Effect of Hydralazine on Alzheimer's Disease (EHSAN)

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: Recruiting
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: Placebo; Drug: Hydralazine hydrochloride 25mg tablets

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 over the age of 49 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.

• Study Type: Interventional
• Enrollment (Anticipated): 424
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Masoud Mirzaei, MD, PhD; Phone Number: +98-913-4509917; Email: mmirzaei@ssu.ac.ir
• Study Contact Backup: Name: Nastaran- Ahmadi, PhD; Phone Number: +98-913-3514827; Email: ahmadi.psy@gmail.com

Study Locations

• Iran, Islamic Republic of
  • Yazd, Iran, Islamic Republic of, 8916713151
    • Recruiting
    • Adineh Health Centre
    • Contact: Behnam Bagheri, MSc.; Phone Number: +98-35-38275414; Email: behnambagheri222@gmail.com
    • Contact: Nastaran Ahmadi, PhD; Phone Number: +98-35-38275414; Email: ahmadi.psy@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 49 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

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), 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 49 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)-IV.
• 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

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

Outcome Measure	Measure Description	Time Frame
The progression of of Alzheimer's disease	The progression of of Alzheimer's disease in the hydralazine-treated group compared to placebo-treated using the Alzheimer's Disease Assessment Scale-Cognitive Sub-scale inventory	Three months after recruitment.
The progression of of Alzheimer's disease	The progression of of Alzheimer's disease in the hydralazine-treated group compared to placebo-treated using the Alzheimer's Disease Assessment Scale-Cognitive Sub-scale inventory	Six months after recruitment.
The progression of of Alzheimer's disease	The progression of of Alzheimer's disease in the hydralazine-treated group compared to placebo-treated using the Alzheimer's Disease Assessment Scale-Cognitive Sub-scale inventory	Nine months after recruitment.
The progression of of Alzheimer's disease	The progression of of Alzheimer's disease in the hydralazine-treated group compared to placebo-treated using the Alzheimer's Disease Assessment Scale-Cognitive Sub-scale inventory	Twelve months after recruitment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Function of patients with Alzheimer's disease	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	Three months after recruitment
Function of patients with Alzheimer's disease	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	Six months after recruitment
Function of patients with Alzheimer's disease	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	Nine months after recruitment
Function of patients with Alzheimer's disease	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	Twelve months after recruitment
Cognition of patients with Alzheimer's disease	Changes in the cognition of the patients with Alzheimer's disease in the hydralazine-treated group compared to placebo-treated using Mini Mental State Examination	Three months after recruitment
Cognition of patients with Alzheimer's disease	Changes in the cognition of the patients with Alzheimer's disease in the hydralazine-treated group compared to placebo-treated using Mini Mental State Examination	Six months after recruitment
Cognition of patients with Alzheimer's disease	Changes in the cognition of the patients with Alzheimer's disease in the hydralazine-treated group compared to placebo-treated using Mini Mental State Examination	Nine months after recruitment
Cognition of patients with Alzheimer's disease	Changes in the cognition of the patients with Alzheimer's disease in the hydralazine-treated group compared to placebo-treated using Mini Mental State Examination	Twelve months after recruitment
Behavior of patients with Alzheimer's disease	Changes in the behaviour of the patients with Alzheimer's disease in the hydralazine-treated group compared to placebo-treated using Nero-Psychiatry Inventory	Three months after recruitment
Behavior of patients with Alzheimer's disease	Changes in the behaviour of the patients with Alzheimer's disease in the hydralazine-treated group compared to placebo-treated using Nero-Psychiatry Inventory	Six months after recruitment
Behavior of patients with Alzheimer's disease	Changes in the behaviour of the patients with Alzheimer's disease in the hydralazine-treated group compared to placebo-treated using Nero-Psychiatry Inventory	Nine months after recruitment
Behavior of patients with Alzheimer's disease	Changes in the behaviour of the patients with Alzheimer's disease in the hydralazine-treated group compared to placebo-treated using Nero-Psychiatry Inventory	Twelve months after recruitment
Caregiver's spent time	Changes in caregiver's spent time for the patients in the hydralazine-treated group compare to placebo using Caregiver Activity Scale	Three months after recruitment
Caregiver's spent time	Changes in caregiver's spent time for the patients in the hydralazine-treated group compare to placebo using Caregiver Activity Scale	Six months after recruitment
Caregiver's spent time	Changes in caregiver's spent time for the patients in the hydralazine-treated group compare to placebo using Caregiver Activity Scale	Nine months after recruitment
Caregiver's spent time	Changes in caregiver's spent time for the patients in the hydralazine-treated group compare to placebo using Caregiver Activity Scale	Twelve months after recruitment
Olfactory sense	the changes in the olfactory sense in the hydralazine-treated group compare to placebo using 'peanut butter smelling test'	Three months after recruitment
Olfactory sense	the changes in the olfactory sense in the hydralazine-treated group compare to placebo using 'peanut butter smelling test'	Six months after recruitment
Olfactory sense	the changes in the olfactory sense in the hydralazine-treated group compare to placebo using 'peanut butter smelling test'	Nine months after recruitment
Olfactory sense	the changes in the olfactory sense in the hydralazine-treated group compare to placebo using 'peanut butter smelling test'	Twelve months after recruitment
Drug side effects	The side effects of hydralazine-treated group compare to placebo-treated	Daily records in the provided notebook and reported three month after recruitment. Urgent matter can be reported any time to the provided hotline.
Drug side effects	The side effects of hydralazine-treated group compare to placebo-treated	Daily records in the provided notebook and reported six month after recruitment. Urgent matter can be reported any time to the provided hotline.
Drug side effects	The side effects of hydralazine-treated group compare to placebo-treated	Daily records in the provided notebook and reported nine month after recruitment. Urgent matter can be reported any time to the provided hotline.
Drug side effects	The side effects of hydralazine-treated group compare to placebo-treated	Daily records in the provided notebook and reported twelve month after recruitment. Urgent matter can be reported any time to the provided hotline.

Collaborators and Investigators

• Sponsor: Shahid Sadoughi University of Medical Sciences and Health Services
• Collaborators: McMaster University; National Institute for Medical Research Development (NIMAD)
• Investigators: Study Chair: Hamid Mirzaei, PhD, Shahid Sadoughi University of Medical Sciences

Publications and helpful links

Helpful Links

• The EHSAN study website
• The study ethics approval.

Study record dates

Study Major Dates

• Study Start (Actual): August 2, 2021
• Primary Completion (Anticipated): June 1, 2023
• Study Completion (Anticipated): December 20, 2023

Study Registration Dates

• First Submitted: April 5, 2021
• First Submitted That Met QC Criteria: April 12, 2021
• First Posted (Actual): April 13, 2021

Study Record Updates

• Last Update Posted (Actual): January 6, 2022
• Last Update Submitted That Met QC Criteria: December 15, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Alzheimer Disease; Early stage; Hydralazine; Olfactory sense
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; Antihypertensive Agents; Vasodilator Agents; Hydralazine
• Other Study ID Numbers: IRCT20200711048075N1

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; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes