Abstract
This study modeled predementia Alzheimer's disease clinical trials. Longitudinal data from cognitively normal (CN) and mild cognitive impairment (MCI) participants in the Alzheimer's Disease Neuroimaging Initiative were used to calculate sample size requirements for trials using outcome measures, including the Clinical Dementia Rating scale sum of boxes, Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-cognitive subscale with and without delayed recall, and the Rey Auditory Verbal Learning Task. We examined the impact on sample sizes of enrichment for genetic and biomarker criteria, including cerebrospinal fluid protein and neuroimaging analyses. We observed little cognitive decline in the CN population at 36 months, regardless of the enrichment strategy. Nonetheless, in CN subjects, using Rey Auditory Verbal Learning Task total as an outcome at 36 months required the fewest subjects across enrichment strategies, with apolipoprotein E genotype ε4 carrier status requiring the fewest (n = 499 per arm to demonstrate a 25% reduction in disease progression). In MCI, enrichment reduced the required sample sizes for trials, relative to estimates based on all subjects. For MCI, the Clinical Dementia Rating scale sum of boxes consistently required the smallest sample sizes. We conclude that predementia clinical trial conduct in Alzheimer's disease is enhanced by the use of biomarker inclusion criteria.
Highlights
Studies of the biology of Alzheimer’s disease (AD) have identified an array of targets for potential disease-modifying therapies [39] but clinical trials in patients with dementia have been unsuccessful so far [14,24,50,52,53]
The initial goal of AD Neuroimaging Initiative (ADNI) was to recruit 800 adults, ages 55 to 90, to participate in the research, approximately 200 cognitively normal older individuals to be followed for three years, 400 people with mild cognitive impairment (MCI) to be followed for three years and 200 people with early AD to be followed for two years.”
The current analyses focused on the first iteration of ADNI, which enrolled a cohort of volunteers who were cognitively normal (CN), MCI, and AD dementia at baseline
Summary
Studies of the biology of Alzheimer’s disease (AD) have identified an array of targets for potential disease-modifying therapies [39] but clinical trials in patients with dementia have been unsuccessful so far [14,24,50,52,53]. We hypothesized that enriching cognitively normal (CN) and MCI trial populations through biomarker criteria would reduce required sample sizes.
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