Trials - Most accessed articles

Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal

David Kent — 2010-08-12T00:00:00Z

Mounting evidence suggests that there is frequently considerable variation in the risk of the outcome of interest in clinical trial populations. These differences in risk will often cause clinically important heterogeneity in treatment effects (HTE) across the trial population, such that the balance between treatment risks and benefits may differ substantially between large identifiable patient subgroups; the "average" benefit observed in the summary result may even be non-representative of the treatment effect for a typical patient in the trial. Conventional subgroup analyses, which examine whether specific patient characteristics modify the effects of treatment, are usually unable to detect even large variations in treatment benefit (and harm) across risk groups because they do not account for the fact that patients have multiple characteristics simultaneously that affect the likelihood of treatment benefit. Based upon recent evidence on optimal statistical approaches to assessing HTE, we propose a framework that prioritizes the analysis and reporting of multivariate risk-based HTE and suggests that other subgroup analyses should be explicitly labeled either as primary subgroup analyses (well-motivated by prior evidence and intended to produce clinically actionable results) or secondary (exploratory) subgroup analyses (performed to inform future research). A standardized and transparent approach to HTE assessment and reporting could substantially improve clinical trial utility and interpretability.

Reporting bias in medical research - a narrative review

Natalie McGauran — 2010-04-13T00:00:00Z

Reporting bias represents a major problem in the assessment of health care interventions. Several prominent cases have been described in the literature, for example, in the reporting of trials of antidepressants, Class I anti-arrhythmic drugs, and selective COX-2 inhibitors. The aim of this narrative review is to gain an overview of reporting bias in the medical literature, focussing on publication bias and selective outcome reporting. We explore whether these types of bias have been shown in areas beyond the well-known cases noted above, in order to gain an impression of how widespread the problem is. For this purpose, we screened relevant articles on reporting bias that had previously been obtained by the German Institute for Quality and Efficiency in Health Care in the context of its health technology assessment reports and other research work, together with the reference lists of these articles.We identified reporting bias in 40 indications comprising around 50 different pharmacological, surgical (e.g. vacuum-assisted closure therapy), diagnostic (e.g. ultrasound), and preventive (e.g. cancer vaccines) interventions. Regarding pharmacological interventions, cases of reporting bias were, for example, identified in the treatment of the following conditions: depression, bipolar disorder, schizophrenia, anxiety disorder, attention-deficit hyperactivity disorder, Alzheimer's disease, pain, migraine, cardiovascular disease, gastric ulcers, irritable bowel syndrome, urinary incontinence, atopic dermatitis, diabetes mellitus type 2, hypercholesterolaemia, thyroid disorders, menopausal symptoms, various types of cancer (e.g. ovarian cancer and melanoma), various types of infections (e.g. HIV, influenza and Hepatitis B), and acute trauma. Many cases involved the withholding of study data by manufacturers and regulatory agencies or the active attempt by manufacturers to suppress publication. The ascertained effects of reporting bias included the overestimation of efficacy and the underestimation of safety risks of interventions.In conclusion, reporting bias is a widespread phenomenon in the medical literature. Mandatory prospective registration of trials and public access to study data via results databases need to be introduced on a worldwide scale. This will allow for an independent review of research data, help fulfil ethical obligations towards patients, and ensure a basis for fully-informed decision making in the health care system.

Managing clinical trials

Barbara Farrell — 2010-07-13T00:00:00Z

Managing clinical trials, of whatever size and complexity, requires efficient trial management. Trials fail because tried and tested systems handed down through apprenticeships have not been documented, evaluated or published to guide new trialists starting out in this important field. For the past three decades, trialists have invented and reinvented the trial management wheel. We suggest that to improve the successful, timely delivery of important clinical trials for patient benefit, it is time to produce standard trial management guidelines and develop robust methods of evaluation.

CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials

Kenneth Schulz — 2010-03-24T00:00:00Z

The CONSORT statement is used worldwide to improve the reporting of randomised controlled trials. Kenneth Schulz and colleagues describe the latest version, CONSORT 2010, which updates the reporting guideline based on new methodological evidence and accumulating experience.To encourage dissemination of the CONSORT 2010 Statement, this article is freely accessible on bmj.com and will also be published in the Lancet, Obstetrics and Gynecology, PLoS Medicine, Annals of Internal Medicine, Open Medicine, Journal of Clinical Epidemiology, BMC Medicine, and Trials.

