NCT04842552 (EHSAN study) is a Phase 3 triple-blind randomized clinical trial evaluating hydralazine hydrochloride as a disease-modifying treatment for early-stage Alzheimer's disease. This trial is conducted by Shahid Sadoughi University of Medical Sciences in Yazd, Iran, with collaboration from McMaster University and funding from the National Institute for Medical Research Development (NIMAD)[1].
Hydralazine represents a novel drug repurposing approach — an FDA-approved antihypertensive being investigated for neuroprotection through three complementary mechanisms: Nrf2 pathway activation, mitochondrial rejuvenation, and autophagy enhancement.
| Parameter | Value |
|---|---|
| NCT Number | NCT04842552 |
| IRCT ID | IRCT20200711048075N1 |
| Acronym | EHSAN |
| Phase | Phase 3 |
| Status | Recruiting (as of 2021) |
| Sponsor | Shahid Sadoughi University of Medical Sciences |
| Collaborators | NIMAD, McMaster University |
| Enrollment | 424 patients |
| Study Type | Interventional |
| Allocation | 1:1 randomized |
| Start Date | August 2, 2021 |
| Expected Completion | December 2023 |
| Duration | 12 months follow-up |
| Location | Adineh Health Centre, Yazd, Iran |
| Masking | Quadruple-blind (participant, caregiver, investigator, outcomes assessor) |
Hydralazine exerts neuroprotective effects through three interconnected pathways that are all impaired in Alzheimer's disease:
The Nrf2 (Nuclear factor erythroid 2–related factor 2) transcription factor controls expression of over 200 antioxidant and cytoprotective genes. In AD, Nrf2 signaling is impaired in the hippocampus, leaving neurons vulnerable to oxidative stress[2].
Mitochondrial dysfunction is an early hallmark of AD, with decreased ATP production, increased reactive oxygen species (ROS), and impaired mitophagy[4].
The autophagy-lysosome pathway is impaired early in AD pathogenesis, leading to accumulation of toxic protein aggregates (Aβ plaques and tau tangles)[6].
The trial targets mild-to-moderate AD (MMSE 12-26) for several reasons:
| Arm | Intervention | Dosage |
|---|---|---|
| Active | Hydralazine hydrochloride 25mg tablets | 25mg TDS (3x daily) for 365 days |
| Placebo | Identical placebo tablets | TDS for 365 days |
| Timepoint | Assessments |
|---|---|
| Baseline | Demographics, medical history, cognitive testing, safety labs |
| 3 months | ADAS-Cog, MMSE, Lawton ADL, NPI, caregiver burden, olfactory test, AE |
| 6 months | ADAS-Cog, MMSE, Lawton ADL, NPI, caregiver burden, olfactory test, AE |
| 9 months | ADAS-Cog, MMSE, Lawton ADL, NPI, caregiver burden, olfactory test, AE |
| 12 months | All endpoints, final safety evaluation |
Mirzaei M, et al. Effect of Hydralazine on Alzheimer's Disease Protocol. Clinical Trial Protocol. 2021. ↩︎
Sivandzade F, et al. Nrf2 activation as a therapeutic target in Alzheimer's disease. Journal of Cellular Physiology. 2019. ↩︎
Zhao X, et al. Hydralazine induces Nrf2 activation via inhibition of Keap1. Journal of Molecular Neuroscience. 2015. ↩︎
Wang X, et al. Mitochondrial dysfunction in Alzheimer's disease. NeuroMolecular Medicine. 2019. ↩︎
Jin J, et al. Hydralazine improves mitochondrial function and biogenesis. Biochemical Pharmacology. 2016. ↩︎
Liu Y, et al. Autophagy failure in Alzheimer's disease and therapeutic potential of autophagy activation. Cellular and Molecular Neurobiology. 2022. ↩︎