Trial Outcomes & Findings for Candesartan's Effects on Alzheimer's Disease And Related Biomarkers (NCT NCT02646982)

NCT ID: NCT02646982

Last Updated: 2022-12-01

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 77 participants
• Primary outcome timeframe: Up to Month 12
• Results posted on: 2022-12-01

Participant Flow

Participants were recruited from the Wesley Woods Health Center of Emory Healthcare in Atlanta, Georgia, USA. Participant enrollment began June 30, 2016 and all follow up was complete by August 17, 2020.

Participant milestones

Measure	Candesartan Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo Participants receiving a placebo to match candesartan once a day orally for 12 months.
Overall Study STARTED	38	39
Overall Study COMPLETED	35	37
Overall Study NOT COMPLETED	3	2

Reasons for withdrawal

Measure	Candesartan Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo Participants receiving a placebo to match candesartan once a day orally for 12 months.
Overall Study Adverse Event	1	1
Overall Study Withdrawal by Subject	2	1

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Candesartan n=38 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=39 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.	Total n=77 Participants Total of all reporting groups
Age, Continuous	66.7 years STANDARD_DEVIATION 8.4 • n=93 Participants	69.5 years STANDARD_DEVIATION 8.5 • n=4 Participants	68.1 years STANDARD_DEVIATION 8.5 • n=27 Participants
Sex: Female, Male Female	23 Participants n=93 Participants	25 Participants n=4 Participants	48 Participants n=27 Participants
Sex: Female, Male Male	15 Participants n=93 Participants	14 Participants n=4 Participants	29 Participants n=27 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=93 Participants	0 Participants n=4 Participants	2 Participants n=27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	36 Participants n=93 Participants	39 Participants n=4 Participants	75 Participants n=27 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Black or African American	8 Participants n=93 Participants	7 Participants n=4 Participants	15 Participants n=27 Participants
Race (NIH/OMB) White	30 Participants n=93 Participants	32 Participants n=4 Participants	62 Participants n=27 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Region of Enrollment United States	38 Participants n=93 Participants	39 Participants n=4 Participants	77 Participants n=27 Participants
Sitting Systolic Blood Pressure	124.7 mmHg STANDARD_DEVIATION 13.6 • n=93 Participants	126.7 mmHg STANDARD_DEVIATION 13.2 • n=4 Participants	125.4 mmHg STANDARD_DEVIATION 13.5 • n=27 Participants
Sitting Diastolic Blood Pressure	67.9 mmHg STANDARD_DEVIATION 9.9 • n=93 Participants	69.8 mmHg STANDARD_DEVIATION 10.1 • n=4 Participants	68.8 mmHg STANDARD_DEVIATION 10.4 • n=27 Participants
Sitting Heart Rate	66.3 beats per minute STANDARD_DEVIATION 11.1 • n=93 Participants	67.3 beats per minute STANDARD_DEVIATION 11.5 • n=4 Participants	66.8 beats per minute STANDARD_DEVIATION 11.2 • n=27 Participants
Montreal Cognitive Assessment (MoCA) Score	20.9 score on a scale STANDARD_DEVIATION 3.9 • n=93 Participants	20.7 score on a scale STANDARD_DEVIATION 2.7 • n=4 Participants	20.8 score on a scale STANDARD_DEVIATION 3.3 • n=27 Participants
Number of Participants Taking Cholinesterase inhibitors or Memantine	18 Participants n=93 Participants	19 Participants n=4 Participants	37 Participants n=27 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Candesartan n=38 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=39 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Number of Participants With a Hypotensive Episode	16 Participants	4 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Candesartan n=38 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=39 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Number of Participants With Symptoms of Hypotension	7 Participants	10 Participants

PRIMARY outcome

Timeframe: Up to Month 12

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

Outcome measures

Measure	Candesartan n=38 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=39 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Number of Participants With Hypotensive Episodes and Symptoms	4 Participants	1 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Candesartan n=38 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=39 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Number of Participants With Elevated Serum Creatinine	0 Participants	0 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Candesartan n=38 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=39 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Number of Participants With Hyperkalemia	0 Participants	1 Participants

PRIMARY outcome

Timeframe: Up to Month 12

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

Outcome measures

Measure	Candesartan n=38 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=39 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Number of Participants Discontinuing Study Medication	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Baseline, Month 12

Population: This analysis includes participants who had CSF samples collected.

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.

