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Results for “Clinical Trials Data Monitoring Committees”

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PubMed2004

International carotid stenting study: protocol for a randomised clinical trial comparing carotid stenting with endarterectomy in symptomatic carotid artery stenosis.

BACKGROUND: Carotid stenting avoids general anaesthesia, cranial nerve injury and the discomforts of surgical treatment of carotid stenosis. A systematic review of the randomised trials showed no overall difference in the major risks of endovascular treatment for carotid stenosis compared with surgery, but the confidence intervals were wide and both methods carried a significant risk of stroke. The use of protection devices appears to improve the safety of endovascular treatment, but there are little randomised data available about long-term outcomes. We have therefore set up an international, multicentre, randomised, controlled, open, prospective clinical trial, namely the International Carotid Stenting Study (ICSS), also known as CAVATAS-2. The objectives of the ICSS are to compare the risks, benefits and cost-effectiveness of a treatment policy of referral for carotid stenting compared with referral for carotid endarterectomy. METHODS: Centres are required to have a team with audited expertise in carotid endarterectomy and stenting procedures, including at least one neurologist or stroke physician, a surgeon and an interventionalist. Attendance at a carotid stenting training course is required. Centres with more limited experience can join the trial as probationary centres, but stenting must then be proctored by an experienced interventionalist. Symptomatic patients are included over the age of 40 years with atherosclerotic carotid stenosis, suitable for both stenting and surgery, and are randomised in equal proportions between carotid endarterectomy and stenting. Stents and other devices are chosen for use at the discretion of the interventionalists but must be approved by the devices committee. The protocol recommends that a cerebral protection system should be used whenever the operator thinks one can be safely deployed. The combination of aspirin and clopidogrel is recommended to cover stenting procedures. Standard or eversion endarterectomy is allowed using local or general anaesthesia, shunts or patches. All patients will receive best medical care. Patients will be followed up by neurologists at 30 days after treatment, 6 months after randomisation and then annually up to 5 years after randomisation. The primary outcome measure is the difference in the long-term rate of fatal or disabling stroke in any territory between patients randomised to stenting or surgery. Secondary outcome measures include any stroke, myocardial infarction or death within 30 days of treatment, treatment- related cranial nerve palsy or haematoma. Restenosis (>70%) on ultrasound follow-up, economic measures and quality of life will also be analysed. The sample size is estimated at 1,500 patients, which will provide 95% confidence intervals of +/- 3.0 percentage points for the outcome measure of 30-day disabling stroke and death rate and +/- 3.3 percentage points for the outcome measure of death or stroke during follow-up. The trial office monitors outcome events at individual centres and a rate of events above a given threshold triggers a blinded assessment of the events, submitted to the chairman of the data-monitoring committee. CONCLUSIONS: The ICSS protocol incorporates a number of novel features to ensure patient safety, including the concept of probationary centres, proctoring of inexperienced investigators and monitoring of individual centre results on an ongoing basis. The protocol is also designed to mirror routine clinical practice as far as possible, so that the results will be widely applicable and relevant to determining the place of carotid stenting in clinical practice in the future.

Carotid Stenosis↗

PubMed2001

Clinical trials in Italy: focus on the protocols submitted to ethics committees.

OBJECTIVE: To describe the main characteristics of clinical research protocols submitted to Italian local ethics committees (LECs). DESIGN: Prospective survey on all research protocols evaluated during the period from 1 September 1998 to 31 July 1999. Data were prospectively collected for each individual study containing information on: general characteristics of the study; study design; population under study; LEC decision; and study monitoring. SETTING: Twenty Italian LECs from nine regions in Italy. MAIN OUTCOME MEASURES: Type of protocols, diseases and drugs under investigation, population under study, methodological characteristics (e.g. sponsorship, multicentricity, presence of a control group). RESULTS: Data on 449 protocols corresponding to 625 evaluations were received. The majority of protocols (83.1%, n=373) were investigational studies on drugs, sponsored 76.8% (n=345) and multicentre 86.4% (n=388). The majority of the drug protocols were on antineoplastic drugs (27.7%, n=104), cardiovascular agents (15.4%, n=58) and systemic anti-infective agents (13.8%, n=52). A few of the drugs investigated were new entities. A few studies focused on subpopulations, e.g. elderly and children (10 and 16, respectively). Early development phases (I and II) were less likely to be sponsored and multicentre. The most represented drug category in phase I-II trials was the antineoplastic agents. CONCLUSION: A small portion of research protocols submitted to LECs in Italy relate to innovative research. The new Italian legislation, which decentralizes approval of clinical trials from central to local levels, will lead to shorter approval times and should stimulate more original research. Surveys on LECs activity give important information on active research areas, methodological quality of current studies and outcome of the studies in terms of trial closure and publication of the results. The latter information may be obtained through a follow-up of the cohort of studies included in the present cross-sectional survey.

Clinical Trials as Topic↗

PubMed1996

Use of a global test for multiple outcomes in stroke trials with application to the National Institute of Neurological Disorders and Stroke t-PA Stroke Trial.

BACKGROUND: The National Institute of Neurological Disorders and Stroke (NINDS) held a workshop on statistical approaches to analysis of acute stroke trials that have multiple pre-specified outcomes. An objective was to plan for statistical analysis of the NINDS t-PA Stroke Trial, a randomized, double-blind, placebo-controlled trial of recombinant tissue plasminogen activator (rt-PA) for patients with acute ischemic stroke. Treatment success was defined as a "consistent and persuasive difference" in the proportion of patients achieving favorable outcomes on the Barthel Index, Modified Rankin Scale, Glasgow Outcome Scale, and National Institutes of Health Stroke Scale. The Data and Safety Monitoring Committee for the trial recommended this outcome because the committee did not believe that a positive result for a single outcome would provide sufficient evidence of efficacy. SUMMARY OF COMMENT: Workshop participants accepted the global test as a viable approach to testing the primary trial hypothesis. Clinician participants advocated categorizing outcomes as favorable/unfavorable, outcomes more clinically meaningful than continuous outcomes for evaluating a drug with potentially serious side effects. They agreed that a global test was appropriate for ischemic stroke when no single outcome is accepted. Hypothetical, special-case examples illustrate that highly correlated outcomes diminish the power of the global test. NINDS t-PA Stroke Trial data demonstrate the clinical interpretability of the global test. CONCLUSIONS: Workshop participants concluded that a global statistic should be used to test the trial's primary hypothesis accompanied by secondary tests of individual outcomes. Workshop participants recommended familiarizing the clinical/scientific community with the global approach.

Acute Disease↗

PubMed1983

A coordinating center in a clinical trial: the Hypertension Detection and Followup Program.

Multicenter clinical trials are often larger and more complex than other methods of clinical inquiry. They tend to involve a number of research or clinical centers and several formal committees. In many of these trials a coordinating center is one of the participating organizational units. This article describes one such coordinating center, that of the Hypertension Detection and Follow-up Program (HDFP). In 1971 the HDFP Coordinating Center was established to assist in planning and implementing this National Heart, Lung, and Blood Institute (NHLBI)-sponsored, multicenter, community-based, randomized, controlled clinical trial. The HDFP Coordinating Center is a large, intricate organization comprised of personnel who perform a wide variety of functions. From 1972 to 1979 it supervised the adherence to a common protocol among the cooperating centers and reported the Program's progress to the various monitoring and review committees, the Steering Committee, and the NHLBI Program Office. The Program screened approximately 159,000 persons ages 30 to 69 years, identifying and following 10,940 hypertensive participants. It has been the responsibility of this Coordinating Center to institute, coordinate, and monitor the data-gathering activities of the study as a whole and to process, store, and analyze the large, multifaceted set of data that were collected.

Clinical Trials as Topic↗

PubMed2006

L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial.

