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:

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.

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.

Individual patient data (IPD) sharing plan will be decided according to the upcoming requests and the ethics committee approval.

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.

All requests should be forwarded to the study email address and agreed by the investigators' committee subject to the ethics committee approval.

Hydralazine hydrochloride was imported directly from a global supplier, packed in 90 tablet bottles with a specific batch number for drug and placebo not revealed to any of the above parties.