SARTAN-AD: Telmisartan vs. Perindopril in Mild-Moderate Alzheimer's Disease Patients
Study Details
Study Description
Brief Summary
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Telmisartan Telmisartan 40 mg or 80 mg/day (depending on age and tolerability) |
Drug: Telmisartan
Telmisartan 40 mg or 80 mg/day (depending on age and tolerability)
Other Names:
|
| Active Comparator: Perindopril Perindopril 2 mg, 4 mg or 8 mg/day (depending on kidney function and tolerability) |
Drug: Perindopril
Perindopril 2 mg, 4 mg or 8 mg/day (depending on kidney function and tolerability)
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Ventricular enlargement [12 months]
Change in ventricular size, on 3D T1 MR imaging, after 12 months of treatment
- Safety - Blood pressure [12 months]
Change in blood pressure (BP) measurements after 12 months of treatment.
- Safety - Vital signs [12 months]
Change in vital sign (heart rate, pulse) measurements after 12 months of treatment.
- Safety - Electrolytes [12 months]
Change in electrolyte measurements (Na, K) after 12 months of treatment.
- Safety - Adverse Events [12 months]
Adverse events and serious adverse events over 12 months of treatment.
Secondary Outcome Measures
- Hippocampal volume [12 months]
Change in hippocampal volume measurements after 12 months of treatment
- Grey/White matter volume [12 months]
Volume of grey and white matter in the cingulate, parietotemporal and dorsolateral frontal regions after 12 months of treatment
- Cognitive and functional measures [6 and 12 months]
Determine comparative efficacy of perindopril vs. telmisartan on cognitive and functional measures and on other structural brain imaging measures in this participant population
Other Outcome Measures
- Neuropsychiatric Measures [6 & 12 months]
Assess the comparative treatment responsiveness of neuropsychiatric measures and obtain pilot data
- Treatment responsiveness of Diffusion Tensor Imaging (DTI) [12 months]
Assess the comparative treatment responsiveness of Diffusion Tensor Imaging (DTI) and obtain pilot data
- Treatment responsiveness of resting state functional MRI (rsfMRI) [12 months]
Assess the comparative treatment responsiveness of multi-modal MRI, resting-state functional MRI (rsfMRI) and arterial spin labeling (in a subset of participants) and obtain pilot data.
- Quality of Life - Caregiver burden [12 months]
Assess the comparative response of caregiver burden after treatment using Zarit burden interview.
- Quality of Life - Health-related [12 months]
Assess health related quality of life after treatment using EQ-5D-5L questionnaire.
Eligibility Criteria
Criteria
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.
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Age 50 years or older
-
Standardized Mini Mental State Examination (SMMSE) score of 16-27 at screening visit
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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
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Average SBP <110mmHg or average DBP <60 mmHg during screening
-
Familial autosomal dominant form of Alzheimer's disease
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Creatinine clearance less than or equal to 30ml/min
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Serum potassium > 5.5 mEq/L
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ALT 3x > the upper limit of normal (ULN)
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History of angioedema
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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
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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
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Inability to perform the study procedures, including claustrophobia or contraindications for MRI
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Currently on or has taken an angiotensin receptor blocker within 12 months of randomization visit
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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)
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Current major depression by clinical history or score greater than 18 on the Cornell Scale for Depression in Dementia
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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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Calgary | Calgary | Alberta | Canada | T2N 4N1 |
| 2 | University of Lethbridge | Lethbridge | Alberta | Canada | T1K 6T5 |
| 3 | UBC Hospital | Vancouver | British Columbia | Canada | V6T 2B5 |
| 4 | Hamilton General Hospital | Hamilton | Ontario | Canada | L8L 2X2 |
| 5 | Parkwood Institute | London | Ontario | Canada | N6C 4R3 |
| 6 | Centre for Memory and Aging | Toronto | Ontario | Canada | M4G 3E8 |
| 7 | Sunnybrook Health Sciences Centre | Toronto | Ontario | Canada | M4N 3M5 |
| 8 | St. Michael's Hospital | Toronto | Ontario | Canada | M5B 1W8 |
| 9 | Baycrest Health Sciences | Toronto | Ontario | Canada | M6A 2E1 |
| 10 | Centre for Addiction and Mental Health (CAMH) | Toronto | Ontario | Canada |
Sponsors and Collaborators
- Sunnybrook Health Sciences Centre
- Alzheimer's Drug Discovery Foundation
- Weston Brain Institute
Investigators
- Principal Investigator: Sandra Black, MD, Sunnybrook Health Sciences Centre
- Principal Investigator: Krista Lanctot, PhD, Sunnybrook Research Institute
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 148-2013