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

• ClinicalTrials.gov Identifier: NCT02646982
• Recruitment Status: Completed
• First Posted: January 6, 2016
• Results First Posted: September 29, 2022
• Last Update Posted: December 1, 2022
• Sponsor: Emory University
• Collaborator: National Institute on Aging (NIA)
• Information provided by (Responsible Party): Ihab Hajjar, Emory University

Study Description

Brief Summary:

This study is intended to investigate the safety of candesartan, a blood pressure medication, in non-hypertensive individuals who have mild cognitive impairment (MCI) due to Alzheimer's disease and its effect on disease biomarkers.

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 using angiotensin receptor blockers (ARBs) is safe in non hypertensive MCI individuals and whether the use of candesartan will be associated with changes in cerebrospinal fluid disease biomarkers.

Study Design

• Study Type: Interventional (Clinical Trial)
• 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

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With a Hypotensive Episode [ Time Frame: Up to Month 12 ]
   Hypotension is defined as blood pressure <100/40 mm Hg. Blood pressure was 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) was used and correct cuff placement (1-2 inches above the brachial pulse on bare arm) was ensured.
2. Number of Participants With Symptoms of Hypotension [ Time Frame: Up to Month 12 ]
   Participants were asked to report any symptoms of hypotension (dizziness, weakness, fatigue and lightheadedness). All participants were given a telephone number to reach physician 24-hours per day to report symptoms they experience. The number of participants reporting symptoms of hypotension is reported here.
3. Number of Participants With Hypotensive Episodes and Symptoms [ Time Frame: Up to Month 12 ]
   The number of participants with reported episodes hypotension as well as symptoms of hypotension.
4. Number of Participants With Elevated Serum Creatinine [ Time Frame: Up to Month 12 ]
   The levels of creatinine were obtained from blood samples. Elevated serum creatinine is defined as levels >2.5 milligram per deciliter (mg/dL). Elevated serum creatinine is indicative of decreased renal function.
5. Number of Participants With Hyperkalemia [ Time Frame: Up to Month 12 ]
   The levels of potassium were obtained from blood samples. Hyperkalemia is defined as potassium levels >5.9 milliequivalent per deciliter (meq/dL). Hyperkalemia is an indication of kidney dysfunction.
6. Number of Participants Discontinuing Study Medication [ Time Frame: Up to Month 12 ]
   The number of participants who discontinued the study medication is presented here.

Secondary Outcome Measures :

