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

A Placebo Controlled Randomized Double-blind Parallel Group 12-month Trial of Fasudil for the Treatment of Early Alzheimer's Disease (FEAD)

The goal of this placebo-controlled double-blind Phase 2 clinical trial is to test in people with early Alzheimer's Disease.

The main questions it aims to answer are:

• Does treatment with fasudil, a ROCK-inhibitor, lead to significant improvement in working memory (based on computer-based working memory composite scores) compared to placebo in individuals with early Alzheimer's disease (AD) over 12 months?
• What is the effect of fasudil treatment for 12 months on other cognitive functions, brain metabolism measured by Fluorodeoxyglucose Positron Emission Tomography (FDG-PET), and other relevant clinical functions and biomarkers in individuals with early Alzheimer's disease (AD)?
• Treatment will be escalated to a maintenance dose of 120 mg total daily dose for up to 50 weeks, with regular clinic visits for efficacy and safety evaluations.
• Assessments will include cognitive tests, FDG-PET scans, and biomarker analyses, with follow-up by the Data and Safety Monitoring Board for ongoing safety review.

The study will compare participants receiving fasudil with those receiving placebo to see if fasudil treatment leads to improvements in cognitive functions, brain metabolism measured by FDG-PET.

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).

Inclusion Criteria:

• Early AD, eg Stage 3 MCI or Stage 4 (mild AD dementia), as recently defined by the FDA (2018; Figure 2)
• A significant change on a validated AD amyloid or tau biomarker (as determined either by visual reading of amyloid PET scans using any of the approved ligands, or CSF Aβ 1-42 levels or blood p-tau 217 cut-offs as determined by the clinical research laboratory)
• A CDR Global rating of 0.5 or 1.0 (Morris 1993) and have an MRI scan within the past two years that has no findings inconsistent with AD
• Capacity to give informed consent based on the clinical judgement of an experienced clinician
• The participant needs to have a reliable study partner with regular contact (a combination of face-to-face visits and telephone contact is acceptable) who has sufficient interaction with the participant to provide meaningful input into rating scales
• Age from 50 years
• Fluency in Norwegian and evidence of adequate premorbid intellectual functioning
• Capable of participating in all scheduled evaluations and complete all required tests
• Female participants must be of non-childbearing potential or have a negative serum pregnancy test within 14 days of baseline assessments and agree to the use of effective birth control throughout their participation in the study

Exclusion Criteria:

• Significant cerebrovascular disease, as indicated by clinical history, neurological examination, or on MRI (including cortical infarction or deep white matter or periventricular white matter hyperintensities with a Fazekas scale score of 3 (Fazekas et al 1987).
• A history of cerebrovascular bleeding or severe bleeding of the digestive tract, lungs, nose or skin
• Severe renal impairment (GFR <30) or serum creatinine or urea nitrogen values ≥3 times Upper normal limit (ULN) at screening or baseline
• Moderate to severe hepatic impairment. Serum alanine transaminase (ALT) or aspartate transaminase levels ≥3 times ULN at screening or baseline
• Currently poorly controlled diabetes as indicated by HbA1c values >9
• White blood cell (WBC) values <3.5 K/μl
• History of paralytic ileus or current severe chronic constipation
• Known allergy to fasudil or established systemic inflammatory disease or autoimmune disease.
• Clinically significant hypotension defined by blood pressure values <90/60 mmHg, regardless of the individual's sitting or standing position and associated with relevant clinical symptoms (e.g., tachycardia, dizziness, syncope)
• Current clinically significant depression or other mental disorder likely to affect cognition or interfere with study participation
• Recent (within 3 months) relevant medication changes. Participants must have been on stable anti-dementia (cholinesterase inhibitors or memantine) or anti-depressive medications for at least three months before the study
• Participants using sedating drugs, if unavoidable, will be excluded from the study. However, short-acting sleep medications can be used if taken as recommended and if the participant has maintained stability on them for a minimum of 3 months prior to the start of the study
• Participation in other drug trials
• Currently ongoing life-threatening disease, such as metastatic cancer, advanced cardiovascular disease, advanced respiratory disease, terminal kidney disease, or advanced stages of infectious diseases
• Any current or past neurological disease unrelated to Alzheimer's disease with cognitive sequelae
• A Corrected QT (QTc) interval ≥ 460 milliseconds for males or ≥ 470 milliseconds for females will be considered abnormal during the ECG assessments