A randomised controlled trial to evaluate the efficacy of a 6 month dietary and physical activity intervention for prostate cancer patients receiving androgen deprivation therapy

Farhana Haseen — 2010-08-12T00:00:00Z

Background: Treatment with Androgen Deprivation Therapy (ADT) for prostate cancer is associated with changes in body composition including increased fat and decreased lean mass; increased fatigue, and a reduction in quality of life. No study to date has evaluated the effect of dietary and physical activity modification on the side-effects related to ADT. The aim of this study is to evaluate the efficacy of a 6-month dietary and physical activity intervention for prostate cancer survivors receiving ADT to minimise the changes in body composition, fatigue and quality of life, typically associated with ADT. Methods: Men are recruited to this study if their treatment plan is to receive ADT for at least 6 months. Men who are randomised to the intervention arm receive a home-based tailored intervention to meet the following guidelines a) ≥ 5 servings vegetables and fruits/day; b) 30%-35% of total energy from fat, and < 10% energy from saturated fat/day; c) 10% of energy from polyunsaturated fat/day; d) limited consumption of processed meats; e) 25-35 gm of fibre/day; f) alcoholic drinks ≤ 28 units/week; g) limited intake of foods high in salt and/or sugar. They are also encouraged to include at least 30 minutes of brisk walking, 5 or more days per week. The primary outcomes are change in body composition, fatigue and quality of life scores. Secondary outcomes include dietary intake, physical activity and perceived stress. Baseline information collected includes: socio-economic status, treatment duration, perceived social support and health status, family history of cancer, co-morbidities, medication and supplement use, barriers to change, and readiness to change their health behaviour. Data for the primary and secondary outcomes will be collected at baseline, 3 and 6 months from 47 intervention and 47 control patients.DiscussionThe results of this study will provide detailed information on diet and physical activity levels in prostate cancer patients treated with ADT and will test the feasibility and efficacy of a diet and physical activity intervention which could provide essential information to develop guidelines for prostate cancer patients to minimise the side effects related to ADT.Trial registrationISRCTN trial number ISCRTN75282423

Study design and rationale of 'Influence of Cilostazol-based triple anti-platelet therapy on ischemic complication after drug-eluting stent implantation (CILON-T)' study: A multicenter randomized trial evaluating the efficacy of Cilostazol on ischemic vascular complications after drug-eluting stent implantation for coronary heart disease

Seung-Pyo Lee — 2010-08-24T00:00:00Z

Background: Current guidelines recommend dual anti-platelet therapy, aspirin and clopidogrel, for patients treated with drug-eluting stent for coronary heart disease. In a few small trials, addition of cilostazol on dual anti-platelet therapy (triple anti-platelet therapy) showed better late luminal loss. In the real-world unselected patients with coronary heart disease, however, the effect of cilostazol on platelet reactivity and ischemic vascular events after drug-eluting stent implantation has not been tested. It is also controversial whether there is a significant interaction between lipophilic statin and clopidogrel. Methods: CILON-T trial was a prospective, randomized, open-label, multi-center, near-all-comer trial to demonstrate the superiority of triple anti-platelet therapy to dual anti-platelet therapy in reducing 6 months' major adverse cardiovascular/cerebrovascular events, composite of cardiac death, nonfatal myocardial infarction, target lesion revascularization and ischemic stroke. It also tested whether triple anti-platelet therapy is superior to dual anti-platelet therapy in inhibiting platelet reactivity in patients receiving percutaneous coronary intervention with drug-eluting stent. Total 960 patients were randomized to receive either dual anti-platelet therapy or triple anti-platelet therapy for 6 months and also, randomly stratified to either lipophilic statin (atorvastatin) or non-lipophilic statin (rosuvastatin) indefinitely. Secondary endpoints included all components of major adverse cardiovascular/cerebrovascular events, platelet reactivity as assessed by VerifyNow P2Y12 assay, effect of statin on major adverse cardiovascular/cerebrovascular events, bleeding complications, and albumin-to-creatinine ratio to test the nephroprotective effect of cilostazol. Major adverse cardiovascular/cerebrovascular events will also be checked at 1, 2, and 3 years to test the 'legacy' effect of triple anti-platelet therapy that was prescribed for only 6 months after percutaneous coronary intervention.DiscussionCILON-T trial will give powerful insight into whether triple anti-platelet therapy is superior to dual anti-platelet therapy in reducing ischemic events and platelet reactivity in the real-world unselected patients treated with drug-eluting stent for coronary heart disease. Also, it will verify the laboratory and clinical significance of drug interaction between lipophilic statin and clopidogrel.Trial Registration. National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov identifier# NCT00776828).

