FTS‐03‐04: TOMMORROW STUDY

The TOMMORROW Study is a global, Phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial to simultaneously: (1) qualify a genetic biomarker risk algorithm for assigning 5-year risk for developing mild cognitive impairment due to Alzheimer's disease (MCI-AD) and (2) evaluate the efficacy of low-dose pioglitazone as a treatment to delay onset of MCI-AD in cognitively normal, high-risk individuals, as identified by the genetic risk algorithm. Potential study subjects are drawn from subject registries at 50 global sites and are randomized to either low-dose pioglitazone or placebo if determined to be in the high–risk stratum. A small group of low-risk subjects is given placebo only. Risk status is not disclosed to maintain study integrity. The trial will enroll approximately 5800 participants between ages 65 and 83, who will be followed with detailed neurocognitive assessments and clinical evaluation every 6 months. The primary endpoint in the trial is a clinical diagnosis of MCI-AD. In this time-to-event, the treatment period is anticipated to be approximately 4 years, with 410 individuals progressing to the MCI-AD endpoint, providing 90% power to detect a treatment effect (alpha = 0.01). The key assessments used in operationalizing the diagnosis of MCI-AD include: 1) neurological examination, 2) the Clinical Dementia Rating Scale, and 3) detailed neuropsychological evaluation with a battery of 12 measures representing 5 key cognitive domains affected in early symptomatic AD (memory, language, executive, attention, and visuospatial function). Assignment of MCI-AD is determined by the site clinician and neuropsychologist and then adjudicated by an independent expert committee with access to blinded study subject information. A key secondary objective is cognitive decline determined by change from baseline in the treatment groups on a composite score derived from the cognitive battery. The study was designed with input from international experts in the field and finalized following discussions with both US and EU regulatory authorities. Enrollment was initiated in August 2013. Collaboration among the CAP group will provide unique insight into the early stages of cognitive decline in the Alzheimer's setting, and the TOMMORROW investigators anticipate working with the CAP group where possible without jeopardizing study integrity.