Outcome measures

Measure	Candesartan n=36 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=37 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Cerebrospinal Fluid (CSF) Total Tau Levels Baseline Total Tau	638.31 Picograms per milliliter (pg/ml) Standard Error 53.61	529.04 Picograms per milliliter (pg/ml) Standard Error 53.50
Cerebrospinal Fluid (CSF) Total Tau Levels Month 12 Total Tau	571.96 Picograms per milliliter (pg/ml) Standard Error 52.89	441.25 Picograms per milliliter (pg/ml) Standard Error 53.02

SECONDARY outcome

Timeframe: Baseline, Month 12

Population: This analysis includes participants who had CSF samples collected.

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.

Outcome measures

Measure	Candesartan n=36 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=37 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Cerebrospinal Fluid (CSF) of Tau Phosphorylated at Threonine 181 (p-tau181) Levels Baseline p-tau	100.29 pg/ml Standard Error 9.09	81.58 pg/ml Standard Error 9.07
Cerebrospinal Fluid (CSF) of Tau Phosphorylated at Threonine 181 (p-tau181) Levels Month 12 p-tau	88.52 pg/ml Standard Error 8.58	68.49 pg/ml Standard Error 8.59

SECONDARY outcome

Timeframe: Baseline, Month 12

Population: This analysis includes participants who had CSF samples collected.

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.

Outcome measures

Measure	Candesartan n=36 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=37 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Cerebrospinal Fluid (CSF) Amyloid Aβ42 Levels Baseline Aβ42	554.80 pg/ml Standard Error 34.09	523.03 pg/ml Standard Error 33.98
Cerebrospinal Fluid (CSF) Amyloid Aβ42 Levels Month 12 Aβ42	557.60 pg/ml Standard Error 27.32	476.32 pg/ml Standard Error 27.43

SECONDARY outcome

Timeframe: Baseline, Month 12

Population: This analysis includes participants who had CSF samples collected.

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

Outcome measures

Measure	Candesartan n=36 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=37 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Cerebrospinal Fluid (CSF) Amyloid Aβ40 Levels Baseline Aβ40	11624.00 pg/ml Standard Error 625.86	10802.00 pg/ml Standard Error 623.82
Cerebrospinal Fluid (CSF) Amyloid Aβ40 Levels Month 12 Aβ40	11769.00 pg/ml Standard Error 571.54	9735.00 pg/ml Standard Error 573.74

SECONDARY outcome

Timeframe: Baseline, Month 12

Population: This analysis includes participants who had CSF samples collected.

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

Outcome measures

Measure	Candesartan n=36 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=37 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Cerebrospinal Fluid (CSF) Amyloid Aβ42/Aβ40 Levels Baseline Aβ42/Aβ40 ratio	0.049 Ratio Standard Error 0.003	0.052 Ratio Standard Error 0.003
Cerebrospinal Fluid (CSF) Amyloid Aβ42/Aβ40 Levels Month 12 Aβ42/Aβ40 ratio	0.050 Ratio Standard Error 0.003	0.051 Ratio Standard Error 0.003

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Candesartan n=38 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=39 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Pulse Wave Velocity (PWV) Baseline	7.81 m/s Interval 7.12 to 8.51	8.73 m/s Interval 8.05 to 9.4
Pulse Wave Velocity (PWV) Month 12	7.71 m/s Interval 7.03 to 8.4	8.14 m/s Interval 7.47 to 8.81

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Candesartan n=38 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=39 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Augmentation Index (AI) Baseline	29.95 percentage of arterial stiffness Interval 25.92 to 33.98	31.22 percentage of arterial stiffness Interval 27.24 to 35.2
Augmentation Index (AI) Month 12	28.36 percentage of arterial stiffness Interval 24.45 to 32.27	26.66 percentage of arterial stiffness Interval 22.81 to 30.51

SECONDARY outcome

Timeframe: Baseline, Month 12

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

Outcome measures

Measure	Candesartan n=38 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=39 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Hippocampal Volume Baseline	6949.82 mm^3 Standard Error 151.66	6662.21 mm^3 Standard Error 151.49
Hippocampal Volume Month 12	6761.12 mm^3 Standard Error 151.42	6521.30 mm^3 Standard Error 152.14

SECONDARY outcome

Timeframe: 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)

Outcome measures

Measure	Candesartan n=38 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=39 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Vasoreactivity	0.27 (ml/100g/min)/mmHg Interval 0.006 to 0.53	-0.17 (ml/100g/min)/mmHg Interval -0.42 to 0.08

