Impact of study partner type on primary endpoint volatility in a phase 3 registration trial of mild-to-moderate Alzheimer’s disease

Abstract

In Alzheimer’s disease (AD) clinical trials, participants are required to enroll with a study partner (SP) who ensures compliance and completes outcomes assessing participant cognitive and functional ability. The SP role is commonly filled by spouses and other family members. Spouse and non-spouse SPs differ in numerous ways, including average time in contact with the participant. These differences may impact volatility of SP-reported assessments, which may in turn impact trial integrity. We quantified the impact of SP type on the variance of SP-reported Disability Assessment for Dementia (DAD) scores. We analyzed data from the Bapineuzumab 301 (ApoE $\epsilon$4 non-carriers) and 302 (ApoE $\epsilon$4 carriers) phase 3 trials in mild-to-moderate AD, provided by the trial sponsor, Janssen Research & Development, LLC for use in these analyses. We compared the sample variances of end-of-study DAD scores for spousal and non-spousal SPs in each trial. 95% confidence intervals (CIs) for the corresponding parameters were computed via bootstrapping. We used similar methods to compare the variances in the difference between baseline and end-of-study DAD scores for SP types. Among the 1,232 and 1,121 participants analyzed from trials 301 and 302, 818 (66.4%) and 837 (74.7%) had spousal SPs at baseline, respectively. On the other hand, 665 (665/973=68.3%) and 697 (697/924=75.4%) spousal SPs in each trial completed the end-of-study visit, respectively. In trial 301, the variance of end-of-study DAD scores for spousal SPs were observed to be 14% lower compared to non-spousal SPs (spousal/non-spousal= 630.41/746.55=0.84, 95% CI=[0.71, 1.03]). In trial 302 this relative decrease was observed to be 9% , though with less precision (spousal /non-spousal=610.85/673.86=0.91, 95% CI=[0.77, 1.12]). Neither trial had significant differences in spousal vs non-spousal variances of the change-from-baseline DAD scores (Trial 301 spousal/non-spousal=378.10/425.17=0.91, 95% CI=[0.66, 1.22]; Trial 302 spousal/non-spousal=354.38/352.22=1.01, 95% CI=[0.77, 1.35]). Differences in the linear trend of DAD variance did not significantly differ between SP types in either trial (Trial 301 Est.=-1.74, 95% CI=[-3.58, 0.23]; Trial 302 Est.=0.94, 95% CI=[-5.83, 4.31]). SP type was not associated with variation in SP-reported study endpoints in this study.

Mary M. Ryan

Assistant Professor
mary [dot] ryan [at] wisc [dot] edu

My research interests include group sequential design and clinical trials, with applications in Alzheimer’s Disease biomarker discovery, as well as pragmatic and cluster randomized trials.