Seamless superiority/non-inferiority clinical trials
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To assess non-inferiority of an experimental product to an active control in a clinical trial, an ideal design is to include a placebo arm to ensure both the experimental product and the active control is superior to placebo. We aim to identify methodology to control Type I error rate and maintain adequate power in a superiority/non-inferiority seamless clinical trial defined as: 1. selecting the best experimental treatment dose vs. placebo out of multiple treatment doses in Stage I; and 2. assessing non-inferiority of the chosen experimental dose to an active control, after adding subjects to yield adequate power for non-inferiority, in Stage II. The trial design here is an antihypertensive trial with change in systolic blood pressure as the outcome. The trial has three experimental treatment doses arms of experimental, a placebo control arm, and an active control arm. A simulation study of 20,000 such trials was conducted. We apply multiple comparison methodologies in Stage I to detect the most beneficial experimental treatment dose versus placebo, and test non-inferiority of the selected experimental dose to the active control in Stage II. Simulated Type I error rate and power for claiming non-inferiority are calculated for various dose-response trends. The need to adjust alpha to control Type I error either stage is assessed, seeking the optimal approach for doing so. Next, type I error and power for various fixed and variable non-inferiority margins are evaluated, exploring a range of margins informed by the first stage results of the study. A variable non-inferiority margin informed completely by the first stage of the trial approach results in inflated error rate which cannot be controlled by suggested multiplicity adjustments. We assess a synthesis approach between the fixed and variable margins, to both control the family-wise error rates and reach adequate power, depending on a tuning parameter defined in our work. We conclude that well-designed and adequately controlled seamless superiority/non-inferiority trials are possible with appropriate multiple comparisons adjustments and could result in less development time and fewer subjects needed to assess efficacy than separate trials.
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D-cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders: a systematic review and meta-analysis of individual participant data Mataix-Cols, David; Fernández de la Cruz, Lorena; Monzani, Benedetta; Rosenfield, David; Andersson, Erik; Pérez-Vigil, Ana; Frumento, Paolo; de Kleine, Rianne A.; Difede, JoAnn; Dunlop, Boadie W.; Farrell, Lara J.; Geller, Daniel; Gerardi, Maryrose; Guastella, Adam J.; Hofmann, Stefan G.; Hendriks, Gert-Jan; Kushner, Matt G.; Lee, Francis S.; Lenze, Eric J.; Levinson, Cheri A.; McConnell, Harry; Otto, Michael W.; Plag, Jens; Pollack, Mark H.; Ressler, Kerry J.; Rodebaugh, Thomas L.; Rothbaum, Barbara O.; Scheeringa, Michael S.; Siewert-Siegmund, Anja; Smits, Jasper A.J.; Storch, Eric A.; Ströhle, Andreas; Tart, Candyce D.; Tolin, David F.; van Minnen, Agnes; Waters, Allison M.; Weems, Carl F.; Wilhelm, Sabine; Wyka, Katarzyna; Davis, Michael; Rück, Christian; DCS Anxiety Consortium; Altemus, Margaret; Anderson, Page; Cukor, Judith; Finck, Claudia; Geffken, Gary R.; Golfels, Fabian; Goodman, Wayne K.; Gutner, Cassidy; Heyman, Isobel; Jovanovic, Tanja; Lewin, Adam B.; McNamara, Joseph P.; Murphy, Tanya K.; Norrholm, Seth; Thuras, Paul (2017-05-01)Importance: Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective: ...
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