Dt‐02‐02: Tommorrow: Results From a Phase 3 Trial to Delay the Onset of Mci Due to Ad and Qualify a Genetic Biomarker Algorithm
Year: 2019
Type: article
Study design: Clinical Trial
Abstract: TOMMORROW was a phase 3, randomized, double-blind, placebo-controlled, parallel-group global clinical trial designed to assess a genetic biomarker risk assignment algorithm (BRAA) for risk prediction of mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and to evaluate the efficacy of pioglitazone 0.8 mg to delay MCI due to AD onset. BRAA testing at screening determined risk status. Cognitively normal high-risk subjects were randomized 1:1 to pioglitazone sustained release 0.8 mg once daily or placebo; low-risk subjects received placebo. Project partners completed informant interviews and questionnaires. Subjects were assessed every 6 months to collect a target of 202 primary endpoint events of incident MCI due to AD in Non-Hispanic/Latino Caucasians, the primary analysis population. Conversion events were determined by an independent adjudication committee and required meeting MCI due to AD core clinical criteria across two consecutive study visits. Co-primary endpoints compared time-to-event (TTE) between the two placebo groups (for BRAA) and between pioglitazone 0.8 mg and placebo in the high-risk group (for drug efficacy). The study was terminated following efficacy futility in January 2018, after approximately one-third of the target event count had occurred. 24,235 individuals were screened, and 3494 randomized (95% non-Hispanic/Latino Caucasians). Most enrolled subjects (mean age = 74.0 years) were APOE ε3/3 or ε3/4. Overall, 96 conversion events occurred. MCI due to AD incidence was greater in the high- vs low-risk placebo group (3.3% vs 1.0% 95% confidence interval [CI] 0.009, 0.036). Converters’ mean age was 76.4 years, and most were ε3/ε4-L/VL (n=22; 23%), ε3/4-S/L (n=21; 22%), and ε3/3-S/VL (n=22; 23%). For BRAA TTE, adjusted hazard ratio (high vs. low) in the primary analysis population (95%CI) = 3.26 (1.177, 9.040). For drug efficacy TTE, adjusted hazard ratio (95%CI) = 0.8 (0.52, 1.23). Pioglitazone was safe and well-tolerated overall. Additional subgroup analyses will be presented. Although terminated early, TOMMORROW demonstrated that the BRAA is an effective enrichment tool and studies at early stages of the cognitive decline continuum are feasible. Lessons learned will benefit future AD clinical trials adopting early intervention strategies.
Source: Alzheimer s & Dementia
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2980980807