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

Primary Purpose

Mild Cognitive Impairment

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Placebo

Candesartan

About this trial

This is an interventional treatment trial for Mild Cognitive Impairment focused on measuring Alzheimer's disease, hypertension medication, Mild Cognitive impairment, Amyloid Beta

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Emory University
Wesley Woods Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Candesartan

Placebo

Arm Description

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).

Participants will receive a matched placebo once a day orally for 12 months.

Outcomes

Primary Outcome Measures

Number of Participants With a Hypotensive Episode

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.

Number of Participants With Symptoms of Hypotension

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.

Number of Participants With Hypotensive Episodes and Symptoms

The number of participants with reported episodes hypotension as well as symptoms of hypotension.

Number of Participants With Elevated Serum Creatinine

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.

Number of Participants With Hyperkalemia

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.

Number of Participants Discontinuing Study Medication

The number of participants who discontinued the study medication is presented here.

Secondary Outcome Measures

Cerebrospinal Fluid (CSF) Total Tau Levels

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.

Cerebrospinal Fluid (CSF) of Tau Phosphorylated at Threonine 181 (p-tau181) Levels

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.

Cerebrospinal Fluid (CSF) Amyloid Aβ42 Levels

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.

Cerebrospinal Fluid (CSF) Amyloid Aβ40 Levels

CSF Aβ40 levels were analyzed from CSF samples obtained via lumbar puncture. Lower values indicate worsening disease and an increased brain accumulation of amyloid.

Cerebrospinal Fluid (CSF) Amyloid Aβ42/Aβ40 Levels

CSF Aβ42/Aβ40 levels were analyzed from CSF samples obtained via lumbar puncture. A lower ratio indicates worsening disease.

Pulse Wave Velocity (PWV)

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.

Augmentation Index (AI)

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.

Hippocampal Volume

Structural MRI images were acquired in order to assess hippocampal volume. Decreased hippocampal volume suggests neurodegenerative changes

Vasoreactivity

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)

Global Standardized Uptake Value Ratio (SUVR) of (11)C-Pittsburgh Compound B ((11)C-PiB)

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.

Global Standardized Uptake Value Ratio (SUVR) of [18F]T807

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.

Clinical Dementia Rating (CDR) Score

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.

EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) Toolbox Composite Score

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.

Hopkins Verbal Learning Test (HVLT) Delayed Recall Score

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.

Trail Making Test (TMT) Part B

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.

Trail Making Test (TMT) Part B - A

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.

Full Information

NCT ID

NCT02646982

First Posted

January 4, 2016

Last Updated

November 29, 2022

Sponsor

Emory University

Collaborators

National Institute on Aging (NIA)

1. Study Identification

Unique Protocol Identification Number

NCT02646982

Brief Title

Candesartan's Effects on Alzheimer's Disease And Related Biomarkers

Acronym

CEDAR

Official Title

Candesartan's Effects on Alzheimer's Disease And Related Biomarkers

Study Type

Interventional

2. Study Status

Record Verification Date

November 2022

Overall Recruitment Status

Completed

Study Start Date

June 30, 2016 (undefined)

Primary Completion Date

August 17, 2020 (Actual)

Study Completion Date

August 17, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Emory University

Collaborators

National Institute on Aging (NIA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Mild Cognitive Impairment

Keywords

Alzheimer's disease, hypertension medication, Mild Cognitive impairment, Amyloid Beta

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

77 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Candesartan

Arm Type

Experimental

Arm Description

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Participants will receive a matched placebo once a day orally for 12 months.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

A matched placebo will be given once daily for 12 months.

Intervention Type

Drug

Intervention Name(s)

Candesartan

Other Intervention Name(s)

Atacand

Intervention Description

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.

Primary Outcome Measure Information:

Title

Number of Participants With a Hypotensive Episode

Description

Time Frame

Up to Month 12

Title

Number of Participants With Symptoms of Hypotension

Description

Time Frame

Up to Month 12

Title

Number of Participants With Hypotensive Episodes and Symptoms

Description

The number of participants with reported episodes hypotension as well as symptoms of hypotension.

Time Frame

Up to Month 12

Title

Number of Participants With Elevated Serum Creatinine

Description

Time Frame

Up to Month 12

Title

Number of Participants With Hyperkalemia

Description

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.

Time Frame

Up to Month 12

Title

Number of Participants Discontinuing Study Medication

Description

The number of participants who discontinued the study medication is presented here.

Time Frame

Up to Month 12

Secondary Outcome Measure Information:

Title

Cerebrospinal Fluid (CSF) Total Tau Levels

Description

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.

Time Frame

Baseline, Month 12

Title

Cerebrospinal Fluid (CSF) of Tau Phosphorylated at Threonine 181 (p-tau181) Levels

Description

Time Frame

Baseline, Month 12

Title

Cerebrospinal Fluid (CSF) Amyloid Aβ42 Levels

Description

Time Frame

Baseline, Month 12

Title

Cerebrospinal Fluid (CSF) Amyloid Aβ40 Levels

Description

CSF Aβ40 levels were analyzed from CSF samples obtained via lumbar puncture. Lower values indicate worsening disease and an increased brain accumulation of amyloid.

Time Frame

Baseline, Month 12

Title

Cerebrospinal Fluid (CSF) Amyloid Aβ42/Aβ40 Levels

Description

CSF Aβ42/Aβ40 levels were analyzed from CSF samples obtained via lumbar puncture. A lower ratio indicates worsening disease.

Time Frame

Baseline, Month 12

Title

Pulse Wave Velocity (PWV)

Description

Time Frame

Baseline, Month 12

Title

Augmentation Index (AI)

Description

Time Frame

Baseline, Month 12

Title

Hippocampal Volume

Description

Structural MRI images were acquired in order to assess hippocampal volume. Decreased hippocampal volume suggests neurodegenerative changes

Time Frame

Baseline, Month 12

Title

Vasoreactivity

Description

Time Frame

Month 12

Title

Global Standardized Uptake Value Ratio (SUVR) of (11)C-Pittsburgh Compound B ((11)C-PiB)

Description

Time Frame

Baseline, 12 Months

Title

Global Standardized Uptake Value Ratio (SUVR) of [18F]T807

Description

Time Frame

Baseline, 12 Months

Title

Clinical Dementia Rating (CDR) Score

Description

Time Frame

Baseline, Month 12

Title

EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) Toolbox Composite Score

Description

Time Frame

Baseline, Month 6, Month 12

Title

Hopkins Verbal Learning Test (HVLT) Delayed Recall Score

Description

Time Frame

Baseline, Month 6, Month 12

Title

Trail Making Test (TMT) Part B

Description

Time Frame

Baseline, Month 6, Month 12

Title

Trail Making Test (TMT) Part B - A

Description

Time Frame

Baseline, Month 6, Month 12

10. Eligibility

Sex

All

Minimum Age & Unit of Time

50 Years

Accepts Healthy Volunteers

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ihab Hajjar, MD

Organizational Affiliation

Emory University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Emory University

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30322

Country

United States

Facility Name

Wesley Woods Center

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30329

Country

United States

12. IPD Sharing Statement

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Candesartan's Effects on Alzheimer's Disease And Related Biomarkers

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