1. Cerebrospinal Fluid (CSF) Total Tau Levels [ Time Frame: Baseline, Month 12 ]
   CSF total tau (t-tau) levels were analyzed from CSF samples obtained via lumbar puncture. Normal values for t-tau are < 450 pg/ml. Elevated levels of t-tau indicate worsening disease.
2. Cerebrospinal Fluid (CSF) of Tau Phosphorylated at Threonine 181 (p-tau181) Levels [ Time Frame: Baseline, Month 12 ]
   CSF levels of p-tau181 were analyzed from CSF samples obtained via lumbar puncture. P-tau181 is a biomarker that is elevated in persons with Alzheimer's disease. Higher values indicate worsening disease.
3. Cerebrospinal Fluid (CSF) Amyloid Aβ42 Levels [ Time Frame: Baseline, Month 12 ]
   CSF Aβ42 levels were analyzed from CSF samples obtained via lumbar puncture. Aβ42 is a biomarker for Alzheimer's disease and lower values indicate worsening disease and an increased accumulation of amyloid in the brain.
4. Cerebrospinal Fluid (CSF) Amyloid Aβ40 Levels [ Time Frame: Baseline, Month 12 ]
   CSF Aβ40 levels were analyzed from CSF samples obtained via lumbar puncture. Lower values indicate worsening disease and an increased brain accumulation of amyloid.
5. Cerebrospinal Fluid (CSF) Amyloid Aβ42/Aβ40 Levels [ Time Frame: Baseline, Month 12 ]
   CSF Aβ42/Aβ40 levels were analyzed from CSF samples obtained via lumbar puncture. A lower ratio indicates worsening disease.
6. Pulse Wave Velocity (PWV) [ Time Frame: Baseline, Month 12 ]
   Arterial stiffness was assessed by Pulse Wave Velocity (PWV). PWV is calculated as PWV=distance (d)/time (t) and the unit of measure is reported as meters per second (m/s). Lower values indicate a preferable measurement of arterial stiffness.
7. Augmentation Index (AI) [ Time Frame: Baseline, Month 12 ]
   Arterial stiffness was assessed by Augmentation Index (AI). The AI is a ratio measure of augmentation of central arterial pressure reflected in a pulse wave; the value is multiplied by 100 to provide a percentage. AI increases with age and is higher in persons with cardiovascular disease states. A lower value indicates a preferable state of arterial stiffness.
8. Hippocampal Volume [ Time Frame: Baseline, Month 12 ]
   Structural MRI images were acquired in order to assess hippocampal volume. Decreased hippocampal volume suggests neurodegenerative changes
9. Vasoreactivity [ Time Frame: Month 12 ]
   Cerebrovascular reactivity (CVR) is assessed with blood oxygenation level-dependent (BOLD) MRI. Vasoreactivity (VR) is the degree of change in BOLD signal relative to change in end tidal CO2. CVR is an indicator of microvascular function (higher indicates better function)
10. Global Standardized Uptake Value Ratio (SUVR) of (11)C-Pittsburgh Compound B ((11)C-PiB) [ Time Frame: Baseline, 12 Months ]
    In-vivo amyloid imaging with positron emission tomography (PET) was conducted after intravenous administration of 15±1.5 millicurie (mCi) of the radiotracer (11)C-PiB. SUVR is a ratio of PET uptake measured in the brain region of interest and a disease free reference region. A higher SUVR is an indication of increased PET radiotracer uptake and worsening disease.
11. Global Standardized Uptake Value Ratio (SUVR) of [18F]T807 [ Time Frame: Baseline, 12 Months ]
    In-vivo tau-PET imaging was conducted using the radiotracer [18F]T807. SUVR is a ratio of PET uptake measured in the brain region of interest and a disease free reference region. A higher SUVR is an indication of increased PET radiotracer uptake and worsening disease.
12. 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.
13. EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) Toolbox Composite Score [ Time Frame: Baseline, Month 6, Month 12 ]
    The EXAMINER toolbox 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). A composite score is calculated where scores range from -1 to +1 and higher are reflective of better executive function.
14. Hopkins Verbal Learning Test (HVLT) Delayed Recall Score [ Time Frame: Baseline, Month 6, 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.
15. Trail Making Test (TMT) Part B [ Time Frame: Baseline, Month 6, 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.
16. Trail Making Test (TMT) Part B - A [ Time Frame: Baseline, Month 6, Month 12 ]
    In Parts A and B of the TMT, participants connect circles labeled with numbers, in ascending order. The score is the amount of time (in seconds) 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 (Part B-A, in seconds) provides a more accurate assessment of executive function. A lower score indicates greater executive function.

Eligibility Criteria

• 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 cerebrospinal fluid (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 lumbar puncture 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

Contacts and Locations

Locations

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

• Principal Investigator: Ihab Hajjar, MD; Emory University

  Study Documents (Full-Text)

Documents provided by Ihab Hajjar, Emory University:

Study Protocol and Statistical Analysis Plan  [PDF] March 23, 2020

Informed Consent Form  [PDF] February 15, 2019

More Information

• 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
• Results First Posted: September 29, 2022
• Last Update Posted: December 1, 2022
• Last Verified: November 2022

• 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; hypertension medication; Mild Cognitive impairment; Amyloid Beta

Additional relevant MeSH terms:

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; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Molecular Mechanisms of Pharmacological Action