Clinical trial NCT04842552: Effect of Hydralazine on Alzheimer's Disease
Official title: The Effect of Hydralazine on the Early Stage of Alzheimer's Disease: A Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Alzheimer Disease
Keywords: Alzheimer Disease
Hydralazine
Early stage
Olfactory sense
Lead sponsor: Shahid Sadoughi University of Medical Sciences and Health Services
Sponsor class: OTHER
Collaborators: name: National Institute for Medical Research Development (NIMAD)
name: McMaster University
First posted: 2021-04-13
Enrollment: 424
Sex: ALL
Minimum age (years): 49
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two arms will be randomly allocated to either hydralazine hydrochloride 25mg TDS or placebo.
Primary purpose: TREATMENT

Brief 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 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:

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.

Eligibility criteria: 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.

Primary outcomes:
measure: The progression of of Alzheimer's disease
timeFrame: Three months after recruitment.
measure: The progression of of Alzheimer's disease
timeFrame: Six months after recruitment.
measure: The progression of of Alzheimer's disease
timeFrame: Nine months after recruitment.
measure: The progression of of Alzheimer's disease
timeFrame: Twelve months after recruitment.
Secondary outcomes:
measure: Function of patients with Alzheimer's disease
timeFrame: Three months after recruitment
measure: Function of patients with Alzheimer's disease
timeFrame: Six months after recruitment
measure: Function of patients with Alzheimer's disease
timeFrame: Nine months after recruitment
measure: Function of patients with Alzheimer's disease
timeFrame: Twelve months after recruitment
measure: Cognition of patients with Alzheimer's disease
timeFrame: Three months after recruitment
measure: Cognition of patients with Alzheimer's disease
timeFrame: Six months after recruitment
measure: Cognition of patients with Alzheimer's disease
timeFrame: Nine months after recruitment
measure: Cognition of patients with Alzheimer's disease
timeFrame: Twelve months after recruitment
measure: Behavior of patients with Alzheimer's disease
timeFrame: Three months after recruitment
measure: Behavior of patients with Alzheimer's disease
timeFrame: Six months after recruitment
measure: Behavior of patients with Alzheimer's disease
timeFrame: Nine months after recruitment
measure: Behavior of patients with Alzheimer's disease
timeFrame: Twelve months after recruitment
measure: Caregiver's spent time
timeFrame: Three months after recruitment
measure: Caregiver's spent time
timeFrame: Six months after recruitment
measure: Caregiver's spent time
timeFrame: Nine months after recruitment
measure: Caregiver's spent time
timeFrame: Twelve months after recruitment
measure: Olfactory sense
timeFrame: Three months after recruitment
measure: Olfactory sense
timeFrame: Six months after recruitment
measure: Olfactory sense
timeFrame: Nine months after recruitment
measure: Olfactory sense
timeFrame: Twelve months after recruitment
measure: Drug side effects
timeFrame: Daily records in the provided notebook and reported three month after recruitment. Urgent matter can be reported any time to the provided hotline.
measure: Drug side effects
timeFrame: Daily records in the provided notebook and reported six month after recruitment. Urgent matter can be reported any time to the provided hotline.
measure: Drug side effects
timeFrame: Daily records in the provided notebook and reported nine month after recruitment. Urgent matter can be reported any time to the provided hotline.
measure: Drug side effects
timeFrame: Daily records in the provided notebook and reported twelve month after recruitment. Urgent matter can be reported any time to the provided hotline.
Other outcomes:
Locations:
city: Yazd
country: Iran, Islamic Republic of
facility: Adineh Health Centre
Study officials:
affiliation: Shahid Sadoughi University of Medical Sciences
name: Hamid Mirzaei, PhD
role: STUDY_CHAIR
References: