CAndesartan vs LIsinopril Effects on the BRain (CALIBREX)

• ClinicalTrials.gov Identifier: NCT01984164
• Recruitment Status: Completed
• First Posted: November 14, 2013
• Results First Posted: February 21, 2021
• Last Update Posted: February 21, 2021
• Sponsor: Emory University
• Collaborator: National Institute on Aging (NIA)
• Information provided by (Responsible Party): Ihab Hajjar, Emory University

Tracking Information

• First Submitted Date: October 27, 2013
• First Posted Date: November 14, 2013
• Results First Submitted Date: December 14, 2020
• Results First Posted Date: February 21, 2021
• Last Update Posted Date: February 21, 2021
• Actual Study Start Date: August 20, 2014
• Actual Primary Completion Date: December 3, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 2, 2021)

• Executive Function [ Time Frame: 12 months ]
  Executive function will be assessed using Trail Making Test (part B-A). Part A was collected to correct for motor speed and visual-perceptual demands on TMT by subtracting completion time for TMT Part A from completion time for Part B (TMT B - A). TMT Part B-A provides a relatively purer measure of executive functioning. It has a timed scale from 0 sec (min) to 300 secs (max). Along this scale, a lower score is better.
• NINDS-initiated EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research or "EXAMINER" Tool Box. [ Time Frame: 12 months ]
  EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research or "EXAMINER" tool box. This test batteryThe battery includes 11 tasks that generate 15 primary variables. Within this set, the EXAMINER includes: working memory, inhibition, set shifting, and fluency. The parts of EXAMINER that were used for this study include: Flanker task (inhibition) which involves responding to a central stimulus while ignoring flanking stimuli that are either compatible or incompatible with the central stimulus; Set-shifting, a measure of mental flexibility; Spatial 1-Back test assesses spatial working memory; Dot Counting test assesses verbal working memory; Verbal Fluency tested using a List Generation test which require the participant to generate words beginning with a specific letter, and category fluency in which the participant generates words from a specified category (e.g., animals, fruits). Higher are reflective of better executive function (-1 to +1)

Original Primary Outcome Measures (submitted: November 7, 2013)

Executive function (EXAMINER score) [ Time Frame: 12 months ]

Executive function will be assessed using the NINDS-initiated EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research or "EXAMINER" tool box. This test battery reliably and validly assesses executive function in clinical trials [http://examiner.ucsf.edu/].

Current Secondary Outcome Measures (submitted: February 2, 2021)

• Memory [ Time Frame: 12 months ]
  To assess episodic memory, the Hopkins Verbal Learning Test-Revised (HVLT-R) will be used. The retention (%) score is calculated by dividing the delayed recall trial by the higher of 3 learning trials. Each trial scores 0 (min) to 12 (max). The HVLT-R retention score is a percentage, and a higher percentage represents a better outcome.
• Language [ Time Frame: 12 months ]
  This will be measured using the Boston Naming Test. BNT is a neuropsychological test used to assess visual confrontation naming and language performance in participants with cognitive decline. Its short 15-item version consists of drawings of objects ranging from common objects to less familiar objects. Scale: 0 (min score) to 15 (max score). For this test, a higher score/response represents a better outcome.
• Attention Measured Using Digit Span Backward [ Time Frame: 12 months ]
  The Digit Span test is a subtest of both the Wechsler Adult Intelligence Scale (WAIS) and the Wechsler Memory Scales (WMS). For the digit span backwards, subjects are read a sequence of numbers and asked to repeat the same sequence back to the examiner in reverse order (backward span). Backward span is an executive task particularly dependent on working memory. The Digit Span backward is scored for backwards performance. Scale: 0 (minimum) to 16 (maximum). A higher score represents a better outcome.
• White Matter Lesion Volume [ Time Frame: 12 months ]
  White Matter Lesion volume: high-resolution anatomical images are acquired for the measurement of microvascular disease. WMH volumes will be obtained from Fluid attenuated inversion recovery (FLAIR) imaging sequence and reported as total volume (in mm3). Higher values means greater WMH
• Cerebral Perfusion [ Time Frame: 12 months ]
  ASL-MRI: Arterial Spin Labeling (ASL) MRI is non-invasive measure of perfusion that does not require contrast, and allows multiple brain regions mapping of perfusion and reserve. ASL-MRI provides measures of cerebral blood flow (CBF). Higher values indicates higher CBF.
• Attention Measured Using Digit Span Forward [ Time Frame: 12 months ]
  This will be measured using Digit Span Forward. The Digit Span test is a subtest of both the Wechsler Adult Intelligence Scale (WAIS) and the Wechsler Memory Scales (WMS). For the digit span forward, subjects are read a sequence of numbers and asked to repeat the same sequence back to the examiner in the correct order (forward span). Forward span captures attention efficiency and capacity. The Digit Span forward is scored for forwards performance. Scale: 0 (minimum) to 16 (maximum). A higher score represents a better outcome.

Original Secondary Outcome Measures (submitted: November 7, 2013)

• Perfusion and Vasoreactivity (VR) [ Time Frame: 12 months ]
  ASL-MRI: Arterial Spin Labeling (ASL)MRI will be used to obtain perfusion measures in the brain. Images will be acquired during normocapnia , hypercapnia, and hypocapnia.
• rs-fMRI [ Time Frame: 12 months ]
  Resting functional MRI (r-fMRI): This protocol assesses the communication or "functional connectivity" between brain regions. Functional connectivity has a key role in important complex cognitive processes. It focuses on spontaneous, rather than task-induced, low frequency (<0.1 Hz) fluctuations in the blood oxygenation level-dependent (BOLD) signals.

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: November 7, 2013)

• Memory [ Time Frame: 12 months ]
  To assess memory we will use the California Verbal Learning Test
• White Matter Hyperintensity (WMH) Volume [ Time Frame: 12 months ]
  Structural MRI and WMH: High-resolution anatomical images will be acquired to identify WMH volumes as a marker of microvascular brain injury.
• Carotid intima-media thickness (CIMT) [ Time Frame: 12 months ]
  High-resolution B-mode ultrasonograms of the right common carotid artery will be obtained to assess the degree of atherosclerosis.
• endothelial progenitor cells [ Time Frame: 12 months ]
  Endothelial progenitor cells (EPC) will also be collected.

Descriptive Information

• Brief Title: CAndesartan vs LIsinopril Effects on the BRain
• Official Title: CAndesartan vs LIsinopril Effects on the BRain and Endothelial Function in eXecutive MCI (CALIBREX)
• Brief Summary: The aim of this study is to conduct a 1-year double blind randomized control trial comparing candesartan to lisinopril in 140 individuals with hypertension and executive mild cognitive impairment in their effects on executive function, neuroimaging markers, and vascular indicators.

Detailed Description

• Hypertension is associated with cognitive impairment even in the absence of clinical dementia. To date, no specific treatment is available for this pattern of mild cognitive impairment related to hypertension.
• Objectives or purpose: The aims of this study are to investigate the effects of candesartan on executive function decline and on changes in cerebral perfusion, cerebrovascular reserve and microvascular brain injury. The study also intends to identify potential underlying mechanisms related to vascular structure and function, including atherosclerosis, vascular inflammation, vascular stiffness, and endothelial progenitor cells, by which candesartan may affect the cognitive and cerebrovascular outcomes.
• Study methodology:This is a double blind randomized clinical trial that will be conducted in 140 individuals (70 in the candesartan group, 70 in the lisinopril group). Our target population is subjects: 55 years or older with hypertension and Executive Mild Cognitive Impairment.
• Endpoints to be measured:Our measures include cognitive function, cerebral perfusion and reserve, markers of vascular brain damage, atherosclerosis, stiffness, vascular inflammation and endothelial function.
• Description of intervention, follow-up, and duration of study: Eligible participants will undergo randomization into 2 groups and will be seen frequently until their blood pressure is controlled (<140/90 mmHg). Participants will be seen at 3, 6 and 12 months afterwards.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Prevention

