Alzheimer DiseasePhase 3EHSANNCT04842552
Effect of Hydralazine on Alzheimer's Disease
A Phase 3 study testing Hydralazine hydrochloride 25mg tablets in people with Alzheimer Disease, run by Shahid Sadoughi University of Medical Sciences and Health Services at 1 site in Iran.
Trial 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… Read more about this study
- Who is it for?
- Ages 50 years and older
- Conditions the study is for
- Alzheimer Disease
- What is being tested?
- Hydralazine hydrochloride 25mg tablets
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 228 participants
- Where
- 1 siteIran
- Study dates
- 2 Aug 2021to 5 Mar 2026
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 50 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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).
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- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
Read the detailed description
Study aim:
- Determination and comparison of the effect of 75mg (25mg TDS) hydralazine vs. placebo in patients with mild to moderate Alzheimer's disease.
- 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.
- 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).
- Conditions
- Alzheimer Disease
- Being tested
- Hydralazine hydrochloride 25mg tablets, Placebo
- Keywords
- Alzheimer Disease, Hydralazine, Early stage, Olfactory sense
- Medical subject headings
- Alzheimer Disease, Anosmia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Hydralazine hydrochloride 25mg tabletsDrug
Hydralazine hydrochloride 25mg tablets three time daily for 365 days (one year)
PlaceboDrug
Placebo
| Study group | Role | What they receive |
|---|---|---|
| Hydralazine hydrochloride 25mg | Active comparator | Hydralazine hydrochloride (25mg tablets) every eight hours (TDS) Receives: Drug: Hydralazine hydrochloride 25mg tablets |
| Placebo | Placebo comparator | Placebo tablets (identical in shape to the active comparator) every eight hours (TDS) Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline, and Months 3, 6, 9, and 12
Secondary outcomes (3)
Change in Lawton Instrumental Activities of Daily Living (IADL) Scale Score from Baseline
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.
Measured: Baseline, and Months 3, 6, 9, and 12
Change in Neuropsychiatric Inventory (NPI) Score from Baseline
Changes in the behaviour of the patients with Alzheimer's disease in the hydralazine-treated group compared to placebo-treated using Neuropsychiatric Inventory
Measured: Baseline, and Months 3, 6, 9, and 12
Change in Caregiver Activity Scale Score from Baseline
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.
Measured: Baseline, and Months 3, 6, 9, and 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Apr 2021
- Study start2 Aug 2021
- Primary completion5 Mar 2026
- Study completion5 Mar 2026
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Alzheimer DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Two arms will be randomly allocated to either hydralazine hydrochloride 25mg TDS or placebo.
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 228 participants (actual)
Sponsor and investigators
- Lead sponsor
- Shahid Sadoughi University of Medical Sciences and Health Services
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute for Medical Research and Development
- Responsible party
- Principal investigator, Masoud Mirzaei, Shahid Sadoughi University of Medical Sciences and Health Services
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04842552
- Sponsor's protocol ID
- NIMAD#964744
- Acronym
- EHSAN
- Status last verified
- Sep 2026
- First submitted
- 5 Apr 2021
- Last updated
- 9 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual patient data (IPD) sharing plan will be decided according to the upcoming requests and the ethics committee approval.
Publications
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.
PubMed 39572624
Study at a glance
From the registry record, last updated by the sponsor on 9 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of Hydralazine on the Early Stage of Alzheimer's Disease: A Randomized Clinical Trial
- ClinicalTrials.gov ID
- NCT04842552
- Acronym / sponsor ID
- EHSAN / NIMAD#964744
- Conditions
- Alzheimer Disease
- Keywords
- Alzheimer Disease, Hydralazine, Early stage, Olfactory sense
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 228 participants (actual)
- Lead sponsor
- Shahid Sadoughi University of Medical Sciences and Health ServicesUniversity, hospital or other
- Collaborators
- National Institute for Medical Research and Development
- Study start
- 2 Aug 2021 (actual)
- Primary completion
- 5 Mar 2026 (actual)
- Study completion
- 5 Mar 2026 (actual)
- First posted
- 13 Apr 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Study aim:
- Determination and comparison of the effect of 75mg (25mg TDS) hydralazine vs. placebo in patients with mild to moderate Alzheimer's disease.
- 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.
- 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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Two arms will be randomly allocated to either hydralazine hydrochloride 25mg TDS or placebo.
| Arm | Type | Receives |
|---|---|---|
| Hydralazine hydrochloride 25mg | Active comparator | Drug: Hydralazine hydrochloride 25mg tabletsHydralazine hydrochloride (25mg tablets) every eight hours (TDS) |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo tablets (identical in shape to the active comparator) every eight hours (TDS) |
Who may qualify
- Ages
- 50 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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.
Key exclusion criteria (9 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Hydralazine hydrochloride 25mg tabletsHydralazine hydrochloride 25mg tablets three time daily for 365 days (one year) | Drug | Hydralazine hydrochloride 25mg |
| PlaceboPlacebo | Drug | Placebo |
Primary outcome
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.
3 secondary outcomes
Change in Lawton Instrumental Activities of Daily Living (IADL) Scale Score from Baseline
Time frame: 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
Change in Caregiver Activity Scale Score from Baseline
Time frame: Baseline, and Months 3, 6, 9, and 12
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Sep 2026.
- Background: PubMed 39572624Mirzaei 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.
- Individual participant dataSharing planned: Yes. Individual patient data (IPD) sharing plan will be decided according to the upcoming requests and the ethics committee approval.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Hydralazine hydrochloride 25mg tablets in people with Alzheimer Disease, run by Shahid Sadoughi University of Medical Sciences and Health Services at 1 site in Iran.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Iran. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score from Baseline (time frame: Baseline, and Months 3, 6, 9, and 12). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04842552, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Sep 2026.