Effect of Hydralazine on Alzheimer's Disease (EHSAN)

September 3, 2026 updated by: Masoud Mirzaei, Shahid Sadoughi University of Medical Sciences and Health Services

The Effect of Hydralazine on the Early Stage of Alzheimer's Disease: A Randomized Clinical Trial

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Study aim:

  1. Determination and comparison of the effect of 75mg (25mg TDS) hydralazine vs. placebo in patients with mild to moderate Alzheimer's disease.
  2. Development of an electronic Case Report Form (CRF) and push notification system to remind patients (and/or caregivers) of drug intake to improve drug intake adherence and reduce follow-up losses.
  3. Evaluation of the prognostic accuracy of olfactory tests to predict the changes in cognition and performance of patients with mild to moderate Alzheimer's disease.

Design:

This is a phase III, triple-blind, parallel double-armed randomized clinical trial with an allocation ratio of 1-1 to the intervention and placebo arms. This trial will be conducted on 424 randomly selected patients using random permuted blocks.

Settings and conduct:

All patients who are identified as potentially eligible by the supporting neurologists and psychiatrists will be referred to Adineh Clinic to evaluate their cognitive function, assess for inclusion and exclusion criteria and obtain informed consent. The two arms of the study are hydralazine 75mg (25mg three times per day) or hydralazine placebo. A follow-up evaluation will continue for one year after drug administration. The participants, outcome assessors, researchers, and data analyzers will be blinded to the study arms.

Participants/Inclusion and exclusion criteria:

patients aged 50 and over who are diagnosed with mild to moderate AD will be included in this study; dementia patients with etiologies other than AD (i.e. vascular dementia) will not be included.

Intervention groups:

The two arms of the study are Hydralazine 75mg (25mg three times per day) or Hydralazine placebo.

Main outcome variables:

Various cognitive and function tests for patients and caregivers, olfactory tests, biochemistry as well as drug side effects will be assessed regularly over the period of follow-up.

Treatment was initiated at 37.5 mg/day (12.5 mg three times daily) and titrated to 75 mg/day (25 mg three times daily) over two weeks. Randomization was stratified by age (under 65 versus 65 and older), sex, and baseline MMSE score (12-18 versus 19-26), using permuted blocks of four generated via Sealed Envelope and integrated into the study eCRF. Independent oversight was provided by a Data Monitoring Committee and a Data and Safety Monitoring Committee, and by the Clinical Trial Centres of Kermanshah and Yazd Universities of Medical Sciences, under the NIMAD ethics committee. Serum hydralazine concentrations were measured at months 6 and 12 to assess adherence. Adherence was supported by an electronic Case Report Form with SMS reminders and participant logbooks. Screening included the Schedule for Affective Disorders and Schizophrenia (SADS) and electrocardiography (ECG).

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
228

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • Iran
    • Yazd Province
      • Yazd, Yazd Province, Iran, 8916713151
        • Adineh Health Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

49 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: Hydralazine hydrochloride 25mg
Hydralazine hydrochloride (25mg tablets) every eight hours (TDS)
Drug: Hydralazine hydrochloride 25mg tablets
Hydralazine hydrochloride 25mg tablets three time daily for 365 days (one year)
Placebo Comparator: Placebo
Placebo tablets (identical in shape to the active comparator) every eight hours (TDS)
Drug: Placebo
Placebo

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score from Baseline
Time Frame: Baseline, and Months 3, 6, 9, and 12
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 Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Change in Lawton Instrumental Activities of Daily Living (IADL) Scale Score from Baseline
Time Frame: Baseline, and Months 3, 6, 9, and 12
Changes in the function of patients with Alzheimer's disease in the hydralazine-treated group compared to placebo- treated using Lawton Activity of Daily Living Scale. Scores range from 0 to 8; higher scores indicate greater independence.
Baseline, and Months 3, 6, 9, and 12
Change in Neuropsychiatric Inventory (NPI) Score from Baseline
Time Frame: Baseline, and Months 3, 6, 9, and 12
Changes in the behaviour of the patients with Alzheimer's disease in the hydralazine-treated group compared to placebo-treated using Neuropsychiatric Inventory
Baseline, and Months 3, 6, 9, and 12
Change in Caregiver Activity Scale Score from Baseline
Time Frame: Baseline, and Months 3, 6, 9, and 12
Changes in caregiver's spent time for the patients in the hydralazine-treated group compare to placebo using Caregiver Activity Scale. Measures caregiver time (hours) over the prior 24 hours across six activities; higher values indicate greater caregiver time.
Baseline, and Months 3, 6, 9, and 12

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Shahid Sadoughi University of Medical Sciences and Health Services

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institute for Medical Research and Development

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Chair: Hamid Mirzaei, PhD, Shahid Sadoughi University of Medical Sciences

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
August 2, 2021

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 5, 2026

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 5, 2026

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
April 5, 2021

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 12, 2021

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 13, 2021

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
September 9, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 3, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • NIMAD#964744

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Individual patient data (IPD) sharing plan will be decided according to the upcoming requests and the ethics committee approval.

IPD Sharing 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.

IPD Sharing Access Criteria

All requests should be forwarded to the study email address and agreed by the investigators' committee subject to the ethics committee approval.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • CSR

Study Data/Documents

  1. Informed Consent Form
    Information comments: All requests should be submitted to the contact us/about at the study website or study.ehsan@gmail.com
  2. Clinical Study Report
    Information comments: All requests should be submitted to the contact us/about at the study website or study.ehsan@gmail.com
  3. Study Protocol
    Information comments: All requests should be submitted to the contact us/about at the study website or study.ehsan@gmail.com
  4. Statistical Analysis Plan
    Information comments: All requests should be submitted to the contact us/about at the study website or study.ehsan@gmail.com

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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