Condition

• Hypertension
• Mild Cognitive Impairment

Intervention

• Drug: Candesartan
  blinded
  Other Name: Atacand
• Drug: Lisinopril
  Blinded

Study Arms

• Active Comparator: Candesartan
  To achieve blood pressure control, we will use a stepwise protocol as follows: candesartan (blinded) 8mg→ 16mg→ 32mg. Both groups will also receive (unblinded) , if needed to achieve blood pressure control, HCTZ 12.5mg→ 25mg, Amlodipine 2.5mg→ 5mg →10mg and metoprolol succinate extended release 12.5mg→ 25mg→ 50mg. Antihypertensive medications will be increased every 2 weeks until control is achieved.
  Intervention: Drug: Candesartan
• Active Comparator: Lisinopril
  To achieve blood pressure control we will use a stepwise protocol as follows: lisinopril (blinded) 10mg→ 20mg→ 40mg. Both groups will also receive (unblinded), if needed to achieve blood pressure control, HCTZ 12.5mg→ 25mg, Amlodipine 2.5mg→ 5mg→ 10mg and metoprolol succinate extended release 12.5mg→ 25mg→ 50mg. Antihypertensive medications will be increased every 2 weeks until control is achieved.
  Intervention: Drug: Lisinopril

• Publications *: Hajjar I, Okafor M, McDaniel D, Obideen M, Dee E, Shokouhi M, Quyyumi AA, Levey A, Goldstein F. Effects of Candesartan vs Lisinopril on Neurocognitive Function in Older Adults With Executive Mild Cognitive Impairment: A Randomized Clinical Trial. JAMA Netw Open. 2020 Aug 3;3(8):e2012252. doi: 10.1001/jamanetworkopen.2020.12252.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 22, 2019): 176
• Original Estimated Enrollment (submitted: November 7, 2013): 140
• Actual Study Completion Date: December 3, 2018
• Actual Primary Completion Date: December 3, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. age: 55 years or older;
2. Hypertension: SBP≥140 mm Hg or DBP≥ 90 mm or receiving antihypertensive medications.

3. Executive MCI will be defined using these criteria:

   1. The Montreal Cognitive Assessment (MoCA) score less than or equal to 26
   2. Executive dysfunction: A performance at the 10th percentile or below on at least one of four screening tests for executive function: Trail Making Test, Part B (TMT-B), modified Stroop interference, Digit Span and Digit Sequencing, and Letter fluency.
   3. Minimal Functional limitation as reflected by the Functional Assessment Questionnaire (FAQ)≤7

Exclusion Criteria:

1. Intolerance to study drugs;
2. SBP >200 or DBP >110 mm Hg;
3. Renal disease or hyperkalemia
4. Active medical or psychiatric problems
5. Uncontrolled congestive heart failure;
6. History of stroke in the past 3 years;
7. Inability to perform the study procedures
8. Women of childbearing potential
9. diagnosis of dementia
10. In those who lack decision capacity, a study surrogate who can sign on their behalf will be required. Since we are enrolling only those with MCI, we anticipate that most participants will have decision capacity
11. Current use of Lithium, as most antihypertensive classes may lead to increased lithium toxic levels.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 55 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01984164
• Other Study ID Numbers: IRB00070087; R01AG042127 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Ihab Hajjar, Emory University
• Original Responsible Party: Ihab Hajjar, University of Southern California, Prinicipal Investigator
• Current Study Sponsor: Emory University
• Original Study Sponsor: Ihab Hajjar
• Collaborators: National Institute on Aging (NIA)

Investigators

• Principal Investigator: Ihab Hajjar, MD, MS; Emory Univeristy

• PRS Account: Emory University
• Verification Date: February 2021