CONTEXT: The amino acid L-arginine is a substrate for nitric oxide synthase and is increasingly used as a health supplement. Prior studies suggest that L-arginine has the potential to reduce vascular stiffness. OBJECTIVE: To determine whether the addition of L-arginine to standard postinfarction therapy reduces vascular stiffness and improves ejection fraction over 6-month follow-up in patients following acute ST-segment elevation myocardial infarction. DESIGN AND SETTING: Single-center, randomized, double-blind, placebo-controlled trial with enrollment from February 2002 to June 2004. PATIENTS: A total of 153 patients following a first ST-segment elevation myocardial infarction were enrolled; 77 patients were 60 years or older. INTERVENTION: Patients were randomly assigned to receive L-arginine (goal dose of 3 g 3 times a day) or matching placebo for 6 months. MAIN OUTCOME MEASURES: Change in gated blood pool-derived ejection fraction over 6 months in patients 60 years or older randomized to receive L-arginine compared with those assigned to receive placebo. Secondary outcomes included change in ejection fraction in all patients enrolled, change in noninvasive measures of vascular stiffness, and clinical events. RESULTS: Baseline characteristics, vascular stiffness measurements, and left ventricular function were similar between participants randomized to receive placebo or L-arginine. The mean (SD) age was 60 (13.6) years; of the participants, 104 (68%) were men. There was no significant change from baseline to 6 months in the vascular stiffness measurements or left ventricular ejection fraction in either of the 2 groups, including those 60 years or older and the entire study group. However, 6 participants (8.6%) in the L-arginine group died during the 6-month study period vs none in the placebo group (P = .01). Because of the safety concerns, the data and safety monitoring committee closed enrollment. CONCLUSIONS: L-arginine, when added to standard postinfarction therapies, does not improve vascular stiffness measurements or ejection fraction and may be associated with higher postinfarction mortality. L-arginine should not be recommended following acute myocardial infarction. Clinical Trial Registration ClinicalTrials.gov, NCT00051376.

Aged↗

PubMedDate not supplied

Missing data in quality of life research in Eastern Cooperative Oncology Group (ECOG) clinical trials: problems and solutions.

Incorporation of quality of life (QOL) investigation into Eastern Cooperative Oncology Group (ECOG) multi-centre clinical trials has led to innovative strategies for protocol design and high quality data collection. A scientific advisory committee reviews protocol design components, measurement selection, timing of assessments and compliance issues. Extensive educational programmes provide information about the scientific and clinical relevance of QOL protocols, as well as practical strategies for data collection and management. Compliance with QOL data collection standards is prospectively monitored and evaluated. Preliminary results from eight ECOG-run protocols found overall compliance to be approximately 85 per cent (94 per cent at baseline and 73 per cent during treatment). Selected patient and institutional factors were evaluated for their association with compliance.

Adult↗

PubMed1993

The use of external monitoring committees in clinical trials of the National Institute of Allergy and Infectious Diseases.

Randomized clinical trials are being conducted and/or sponsored by all scientific divisions of the National Institute of Allergy and Infectious Diseases (NIAID). External committees to review the progress of ongoing trials and to make recommendations to the Institute concerning continuation or termination are an integral part of many of these trials. These committees have evolved considerably from the ad hoc committees, called together when a need arose, which were used beginning in the mid 1970s. Currently, there are many monitoring committees operating for NIAID-sponsored trials. They function in a variety of ways, based partially on historical precedent and partially on the specialized requirements of the particular trial; there is no 'standard operating procedure' for the Institute, or even for divisions within the Institute. One of the major issues faced in establishing the data and safety monitoring board for AIDS treatment trials was access to the meetings of this board and to the reports of interim data that the board reviewed. After much discussion, procedures were established that restrict such access to a very limited group of programme and statistical centre staff. These procedures, while remaining controversial, appear necessary to ensure confidentiality and the integrity of the clinical trials process.

Acquired Immunodeficiency Syndrome↗

PubMed1994

Clinical advisory: carotid endarterectomy for patients with asymptomatic internal carotid artery stenosis.

The investigators of the Asymptomatic Carotid Atherosclerosis Study (ACAS) are reporting the interim results of a randomized controlled clinical trial of carotid endarterectomy in patients who have asymptomatic carotid stenosis of greater than 60% reduction in diameter. In addition to aspirin and aggressive management of modifiable risk factors, one half of the patients were randomly assigned to receive surgery after angiographic confirmation of the lesion. Carotid endarterectomy is beneficial with a statistically significant absolute reduction of 5.8% in the risk of the primary end point of stroke within 5 years and a relative risk reduction of 55%. As a consequence of the trial reaching statistical significance in favor of endarterectomy, and on the recommendation of the study's data monitoring committee, physicians participating in the study were immediately notified and advised to reevaluate patients who did not receive surgery. It is important to note that the success of the operation is dependent on medical centers and surgeons who have a documented perioperative morbidity and mortality of less than 3%, careful selection of patients, and postoperative management of modifiable risk factors.

Adult↗

PubMed2006

Maintenance or consolidation therapy in advanced ovarian cancer.

Most patients with advanced epithelial ovarian cancer (EOC) achieve a clinical complete response (CR) or have no clinical evidence of disease after aggressive cytoreductive surgery and 6 cycles of platinum-/taxane-based chemotherapy. From the reported randomized trials using different durations or different cycles of chemotherapy, none of these showed improvement in survival beyond 6 cycles. Data from the literature do not support a relationship between the number of cycles and response or between the cumulative dose and response. In addition, no benefit in survival was detected with high-dose and intensity chemotherapy administered for a short time compared with standard-dose chemotherapy given for a longer time. However, statistically significant differences in progression-free survival were found in patients who achieved a clinically defined CR to a platinum (CDDP)-/paclitaxel-based chemotherapy and who continued single-agent paclitaxel for an extended time period. Notably, this randomized trial most likely did not offer any survival advantage, as it was closed prematurely by the Data Safety Monitoring Committee in accordance with the guidelines planned for interim analysis of primary end-points.

Antineoplastic Agents↗

PubMedDate not supplied

Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial.

BACKGROUND: Corticosteroids have been used to treat head injuries for more than 30 years. In 1997, findings of a systematic review suggested that these drugs reduce risk of death by 1-2%. The CRASH trial--a multicentre international collaboration--aimed to confirm or refute such an effect by recruiting 20000 patients. In May, 2004, the data monitoring committee disclosed the unmasked results to the steering committee, which stopped recruitment. METHODS: 10008 adults with head injury and a Glasgow coma score (GCS) of 14 or less within 8 h of injury were randomly allocated 48 h infusion of corticosteroids (methylprednisolone) or placebo. Primary outcomes were death within 2 weeks of injury and death or disability at 6 months. Prespecified subgroup analyses were based on injury severity (GCS) at randomisation and on time from injury to randomisation. Analysis was by intention to treat. Effects on outcomes within 2 weeks of randomisation are presented in this report. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN74459797. FINDINGS: Compared with placebo, the risk of death from all causes within 2 weeks was higher in the group allocated corticosteroids (1052 [21.1%] vs 893 [17.9%] deaths; relative risk 1.18 [95% CI 1.09-1.27]; p=0.0001). The relative increase in deaths due to corticosteroids did not differ by injury severity (p=0.22) or time since injury (p=0.05). INTERPRETATION: Our results show there is no reduction in mortality with methylprednisolone in the 2 weeks after head injury. The cause of the rise in risk of death within 2 weeks is unclear.

Adolescent↗

PubMed1991

Guidelines for medical technology in critical care. Technology Subcommittee of the Working Group on Critical Care, Ontario Ministry of Health.

OBJECTIVE: To examine the current status of technology in critical care medicine and to present guidelines for technologies commonly used in Ontario critical care units. DATA SOURCES: A computerized search of the medical literature, interviews with relevant people and a review of existing guidelines or standards were conducted. STUDY SELECTION: Nonrandomized trials and retrospective reviews were included because of a paucity of prospective randomized controlled trials. DATA EXTRACTION: Technologies were assessed by individual committee members. The validity of the technologies was compared with accepted standards when available. All published clinical data were used to assess efficacy. DATA SYNTHESIS: After review of the data, discussion papers on ventilation, and electrocardiographic, hemodynamic and intracranial pressure monitoring were written by committee members and then reviewed by the subcommittee as a whole. For each technology an attempt was made to match need with the patient classifications of the Working Group on Critical Care. Critical care guidelines were then developed through the use of the nominal group and Delphi consensus-gathering techniques. The guidelines were reviewed by external experts. CONCLUSIONS: These guidelines should help in assessing quality assurance and the resources necessary for critical care. Also, they should enable health care providers and hospital administrators to make better decisions when acquiring critical care technology. Since the guidelines represent the current state of knowledge there must be a continuing assessment of the technology and review of the guidelines.

Critical Care↗

PubMed2002

Rationale and design of the carvedilol or metoprolol European trial in patients with chronic heart failure: COMET.

In large clinical trials both carvedilol and metoprolol have been shown to reduce mortality and morbidity in patients with chronic heart failure. Carvedilol is an adrenoceptor antagonist, which inhibits beta(1)-, beta(2)-, and alpha(1)-adrenergic receptors. Carvedilol has additional metabolic and antioxidant properties. Metoprolol is a selective antagonist of beta(1)-adrenergic receptors. The carvedilol or metoprolol European trial (COMET) is the first study to investigate whether beta-blocking agents with differing pharmacological profiles exert different effects on morbidity and mortality in patients with chronic heart failure. 3029 patients from 15 different European countries were enrolled into COMET and will be followed until 1020 fatal events have been observed, unless the data and safety monitoring committee (DSMC) recommends early termination. The target dose for carvedilol is 25 mg bid and for metoprolol tartrate 50 mg bid. This manuscript outlines the rationale, design and possible outcomes of COMET.

Adrenergic beta-Antagonists↗

PubMed1989

Quality assurance and monitoring in the Hypertension Prevention Trial. Hypertension Prevention Trial Research Group.

The Hypertension Prevention Trial (HPT), was a randomized, controlled, multicenter (four clinics, four resource centers) trial designed to test the feasibility of achieving and sustaining dietary changes in the intake of calories, sodium, and potassium and to assess the effect of those changes on blood pressure in a normotensive population. The trial involved 841 men and women (plus a test cohort of 78) who, at the first baseline (BL) examination were in the age range of 25-49 years and had diastolic blood pressure (DBP) greater than or equal to 76 but less than 100 mm Hg (average of two readings), and at the examination prior to randomization (BL 2) had DBP greater than or equal to 78 but less than 90 mm Hg (also averaged). Participants were randomly assigned to a control treatment group (no dietary counseling) or to one of four dietary treatment groups involving counseling designed to reduce calorie intake, reduce sodium intake, reduce sodium and calorie intake, and reduce sodium and increase potassium intake. This chapter describes HPT procedures for training and certifying clinic staff, for data entry checks and data audits of its distributed data entry system, and for inspecting clinical equipment. Replicate analyses were performed regularly by the two arms of the Data Coordinating Center. The Food Coding Center and the Central Laboratory were evaluated by both internal and external monitoring techniques. The performance monitoring report, prepared semiannually for the governing committees of the HPT, reported on the effectiveness of quality assurance procedures and served to alert staff to developing problems.

Adult↗

PubMed2006

Management of APL in developing countries: epidemiology, challenges and opportunities for international collaboration.

Acute promyelocytic leukemia (APL), a relatively rare hematologic malignancy, is highly curable with current treatment strategies. However, these strategies may be unavailable in countries with limited resources. A review of records in several Latin American countries revealed that approximately 30% of deaths among children and adults with APL were caused by early complications associated with the disease or its treatment. Further, APL accounts for 20% to 25% of cases of AML in these countries, consistent with the previous observation of increased incidence of APL in Latin Americans. The lack of population-based registries in developing countries has made it difficult to determine the real incidence of APL. Moreover, APL appears to have other unique epidemiologic characteristics, including association of primary APL with an increased body mass index at diagnosis and association of secondary APL with breast cancer. To facilitate the development of local capacity and implement effective treatment of APL in developing countries, the International Committee of the American Society of Hematology has assembled a working group to formulate treatment guidelines based on evidence from clinical trials results in the developed world but adapted to local resources. It is hoped that uniform treatment, careful documentation of specific outcome data, and ongoing monitoring of treatment efficacy and toxicity will improve the cure rate and provide biologic and epidemiologic information about APL in developing countries. This initial demonstration project may be joined by other countries, providing a framework for additional clinical investigation in this highly curable form of leukemia.

Developing Countries↗

PubMed2000

Adjusting survival analysis for the presence of unadjudicated study events.

In the Coumadin Aspirin Reinfarction Study (CARS), the primary (efficacy) endpoint was time to the first occurrence of reinfarction, ischemic stroke, or cardiovascular death. Study events likely to be a component of the primary endpoint were reviewed by a blinded Events Classification Committee (ECC). To accommodate the inherent delay imposed by the adjudication process, we used the results of prior adjudication to predict classifications for selected unadjudicated study events in order to conduct "up-to-date" interim analyses for the Data and Safety Monitoring Committee (DSMC). Rates at which previously adjudicated study events were confirmed as primary event components were used to adjust the Kaplan-Meier estimates of survival and the log-rank statistics. Multiple events for a given subject were weighted according to the probability that prior events would be confirmed. Once all study events were adjudicated, final analyses confirmed the results of the adjusted interim analysis. For monitoring clinical trials with adjudicated endpoint events, models based on prior adjudication histories can be reliably used to predict event classifications for unadjudicated events and support accurate, contemporary interim analyses.

Anticoagulants↗

PubMed1994

Outcome measures for clinical trials in cystic fibrosis. Summary of a Cystic Fibrosis Foundation consensus conference.

The CFF Consensus Conference concluded with a summary of those outcome measures that would be most useful in studies of patients 6 years of age and older and those measures that would be most useful in studies of the younger population (< 6 years of age) (Table). These measures were further divided into biologic markers most appropriate for initial (phase I and phase II) clinical trials and those especially useful in large, multicenter (phase III) pivotal trials. There is an ongoing need to improve the accuracy and validity of currently available measures of biologic activity and clinical efficacy in CF, especially in the younger population. The conference participants recommended that the following eight issues be addressed as soon as possible: (1) definition of pulmonary exacerbation, (2) broadly applicable methods of testing pulmonary function in small children (ideally a single test for all ages), (3) a comprehensive severity-of-disease score for young children, (4) reliable methods of quantifying chest x-ray and CT scan changes in young patients, (5) simple, inexpensive measures of lung inflammation, (6) a centralized, uniform approach to the establishment of data monitoring committees, (7) a quality of well-being scale for small children, and (8) reliable, reproducible aerosol delivery systems with defined characteristics. In addition, participants recommended that better methods be developed for assessing patients' adherence to research protocols.

Adolescent↗

PubMed2003

Guidelines for conscious sedation and monitoring during gastrointestinal endoscopy.

This is one of a series of statements discussing the utilization of GI endoscopy in common clinical situations. The Standards of Practice Committee of the American Society for Gastrointestinal Endoscopy prepared this text. In preparing this guideline, a MEDLINE literature search was performed, and additional references were obtained from the bibliographies of the identified articles and from recommendations of expert consultants. When little or no data exist from well-designed prospective trials, emphasis is given to results from large series and reports from recognized experts. Guidelines for appropriate utilization of endoscopy are based on a critical review of the available data and expert consensus. Further controlled clinical studies are needed to clarify aspects of this statement, and revision may be necessary as new data appear. Clinical consideration may justify a course of action at variance to these recommendations.

Anesthesia, General↗

PubMed1994

The early termination of clinical trials: causes, consequences, and control. With special reference to trials in the field of arrhythmias and sudden death. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology.

The early termination of clinical trials, for either benefit or harm, often generates undue enthusiasm or alarm. The enhanced publicity attending early termination of a trial promotes inappropriate interpretations because of the inherent difficulty of a prompt and comprehensive data review. Furthermore, the process of monitoring the accumulating outcome data for early evidence of treatment benefit or harm is fraught with many statistical and methodological difficulties. This report from a Task Force convened by the Working Group on Arrhythmias of the European Society of Cardiology incorporates first, a series of trials terminated appropriately or inappropriately for benefit or harm and used as examples to illustrate the importance of suitable trial design and of proper stopping rules; second, a description of the committee structure of a clinical trial; third, an analysis of the general design issues; fourth, a review of the main issues in interim analysis with special reference to main strategies for reducing the rate of false-positive claims that could result from early trial termination; and finally, a series of specific recommendations concerning the design, structure, analysis, interpretation, and presentation of a clinical trial.

Anti-Arrhythmia Agents↗