A Phase 3 interventional study of Hydralazine hydrochloride 25mg tablets and Placebo in Alzheimer Disease, sponsored by Shahid Sadoughi University of Medical Sciences and Health Services. Completed at 1 site in Iran. Open to participants aged 50 Years and older. Per ClinicalTrials.gov, last updated 2026-09-09.
Sponsored by Shahid Sadoughi University of Medical Sciences and Health Services · Phase 3, Interventional, and Treatment
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 aim:
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).
Exclusion Criteria:
Hydralazine hydrochloride (25mg tablets) every eight hours (TDS)
Drug: Hydralazine hydrochloride 25mg tablets
Placebo tablets (identical in shape to the active comparator) every eight hours (TDS)
Drug: Placebo
Hydralazine hydrochloride 25mg tablets three time daily for 365 days (one year)
Placebo
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.
Time frame: Baseline, and Months 3, 6, 9, and 12
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.
Time frame: 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
Time frame: 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.
Time frame: Baseline, and Months 3, 6, 9, and 12
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — Individual patient data (IPD) sharing plan will be decided according to the upcoming requests and the ethics committee approval.
Supporting information: Study protocol, Sap, Icf, Csr
This study is completed, as verified in Sep 2026. You cannot join it, but the record below documents what was studied.
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Shahid Sadoughi University of Medical Sciences and Health Services