Fasudil for Early Alzheimer's Disease (FEAD) - NCT06362707

Fasudil for Early Alzheimer's Disease (FEAD Trial)

Overview

Fasudil for Early Alzheimer's Disease (FEAD Trial)

Overview

The FEAD (Fasudil for Early Alzheimer's Disease) trial is a Phase 2 placebo-controlled, randomized, double-blind, parallel-group clinical study evaluating the safety and efficacy of fasudil, a Rho-kinase (ROCK) inhibitor, in patients with early Alzheimer's disease (AD). This trial represents a significant step in repurposing ROCK inhibitors—already approved in Japan and China for cerebral vasospasm—for neurodegenerative disease treatment [@nct06362707].

The trial is being conducted across multiple sites in Norway and is sponsored by Helse Stavanger HF, with collaboration from the University of Exeter and several Norwegian university hospitals. The study aims to determine whether 12 months of fasudil treatment can improve working memory and other cognitive functions in patients with early AD, while also assessing effects on brain metabolism measured by FDG-PET and various AD biomarkers.

Trial Details

| Field | Value |
|-------|-------|
| NCT ID | NCT06362707 |
| Official Title | A Placebo Controlled Randomized Double-blind Parallel Group 12-month Trial of Fasudil for the Treatment of Early Alzheimer's Disease (FEAD) |
| Acronym | FEAD |
| Status | RECRUITING (as of October 2024) |
| Phase | Phase 2 |
| Enrollment | 200 participants (estimated) |
| Study Type | Interventional |
| Allocation | Randomized (1:1) |
| Intervention Model | Sequential |
| Masking | Double-blind (participants and investigators) |
| Start Date | August 1, 2024 |
| Primary Completion | October 2025 (estimated) |
| Completion Date | October 2026 (estimated) |
| Duration | 12 months |
| Sponsor | Helse Stavanger HF (Norway) |
| Collaborators | University of Exeter, Helse Fonna, St. Olavs Hospital, University Hospital Akershus, Haraldsplass Deaconess Hospital |

Study Design

Rationale

Fasudil is a ROCK inhibitor that has been used clinically in Japan and China since 1995 for treating cerebral vasospasm following subarachnoid hemorrhage. Preclinical evidence has demonstrated that fasudil exerts neuroprotective effects in multiple models of AD through several mechanisms:

• Cytoskeletal regulation: ROCK inhibitors promote neurite outgrowth and dendritic spine formation [@couch_2010]
• Amyloid pathology reduction: Studies in APP/PS1 mice showed fasudil reduced Aβ plaque burden and improved memory [@fasudil_app_ps1]
• Tau pathology modulation: ROCK inhibition reduces tau phosphorylation via the GSK3β pathway [@rock_gsktau]
• Synaptic protection: Fasudil blocks amyloid-beta-induced synaptotoxicity through Wnt-PCP pathway modulation [@amyloid_beta_wnt]
• Neuroinflammation reduction: ROCK inhibitors reduce microglial activation and pro-inflammatory cytokine production [@rock_neuroinflammation]
• Pro-survival signaling: Fasudil activates AKT/CREB signaling pathways [@rock_akt_creb]

Population

The trial enrolls patients with early AD defined as:

• Stage 3 (MCI) or Stage 4 (mild AD dementia) according to FDA guidance
• Clinical Dementia Rating (CDR) Global rating of 0.5 or 1.0
• Significant change on a validated AD amyloid or tau biomarker:
• Positive amyloid PET scan, OR
• CSF Aβ1-42 levels below cutoff, OR
• Blood p-tau217 levels above cutoff
• Age 50-100 years
• Ability to provide informed consent
• Reliable study partner available

Treatment Arms

| Arm | Description | Dose |
|-----|-------------|------|
| Fasudil | Experimental group | 60 mg/day (titration) → 120 mg/day (maintenance) |
| Placebo | Control group | Matching tablets |

Dosing Schedule:

• Titration Phase: 2 weeks at 60 mg total daily dose (20 mg tds)
• Maintenance Phase: 50 weeks at 120 mg total daily dose (40 mg tds)

Cohort Structure

Participants will be enrolled in three successive cohorts:

The Data Safety Monitoring Board (DSMB) conducts unblinded reviews of safety and pharmacokinetic data after Cohort 1 completes at least 3 months of treatment.

Endpoints

Primary Endpoints

• Measure: FLAME (Factors of Longitudinal Attention, Memory and Executive Function) computer-based working memory composite
• Timeframe: Baseline and every 3 months until last visit (up to 1 year)
• Significance: FLAME is a validated computerized neuropsychological battery specifically designed for early dementia trials [@flame_battery]

• Measure: FDG-PET (Fluorodeoxyglucose Positron Emission Tomography)
• Timeframe: Baseline to 12 months
• Significance: FDG-PET measures brain metabolism as a proxy for synaptic function, correlating well with cognitive decline in AD [@fdg_pet_ad]

