Clinical trial NCT02085265: Telmisartan vs. Perindopril in Mild-Moderate Alzheimer's Disease Patients
Official title: The SARTAN-AD Trial: A Randomized, Open Label, Proof of Concept Study of Telmisartan vs. Perindopril in Mild-Moderate Alzheimer's Disease Patients
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Alzheimer's Disease
Keywords: Alzheimer's Disease
Perindopril
Telmisartan
Brain atrophy
Lead sponsor: Sunnybrook Health Sciences Centre
Sponsor class: OTHER
Collaborators: name: Alzheimer's Drug Discovery Foundation
name: Weston Brain Institute
First posted: 2014-03-12
Enrollment: 23
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Eligibility criteria: Inclusion criteria

1. 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.
2. Previous brain MRI or CT scan to rule out exclusionary pathology, and absence of stepwise decline since the previous scan.
3. Age 50 years or older
4. Standardized Mini Mental State Examination (SMMSE) score of 16-27 at screening visit
5. Sufficient hearing and vision to participate in testing as per investigator's judgement
6. Sufficient fluency in English to understand instructions and to be able to complete SMMSE
7. 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
8. 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
9. 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

1. Intolerance, or any contraindications, to study medications
2. Average SBP \<110mmHg or average DBP \<60 mmHg during screening
3. Familial autosomal dominant form of Alzheimer's disease
4. Creatinine clearance less than or equal to 30ml/min
5. Serum potassium \> 5.5 mEq/L
6. ALT 3x \> the upper limit of normal (ULN)
7. History of angioedema
8. 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
9. 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
10. Inability to perform the study procedures, including claustrophobia or contraindications for MRI
11. Currently on or has taken an angiotensin receptor blocker within 12 months of randomization visit
12. 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)
13. Current major depression by clinical history or score greater than 18 on the Cornell Scale for Depression in Dementia
14. 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

Primary outcomes:
measure: Ventricular enlargement
timeFrame: 12 months
measure: Safety - Blood pressure
timeFrame: 12 months
measure: Safety - Vital signs
timeFrame: 12 months
measure: Safety - Electrolytes
timeFrame: 12 months
measure: Safety - Adverse Events
timeFrame: 12 months
Secondary outcomes:
measure: Hippocampal volume
timeFrame: 12 months
measure: Grey/White matter volume
timeFrame: 12 months
measure: Cognitive and functional measures
timeFrame: 6 and 12 months
Other outcomes:
measure: Neuropsychiatric Measures
timeFrame: 6 & 12 months
measure: Treatment responsiveness of Diffusion Tensor Imaging (DTI)
timeFrame: 12 months
measure: Treatment responsiveness of resting state functional MRI (rsfMRI)
timeFrame: 12 months
measure: Quality of Life - Caregiver burden
timeFrame: 12 months
measure: Quality of Life - Health-related
timeFrame: 12 months
Locations:
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Lethbridge
country: Canada
facility: University of Lethbridge
state: Alberta
city: Vancouver
country: Canada
facility: UBC Hospital
state: British Columbia
city: Hamilton
country: Canada
facility: Hamilton General Hospital
state: Ontario
city: London
country: Canada
facility: Parkwood Institute
state: Ontario
city: Toronto
country: Canada
facility: Centre for Memory and Aging
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Baycrest Health Sciences
state: Ontario
city: Toronto
country: Canada
facility: Centre for Addiction and Mental Health (CAMH)
state: Ontario
Study officials:
affiliation: Sunnybrook Health Sciences Centre
name: Sandra Black, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sunnybrook Research Institute
name: Krista Lanctot, PhD
role: PRINCIPAL_INVESTIGATOR
References: