Effect of Hydralazine on Alzheimer's Disease

Study aim:

• Determination and comparison of the effect of 75mg (25mg TDS) hydralazine vs. placebo in patients with mild to moderate Alzheimer's disease.
• 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.
• 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 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).

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), memantine (5-21mg/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 50 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)-5.
• 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.