A novel approach to delayed-start analyses for demonstrating disease-modifying effects in Alzheimer's disease

PloS One
Hong Liu-SeifertEric Siemers

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...Continue Reading

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Citations

May 31, 2016·Alzheimer's & Dementia : Diagnosis, Assessment & Disease Monitoring·Eric SiemersHong Liu-Seifert
Apr 4, 2017·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Adam S FleisherMark A Mintun
Aug 2, 2017·Amyloid : the International Journal of Experimental and Clinical Investigation : the Official Journal of the International Society of Amyloidosis·Fabio A BarrosoMarla B Sultan
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May 16, 2018·Statistics in Medicine·Guoqiao WangUNKNOWN Dominantly Inherited Alzheimer Network Trials Unit
Jul 26, 2015·Alzheimer's & Dementia : Translational Research & Clinical Interventions·Hong Liu-SeifertPaul Aisen

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Clinical Trials Mentioned

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