Protocol for the adolescent hayfever trial: cluster randomised controlled trial of an educational intervention for healthcare professionals for the management of school-age children with hayfever

Victoria Hammersley — 2010-08-05T00:00:00Z

Background: Seasonal allergic rhinitis (hayfever) is common and can contribute to a considerable reduction in the quality of life of adolescents. This study aims to examine the effectiveness of standardised allergy training for healthcare professionals in improving disease-specific quality of life in adolescents with hayfever.Methods/DesignAdolescents with a history of hayfever registered in general practices in Scotland and England were invited to participate in a cluster randomised controlled trial. The unit of randomisation is general practices.The educational intervention for healthcare professionals consists of a short standardised educational course, which focuses on the management of allergic rhinitis. Patients in the intervention arm of this cluster randomised controlled trial will have a clinic appointment with their healthcare professional who has attended the training course. Patients in the control arm will have a clinic appointment with their healthcare professional and will receive usual care.The primary outcome measure is the change in the Rhinoconjunctivitis Quality of Life Questionnaire with Standardised Activities (RQLQ(S)) score between baseline and six weeks post-intervention in the patient intervention and control groups.Secondary outcome measures relate to healthcare professionals' understanding and confidence in managing allergic rhinitis, changes in clinical practice, numbers of consultations for hayfever and adolescent exam performance.A minimum of 11 practices in each arm of the trial (10 patients per cluster) will provide at least 80% power to demonstrate a minimal clinically important difference of 0.5 in RQLQ(S) score at a significance level of 5% based on an Intraclass Correlation Coefficient (ICC) of 0.02.DiscussionAt the time of submission, 24 general practices have been recruited (12 in each arm of the trial) and the interventions have been delivered. Follow-up data collection is complete. 230 children consented to take part in the trial; however complete primary outcome data are only available for 160. Further recruitment of general practices and patients will therefore take place in the summer of 2010.Trial RegistrationCurrent Controlled Trials ISRCTN95538067

Heterogeneity prevails: the state of clinical trial data management in Europe - results of a survey of ECRIN centres

Wolfgang Kuchinke — 2010-07-21T00:00:00Z

Background: The use of Clinical Data Management Systems (CDMS) has become essential in clinical trials to handle the increasing amount of data that must be collected and analyzed. With a CDMS trial data are captured at investigator sites with "electronic Case Report Forms". Although more and more of these electronic data management systems are used in academic research centres an overview of CDMS products and of available data management and quality management resources for academic clinical trials in Europe is missing. Methods: The ECRIN (European Clinical Research Infrastructure Network) data management working group conducted a two-part standardized survey on data management, software tools, and quality management for clinical trials. The questionnaires were answered by nearly 80 centres/units (with an overall response rate of 47% and 43%) from 12 European countries and EORTC. Results: Our survey shows that about 90% of centres have a CDMS in routine use. Of these CDMS nearly 50% are commercial systems; Open Source solutions don't play a major role. In general, solutions used for clinical data management are very heterogeneous: 20 different commercial CDMS products (7 Open Source solutions) in addition to 17/18 proprietary systems are in use. The most widely employed CDMS products are MACRO™ and Capture System™, followed by solutions that are used in at least 3 centres: eResearch Network™, CleanWeb™, GCP Base™ and SAS™. Although quality management systems for data management are in place in most centres/units, there exist some deficits in the area of system validation. Conclusions: Because the considerable heterogeneity of data management software solutions may be a hindrance to cooperation based on trial data exchange, standards like CDISC (Clinical Data Interchange Standard Consortium) should be implemented more widely. In a heterogeneous environment the use of data standards can simplify data exchange, increase the quality of data and prepare centres for new developments (e.g. the use of EHR for clinical research). Because data management and the use of electronic data capture systems in clinical trials are characterized by the impact of regulations and guidelines, ethical concerns are discussed. In this context quality management becomes an important part of compliant data management. To address these issues ECRIN will establish certified data centres to support electronic data management and associated compliance needs of clinical trial centres in Europe.

