethics Committee in The Capital Region of Denmark (H-2-2011-056) and The Danish Data Protection Agency (2013-41-1710). The trial is registered at ClinicalTrials.gov as NCT01446406.

Value of information analysis optimizing future trial design from a pilot study on catheter securement devices.

PubMed

Tuffaha, Haitham W; Reynolds, Heather; Gordon, Louisa G; Rickard, Claire M; Scuffham, Paul A

2014-12-01

Value of information analysis has been proposed as an alternative to the standard hypothesis testing approach, which is based on type I and type II errors, in determining sample sizes for randomized clinical trials. However, in addition to sample size calculation, value of information analysis can optimize other aspects of research design such as possible comparator arms and alternative follow-up times, by considering trial designs that maximize the expected net benefit of research, which is the difference between the expected cost of the trial and the expected value of additional information. To apply value of information methods to the results of a pilot study on catheter securement devices to determine the optimal design of a future larger clinical trial. An economic evaluation was performed using data from a multi-arm randomized controlled pilot study comparing the efficacy of four types of catheter securement devices: standard polyurethane, tissue adhesive, bordered polyurethane and sutureless securement device. Probabilistic Monte Carlo simulation was used to characterize uncertainty surrounding the study results and to calculate the expected value of additional information. To guide the optimal future trial design, the expected costs and benefits of the alternative trial designs were estimated and compared. Analysis of the value of further information indicated that a randomized controlled trial on catheter securement devices is potentially worthwhile. Among the possible designs for the future trial, a four-arm study with 220 patients/arm would provide the highest expected net benefit corresponding to 130% return-on-investment. The initially considered design of 388 patients/arm, based on hypothesis testing calculations, would provide lower net benefit with return-on-investment of 79%. Cost-effectiveness and value of information analyses were based on the data from a single pilot trial which might affect the accuracy of our uncertainty estimation. Another limitation was that different follow-up durations for the larger trial were not evaluated. The value of information approach allows efficient trial design by maximizing the expected net benefit of additional research. This approach should be considered early in the design of randomized clinical trials. © The Author(s) 2014.

How can point-of-care HbA1c testing be integrated into UK primary care consultations? - A feasibility study.

PubMed

Hirst, J A; Stevens, R J; Smith, I; James, T; Gudgin, B C; Farmer, A J

2017-08-01

Point-of-care (POC) HbA1c testing gives a rapid result, allowing testing and treatment decisions to take place in a single appointment. Trials of POC testing have not been shown to improve HbA1c, possibly because of how testing was implemented. This study aimed to identify key components of POC HbA1c testing and determine strategies to optimise implementation in UK primary care. This cohort feasibility study recruited thirty patients with type 2 diabetes and HbA1c>7.5% (58mmol/mol) into three primary care clinics. Patients' clinical care included two POC HbA1c tests over six months. Data were collected on appointment duration, clinical decisions, technical performance and patient behaviour. Fifty-three POC HbA1c consultations took place during the study; clinical decisions were made in 30 consultations. Five POC consultations with a family doctor lasted on average 11min and 48 consultations with nurses took on average 24min. Five POC study visits did not take place in one clinic. POC results were uploaded to hospital records from two clinics. In total, sixty-three POC tests were performed, and there were 11 cartridge failures. No changes in HbA1c or patient behaviour were observed. HbA1c measurement with POC devices can be effectively implemented in primary care. This work has identified when these technologies might work best, as well as potential challenges. The findings can be used to inform the design of a pragmatic trial to implement POC HbA1c testing. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Results from the Xylitol for Adult Caries Trial (X-ACT)

PubMed Central

Bader, James D.; Vollmer, William M.; Shugars, Daniel A.; Gilbert, Gregg H.; Amaechi, Bennett T.; Brown, John P.; Laws, Reesa L.; Funkhouser, Kimberly A.; Makhija, Sonia K.; Ritter, André V.; Leo, Michael C.

