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Candesartan's Effects on Alzheimer's Disease And Related Biomarkers (CEDAR)

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ClinicalTrials.gov Identifier: NCT02646982
Recruitment Status : Completed
First Posted : January 6, 2016
Last Update Posted : August 20, 2021
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Ihab Hajjar, Emory University

Brief Summary:
This study is intended to investigate the effect of candesartan, a blood pressure medication, on cognitive function and thinking skills in those who have early or mild memory difficulties, also called mild cognitive impairment or MCI.

Condition or disease Intervention/treatment Phase
Mild Cognitive Impairment Drug: Placebo Drug: Candesartan Phase 2

Detailed Description:
This is a double-blind placebo-control randomized clinical trial that compares candesartan to placebo in individuals with mild cognitive impairment (MCI) who also have positive Alzheimer's Disease (AD) biomarkers. The investigators will assess if blocking the effect of Ang II, a crucial mediator of neuro-vascular injury, using angiotensin receptor blockers (ARBs) will address shortcomings of current treatment regimens. This study will also assess the safety and dose-response of target engagement for treatment with escalating doses of candesartan.

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Study Type : Interventional
Actual Enrollment : 77 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Candesartan's Effects on Alzheimer's Disease And Related Biomarkers
Study Start Date : June 30, 2016
Actual Primary Completion Date : August 17, 2020
Actual Study Completion Date : August 17, 2020


Arm Intervention/treatment
Experimental: Candesartan
Candesartan will be given orally once a day in a stepwise manner as follows: All participants will be initiated on 8 mg candesartan. The dose will be increased in 2 week increments to 16 mg and 32 mg as long as the systolic blood pressure (SBP) >100 mm Hg, diastolic blood pressure (DBP) >40 mm Hg and participant reports no symptoms of hypotension (dizziness or weakness). The highest achievable dose will be the Maximal Tolerated Dose (MTD) and the participant will receive this dose for the remaining duration of the study (participants will be treated for 1 year).
Drug: Candesartan
Candesartan will be started at 8 mg orally, once daily. The dose will be increased in 2 week increments to 16 mg and 32 mg orally, once a day, as long as SBP>100 mm Hg, DBP>40 mm Hg and there are no reported symptoms of hypotension (dizziness or weakness). Candesartan will be given for a total of 12 months.
Other Name: Atacand

Placebo Comparator: Placebo
Participants will receive a matched placebo once a day orally for 12 months.
Drug: Placebo
A matched placebo will be given once daily for 12 months.




Primary Outcome Measures :
  1. Number of hypotensive episodes [ Time Frame: Baseline to Month 12 ]
    Hypotension is defined as blood pressure <100/40 mm Hg. Blood pressure will be measured according to the American Heart Association guidelines with the subject in the sitting position and rested for 5 minutes. An appropriate cuff size (covering 60% of upper arm length and 80% of arm circumference)will be used and correct cuff placement (1-2 inches above the brachial pulse on bare arm) will be ensured.

  2. Number of participants with symptoms of hypotension [ Time Frame: Baseline to Month 12 ]
    Participants will be asked to report any symptoms of hypotension (dizziness, weakness and cough). All subjects will be given a telephone number to reach physician 24-hours per day to report symptoms they experience. The number of subjects reporting symptoms of hypotension will be recorded.

  3. Number of participants with elevated serum creatinine [ Time Frame: Baseline to Month 12 ]
    The levels of creatinine will be obtained from blood samples. Increased levels (>2.5 mg/dl) are indicative of decreased renal function.

  4. Number of participants with hyperkalemia [ Time Frame: Baseline to Month 12 ]
    The levels of potassium will be obtained from blood samples (>5.9meq/dl). Hyperkalemia is an indication of kidney dysfunction.

  5. Number of participants discontinuing the study medication [ Time Frame: Baseline to Month 12 ]
    The number of participants who discontinue study medication will be recorded.


