Controlled clinical trials最新文献

Patients with severe ventricular dysfunction and coronary disease have high morbidity and mortality. They may benefit from revascularization but have significant perioperative morbidity and mortality. Positron emission tomography (PET) imaging with F-18-fluorodeoxyglucose (FDG) can detect viable myocardium that may recover from revascularization in such patients. It is unclear whether use of FDG PET in this population improves outcome or is cost-effective. The principal aim of this study is to determine whether FDG PET-guided therapy improves clinical outcome compared to standard care. Secondary objectives are to determine whether FDG PET-guided therapy improves left ventricular (LV) function, improves quality of life, and provides a cost benefit versus standard care. Included in this multicenter randomized controlled trial are patients with coronary artery disease and severe LV dysfunction who are referred for revascularization, heart failure, or cardiac transplantation or in whom FDG PET is potentially useful. Consenting subjects will be randomized to therapy directed by FDG PET or standard care. The primary outcome is the composite cardiovascular endpoint of cardiac death, myocardial infarction, transplantation, or rehospitalization for unstable angina or heart failure. Secondary outcomes include health-related quality of life, costs, mortality, cardiovascular events, and LV function. Assuming two-sided alpha = 0.05, power = 80%, a sample size of 206 patients per group is required to detect a 15% absolute difference in the primary outcome between PET-directed therapy compared to standard care. Analyses will be conducted on an intention-to-treat basis. To our knowledge, this is the first large trial to evaluate whether FDG PET-directed therapy is effective and provides a cost benefit in patients with severe LV dysfunction. If so, thousands of such patients can be risk-stratified to select who is likely to benefit from revascularization.

The Digitalis Investigation Group (DIG) trial was the first large simple trial conducted by the National Heart, Lung, and Blood Institute in conjunction with the Department of Veterans Affairs. A large simple trial is a major undertaking. Simplification at the sites requires careful planning and discipline. Lessons learned from the DIG trial were: (1) keep a large simple trial very simple and keep all study procedures very simple; (2) ancillary studies are important and can complement a large simple trial but require careful advanced planning; (3) anticipate special needs when shipping study drugs internationally; (4) regional coordinating centers can be very useful; (5) recruit as many capable sites as possible; (6) provide research-inexperienced sites/investigators with extra help to obtain federalwide assurance statements from the Office for Human Research Protections and institutional review board approvals; (7) adequately reimburse sites for the work completed; (8) maintain investigator enthusiasm; (9) monitor the slow performers and sites with numerous personnel changes; (10) choose an endpoint that is easy to ascertain; (11) keep the trial simple for participants; and (12) plan early for closeout and for activities between the end of the trial and publication of results.

The Digitalis Investigation Group (DIG) trial was a large simple clinical trial that involved 302 participating centers in the United States and Canada. In order to encourage participation by Canadian investigators, to provide additional help to what were expected to be largely research-inexperienced investigators in Canada, and to provide the study's data coordinating center with resources in Canada to deal with potentially different rules, regulations, and cultural differences, regional coordinating centers were established in four regions of Canada: the maritime provinces, Quebec, Ontario, and western Canada. Canadian centers recruited significantly better than their U.S. counterparts and had slightly better retention and follow-up. While it is not possible to declare that the regional coordinating centers were responsible for this improvement, it is believed that these regional centers did play a role. This role included being able to identify investigators who could be expected to do well, providing one-on-one training and instruction to investigators, and being able to solve problems and implement change in the relatively fewer centers in their regions. The regional coordinating center also reduced the intensity of the workload on the data coordinating center by serving as the primary point of contact for Canadian investigators. The use of regional coordinating centers in studies with a large number of participating centers is highly recommended.

The Osteoporosis Prevention and Arterial effects of tiboLone (OPAL) trial is a three-arm, randomized, placebo-controlled, double-blind study to determine the effect of tibolone 2.5 mg (Org OD 14) and continuous combined conjugated equine estrogens plus medroxyprogesterone acetate (0.625 mg/2.5 mg respectively) on progression of intima-media thickness of the carotid arteries and bone mineral density of the lumbar vertebrae and proximal femur in postmenopausal women. A total of 866 healthy postmenopausal women were recruited in six U.S. centers and five European centers. Duplicate carotid ultrasound examinations of the common carotid artery, the carotid bifurcation, and the internal carotid artery were performed at baseline. Single measurements of bone mineral density of the lumbar vertebrae and proximal femur were obtained at baseline. After randomization, ultrasound examinations were repeated every 6 months for 36 months following baseline, with a duplicate examination at the end of the study. Bone mineral density was measured every 12 months throughout the trial. The primary outcome is change in mean common carotid intima-media thickness (CIMT), defined as the average of the intima-media thickness measurements performed circumferentially at predefined angles for the near and far wall of 10-mm segments of the right and left distal common carotid arteries. Unique new features of the OPAL study are the specifically developed OPAL ultrasound protocol, yielding highly reproducible CIMT measurements, and the use of two experienced core laboratories for CIMT readings (one in the United States and one in Europe) with one common quality assurance and control program. The OPAL study is a large, placebo-controlled trial evaluating the effects of tibolone, as well as one of the first large randomized studies to determine the effects of continuous combined estrogen-progestin therapy on carotid atherosclerosis in healthy postmenopausal women. The OPAL study results are expected to complement other studies on atherosclerosis progression in healthy postmenopausal women.

The Digitalis Investigation Group (DIG) trial was a randomized, double-blind placebo-controlled trial whose primary objective was to determine whether digoxin had beneficial, harmful, or no effect on total mortality in patients with heart failure who were in sinus rhythm and whose ejection fraction was ⩽0.45. The study was designed as a large simple trial with a large number of centers (302) in the United States and Canada, many of which were inexperienced in research. To ensure that the results of the trial would be reported accurately without possible bias due to missing data, the study leadership decided that no outcome results would be reported until the vital status at the end of the study was known for at least 97% of the study participants. Planning for closeout of the study began a year prior to the common end date of December 31, 1995 and included plans for obtaining vital status on December 31, 1995. Participants were given postcards at their final study visit to be completed and mailed on or after January 1, 1996. Of 5602 postcards distributed, 5070 (90.5%) were completed and returned. A contract search agency was hired to locate the remaining participants. Of the total 7788 participants entered into the DIG trial, only 97 participants (1.2%) could not have their vital status as of December 31, 1995 determined. It is recommended that investigators having an outcome measure with a common end date include plans in their protocols for obtaining their measures and activate those plans as early as possible during the course of the study.

Before any clinical trial can begin to recruit patients, participating clinical centers must obtain approval from their institutional review board (IRB). When studies are federally funded, such as by the U.S. Department of Health and Human Services (DHHS), centers must also have or obtain a federal compliance agreement from the Office of Human Research Protections (formerly the Office for Protection from Research Risks [OPRR]). The Digitalis Investigation Group trial was a large, international, double-blind, DHHS-funded randomized trial on the effect of digoxin on mortality in heart failure. Due to the anticipated number of centers (>200), the study's data coordinating center (DCC) was requested to assume additional responsibilities that included: (1) acting as a liaison between the OPRR and all study centers; (2) reviewing and correcting all assurance statements before submission to the OPRR; (3) reviewing and approving all centers' informed consent forms; and (4) helping the many research-inexperienced centers to establish IRBs or to locate an IRB in their region that would accept IRB responsibility for them. Although a heavy burden was placed on the DCC, the IRB and OPRR approval process was probably shortened by many weeks at those centers not already possessing a federal compliance agreement. This enabled the study to be completed on schedule and within budget.