Abstract
INTRODUCTION: Practice effects (PEs) are a well-known potential confound in natural history studies of longitudinal cognitive decline in aging and early-stage Alzheimer's disease. The implication of PEs on Alzheimer's disease clinical trials is less well understood, although we have previously speculated that a "run-in" period of repeated cognitive assessments prior to randomization may improve the efficiency of clinical trials [Jacobs et al. Alzheimer's & Dementia 2017;3(4):531-535]. We have also described how the performance of composite outcome measures depends on parameters that may be influenced by PEs. METHODS: To investigate this, we used the cognitive battery within the National Alzheimer's Coordinating Center (NACC) Uniform Data Set to characterize the potential impact of PEs on clinical trial design and outcome measures. The analysis restricted to N = 1094 amnestic mild cognitively impaired participants with 3 years of follow-up data. Linear mixed effects models estimate the magnitude of PEs observed in aMCI participants. Power calculations informed by the pattern of progression in the NACC sample were used to describe the net impact of PEs on trials with and without a run-in phase. Weighting parameters of optimal composite measures constructed from the NACC battery were also compared. RESULTS: PEs were large, often exceeding the magnitude of annual rate of change observed in later assessments. Annualized rate of change, and therefore target treatment effect sufficient to achieve a specified percentage reduction in rate of decline, was larger after run-in. Sample size projections for the run-in design were a fraction of those required for trials without run-in. Weighting parameters that optimize composite outcome performance were also different for the two designs, underscoring the importance of considering design in the construction of composite outcomes. DISCUSSION: Clinical trials randomizing after a run-in period measure treatment efficacy relative to decline unbiased by PEs, and require smaller sample size. HIGHLIGHTS: In the National Alzheimer's Coordinating Center (NACC), amnestic mild cognitive impairment (aMCI) cohort practice effects often exceed annualized rate of change.Run-in clinical trial designs can be used to extinguish practice effects.Rate of decline after run-in is faster and unbiased by practice effects.Run-in designs correctly target the most clinically relevant outcome signal.Practice effects also impact weighting of optimal composite measures.