Secondary Endpoints

Biomarker Outcomes:
| Biomarker | Sample | Timepoints |
|-----------|--------|------------|
| Plasma p-tau217 | Blood | Baseline, 12 months |
| Plasma NfL (Neurofilament Light Chain) | Blood | Baseline, 12 months |
| CSF Aβ1-40 and Aβ1-42 | CSF | Baseline, 12 months |
| CSF total tau and p-tau | CSF | Baseline, 12 months |

Clinical Outcomes:

• Clinical Global Impression of Change (CGIC)
• Clinical Dementia Rating (CDR)
• Neuropsychiatric Inventory (NPI)
• Amsterdam IADL Scale (instrumental activities of daily living)
• DEMQOL (quality of life)

• Adverse events monitoring
• Vital signs (blood pressure, pulse)
• Laboratory tests (blood chemistry, hematology, urinalysis)
• Electrocardiogram (ECG)
• Columbia-Suicide Severity Rating Scale (C-SSRS)

Study Sites

| Facility | City | Status |
|----------|------|--------|
| Stavanger University Hospital | Stavanger | RECRUITING |
| Haraldsplass Deaconess Hospital | Bergen | ENROLLING_BY_INVITATION |
| University Hospital of North Norway | Tromsø | NOT_YET_RECRUITING |
| Akershus Hospital | Oslo | NOT_YET_RECRUITING |
| Haugesund Hospital | Haugesund | NOT_YET_RECRUITING |
| St. Olavs Hospital | Trondheim | NOT_YET_RECRUITING |

Lead Investigators

• Dag Aarsland, PhD (Principal Investigator) - Stavanger University Hospital
• Nicolas Castellanos Perilla, MD - Stavanger University Hospital
• Ole Grønli, PhD - University Hospital of North Norway
• Tormod Fladby, PhD - Akershus Hospital/University of Oslo
• Arvid Rongve, PhD - Haugesund Hospital
• John C. Fløvig - St. Olavs Hospital

Scientific Background

ROCK Signaling in AD

The Rho-associated coiled-coil containing protein kinases (ROCK1 and ROCK2) are key effectors of the small GTPase RhoA and regulate numerous cellular processes that become dysregulated in AD:

Fasudil Pharmacology

Fasudil (HA-1077, AT877) is a potent, selective ROCK inhibitor:

• IC50: ~0.5 μM for ROCK1, ~0.4 μM for ROCK2
• Approved indication: Cerebral vasospasm (Japan, China)
• Formulations: IV (fasudil), Oral (AT877)
• CNS penetration: Demonstrated in animal models
• Safety profile: Well-established from Japanese clinical use [@fasudil_clinical]

Preclinical Evidence Summary

| Study Model | Finding | Reference |
|-------------|---------|-----------|
| APP/PS1 mice | Reduced Aβ plaque burden, improved memory | [@fasudil_app_ps1] |
| APP/PS1 mice | Increased dendrite branching | [@couch_2010] |
| Aβ-treated neurons | Blocked synaptotoxicity via Wnt-PCP | [@amyloid_beta_wnt] |
| Multiple models | Reduced tau phosphorylation | [@rock_gsktau] |
| Multiple models | Reduced neuroinflammation | [@rock_neuroinflammation] |

Clinical Context

Previous ROCK Inhibitor Trials in AD

The FEAD trial builds on earlier clinical experience:

• Showed generally good tolerability
• Demonstrated cognitive improvement signals
• Established safety profile in AD population [@saferock_trial]

AD Drug Development Landscape

The AD field has seen significant recent progress with disease-modifying therapies. ROCK inhibitors represent a complementary approach targeting:

• Multiple downstream pathways simultaneously
• Non-amyloid/tau mechanisms (cytoskeleton, inflammation)
• Potential for combination therapies

Safety Considerations

Known Safety Profile

From clinical experience with fasudil in Japan:

| System | Adverse Event | Frequency |
|--------|---------------|-----------|
| CNS | Headache | 10-15% |
| CNS | Dizziness | 5-10% |
| CV | Hypotension | 3-8% |
| GI | Nausea | 2-5% |
| Skin | Rash | 1-3% |

Trial-Specific Monitoring

• Blood pressure monitored at all visits
• Monthly adverse event assessment
• Regular ECG monitoring (QTc interval)
• Laboratory tests (hematology, chemistry)
• Columbia-Suicide Severity Rating Scale at screening, month 6, and month 12

Risk Mitigation

• Titration period (2 weeks at lower dose)
• DSMB oversight after Cohort 1
• Exclusion of patients with significant hypotension
• Careful monitoring of drug interactions

Cross-References

Related Pages

• [ROCK Inhibitor Therapy for Neurodegeneration](/therapeutics/rock-inhibitor-therapy)
• [ROCK1 Gene](/genes/rock1)
• [ROCK2 Gene](/genes/rock2)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [ROCK Inhibitor in PSP/CBS (NCT04734379)](/clinical-trials/rock-inhibitor-fasudil-psp-cbs-nct04734379)

External Links

• [ClinicalTrials.gov: NCT06362707](https://clinicaltrials.gov/study/NCT06362707)
• [FLAME Cognitive Battery](https://alzres.biomedcentral.com/articles/10.1002/dad2.12098)

References