Phase 2 Futility Trials in Alzheimer Disease and Mild Cognitive Impairment

Background and ObjectivesThe cost and complexity of phase 2 randomized-controlled trials (RCTs) hinder further development of promising treatment candidates for Alzheimer disease (AD). The Simon Two-Stage futility trial design, originally developed for oncology, offers a streamlined approach to evaluate potential disease-modifying therapies by comparing single-arm outcomes with historical controls, but is predicated on identifying outcome measures that reliably worsen with the natural history of the disease, with minimal risk of improvement. We sought to determine the feasibility of such futility trials in AD-associated dementia and mild cognitive impairment (MCI) using a large prospective cohort. MethodsWe analyzed longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitive decline was assessed using AD Assessment Scale-Cognitive Subscale (ADAS-Cog 11 and ADAS-Cog 13), Clinical Dementia Rating-Sum of Boxes (CDR-SB), and Mini-Mental State Examination (MMSE) at 6, 12, and 24 months using different thresholds for worsening vs improvement. Binary logistic regression models examined baseline factors associated with cognitive worsening using different thresholds of worsening for each outcome of interest to assess what additional selection criteria may be needed for futility trials in AD-associated dementia vs MCI. Sample size estimates were derived based on expected rates of decline. ResultsAmong 2,665 participants (mean age 73.4 years [SD: 7.5], 1,260 [47.3%] female, 424 with AD-associated dementia), the CDR-SB exhibited the largest percentage of decline in AD-associated dementia and MCI, with 60.6% of patients with AD-associated dementia showing worsening when using a threshold of ≥1.0 points at 12 months vs 6.2% showing improvement. ADAS-Cog 11 and 13 showed similar decline patterns; for example, 41.7% with AD-associated dementia worsened by ≥ 5 points at 12 months on ADAS-Cog 13, whereas 5.8% improved. MMSE exhibited lower sensitivity; 25.8% with AD-associated dementia worsened by ≥ 5 points at 12 months, whereas 2.9% improved. Shorter trials (6-12 months) with 35–62 participants seemed feasible in AD-associated dementia, whereas MCI trials seemed to require 24 months and specific entry criteria based on age, apolipoprotein E ε4 status, and baseline CDR-SB performance. DiscussionFutility trials seem feasible in AD-associated dementia, offering a faster, cost-effective alternative to traditional phase 2 RCTs. CDR-SB seems to be the optimal primary outcome. Further validation in clinical trial data sets is warranted.