2013-01-01

Background Although caries is prevalent in adults, few preventive therapies have been tested in adult populations. This randomized clinical trial evaluated the effectiveness of xylitol lozenges in preventing caries in elevated caries-risk adults. Methods X-ACT was a three-site placebo-controlled randomized trial. Participants (n=691) ages 21–80 consumed five 1.0 g xylitol or placebo lozenges daily for 33 months. Clinical examinations occurred at baseline, 12, 24 and 33 months. Results Xylitol lozenges reduced the caries increment 11%. This reduction, which represented less than one-third of a surface per year, was not statistically significant. There was no indication of a dose-response effect. Conclusions Daily use of xylitol lozenges did not result in a statistically or clinically significant reduction in 33-month caries increment among elevated caries-risk adults. Clinical Implications These results suggest that xylitol used as a supplement in adults does not significantly reduce their caries experience. PMID:23283923

Development of questionnaires to measure patient preferences for intranasal corticosteroids in patients with allergic rhinitis.

PubMed

Meltzer, Eli O; Hadley, James; Blaiss, Michael; Benninger, Michael; Kimel, Miriam; Kleinman, Leah; Dupclay, Leon; Garcia, Jorge; Leahy, Michael; Georges, George

2005-02-01

To develop a questionnaire to evaluate preferences for attributes of intranasal corticosteroids (INSs) in clinical trials with allergic rhinitis (AR) patients. Established questionnaire development practices were used, including performance of a literature review and use of patient and physician focus groups, cognitive debriefing interviews, and pilot testing before validation. Findings from patient and physician focus groups suggest that sensory attributes are relevant to AR patients when choosing INSs. Physician focus groups identified the need for 2 distinct preference instruments, a clinical trial patient preference questionnaire (CTPPQ) and a clinical practice preference questionnaire (CPPPQ). A pilot study suggests that the CTPPQ is capable of discriminating between 2 INSs in the clinical trial setting. Initial findings suggest that items in the CTPPQ and CPPPQ are easy to understand and relevant to patients. Further validation studies with larger sample sizes are needed to assess the psychometric properties of both questionnaires. B-20.

The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study.

PubMed

Millward, M J; House, C; Bowtell, D; Webster, L; Olver, I N; Gore, M; Copeman, M; Lynch, K; Yap, A; Wang, Y; Cohen, P S; Zalcberg, J

2006-10-09

Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases. In mice, midostaurin slows growth and delays lung metastasis of melanoma cell lines. We aimed to test midostaurin's safety, efficacy and biologic activity in a Phase IIA clinical trial in patients with metastatic melanoma. Seventeen patients with advanced metastatic melanoma received midostaurin 75 mg p.o. t.i.d., unless toxicity or disease progression supervened. Patient safety was assessed weekly, and tumour response was assessed clinically or by CT. Tumour biopsies and plasma samples obtained at entry and after 4 weeks were analysed for midostaurin concentration, PKC activity and multidrug resistance. No tumour responses were seen. Two (12%) patients had stable disease for 50 and 85 days, with minor response in one. The median overall survival was 43 days. Seven (41%) discontinued treatment with potential toxicity, including nausea, vomiting, diarrhoea and/or fatigue. One patient had >50% reduction in PKC activity. Tumour biopsies showed two PKC isoforms relatively insensitive to midostaurin, out of three patients tested. No modulation of multidrug resistance was demonstrated. At this dose schedule, midostaurin did not show clinical or biologic activity against metastatic melanoma. This negative trial reinforces the importance of correlating biologic and clinical responses in early clinical trials of targeted therapies.

Safety and Tolerability of Essential Oil from Cinnamomum zeylanicum Blume Leaves with Action on Oral Candidosis and Its Effect on the Physical Properties of the Acrylic Resin

PubMed Central

Oliveira, Julyana de Araújo; da Silva, Ingrid Carla Guedes; Trindade, Leonardo Antunes; Lima, Edeltrudes Oliveira; Carlo, Hugo Lemes; Cavalcanti, Alessandro Leite; de Castro, Ricardo Dias

