Impact of study partner replacement in a mild cognitive impairment clinical trial

In Alzheimer's disease (AD) clinical trials, including trials enrolling patients with mild cognitive impairment (MCI), participants must enroll with a study partner (SP). SPs ensure compliance and are a source of study data, including assessments of the participant's cognition and function. Consistency in SP reporting is essential to trial data integrity.

We quantified SP replacement and its impact on bias and variance of SP-reported AD Cooperative Study Activities of Daily Living for MCI (ADCS-ADL-MCI) in the ADCS Vitamin E/Donepezil MCI Trial. We used logistic regression to estimate the association between SP type (spouse or non-spouse) and the odds of experiencing SP change. We used generalized estimating equations to longitudinally model the differences in consecutively recorded ADCS-ADL-MCI scores as a function of whether SP change occurred. We used a similar model to quantify end-of-study change from baseline in ADCS-ADL-MCI scores.

Among 768 participants, 40 (5%) experienced at least one SP change. We estimated that the odds of experiencing a SP change were 65% lower for spousal dyads when compared to non-spousal dyads (odds ratio [OR] = 0.35; 95% confidence interval [CI]: [0.18-0.67]). Compared to those with a consistent SP, participants who experienced a SP change had, on average, a consecutive visit absolute score difference that was 1.60 points greater in magnitude (95% CI: [0.62-2.57]), suggesting greater volatility. ADCS-ADL-MCI scores were neither systematically higher nor lower when SP change occurred, on average (-0.23; 95% CI: [-1.60, 1.14]), suggesting minimal bias. The estimated difference in variance for end-of-study change from baseline ADCS-ADL-MCI was observed to be higher for those with SP change compared to those without, but the difference was not statistically significant (1.29; 95% CI: [0.47-1.17]).

SP replacement occurred for a meaningful number of participants but did not result in systematic bias on a functional outcome in this trial, but it did increase variability.Highlights: Among participants in a mild cognitive impairment trial, approximately 5% experienced at least one study partner replacement.The estimated odds of replacement were 60% lower for participants with a spousal study partner at baseline, compared to those with a non-spouse partner.We observed increased variance, but not bias, in the mean within-participant change in consecutive ADCS-ADL-MCI scores among participants experiencing study partner replacement.We observed greater variance for end-of-study change from baseline ADCS-ADL-MCI for those who experienced a study partner replacement, compared to those who did not.