Methods All patients were suffering from nonerosive reflux disease or functional ulcer-like dyspepsia and were prescribed a proton pump inhibitor to be taken as needed for relief of epigastric pain. The primary endpoint was a score variable that expresses the magnitude of gastro-intestinal symptoms at 8 weeks after randomization. We developed linear and loglinear versions of the structural mean models to derive an unbiased estimator of the reduction in symptom score as a function of exposure to the test drug. Semi-parametric models based on splines and corresponding simultaneous confidence bands identified the presence of potential interactions between drug exposure and baseline covariates.
Results The on-demand dosing regimen generated a wide range of drug exposure. Application of SMM showed that the potential treatment-induced reduction in symptom score was much greater than the average treatment reduction observed in this population of patients. Our diagnostic tool was useful for detecting the interaction between drug exposure and baseline covariates. Limitations Analysis could only be performed over the first 2 months after randomization because, afterwards, many patients dropped out from the placebo group. Conclusions The structural mean model approach allows one to estimate treatment efficacy in the presence of variable drug exposure. Similar results were obtained using linear and loglinear structural mean model. Clinical Trials 2009; 6: 403—415. http://ctj.sagepub.com
]]>Purpose As a case study, to examine the overlap of study cohorts in two large randomized controlled clinical trials that assess interventions to reduce risk of major cardiovascular disease events in adults with type 2 diabetes in order to explore the feasibility of cross-trial comparisons
Methods The Action for Health in Diabetes (Look AHEAD) and The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trials enrolled 5145 and 10,251 adults with type 2 diabetes, respectively. Look AHEAD assesses the efficacy of an intensive lifestyle intervention designed to produce weight loss; ACCORD tests pharmacological therapies for control of glycemia, hyperlipidemia, and hypertension. Incidence of major cardiovascular disease events is the primary outcome for both trials. A sample was constructed to include participants from each trial who appeared to meet eligibility criteria and be appropriate candidates for the other trial’s interventions. Demographic characteristics, health status, and outcomes of members and nonmembers of this constructed sample were compared.
Results Nearly 80% of Look AHEAD participants were projected to be ineligible for ACCORD; ineligibility was primarily due to better glycemic control or no early history of cardiovascular disease. Approximately 30% of ACCORD participants were projected to be ineligible for Look AHEAD, often for reasons linked to poorer health. The characteristics of participants projected to be jointly eligible for both trials continued to reflect differences between trials according to factors likely linked to retention, adherence, and study outcomes.
Limitations Accurate ascertainment of cross-trial eligibility was hampered by differences between protocols.
Conclusions Despite several similarities, the Look AHEAD and ACCORD cohorts represent distinct populations. Even within the subsets of participants who appear to be eligible and appropriate candidates for trials of both modes of intervention, differences remained. Direct comparisons of results from separate trials of lifestyle and pharmacologic interventions are compromised by marked differences in enrolled cohorts. Clinical Trials 2009; 6: 416—429. http://ctj.sagepub.com
]]>Purpose SPERT’s goal was to propose a pharmaceutical industry standard for safety planning, data collection, evaluation, and reporting, beginning with planning first-in-human studies and continuing through the planning of the post-product-approval period.
Methods SPERT’s recommendations are based on our review of relevant literature and on consensus reached in our discussions.
Results An important recommendation is that sponsors create a Program Safety Analysis Plan early in development. We also give recommendations for the planning of repeated, cumulative meta-analyses of the safety data obtained from the studies conducted within the development program. These include clear definitions of adverse events of special interest and standardization of many aspects of data collection and study design. We describe a 3-tier system for signal detection and analysis of adverse events and highlight proposals for reducing "false positive" safety findings. We recommend that sponsors review the aggregated safety data on a regular and ongoing basis throughout the development program, rather than waiting until the time of submission.
Limitations We recognize that there may be other valid approaches.
Conclusions The proactive approach we advocate has the potential to benefit patients and health care providers by providing more comprehensive safety information at the time of new product marketing and beyond. Clinical Trials 2009; 6: 430—440. http://ctj.sagepub.com
]]>Purpose The purpose of this project was to automate the adverse event reporting process, replacing paper-based processes with computer-based processes, so that personnel effort and time required for serious adverse event reporting was reduced, and the monitoring of reporting performance and adverse event characteristics was facilitated.
Methods Use case analysis was employed to understand the reporting workflow and generate software requirements. The automation of the workflow was then implemented, employing computer databases, web-based forms, electronic signatures, and email communication.
Results In the initial year (2007) of full deployment, 588 SAE reports were processed by the automated system, eSAEyTM. The median time from initiation to Principal Investigator electronic signature was <2 days (mean 7 ± 0.7 days). This was a significant reduction from the prior paper-based system, which had a median time for signature of 24 days (mean of 45 ± 5.7 days). With eSAEyTM, reports on adverse event characteristics (type, grade, etc.) were easily obtained and had consistent values based on standard terminologies.
