title: A novel approach to delayed-start analyses for demonstrating disease-modifying effects in Alzheimer's disease.
abstract: One method for demonstrating disease modification is a delayed-start design, consisting of a placebo-controlled period followed by a delayed-start period wherein all patients receive active treatment. To address methodological issues in previous delayed-start approaches, we propose a new method that is robust across conditions of drug effect, discontinuation rates, and missing data mechanisms. We propose a modeling approach and test procedure to test the hypothesis of noninferiority, comparing the treatment difference at the end of the delayed-start period with that at the end of the placebo-controlled period. We conducted simulations to identify the optimal noninferiority testing procedure to ensure the method was robust across scenarios and assumptions, and to evaluate the appropriate modeling approach for analyzing the delayed-start period. We then applied this methodology to Phase 3 solanezumab clinical trial data for mild Alzheimer's disease patients. Simulation results showed a testing procedure using a proportional noninferiority margin was robust for detecting disease-modifying effects; conditions of high and moderate discontinuations; and with various missing data mechanisms. Using all data from all randomized patients in a single model over both the placebo-controlled and delayed-start study periods demonstrated good statistical performance. In analysis of solanezumab data using this methodology, the noninferiority criterion was met, indicating the treatment difference at the end of the placebo-controlled studies was preserved at the end of the delayed-start period within a pre-defined margin. The proposed noninferiority method for delayed-start analysis controls Type I error rate well and addresses many challenges posed by previous approaches. Delayed-start studies employing the proposed analysis approach could be used to provide evidence of a disease-modifying effect. This method has been communicated with FDA and has been successfully applied to actual clinical trial data accrued from the Phase 3 clinical trials of solanezumab.
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana, United States of America.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu-Seifert
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana, United States of America.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Andersen
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana, United States of America.
authors.forename: Ilya
authors.initials: I
authors.lastname: Lipkovich
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana, United States of America.
authors.forename: Karen C
authors.initials: KC
authors.lastname: Holdridge
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Siemers
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D016032:Randomized Controlled Trials as Topic
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C550616:solanezumab