Secondary Outcome Measures :
  1. Change in Cerebrospinal Fluid (CSF) Tau Levels [ Time Frame: Baseline, Month 12 ]
    CSF tau levels (total and pTau) will be analyzed from CSF samples obtained via lumbar puncture (LP).

  2. Change in Pulse Wave Velocity (PWV) [ Time Frame: Baseline, Month 12 ]
    Arterial stiffness will be assessed by Pulse Wave Velocity (PWV).

  3. Change in Augmentation Index (AI) [ Time Frame: Baseline, Month 12 ]
    Arterial stiffness will be assessed by Augmentation Index (AI).

  4. Change in Brain Perfusion [ Time Frame: Baseline, Month 12 ]
    Arterial spin labeling magnetic resonance imaging (ASL-MRI) images will be acquired using a custom 3D stack of interleaved spirals fast spin echo sequence and will be averaged in order to improve the signal-to-noise ratio. Brain perfusion assesses the amount of blood uptake in different areas of the brain. Greater blood supply indicates increased brain activity.

  5. Change in Hippocampal Volume [ Time Frame: Baseline, Month 12 ]
    Arterial spin labeling magnetic resonance imaging (ASL-MRI) images will be acquired using a custom 3D stack of interleaved spirals fast spin echo sequence and will be averaged in order to improve the signal-to-noise ratio. Decreased hippocampal volume indicates functional deficits in the impacted brain areas.

  6. Change in Vasoreactivity [ Time Frame: Baseline, Month 12 ]
    Cerebrovascular reactivity (CVR) is assessed with blood oxygenation level-dependent (BOLD) MRI. Vasoreactivity (VR) is the slope of the regression between cerebral perfusion and end-tidal carbon dioxide (CO2), in ml/100g/min per millimeter of mercury (mm Hg) during normal and hypercapnia. Decreased vasoreactivity is associated with cognitive decline.

  7. Global Standardized Uptake Value Ratio (SUVR) of (11)C-Pittsburgh compound B (PiB) [ Time Frame: Baseline, 12 Months ]
    In-vivo amyloid imaging will be conducted after intravenous administration of 15±1.5 mCi of the radiotracer [11C] PiB.

  8. Global Standardized Uptake Value Ratio (SUVR) of [18F]T807 [ Time Frame: Baseline, 12 Months ]
    In-vivo Tau-PET imaging will be conducted using the radiotracer [18F]T807.

  9. Change in Clinical Dementia Rating (CDR) Score [ Time Frame: Baseline, Month 12 ]
    The CDR rates each of the six general domains involving memory, orientation, judgment and problem-solving, community affairs, home and hobbies, and personal care. An overall score, ranging from 0 to 3, can be calculated. A score of 0 = normal, 0.5 = very mild dementia, 1 = mild dementia, 2 = moderate dementia, and 3 = severe dementia.

  10. Change in EXAMINER Assessment Phonemic Fluency Score [ Time Frame: Baseline, Month 12 ]
    Executive function is assessed using the phonemic fluency task of the EXAMINER Assessments. Participants list as many words as they can that begin with a particular letter, in 60 seconds. A greater number of words correctly meeting the task criteria indicate greater executive function.

  11. Change in EXAMINER Assessment Category Fluency Score [ Time Frame: Baseline, Month 12 ]
    Executive function is assessed using the category fluency task of the EXAMINER Assessments. Participants list as many words as they can that belong in a particular category, in 60 seconds. A greater number of words correctly meeting the task criteria indicate greater executive function.

  12. Change in Hopkins Verbal Learning Test (HVLT) Delayed Recall Score [ Time Frame: Baseline, Month 12 ]
    The Hopkins Verbal Learning Test (HVLT) is used to assess memory domains. Participants are read a list of 12 words and are asked to recall as many as they can remember. This is repeated for 3 trials followed by a 20 minute delay, and then participants are asked to recall as many words as they can. The delayed recall score ranges from 0 to 12 and higher scores indicate better memory.

