Effect of Hydralazine on Alzheimer's Disease

NCT04842552 | Completed Phase 3 DMC

• 1 other identifier: NIMAD#964744
• Study Type: interventional
• Target: 228
• Locations: 1 country
• Sites: 1

Brief Summary

It has been recently discovered that the FDA-approved drug, hydralazine, has anti-neurodegenerative efficacy based on three intriguing observations. hydralazine; 1) activates the Nrf2 pathway that controls more than 200 antioxidant proteins, 2) rejuvenates mitochondria and increases their respiration capacity and adenosine triphosphate production, 3) activates autophagy which has pathophysiological roles such as intracellular aggregate clearance. There is an emerging agreement that autophagy-lysosome defects occur early in the pathogenesis of Alzheimer's disease (AD). Nrf2 is another pathway known to be impaired in the hippocampus of AD patients who need antioxidant protection the most. Rejuvenation of mitochondria is crucial for fighting AD, as neuronal cells need more energy to afford activation of pathways such as autophagy and Nrf2. The prime objective of this application is to conduct a randomized clinical trial to assess the efficacy of hydralazine in early-stage AD patients who take one of the acetylcholinesterase inhibitor (AChEI) donepezil, rivastigmine, or galantamine.

Conditions

Alzheimer Disease

Keywords

Alzheimer Disease; Hydralazine; Early stage; Olfactory sense

Outcome Measures

Primary Outcomes (1)

• Change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score from Baseline

  Change from baseline to Month 12 in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) total score, hydralazine compared with placebo. The ADAS-Cog total score ranges from 0 to 70; higher scores indicate greater cognitive impairment. The primary endpoint is analyzed using a mixed-effects model for repeated measures (MMRM) across assessments at 3, 6, 9, and 12 months.

  Baseline, and Months 3, 6, 9, and 12

Secondary Outcomes (3)

• Change in Lawton Instrumental Activities of Daily Living (IADL) Scale Score from Baseline

  Baseline, and Months 3, 6, 9, and 12

• Change in Neuropsychiatric Inventory (NPI) Score from Baseline

  Baseline, and Months 3, 6, 9, and 12

• Change in Caregiver Activity Scale Score from Baseline

  Baseline, and Months 3, 6, 9, and 12

Study Arms (2)

Hydralazine hydrochloride 25mg

ACTIVE COMPARATOR

Hydralazine hydrochloride (25mg tablets) every eight hours (TDS)

Drug: Hydralazine hydrochloride 25mg tablets

Placebo

PLACEBO COMPARATOR

Placebo tablets (identical in shape to the active comparator) every eight hours (TDS)

Drug: Placebo

Interventions

Hydralazine hydrochloride 25mg tablets DRUG

Hydralazine hydrochloride 25mg tablets three time daily for 365 days (one year)

Hydralazine hydrochloride 25mg

Placebo DRUG

Placebo

Placebo

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnoses of Alzheimer's disease according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria.
• Presence of a caregiver (friend or relative) who can assume responsibility for medication administrations, accompany the patient to all visits, and rate patient's condition.
• Written informed consent form from both the patient (or surrogate) and caregiver.
• A Mini-Mental State Examination score between 12 and 26 inclusive.
• Prescription of donepezil (5-10mg/d), memantine (5-21mg/d), rivastigmine (3-6mg/d), galantamine or galantamine ER (8-16mg/d) for a minimum of 4 weeks prior to randomization.
• Agreement not to take hydralazine.
• Age 50 and over.

You may not qualify if:

• Non-Alzheimer primary dementia diagnosis (e.g., vascular dementia, Lewy body dementia, frontotemporal dementia, vitamin B-12 deficiency, hypothyroidism).
• Diagnosis of any of the following conditions; major depression, delirium, alcohol or psychoactive substance abuse or dependency, schizophrenia, or delusional disorder as defined by Diagnostic and Statistical Manual (DSM)-5.
• Diagnosis of systemic illnesses that would interfere with participation in the study or decrease the life expectancy to less than one year.
• Currently being treated with hydralazine or a history of intolerance to oral therapy with hydralazine
• Any intravenous treatment for heart failure, except IV furosemide (e.g. IV inotropes, pressors, nitrates or nesiritide) at the time of screening.
• Systolic blood pressure \<100 mmHg, reversible etiology of acute heart failure such as myocarditis, acute myocardial infarction-over the past 4 weeks, arrhythmia and existence of pacing device (Acute myocardial infarction is defined as symptoms and major electrocardiogram (ECG) changes (i.e., ST segment elevations), and arrhythmia includes unstable heart rates above 120/min or below 50/min).
• Existence of severe congenital heart disease (such as uncorrected tetralogy of fallot or transposition of the aorta) and severe aortic or mitral stenosis or severe rheumatic mitral regurgitation.
• Concurrent use of phosphodiesterase type 5 (PDE5) inhibitors (e.g. Viagra, Etc.)
• Cardiac revascularization within the last 3 months or likelihood of requiring coronary revascularization within the study period. eGFR (Glomerular Filtration Rate) \< 15ml/min/1.73m2, or on regular dialysis, or planned dialysis within the study period.

Sponsors & Collaborators

• Shahid Sadoughi University of Medical Sciences and Health Services: lead
• National Institute for Medical Research and Development: collaborator

Study Sites (1)

Adineh Health Centre

Yazd, Yazd Province, 8916713151, Iran

Location

Related Publications (1)

• Mirzaei M, Ahmadi N, Bagheri Fahraji B, Ardekani AM, Rahimdel A, Soltani MH, Ardekani SMY, Bidaki R, Kasnavie FH, Dastjerdi G, Aboutorabi M, Mirzaei H. A randomized clinical trial evaluating Hydralazine's efficacy in early-stage Alzheimer's disease: The EHSAN Study. Sci Rep. 2024 Nov 21;14(1):28837. doi: 10.1038/s41598-024-79616-4.

  PMID: 39572624 BACKGROUND

MeSH Terms

Conditions

Alzheimer Disease; Anosmia

Interventions

Hydralazine

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Olfaction Disorders; Sensation Disorders; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phthalazines; Pyridazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Hydralazine hydrochloride was imported directly from a global supplier, packed in 90 tablet bottles with a specific batch number for drug and placebo not revealed to any of the above parties.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Two arms will be randomly allocated to either hydralazine hydrochloride 25mg TDS or placebo.

Study Record Dates

• First Submitted: April 5, 2021
• First Posted: April 13, 2021
• Study Start: August 2, 2021
• Primary Completion: March 5, 2026
• Study Completion: March 5, 2026
• Last Updated: September 9, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Informed consent form will be shared after recruitment started. CSR and SAP will be shared after recruitment phase was concluded. Study Protocol will be shared after publication.
• Access Criteria: All requests should be forwarded to the study email address and agreed by the investigators' committee subject to the ethics committee approval.

Locations

IR (1)