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CAndesartan vs LIsinopril Effects on the BRain (CALIBREX)

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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:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Ihab Hajjar, Emory University

Tracking Information
First Submitted Date  ICMJE October 27, 2013
First Posted Date  ICMJE November 14, 2013
Results First Submitted Date  ICMJE December 14, 2020
Results First Posted Date  ICMJE February 21, 2021
Last Update Posted Date February 21, 2021
Actual Study Start Date  ICMJE August 20, 2014
Actual Primary Completion Date December 3, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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/].
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE CAndesartan vs LIsinopril Effects on the BRain
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Condition  ICMJE
  • Hypertension
  • Mild Cognitive Impairment
Intervention  ICMJE
  • Drug: Candesartan
    blinded
    Other Name: Atacand
  • Drug: Lisinopril
    Blinded
Study Arms  ICMJE
  • 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 22, 2019)
176
Original Estimated Enrollment  ICMJE
 (submitted: November 7, 2013)
140
Actual Study Completion Date  ICMJE December 3, 2018
Actual Primary Completion Date December 3, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 55 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01984164
Other Study ID Numbers  ICMJE 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  ICMJE Not Provided
Current Responsible Party Ihab Hajjar, Emory University
Original Responsible Party Ihab Hajjar, University of Southern California, Prinicipal Investigator
Current Study Sponsor  ICMJE Emory University
Original Study Sponsor  ICMJE Ihab Hajjar
Collaborators  ICMJE National Institute on Aging (NIA)
Investigators  ICMJE
Principal Investigator: Ihab Hajjar, MD, MS Emory Univeristy
PRS Account Emory University
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP