Multicrossover Randomized Controlled Trial Designs in Alzheimer Disease

Abstract

Conventional parallel group randomized controlled clinical trials (RCT) in Alzheimer’s disease (AD) are too large, long, expensive and insensitive to clinical change to meet the urgent need for an effective treatment. While providing good evidence for a treatment’s benefit, parallel group RCTs in AD must have very large samples and broad measures of change to accommodate the marked heterogeneity of demographics, genetics, symptoms, pathophysiologies, comorbidities and rates of progression. Multi-crossover, placebo-controlled, double-blind RCTs, including those with sample sizes as small as a single subject (“N-of-1”), are robust designs wherein subjects serve as their own controls in repeated blocks of randomly sequenced crossover treatments. Heterogeneities are inherently controlled and the sensitivity, specificity and clinical relevance of outcomes can be enhanced further by including personalized outcome measures for each individual. Multi-crossover N-of-1 RCTs enable unbiased estimation of efficacy for single subjects, and joint analysis of multiple N-of-1 trials enables estimation of efficacy for populations with much smaller sample sizes than those needed in conventional parallel group studies. It is important to identify carryover effects and natural history time trends to achieve unbiased estimation and testing of the treatment effect. We assert that in AD, multi-crossover RCTs offer many advantages over standard parallel group trials for drugs or other treatments with suitable mechanisms of action, pharmacokinetics and pharmacodynamics; despite the fact that they are almost never conducted. They may be especially useful for therapies directed at symptomatic improvement of cognitive and neuropsychiatric symptoms, but also can be used in early phase studies of disease modifying treatments with biomarker outcome measures.

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