Telmisartan vs. Perindopril in Mild-Moderate Alzheimer's Disease Patients

Study Overview
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Brief Summary
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To conduct a proof of concept study in patients with mild to moderate Alzheimer's Disease in order to determine if there is less global brain atrophy over one year, as measured by ventricular enlargement as a primary outcome measure, when patients are randomized to treatment with an angiotensin receptor blocker (ARB) compared to an angiotensin converting enzyme inhibitor (ACEI).

Detailed Description
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This study uses a simple validated measure of brain atrophy as a surrogate marker in a repurposing effort that could recast an antihypertensive medication as a cognitive enhancer/neuroprotective agent and possibly as a drug of choice for Alzheimer patients and patients at risk for AD. If the proof of concept result is positive, a larger study would be warranted with potential practice-changing impact.

Official Title
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The SARTAN-AD Trial: A Randomized, Open Label, Proof of Concept Study of Telmisartan vs. Perindopril in Mild-Moderate Alzheimer's Disease Patients

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Perindopril
* Drug: Telmisartan


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Diagnosis of Probable AD dementia or Possible AD dementia due to concomitant cerebrovascular disease (as permitted by the study exclusion criteria), using the 2011 McKhann criteria. Previous brain MRI or CT scan to rule out exclusionary pathology, and absence of stepwise decline since the previous scan. Age 50 years or older Standardized Mini Mental State Examination (SMMSE) score of 16-27 at screening visit Sufficient hearing and vision to participate in testing as per investigator's judgement Sufficient fluency in English to understand instructions and to be able to complete SMMSE A study partner who in the opinion of the study investigator has regular interaction with the participant, can be present for study visits, can provide a collateral history and can ensure compliance with study procedures HbA1C <8.5%. Patients with stable type II diabetes are eligible for the study if there have been no severe hypoglycemic events requiring third party intervention (e.g. emergency department visit) for 6 months prior to randomization Patients on cholinesterase inhibitors or memantine, medications for vascular risk factors (e.g., hypertension, cholesterol, diabetes), or on psychotropic medications must be on a stable dose for 30 days prior to randomization. Exclusion criteria Intolerance, or any contraindications, to study medications Average SBP <110mmHg or average DBP <60 mmHg during screening Familial autosomal dominant form of Alzheimer's disease Creatinine clearance less than or equal to 30ml/min Serum potassium > 5.5 mEq/L ALT 3x > the upper limit of normal (ULN) History of angioedema Co-morbid acute or chronic conditions (including type I diabetes mellitus, other neurological conditions such as Parkinson's disease, psychiatric disorders, and severe or unstable medical conditions) that could confound assessments or would, in the judgment of the investigator, make the subject inappropriate for entry into this study Any of the following findings on previous CT/MRI or on screening MRI: Exclusionary Finding: Malignant tumour Brain Location: Anywhere Size: Any Exclusionary Number: Any Exclusionary Finding: Tumour with significant mass effect Brain Location: Anywhere Size: Sufficient for mass effect Exclusionary Number: Any Exclusionary Finding: Vascular malformations Brain Location: Anywhere Size: Any Exclusionary Number: Any Exclusionary Finding: Subdural hematoma Brain Location: Anywhere Size: Any Exclusionary Number: Any Exclusionary Finding: Intracerebral hemorrhage Brain Location: Anywhere Size: Any Exclusionary Number: Any Exclusionary Finding: Cerebral microbleeds, Brain Location: Anywhere Size: Any Exclusionary Number: more than 5 Exclusionary Finding: Superficial siderosis (SS) Brain Location: Cortex Size: Any Exclusionary Number: >1 instance of focal SS Exclusionary Finding: Ischemic infarct Brain Location: Cortex Size: >1.5 cm in diameter Exclusionary Number: Any Exclusionary Finding: Ischemic infarct Brain Location: Cortex Size: ≤1.5 cm in diameter Exclusionary Number: more than 1 Exclusionary Finding: Fazekas score 3 with white matter hyperintensity band along the lateral surface of the ventricles >0.5 cm in width Exclusionary Finding: Ischemic infarct Brain Location: White matter Size: >1.5 cm in diameter Exclusionary Number: Any Exclusionary Finding: Ischemic infarct Brain Location: White matter Size: 1.0-1.5 cm in diameter Exclusionary Number: More than 2 Exclusionary Finding: Ischemic infarct Brain Location: Basal ganglia Size: >1.0 cm in diameter Exclusionary Number: Any Exclusionary Finding: Ischemic infarct Brain Location: Basal ganglia and white matter Size: ≤1.0 cm in diameter Exclusionary Number: More than 4 Exclusionary Finding: Strategic infarct Brain Location: Thalamus Size: Any Exclusionary Number: Any Exclusionary Finding: Strategic infarct Brain Location: Hippocampus, Size: Any Exclusionary Number: Any Inability to perform the study procedures, including claustrophobia or contraindications for MRI Currently on or has taken an angiotensin receptor blocker within 12 months of randomization visit Resides in a nursing home (participants who reside in retirement homes may be included if they have a study partner who meets inclusion criterion #8) Current major depression by clinical history or score greater than 18 on the Cornell Scale for Depression in Dementia Documented potential cardiac source of brain infarction such as mechanical valve or atrial fibrillation that is untreated or treated with warfarin or an antiplatelet agent; atrial fibrillation treated with a novel oral anticoagulant is permitted, as is a history of remote, transient atrial fibrillation that has not recurred

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Telmisartan<br>Telmisartan 40 mg or 80 mg/day (depending on age and tolerability) | Drug: Telmisartan<br>* Telmisartan 40 mg or 80 mg/day (depending on age and tolerability)<br>* Other names: Micardis;|
| Active Comparator: Perindopril<br>Perindopril 2 mg, 4 mg or 8 mg/day (depending on kidney function and tolerability) | Drug: Perindopril<br>* Perindopril 2 mg, 4 mg or 8 mg/day (depending on kidney function and tolerability)<br>* Other names: Coversyl;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventricular enlargement | Change in ventricular size, on 3D T1 MR imaging, after 12 months of treatment | 12 months | 
| Safety - Blood pressure | Change in blood pressure (BP) measurements after 12 months of treatment. | 12 months | 
| Safety - Vital signs | Change in vital sign (heart rate, pulse) measurements after 12 months of treatment. | 12 months | 
| Safety - Electrolytes | Change in electrolyte measurements (Na, K) after 12 months of treatment. | 12 months | 
| Safety - Adverse Events | Adverse events and serious adverse events over 12 months of treatment. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hippocampal volume | Change in hippocampal volume measurements after 12 months of treatment | 12 months | 
| Grey/White matter volume | Volume of grey and white matter in the cingulate, parietotemporal and dorsolateral frontal regions after 12 months of treatment | 12 months | 
| Cognitive and functional measures | Determine comparative efficacy of perindopril vs. telmisartan on cognitive and functional measures and on other structural brain imaging measures in this participant population | 6 and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's Disease, Perindopril, Telmisartan, Brain atrophy