2014-01-01

The anti-Candida activity of essential oil from Cinnamomum zeylanicum Blume, as well as its effect on the roughness and hardness of the acrylic resin used in dental prostheses, was assessed. The safety and tolerability of the test product were assessed through a phase I clinical trial involving users of removable dentures. Minimum inhibitory concentration (MIC) and minimum fungicidal concentrations (MFC) were determined against twelve Candida strains. Acrylic resin specimens were exposed to artificial saliva (GI), C. zeylanicum (GII), and nystatin (GIII) for 15 days. Data were submitted to ANOVA and Tukey posttest (α = 5%). For the phase I clinical trial, 15 healthy patients used solution of C. zeylanicum at MIC (15 days, 3 times a day) and were submitted to clinical and mycological examinations. C. zeylanicum showed anti-Candida activity, with MIC = 625.0 µg/mL being equivalent to MFC. Nystatin caused greater increase in roughness and decreased the hardness of the material (P < 0.0001), with no significant differences between GI and GII. As regards the clinical trial, no adverse clinical signs were observed after intervention. The substance tested had a satisfactory level of safety and tolerability, supporting new advances involving the clinical use of essential oil from C. zeylanicum. PMID:25574178

Unreported links between trial registrations and published articles were identified using document similarity measures in a cross-sectional analysis of ClinicalTrials.gov.

PubMed

Dunn, Adam G; Coiera, Enrico; Bourgeois, Florence T

2018-03-01

Trial registries can be used to measure reporting biases and support systematic reviews, but 45% of registrations do not provide a link to the article reporting on the trial. We evaluated the use of document similarity methods to identify unreported links between ClinicalTrials.gov and PubMed. We extracted terms and concepts from a data set of 72,469 ClinicalTrials.gov registrations and 276,307 PubMed articles and tested methods for ranking articles across 16,005 reported links and 90 manually identified unreported links. Performance was measured by the median rank of matching articles and the proportion of unreported links that could be found by screening ranked candidate articles in order. The best-performing concept-based representation produced a median rank of 3 (interquartile range [IQR] 1-21) for reported links and 3 (IQR 1-19) for the manually identified unreported links, and term-based representations produced a median rank of 2 (1-20) for reported links and 2 (IQR 1-12) in unreported links. The matching article was ranked first for 40% of registrations, and screening 50 candidate articles per registration identified 86% of the unreported links. Leveraging the growth in the corpus of reported links between ClinicalTrials.gov and PubMed, we found that document similarity methods can assist in the identification of unreported links between trial registrations and corresponding articles. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of distance learning on clinical management of LUTS in primary care: a randomised trial.

PubMed

Wolters, René; Wensing, Michel; Klomp, Maarten; Lagro-Jansen, Toine; Weel, Chris van; Grol, Richard

2005-11-01

To determine the effect of a distance learning programme on general practice management of men with lower urinary tract symptoms (LUTS). A cluster randomised controlled trial was performed. General practitioners (GPs) were randomised to a distance learning programme accompanied with educational materials or to a control group only receiving mailed clinical guidelines on LUTS. Clinical management was considered as outcome. Sixty-three GPs registered care management of 187 patients older than 50 years attending the practice because of LUTS. The intervention group showed a lower referral rate to a urologist (OR: 0.08 (95% CI: 0.02-0.40)), but no effect on PSA testing or prescription of medication. PSA testing tended to be requested more frequently by intervention group GPs. Secondary analysis showed patients in the intervention group received more educational materials (OR: 75.6 (95% CI: 13.60-419.90)). The educational programme had impact on clinical management without changing PSA testing. Distance learning is an promising method for continuing education. Activating distance learning packages are a potentially effective method for improving professional performance. Emotional matters as PSA testing probably need a more complex approach.

Antenatal care trial interventions: a systematic scoping review and taxonomy development of care models.

PubMed

Symon, Andrew; Pringle, Jan; Downe, Soo; Hundley, Vanora; Lee, Elaine; Lynn, Fiona; McFadden, Alison; McNeill, Jenny; Renfrew, Mary J; Ross-Davie, Mary; van Teijlingen, Edwin; Whitford, Heather; Alderdice, Fiona

2017-01-06

Antenatal care models vary widely around the world, reflecting local contexts, drivers and resources. Randomised controlled trials (RCTs) have tested the impact of multi-component antenatal care interventions on service delivery and outcomes in many countries since the 1980s. Some have applied entirely new schemes, while others have modified existing care delivery approaches. Systematic reviews (SRs) indicate that some specific antenatal interventions are more effective than others; however the causal mechanisms leading to better outcomes are poorly understood, limiting implementation and future research. As a first step in identifying what might be making the difference we conducted a scoping review of interventions tested in RCTs in order to establish a taxonomy of antenatal care models. A protocol-driven systematic search was undertaken of databases for RCTs and SRs reporting antenatal care interventions. Results were unrestricted by time or locality, but limited to English language. Key characteristics of both experimental and control interventions in the included trials were mapped using SPIO (Study design; Population; Intervention; Outcomes) criteria and the intervention and principal outcome measures were described. Commonalities and differences between the components that were being tested in each study were identified by consensus, resulting in a comprehensive description of emergent models for antenatal care interventions. Of 13,050 articles retrieved, we identified 153 eligible articles including 130 RCTs in 34 countries. The interventions tested in these trials varied from the number of visits to the location of care provision, and from the content of care to the professional/lay group providing that care. In most studies neither intervention nor control arm was well described. Our analysis of the identified trials of antenatal care interventions produced the following taxonomy: Universal provision model (for all women irrespective of health state or complications); Restricted 'lower-risk'-based provision model (midwifery-led or reduced/flexible visit approach for healthy women); Augmented provision model (antenatal care as in Universal provision above but augmented by clinical, educational or behavioural intervention); Targeted 'higher-risk'-based provision model (for woman with defined clinical or socio-demographic risk factors). The first category was most commonly tested in low-income countries (i.e. resource-poor settings), particularly in Asia. The other categories were tested around the world. The trials included a range of care providers, including midwives, nurses, doctors, and lay workers. Interventions can be defined and described in many ways. The intended antenatal care population group proved the simplest and most clinically relevant way of distinguishing trials which might otherwise be categorised together. Since our review excluded non-trial interventions, the taxonomy does not represent antenatal care provision worldwide. It offers a stable and reproducible approach to describing the purpose and content of models of antenatal care which have been tested in a trial. It highlights a lack of reported detail of trial interventions and usual care processes. It provides a baseline for future work to examine and test the salient characteristics of the most effective models, and could also help decision-makers and service planners in planning implementation.

Evaluation of the impact of immediate versus WHO recommendations-guided antiretroviral therapy initiation on HIV incidence: the ANRS 12249 TasP (Treatment as Prevention) trial in Hlabisa sub-district, KwaZulu-Natal, South Africa: study protocol for a cluster randomised controlled trial

PubMed Central

2013-01-01

Background Antiretroviral therapy (ART) suppresses HIV viral load in all body compartments and so limits the risk of HIV transmission. It has been suggested that ART not only contributes to preventing transmission at individual but potentially also at population level. This trial aims to evaluate the effect of ART initiated immediately after identification/diagnosis of HIV-infected individuals, regardless of CD4 count, on HIV incidence in the surrounding population. The primary outcome of the overall trial will be HIV incidence over two years. Secondary outcomes will include i) socio-behavioural outcomes (acceptability of repeat HIV counselling and testing, treatment acceptance and linkage to care, sexual partnerships and quality of life); ii) clinical outcomes (mortality and morbidity, retention into care, adherence to ART, virologic failure and acquired HIV drug resistance), iii) cost-effectiveness of the intervention. The first phase will specifically focus on the trial’s secondary outcomes. Methods/design A cluster-randomised trial in 34 (2 × 17) clusters within a rural area of northern KwaZulu-Natal (South Africa), covering a total population of 34,000 inhabitants aged 16 years and above, of whom an estimated 27,200 would be HIV-uninfected at start of the trial. The first phase of the trial will include ten (2 × 5) clusters. Consecutive rounds of home-based HIV testing will be carried out. HIV-infected participants will be followed in dedicated trial clinics: in intervention clusters, they will be offered immediate ART initiation regardless of CD4 count and clinical stage; in control clusters they will be offered ART according to national treatment eligibility guidelines (CD4 <350 cells/μL, World Health Organisation stage 3 or 4 disease or multidrug-resistant/extensively drug-resistant tuberculosis). Following proof of acceptability and feasibility from the first phase, the trial will be rolled out to further clusters. Discussion We aim to provide proof-of-principle evidence regarding the effectiveness of Treatment-as-Prevention in reducing HIV incidence at the population level. Data collected from the participants at home and in the clinics will inform understanding of socio-behavioural, economic and clinical impacts of the intervention as well as feasibility and generalizability. Trial registration Clinicaltrials.gov: NCT01509508; South African Trial Register: DOH-27-0512-3974. PMID:23880306