  13. Change in Trail Making Test (TMT) Part B [ Time Frame: Baseline, Month 12 ]
    The Trail Making Test assesses executive function. In Part B of the TMT participants connect circles labeled with letters and numbers, in ascending order. The score is the amount of time it takes for the participant to complete the task. The average time is 75 seconds and times greater than 273 seconds indicate a deficit with executive function.

  14. Change in Trail Making Test (TMT) Part B - A [ Time Frame: Baseline, Month 12 ]
    In Part A of the TMT participants connect circles labeled with numbers, in ascending order. The score is the amount of time it takes for the participant to complete the task. The TMT Part A score reflects visuoperceptual abilities and subtracting the score for Part A from the score from Part B provides a more accurate assessment of executive function. Lower scores indicate greater executive function.



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Mild Cognitive Impairment, defined by:

    • Subjective memory concern
    • Abnormal memory function documented using the Logical Memory subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale-Revised (the maximum score is 25): [<11 for 16 or more years of education; <9 for 8-15 years of education; <6 for <7 years of education]
    • Montreal Cognitive Assessment (MoCA) < 26
    • Clinical Dementia Rating scale /Memory sum Box score=0.5
    • General functional performance sufficiently preserved (Functional Assessment Questionnaire<9)
  • Amyloid positivity determined by measuring the amyloid content in the brain. This can be determined by either CSF amyloid level or an amyloid scan (PIB-PET)

Exclusion Criteria:

  • Intolerance to ARBs
  • Current use of ARBs, angiotensin-converting enzyme inhibitors (ACEIs) (use of antihypertensive medications other than ACEI or ARBs for other indications is allowed)
  • Current diagnosis of hypertension or current use of antihypertensive medication that is prescribed specifically for hypertensive therapy
  • SBP less than 110 or DBP less than 40 mm Hg
  • Renal disease (Creatinine >2.0 mg/dl), hyperkalemia (K>5.5 meq/dl), platelets<50,000/μl, or international normalized ratio (INR)>1.9
  • Active medical or psychiatric diseases that in the judgment of the investigator would affect the safety of the subject or scientific integrity of the study
  • Uncontrolled congestive heart failure reflected by poor exercise tolerance and shortness of breath
  • History of stroke in the past 3 years
  • Inability to have MRI (eg metal implants or cardiac pacemaker) with an exception for those who cannot have an MRI, if all other parts of the study are obtained successfully they may still be enrolled in the study, or cognitive assessment or inability to assess amyloid positivity (no LP and no amyloid scan)
  • History of increased intracranial pressure (ICP) or bleeding diathesis (from disease states or from use of anticoagulants such as warfarin, heparin and related products, rivaroxaban or Xarelto, apixaban or Eliquis, edoxaban or Savaysa, dabigatran or Pradaxa)
  • Women of childbearing potential (non-menopausal)
  • In those who are unable to demonstrate that they understood the details of the study (ie lack of decisional-capacity to consent), a study partner/surrogate who can sign on their behalf will be required, otherwise they will be excluded
  • Current use of Lithium, as candesartan may increase lithium concentration to toxic levels

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02646982


Locations
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United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
Wesley Woods Center
Atlanta, Georgia, United States, 30329
Sponsors and Collaborators
Emory University
National Institute on Aging (NIA)
Investigators
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Principal Investigator: Ihab Hajjar, MD Emory University
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Responsible Party: Ihab Hajjar, Associate Professor, Emory University
ClinicalTrials.gov Identifier: NCT02646982    
Other Study ID Numbers: IRB00084574
R01AG049752 ( U.S. NIH Grant/Contract )
First Posted: January 6, 2016    Key Record Dates
Last Update Posted: August 20, 2021
Last Verified: August 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ihab Hajjar, Emory University:
Alzheimer's disease
Vascular function
Neuroinflammation
Additional relevant MeSH terms:
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Alzheimer Disease
Cognitive Dysfunction
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Cognition Disorders
Candesartan
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action