Limitation The automated system described was designed specifically for the workflow at Thomas Jefferson University. While the methodology for system design, and the system requirements derived from common clinical trials adverse reporting procedures are applicable in general, specific workflow details may not be relevant at other institutions.
Conclusion The system facilitated analysis of individual investigator reporting performance, as well as the aggregation and analysis of the nature of reported adverse events. Clinical Trials 2009; 6: 446—454. http://ctj.sagepub.com
]]>Purpose (1) Evaluate the efficacy of PD stenting to ameliorate abdominal pain in patients with CP and ductal strictures; (2) evaluate the placebo response rate from sham endoscopic therapy; (3) compare pain medication usage, healthcare utilization, psychological distress, and quality of life before and after endoscopic stenting; (4) prospectively evaluate the durability of the response.
Methods Patients with typical abdominal pain, imaging confirmation of CP and endoscopic retrograde cholangiopancreatography (ERCP) confirmation of PD stricture will complete questionnaires to assess quality of life, psychological distress, pain intensity/unpleasantness, pain medication usage, and healthcare utilization. Enrolled patients will be randomized to ERCP with sphincterotomy and PD stenting versus sham procedure. Pain level and medication usage will be assessed weekly with telephone interviews. At 6—8 weeks, patients treated with stents will undergo stent removal; those randomized to the sham procedure without significant improvement (<50% reduction in pain score) will cross over to the treatment group; and those randomized to sham procedure who experienced improvement (>50% reduction) will be followed clinically. Patients will be followed in clinic or by phone biannually (up to 3 years). The primary endpoint is improvement in abdominal pain. The secondary endpoints are reduction in narcotic use, healthcare utilization, and work days missed; return to employment; improvement in quality of life and weight gain.
Results Proposed study.
Limitations Strict inclusion criteria may limit enrollment.
Conclusion The proposed study represents the first trial of endoscopic stenting for symptomatic CP and ductal strictures with a credible sham procedure, assessment of multiple dimensions of pain, and psychosocial factors. Clinical Trials 2009; 6: 455—463. http://ctj.sagepub.com
]]>Purpose To report on the implementation of an international trial — CONTROL — intended to assess the efficacy and safety of rFVIIa in trauma, and discuss trauma research study design in light of this experience.
Methods The CONTROL trial international steering committee confronted a number of barriers in the design of the CONTROL trial. They addressed methodologies for (1) standardizing entry criteria for trauma patients suffering inherently heterogeneous injuries, (2) obtaining informed consent in an acutely injured population with altered levels of consciousness, (3) avoiding futile care, while recruiting subjects with incompletely diagnosed injuries, (4) standardizing trauma intensive care across different investigating sites and countries, and (5) establishing study endpoints that were both clinically relevant and convincing to regulatory authorities. The resulting study methodology is reported.
Results The CONTROL trial began active recruitment in October 2005, and was halted on June 11, 2008 because the observed mortality in the 576 enrolled patients was so far below expectations that the study would lack sufficient statistical power at the planned number of subjects to demonstrate a benefit. The utility of the endpoints selected for study will not be known until completion of data analysis. Limitations Any clinical trial in trauma patients must cope with the urgency of care required, issues of patient heterogeneity, standardization of care across multiple centers, and the difficulties of obtaining informed consent.
Conclusion Research in acutely hemorrhaging trauma patients presents numerous scientific and ethical challenges. The methodology of the CONTROL study is presented as an example of how some of these challenges can be approached and managed, and of the pitfalls that may arise. Clinical Trials 2009; 6: 467—479. http://ctj.sagepub.com
]]>Purpose Our goal is to propose a design for utilizing a sequential, multiple assignment, randomized trial design for patients with malignant melanoma to test the relative efficacy of drugs that target serotonin versus dopamine metabolism during 4 weeks of intravenous, then 8 weeks of subcutaneous, interferon-alpha therapy.
Methods Patients will be offered participation in a double-blinded, randomized, controlled, 14-week trial involving two treatment phases. During the first month of intravenous interferon-alpha therapy, we will test the hypotheses that escitalopram will be more effective in reducing depressed mood, anxiety, and irritability, whereas methylphenidate will be more effective in diminishing interferon-alpha-induced neurovegetative symptoms, such as fatigue and psychomotor slowing. During the next 8 weeks of subcutaneous interferon therapy, participants whose symptoms do not improve significantly will be randomized to the alternate agent alone versus escitalopram and methylphenidate together.
Results We present a prototype for a single-center, sequential, multiple assignment, randomized trial, which seeks to determine the efficacy of sequenced and targeted treatment for the two distinct symptom complexes suffered by patients treated with interferon-alpha.
Limitations Because we cannot completely control for external factors, a relevant question is whether or not ‘short-term’ neuropsychiatric interventions can increase the number of interferon-alpha doses tolerated and improve long-term survival. Conclusions This sequential, multiple assignment, randomized trial proposes a framework for developing optimal treatment strategies; however, additional studies are needed to determine the best strategy for treating or preventing neurobehavioral symptoms induced by the immunotherapy interferon-alpha. Clinical Trials 2009; 6: 480—490. http://ctj.sagepub.com
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