Treffer: Sequential Parallel Comparison Design for Assessing Induction, Maintenance, Long-Term, and Other Treatment Effects on a Binary Endpoint.
W. J. Sandborn, B. G. Feagan, P. Rutgeerts, et al., “Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease,” New England Journal of Medicine 369 (2013): 711–721.
W. J. Sandborn, S. Vermeire, L. Peyrin‐Biroulet, et al., “Etrasimod as Induction and Maintenance Theray for Ulcerative Colitis (ELEVATE): Two Randomized, Double ‐Blind, Placebo‐Controlled, Phase 3 Studies,” Lancet 401 (2023): 1159–1171.
FDA, “Draft Guidance: Crohn's Disease: Developing Drugs for Treatment, Guidance for Industry,” 2022.
FDA, “Draft Guidance: Ulcerative Colitis: Developing Drugs for Treatment, Guidance for Industry,” 2022.
K. Weimer, L. Colloca, and P. Enck, “Placebo Effects in Psychiatry: Mediators and Moderators,” Lancet Psychiatry 2 (2015): 246–257.
R. de la Fuente‐Fernandez, M. Schulzer, and A. J. Stoessl, “The Placebo Effect in Neurological Disorders,” Lancet Neurology 1 (2002): 85–91.
M. Fava, A. E. Evins, D. J. Dorer, and D. A. Schoenfeld, “The Problem of Placebo Response in Clinical Trials for Psychiatric Disorders: Culprits, Possible Remedies, and a Novel Study Design Approach,” Psychotherapy and Psychosomatics 72 (2003): 115–127.
R. N. Tamural, X. Huang, and D. D. Boos, “Estimation of Treatment Effect for the Sequential Parallel Design,” Statistics in Medicine 0 (2011): 3496–3506.
A. Ivanova, B. Qaqish, and D. A. Schoenfeld, “Optimality, Sample Size, and Power Calculations for the Sequential Parallel Comparison Design,” Statistics in Medicine 30 (2011): 2793–2803.
X. Huang and R. N. Tamura, “Comparison of Test Statistics for the Sequential Parallel Design,” Statistics in Biopharmaceutical Research 2 (2010): 42–50.
H. Quan, X. Chen, J. Luo, and X. Chen, “A Generalized Weighted Combination Test of Treatment Effect for Clinical Trials With a Sequential Parallel Comparison Design and Binary Endpoint,” Statistics in Medicine 41 (2022): 2725–2744.
B. G. Feagan, P. Rutgeers, B. E. Sands, et al., “Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis,” New England Journal of Medicine 369 (2013): 699–710.
M. Benatar, H. Wiendl, R. Nowak, Y. Zheng, and W. Macias, “Batoclimab as Induction and Maintenance Therapy in Patients With Myasthenia Gravis: Rationale and Study Design of a Phase 3 Clinical Trial,” BMJ Neurol Open 6 (2024): e000536, https://doi.org/10.1136/bmjno‐2023‐000536.
Y. F. Chen, Y. Yang, H. M. J. Hung, and S. J. Wang, “Evaluation of Performance of Some Enrichment Designs Dealing With High Placebo Response in Psychiatric Clinical Trials,” Contemporary Clinical Trials 32 (2011): 592–604.
G. Homma and T. Daimon, “A Simple Test for the Treatment Effect in Clinical Trials With a Sequential Parallel Comparison Design and Negative Binomial Outcomes,” Pharmaceutical Statistics 18 (2019): 184–197.
A. Ivanova and R. N. Tamura, “A Two‐Way Enriched Clinical Trial Design: Combining Advantages of Placebo Lead‐In and Randomized Withdrawal,” Statistical Methods in Medical Research 24 (2015): 871–890.
H. Quan, D. Zhang, J. Zhang, and L. Devlamynck, “Analysis of a Binary Composite Endpoint With Missing Data in Components,” Statistics in Medicine 26 (2007): 4703–4718.
D. Rubin, “Inference and Missing Data,” Biometrika 63 (1976): 581–592.
H. Quan, L. Qi, X. Luo, and L. Darchy, “Considerations of Multiple Imputation Approaches for Handling Missing Data in Clinical Trials,” Contemporary Clinical Trials 70 (2018): 62–71.
D. Rubin, “Multiple Imputation After 18+ Years,” Journal of the American Statistical Association 91 (1996): 473–489.
Weitere Informationen
For a chronic disease, besides the treatment induction effect, it is also important to demonstrate the maintenance effect of long-term treatment use. To fulfill these and other objectives for a clinical study, we often apply one of three designs: the active treatment lead-in followed by randomized maintenance design, the randomized induction followed by re-randomized withdrawal maintenance design and the treat-through design (FDA 2022). Separately, a two-stage sequential parallel comparison design (SPCD) is frequently used in therapeutic areas where placebo has a large effect. In this paper, we use a SPCD for a clinical trial with a binary endpoint for induction, maintenance, long-term and other treatment effect assessments. This SPCD can actually be treated as a hybrid of the above three designs and has some additional advantages. For example, compared to the re-randomized withdrawal maintenance design, the SPCD does not need a re-randomization to simplify trial operation and it also provides controlled data for formal long-term efficacy and safety analyses. To fully utilize all available data of the two stages for an overall treatment effect evaluation, a weighted combination test is considered with the incorporation of correlations of the components. Further, a multiple imputation approach is applied to handle missing not at random data. Simulations are conducted to evaluate the performances of the methods and a data example is employed to illustrate the applications of the methods.
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