Sample size estimation for clinical trials with tau‐PET SUVR as the primary outcome in dominantly inherited Alzheimer’s disease

Abstract

AbstractBackgroundIn addition to anti‐Aβ immunization therapeutics completing phase II/III clinical trials1, drugs targeting tau, inflammation, and apolipoprotein E, are in clinical development. Due to its close association with cognitive and clinical impairment, tau is one of the most promising targets currently ready for phase II trials. In this study, using the longitudinal tau‐PET data from the DIAN‐TU‐001 trial in Dominantly Inherited Alzheimer’s Disease (DIAD), we estimated the sample sizes for clinical trials with Tau‐PET as the primary outcome.MethodDIAN‐TU‐001 is a phase II/III randomized, double‐blind, placebo‐controlled, cognitive endpoint, multicenter study of potential disease modifying therapies (gantenerumab or solanezumab) in individuals with DIAD. Sample sizes will be estimated using the longitudinal Tau PET with AV1451 from the placebo arm (N=40, mean (SD) of follow‐up: 2.6 (0.89) years, CDR 0 to 1 at baseline, No DIAN observational data) based on change from baseline for asymptomatic and symptomatic cohorts, respectively. To avoid bias from potential drug effect on Tau‐PET SUVR measurement, the Tau PET data from the active drug randomized participants were not used for sample size estimation, and only for comparison with the placebo arm.ResultBased on two‐sided two‐sample t‐test with type I error of 0.05, the estimated sample sizes for a 2‐year clinical trial enrolling only symptomatic participants with 1:1 randomization ratio and change from baseline as primary outcome was presented in Table 1 for several ROIs. Similar estimations will also be presented for the asymptomatic cohort and for several Tau PET SUVR composites.ConclusionLarge increases in Tau PET SUVR were observed in the placebo arm in many regions with inferior temporal region showing a very high effect size for both asymptomatic and symptomatic participants. Phase II clinical trials with Tau PET SUVR as the primary outcome in DIAD can be conducted with relatively small sample sizes for some ROIs or composite ROIs.