Banha-sasim-tang as an herbal formula for the treatment of functional dyspepsia: a randomized, double-blind, placebo-controlled, two-center trial

Jae-Woo Park — 2010-07-30T00:00:00Z

Background: Functional dyspepsia (FD) is characterized by a high prevalence rate and no standard conventional treatments. Alternative therapies, such as herbal formulas, are widely used to treat FD. However, there are inadequate evidences regarding the safety and efficacy of these formulas. Moreover, the mechanisms by which herbal formulas act in the gastrointestinal tract are controversial. In traditional Korean medicine, Banha-sasim-tang has long been one of the most frequently prescribed herbal formulas for treating dyspepsia. The current study is designed to evaluate the efficacy and safety of Banha-sasim-tang for FD patients and to examine whether there will be a significant correlation between cutaneous electrogastrography recordings and dyspeptic symptoms in FD patients, and between changes in gastric myoelectrical activity and improvement in dyspeptic symptoms during Banha-sasim-tang administration. Methods: This randomized, double-blind, placebo-controlled trial will be performed at two centers and will include a Banha-sasim-tang group and placebo group. Each group will consist of 50 FD patients. Six weeks of administration of Banha-sasim-tang or placebo will be conducted. During the subsequent 2 months, follow-up observations of primary and secondary outcomes will be performed. The primary outcomes are differences as measured on the gastrointestinal symptom scale, and the secondary outcomes are differences as measured on the visual analogue scale for dyspepsia and on the questionnaire for FD-related quality of life. All outcomes will be measured at baseline, at 2, 4, and 6 weeks of treatment, and at the 1 and 2 month follow-up. Cutaneous electrogastrography will be performed and assessed at baseline and at 6 weeks.DiscussionThis trial will provide evidence of the safety and efficacy of Banha-sasim-tang for the treatment for FD. Furthermore, based on the assessment of the relationship between cutaneous electrogastrography recordings and dyspeptic symptoms in this trial, the possibility of clinical applications of cutaneous electrogastrography in the treatment of FD will be elucidated.Trial RegistrationCurrent Controlled Trials (ISRCTN 51910678); Clinical Trials.gov Identifier: NCT00987805

Protocol for a phase 1 homeopathic drug proving trial

Michael Teut — 2010-07-22T00:00:00Z

Background: This study protocol adapts the traditional homeopathic drug proving methodology to a modern clinical trial design.MethodMulti-centre, randomised, double-blind, placebo-controlled phase 1 trial with 30 healthy volunteers. The study consists of a seven day run-in period, a five day intervention period and a 16 day post-intervention observation period. Subjects, investigators and the statisticians are blinded from the allocation to the study arm and from the identity of the homeopathic drug. The intervention is a highly diluted homeopathic drug (potency C12 = 1024), Dose: 5 globules taken 5 times per day over a maximum period of 5 days. The placebo consists of an optically identical carrier substance (sucrose globules). Subjects document the symptoms they experience in a semi-structured online diary. The primary outcome parameter is the number of specific symptoms that characterise the intervention compared to the placebo after a period of three weeks. Secondary outcome parameters are qualitative differences in profiles of characteristic and proving symptoms and the total number of all proving symptoms. The number of symptoms will be quantitatively analysed on an intention-to-treat basis using ANCOVA with the subject's expectation and baseline values as covariates. Content analysis according to Mayring is adapted to suit the homeopathic qualitative analysis procedure.DiscussionHomeopathic drug proving trials using the terminology of clinical trials according GCP and fulfilling current requirements for research under the current drug regulations is feasible. However, within the current regulations, homeopathic drug proving trials are classified as phase 1 trials, although their aim is not to explore the safety and pharmacological dynamics of the drug, but rather to find clinical indications according to the theory of homeopathy. To avoid bias, it is necessary that neither the subjects nor the investigators know the identity of the drug. This requires a modification to the informed consent process and blinded study materials. Because it is impossible to distinguish between adverse events and proving symptoms, both must be documented together.Trial registrationClinicalTrials.gov identifier: NCT01061229.