Seamless superiority/non-inferiority clinical trials
Permanent Link
https://hdl.handle.net/2144/34904Abstract
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.
Collections
Related items
Showing items related by title, author, creator and subject.
-
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: ... -
Trial-based cognitive therapy: efficacy of a new CBT approach for treating social anxiety disorder with comorbid depression
Caetano, Katia A. S.; Depreeuw, Barbara; Papenfuss, Inka; Curtiss, Joshua; Langwerden, Robbert J.; Hofmann, Stefan G.; Neufeld, Carmem B. (SPRINGER International Publishing AG, 2018-09-01)The present study aims to evaluate the efficacy of Trial-Based Cognitive Therapy (TBCT), a new cognitive-behavioral therapy approach, for generalized social anxiety disorder (GSAD) in a population with high rates of comorbid ... -
Can Clinical Trials Requiring Frequent Participant Contact Be Conducted Over the Internet? Results From an Online Randomized Controlled Trial Evaluating a Topical Ointment for Herpes Labialis
Formica, Margaret; Kabbara, Karim; Clark, Rachael; McAlindon, Tim (Gunther Eysenbach, 2004-2-17)BACKGROUND The Internet has tremendous appeal for conducting randomized clinical trials and may be especially applicable to trials requiring frequent participant contact. Trials of cold sore remedies, for example, often ...