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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 : Recruiting
First Posted : January 6, 2016
Last Update Posted : February 9, 2018
Sponsor:
Information provided by (Responsible Party):
Ihab M. 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. They will also assess the safety and dose-response of target engagement for treatment with escalating doses of candesartan in this study.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 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 2016
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : September 2021


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) >110 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>110 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. Change in the number hypotensive episodes [ Time Frame: Baseline; 12 months ]
    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. Change in the number of subjects with symptoms of hypotension [ Time Frame: Baseline; 12 months ]
    Subjects 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. Changes in the levels of serum creatinine [ Time Frame: Baseline,12 months ]
    The levels of creatinine will be obtained from blood samples. Increased levels ( >2.5 mg/dl) are indicative of decreased renal function.

  4. Change in the levels of serum potassium [ Time Frame: Baseline,12 months ]
    The levels of potassium will be obtained from blood samples. Increased levels of potassium >5.9meq/dl are indicative of decreased renal function.

  5. Number of subjects discontinuations of candesartan [ Time Frame: At 12 months ]
    The number of subjects who discontinue candesartan due to any reason will be recorded.


Secondary Outcome Measures :
  1. Changes in cerebrospinal fluid (CSF) phospho-tau181P levels [ Time Frame: Baseline, 12 months ]
    CSF tau levels will be analyzed from CSF samples obtained via lumbar puncture (LP). Approximately 30-40 ml of CSF will be collected with 24-g Sprotte atraumatic spinal needle. CSF-phospho-tau (p-tau) 181p will be measured using the multiplex xMAP Luminex platform (Luminex Corp, Austin, TX) with Innogenetics (INNO-BIA AlzBio3; Ghent, Belgium; for research use-only reagents) immunoassay kit-based reagents. Higher levels indicate a decrease in cognitive function.

  2. Changes in cerebrospinal fluid (CSF) amyloid β1-42 levels [ Time Frame: Baseline, 12 months ]
    CSF amyloid β1-42 levels will be analyzed from CSF samples obtained via lumbar puncture (LP). Approximately 30-40 ml of CSF will be collected with 24-g Sprotte atraumatic spinal needle. Amyloid β1-42 will be measured using the multiplex xMAP Luminex platform (Luminex Corp, Austin, TX) with Innogenetics (INNO-BIA AlzBio3; Ghent, Belgium; for research use-only reagents) immunoassay kit-based reagents. Higher levels indicate a decrease in cognitive function.

  3. Changes in levels of cerebrospinal fluid cytokines [ Time Frame: Baseline,12 months ]
    The levels of cytokines in the CSF will be assessed to measure inflammation. Higher levels indicate a decrease in cognitive function.

  4. Change in arterial stiffness, assessed by Pulse Wave Velocity (PWV) [ Time Frame: Baseline,12 months ]
    PWV will be measured between the carotid and femoral arteries using the SphygmoCor device to assess aortic stiffness. Pressure waveforms at the carotid and femoral arteries will be acquired using EKG gating. Velocity (distance per time in seconds) will be calculated using the foot-to-foot method and the distance between the sites will be measured manually.

  5. Changes in aortic stiffness, assessed by Augmentation Index [ Time Frame: Baseline, 12 months ]
    The Augmentation Index (AI) is a measure of enhanced wave reflection and a measure of aortic stiffness. AI is calculated as augmentation pressure (AG) divided by pulse pressure (PP) ×100 to give a percentage.

  6. Changes in levels of circulating Endothelial Progenitor Cells (EPCs) [ Time Frame: Baseline, 12 months ]
    The levels of circulating progenitor-enriched population of endothelial cells will be measured by the expression of surface antigens using direct flow cytometry.

  7. Change in Alzheimer's Disease Assessment Scale (ADAS-cog) scores [ Time Frame: Baseline, 12 months ]
    The ADAS-cog consists of 11 items that evaluate selected aspects of memory, orientation, attention, language, reasoning, and praxis. Scores range from 0 (no impairment) to 70 (very severe impairment).

  8. Change in Clinical Dementia Rating (CDR) scores [ Time Frame: Baseline, 12 months ]
    The CDR rates each of the six general domains involving memory, orientation, judgment and problem-solving, community affairs, home and hobbies, and personal care. A global rating is then generated, ranging from 0=no impairment to 3=severe impairment.

  9. Change in executive function, assessed by the EXAMINER score [ Time Frame: Baseline, 12 months ]
    The Examiner will be used to measure a participant's attention and inhibitory control. The test requires the participant to focus on a given stimulus while inhibiting attention to stimuli flanking it. Scoring is based on a combination of accuracy and reaction time.

  10. Change in executive function, assessed by the Spatial 1-Back test [ Time Frame: Baseline, 12 months ]
    The spatial 1-Back test will be used to assess the spatial working memory component of executive function.

  11. Change in cerebral vasoreactivity, assessed by MRI [ Time Frame: Baseline, 12 months ]
    MRI Perfusion Imaging will be used to determine cerebral vasoreactivity. Vasoreactivity (VR)=slope of the regression between cerebral perfusion and end-tidal carbon dioxide (CO2), in ml/100g/min per mm of Hg during normal and hypercapnia.

  12. Change in white matter hyperintensities (WMH), assessed by structural MRI [ Time Frame: Baseline, 12 months ]
    High-resolution anatomical images will be acquired using a 3D-Fast Spoiled Gradient Recalled Echo (FSPGR) Sequence. WMH regions will be identified by a 3D T2 Fluid Attenuated Inversion Recovery (FLAIR) Fast Spin Echo sequence.

  13. Change in functional connectivity, assessed by rs-fMRI [ Time Frame: Baseline, 12 months ]
    Resting state functional MRI (rs-fMRI) will be used to assess "functional connectivity" between brain regions. The spontaneous, low frequency (<0.1 Hz) fluctuations in the blood oxygenation level-dependent (BOLD) signals will be assessed.



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


Contacts
Contact: Ihab Hajjar, MD 404-712-7250 ihabhajjar@emory.edu

Locations
United States, Georgia
Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Ihab Hajjar, MD    404-712-7250    ihajjar@emory.edu   
Principal Investigator: Ihab Hajjar, MD         
Wesley Woods Center Recruiting
Atlanta, Georgia, United States, 30329
Contact: Ihab Hajjar, MD    404-712-7250    ihajjar@emory.edu   
Sponsors and Collaborators
Emory University
Investigators
Principal Investigator: Ihab Hajjar, MD Emory University

Responsible Party: Ihab M. Hajjar, Associate Professor, Emory University
ClinicalTrials.gov Identifier: NCT02646982     History of Changes
Other Study ID Numbers: IRB00084574
First Posted: January 6, 2016    Key Record Dates
Last Update Posted: February 9, 2018
Last Verified: February 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ihab M. Hajjar, Emory University:
Alzheimer's disease
Vascular function
Neuroinflammation

Additional relevant MeSH terms:
Antihypertensive Agents
Alzheimer Disease
Cognitive Dysfunction
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Cognition Disorders
Candesartan
Candesartan cilexetil
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action