Acetyl-L-Carnitine as an Adjunctive Therapy in the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: A Placebo-Controlled Trial

ERIC Educational Resources Information Center

Abbasi, Seyed-Hesameddin; Heidari, Shahram; Mohammadi, Mohammad-Reza; Tabrizi, Mina; Ghaleiha, Ali; Akhondzadeh, Shahin

2011-01-01

The objective of this study was to test whether a previous observed Acetyl-L-carnitine (ALC) treatment effect could be repeated in an ALC adjunctive therapy treatment trial of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. This was a six-week, randomized clinical trial undertaken in an outpatient child and adolescent…

Combination therapy for advanced or metastatic non-small cell lung cancer will be tested in new clinical trial | Center for Cancer Research

Cancer.gov

Non-small cell lung cancer (NSCLC) develops when abnormal lung cells begin to grow out of control. These cells can form into a tumor and spread to other areas of the body. David Schrump, M.D., of the Thoracic and Gastrointestinal Oncology Branch is leading a clinical trial of a new combination treatment for patients with advanced or metastatic NSCLC that cannot be treated surgically. Read more... 

Pilot clinical trial of a robot-aided neuro-rehabilitation workstation with stroke patients

NASA Astrophysics Data System (ADS)

Krebs, Hermano I.; Hogan, Neville; Aisen, Mindy L.; Volpe, Bruce T.

1996-12-01

This paper summarizes our efforts to apply robotics and automation technology to assist, enhance, quantify, and document neuro-rehabilitation. It reviews a pilot clinical trial involving twenty stroke patients with a prototype robot-aided rehabilitation facility developed at MIT and tested at Burke Rehabilitation Hospital. In particular, we present a few results: (a) on the patient's tolerance of the procedure, (b) whether peripheral manipulation of the impaired limb influences brain recovery, (c) on the development of a robot-aided assessment procedure.

Outcomes of high-dose levofloxacin therapy remain bound to the levofloxacin minimum inhibitory concentration in complicated urinary tract infections.

PubMed

Armstrong, Eliana S; Mikulca, Janelle A; Cloutier, Daniel J; Bliss, Caleb A; Steenbergen, Judith N

2016-11-25

Fluoroquinolones are a guideline-recommended therapy for complicated urinary tract infections, including pyelonephritis. Elevated drug concentrations of fluoroquinolones in the urine and therapy with high-dose levofloxacin are believed to overcome resistance and effectively treat infections caused by resistant bacteria. The ASPECT-cUTI phase 3 clinical trial (ClinicalTrials.gov, NCT01345929 and NCT01345955 , both registered April 28, 2011) provided an opportunity to test this hypothesis by examining the clinical and microbiological outcomes of high-dose levofloxacin treatment by levofloxacin minimum inhibitory concentration. Patients were randomly assigned 1:1 to ceftolozane/tazobactam (1.5 g intravenous every 8 h) or levofloxacin (750 mg intravenous once daily) for 7 days of therapy. The ASPECT-cUTI study provided data on 370 patients with at least one isolate of Enterobacteriaceae at baseline who were treated with levofloxacin. Outcomes were assessed at the test-of-cure (5-9 days after treatment) and late follow-up (21-42 days after treatment) visits in the microbiologically evaluable population (N = 327). Test-of-cure clinical cure rates above 90% were observed at minimum inhibitory concentrations ≤4 μg/mL. Microbiological eradication rates were consistently >90% at levofloxacin minimum inhibitory concentrations ≤0.06 μg/mL. Lack of eradication of causative pathogens at the test-of-cure visit increased the likelihood of relapse by the late follow-up visit. Results from this study do not support levofloxacin therapy for complicated urinary tract infections caused by organisms with levofloxacin minimum inhibitory concentrations ≥4 μg/mL. ClinicalTrials.gov, NCT01345929 and NCT01345955.

