Fasudil Trial for Treatment of Early Alzheimer's Disease (FEAD)

This is a 2-arm, parallel-group, 12-month, randomized, placebo-controlled double-blind Phase 2 trial of fasudil in up to 200 people with early AD. Fasudil is a ROCK-inhibitor (rho-associated protein kinase inhibitor), a vasodilator that is approved for treating vasospasms following subarachnoidal bleeding in Japan and China. The drug has acceptable safety and tolerability and has been shown to protect neurons and synapses in animal models of AD. Eligible participants must have Stage 3-4 mild cognitive impairment (MCI) or mild dementia due to AD, as recently defined by FDA Guidance, and have shown a significant change on a validated AD biomarker (e.g. amyloid PET scans or CSF Aβ 1-42 or blood p-tau 217 levels). In addition, they must have a CDR Global rating of 0.5 or 1.0 and an MRI scan within the past two years that has no findings inconsistent with AD. People who meet all inclusion criteria will be enrolled in three successive cohorts of 20, 50, and 130 people, respectively. Participants will be randomized 1:1 to receive fasudil or a matching placebo. All participants will undergo a 2-week titration period at a total daily dose of 60 mg (20 mg tds) before being escalated to the maintenance dose of 120 mg total daily dose (40 mg tds) for up to 50 additional weeks of treatment. The selected dose of 120 mg per day is optimized for potential efficacy over the planned 12-month treatment while providing a reasonable margin of safety based on available clinical and nonclinical data. Participants will visit the clinic for efficacy and/or safety evaluations at 2-week intervals for the first month and then monthly thereafter (see Table 1. Schedule of Assessments). The Data and Safety Monitoring Board (DSMB) will perform an unblinded review of the safety and pharmacokinetic (PK) data once all ongoing patients in Cohort 1 have completed at least 3 months of treatment and make recommendations to the study team that may include stopping or continuing the study (with or without changes to the study procedures). The DSMB will continue to review all data available from Cohorts 1-3 for the remainder of the study at 3-monthly intervals, or more frequently if warranted by emergent data, and recommend any changes to the study procedures to ensure appropriate safety oversight and management of study participants through completion of the study. The primary efficacy outcome is the FLAME (Factors of Longitudinal Attention, Memory and Executive Function) computer-based working memory composite. The key secondary outcomes are based on the expression of the AD-like hypometabolic pattern on FDG-PET and additional cognitive tests from the FLAME battery, including memory, working memory, attention, and executive functions. Additional secondary outcomes include CSF and blood-based AD biomarkers, and clinical measures including Clinical Global Impression of Change (CGIC), and Clinical Dementia Rating (CDR), neuropsychiatric symptoms (NPI), instrumental activities of daily living (Amsterdam IADL scale) and quality of life (DEMQOL). Standard safety measures include monthly assessments of adverse events (AEs), vital signs, and laboratory tests (including blood and urine analyses) as well as ECGs and the Columbia-Suicide Severity Rating Scale (C-SSRS).