Outcome selection and role of patient reported outcomes in contemporary cardiovascular trials: systematic review

PubMed Central

Malhotra, Aneil; Banning, Adrian P; Jenkinson, Crispin

2010-01-01

Objectives To systematically assess the type of outcomes selected and the prevalence of patient reported outcomes in contemporary cardiovascular trials and to quantify any misuse or underuse of patient reported outcomes using a specially developed tool that would allow estimation of the relevance of such outcomes to clinical decision making. Design Systematic review. Data sources Medline and Embase. Study selection Randomised controlled trials of the treatment for or prevention of cardiovascular disease published in 10 leading general medical and cardiology journals from January 2005 to December 2008. Results Primary outcomes were patient important (death, morbidity, or patient reported outcomes) in only 93 of 413 trials (23%, SE 2%), whereas another 92 (22%, SE 2%) combined these outcomes with other less important ones into a composite. Sixty five trials (16%; SE 2%) used at least one instrument to measure patient reported outcomes, mostly in trials where such information would have been important or crucial for clinical decision making (52 trials). Patient reported outcomes were judged to be of little incremental value to a large number of, mostly explanatory, cardiovascular trials (152 trials). However, many trials in which patient reported outcomes would have been important or crucial for clinical decision making did not report such outcomes (122 of 174 trials, 70%). These included several trials that primarily aimed to improve symptoms or functional status, trials that tested interventions with a considerable potential for causing harm (mainly bleeding) that were not meaningfully measured, and trials with composite outcomes that were dominated by outcomes of questionable importance to patients. Conclusions Despite a continued rise in the reporting of patient reported outcomes with no evidence for their misuse in more recent cardiovascular trials, they seem to be still underused once their relevance to clinical decision making has been taken into account. This was largely explained by inappropriate use of composite outcomes and inadequate measurement of harms. PMID:21041324

A pilot study of simple interventions to improve informed consent in clinical research: feasibility, approach, and results.

PubMed

Kass, Nancy E; Taylor, Holly A; Ali, Joseph; Hallez, Kristina; Chaisson, Lelia

2015-02-01

Research suggests that participants do not always adequately understand studies. While some consent interventions increase understanding, methodologic challenges have been raised in studying consent outside of actual trial settings. This study examined the feasibility of testing two consent interventions in actual studies and measured effectiveness of interventions in improving understanding. Participants enrolling in any of eight ongoing clinical trials were sequentially assigned to one of three different informed consent strategies for enrollment in their clinical trial. Control participants received standard consent procedures for their trial. Participants in the first intervention arm received a bulleted fact sheet summarizing key study information. Participants in the second intervention arm received the bulleted fact sheet and also engaged in a feedback Q&A session. Later, patients answered closed- and open-ended questions to assess patient understanding and literacy. Descriptive statistics, Wilcoxon -Mann -Whitney and Kruskal-Wallis tests were generated to assess correlations; regression analysis determined predictors of understanding. 144 participants enrolled. Using regression analysis, participants receiving the second intervention scored 7.6 percentage points higher (p = .02) on open-ended questions about understanding than participants in the control, although unadjusted comparisons did not reach statistical significance. Our study supports the hypothesis that patients receiving both bulleted fact sheets and a Q&A session had higher understanding compared to standard consent. Fact sheets and short structured dialog are quick to administer and easy to replicate across studies and should be tested in larger samples. © The Author(s) 2014.

Novel methods to optimize the effects of transcranial direct current stimulation: a systematic review of transcranial direct current stimulation patents.

PubMed

Malavera, Alejandra; Vasquez, Alejandra; Fregni, Felipe

2015-01-01

Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that has been extensively studied. While there have been initial positive results in some clinical trials, there is still variability in tDCS results. The aim of this article is to review and discuss patents assessing novel methods to optimize the use of tDCS. A systematic review was performed using Google patents database with tDCS as the main technique, with patents filling date between 2010 and 2015. Twenty-two patents met our inclusion criteria. These patents attempt to address current tDCS limitations. Only a few of them have been investigated in clinical trials (i.e., high-definition tDCS), and indeed most of them have not been tested before in human trials. Further clinical testing is required to assess which patents are more likely to optimize the effects of tDCS. We discuss the potential optimization of tDCS based on these patents and the current experience with standard tDCS.

Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial

PubMed Central

Féron, F.; Cochrane, J.; Bassingthwaighte, L.; Bayliss, C.; Davies, W.; Fronek, P.; Gray, C.; Kerr, G.; Licina, P.; Nowitzke, A.; Perry, C.; Silburn, P.A.S.; Urquhart, S.; Geraghty, T.

2008-01-01

Olfactory ensheathing cells show promise in preclinical animal models as a cell transplantation therapy for repair of the injured spinal cord. This is a report of a clinical trial of autologous transplantation of olfactory ensheathing cells into the spinal cord in six patients with complete, thoracic paraplegia. We previously reported on the methods of surgery and transplantation and the safety aspects of the trial 1 year after transplantation. Here we address the overall design of the trial and the safety of the procedure, assessed during a period of 3 years following the transplantation surgery. All patients were assessed at entry into the trial and regularly during the period of the trial. Clinical assessments included medical, psychosocial, radiological and neurological, as well as specialized tests of neurological and functional deficits (standard American Spinal Injury Association and Functional Independence Measure assessments). Quantitative test included neurophysiological tests of sensory and motor function below the level of injury. The trial was a Phase I/IIa design whose main aim was to test the feasibility and safety of transplantation of autologous olfactory ensheathing cells into the injured spinal cord in human paraplegia. The design included a control group who did not receive surgery, otherwise closely matched to the transplant recipient group. This group acted as a control for the assessors, who were blind to the treatment status of the patients. The control group also provided the opportunity for preliminary assessment of the efficacy of the transplantation. There were no adverse findings 3 years after autologous transplantation of olfactory ensheathing cells into spinal cords injured at least 2 years prior to transplantation. The magnetic resonance images (MRIs) at 3 years showed no change from preoperative MRIs or intervening MRIs at 1 and 2 years, with no evidence of any tumour of introduced cells and no development of post-traumatic syringomyelia or other adverse radiological findings. There were no significant functional changes in any patients and no neuropathic pain. In one transplant recipient, there was an improvement over 3 segments in light touch and pin prick sensitivity bilaterally, anteriorly and posteriorly. We conclude that transplantation of autologous olfactory ensheathing cells into the injured spinal cord is feasible and is safe up to 3 years of post-implantation, however, this conclusion should be considered preliminary because of the small number of trial patients. PMID:18689435

Single dental implant retained mandibular complete dentures – influence of the loading protocol: study protocol for a randomized controlled trial

PubMed Central

2014-01-01

Background Over the years, there has been a strong consensus in dentistry that at least two implants are required to retain a complete mandibular denture. It has been shown in several clinical trials that one single median implant can retain a mandibular overdenture sufficiently well for up to 5 years without implant failures, when delayed loading was used. However, other trials have reported conflicting results with in part considerable failure rates when immediate loading was applied. Therefore it is the purpose of the current randomized clinical trial to test the hypothesis that immediate loading of a single mandibular midline implant with an overdenture will result in a comparable clinical outcome as using the standard protocol of delayed loading. Methods/design This prospective nine-center randomized controlled clinical trial is still ongoing. The final patient will complete the trial in 2016. In total, 180 edentulous patients between 60 and 89 years with sufficient complete dentures will receive one median implant in the edentulous mandible, which will retain the existing complete denture using a ball attachment. Loading of the median implant is either immediately after implant placement (experimental group) or delayed by 3 months of submerged healing at second-stage surgery (control group). Follow-up of patients will be performed for 24 months after implant loading. The primary outcome measure is non-inferiority of implant success rate of the experimental group compared to the control group. The secondary outcome measures encompass clinical, technical and subjective variables. The study was funded by the Deutsche Forschungsgemeinschaft (German research foundation, KE 477/8-1). Discussion This multi-center clinical trial will give information on the ability of a single median implant to retain a complete mandibular denture when immediately loaded. If viable, this treatment option will strongly improve everyday dental practice. Trial registration The trial has been registered at Deutsches Register Klinischer Studien (German register of clinical trials) under DRKS-ID: DRKS00003730 since 23 August 2012. (http://www.germanctr.de). PMID:24884848