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Candesartan n=38 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=39 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Global Standardized Uptake Value Ratio (SUVR) of (11)C-Pittsburgh Compound B ((11)C-PiB) Baseline	1.32 Ratio of target and reference regions Interval 1.23 to 1.4	1.42 Ratio of target and reference regions Interval 1.32 to 1.52
Global Standardized Uptake Value Ratio (SUVR) of (11)C-Pittsburgh Compound B ((11)C-PiB) Month 12	1.34 Ratio of target and reference regions Interval 1.23 to 1.45	1.46 Ratio of target and reference regions Interval 1.34 to 1.59

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Candesartan n=38 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=39 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Global Standardized Uptake Value Ratio (SUVR) of [18F]T807 Baseline	1.33 Ratio of target and reference regions Standard Error 0.05	1.36 Ratio of target and reference regions Standard Error 0.04
Global Standardized Uptake Value Ratio (SUVR) of [18F]T807 Month 12	1.34 Ratio of target and reference regions Standard Error 0.06	1.34 Ratio of target and reference regions Standard Error 0.05

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Candesartan n=38 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=39 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Clinical Dementia Rating (CDR) Score Baseline	1.86 score on a scale Standard Error 0.15	1.85 score on a scale Standard Error 0.14
Clinical Dementia Rating (CDR) Score Month 12	2.18 score on a scale Standard Error 0.28	2.21 score on a scale Standard Error 0.27

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Candesartan n=38 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=39 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) Toolbox Composite Score Baseline	0.03 score on a scale Standard Error 0.11	-0.05 score on a scale Standard Error 0.11
EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) Toolbox Composite Score Month 6	0.18 score on a scale Standard Error 0.14	0.04 score on a scale Standard Error 0.14
EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) Toolbox Composite Score Month 12	0.07 score on a scale Standard Error 0.14	-0.06 score on a scale Standard Error 0.14

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Candesartan n=38 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=39 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Hopkins Verbal Learning Test (HVLT) Delayed Recall Score Baseline	4.83 number of words recalled Standard Error 0.53	5.29 number of words recalled Standard Error 0.52
Hopkins Verbal Learning Test (HVLT) Delayed Recall Score Month 6	5.40 number of words recalled Standard Error 0.52	5.08 number of words recalled Standard Error 0.51
Hopkins Verbal Learning Test (HVLT) Delayed Recall Score Month 12	5.10 number of words recalled Standard Error 0.52	5.39 number of words recalled Standard Error 0.51

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Candesartan n=38 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=39 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Trail Making Test (TMT) Part B Baseline	149.44 seconds Standard Error 14.00	142.93 seconds Standard Error 13.88
Trail Making Test (TMT) Part B Month 6	122.04 seconds Standard Error 13.49	152.91 seconds Standard Error 13.35
Trail Making Test (TMT) Part B Month 12	148.06 seconds Standard Error 16.01	152.96 seconds Standard Error 15.65

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Candesartan n=38 Participants Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=39 Participants Participants receiving a placebo to match candesartan once a day orally for 12 months.
Trail Making Test (TMT) Part B - A Baseline	108.08 seconds Standard Error 14.06	91.56 seconds Standard Error 13.87
Trail Making Test (TMT) Part B - A Month 6	81.59 seconds Standard Error 11.56	102.38 seconds Standard Error 11.45
Trail Making Test (TMT) Part B - A Month 12	103.64 seconds Standard Error 13.90	103.50 seconds Standard Error 13.52

Adverse Events

Candesartan

Serious events: 0 serious events

Other events: 20 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 17 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Candesartan n=38 participants at risk Participants receiving candesartan given orally once a day in a stepwise manner. Participants were initiated on 8 mg candesartan. The dose was increased in 2 week increments to 16 mg and 32 mg, as tolerated. The highest achievable dose was the Maximal Tolerated Dose (MTD) and the participant received this dose for the remaining duration of the study (12 months total).	Placebo n=39 participants at risk Participants receiving a placebo to match candesartan once a day orally for 12 months.
General disorders Dizziness	15.8% 6/38 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).	12.8% 5/39 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).
General disorders Fatigue, tiredness, weakness	10.5% 4/38 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).	10.3% 4/39 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).
General disorders Headache	5.3% 2/38 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).	12.8% 5/39 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).
Musculoskeletal and connective tissue disorders Back pain	5.3% 2/38 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).	0.00% 0/39 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).
General disorders Lightheadedness	2.6% 1/38 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).	2.6% 1/39 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).
Skin and subcutaneous tissue disorders Rash	2.6% 1/38 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).	0.00% 0/39 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).
Injury, poisoning and procedural complications Fall	2.6% 1/38 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).	0.00% 0/39 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).
General disorders Pain at back of head	2.6% 1/38 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).	0.00% 0/39 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).
Psychiatric disorders Panic attack	2.6% 1/38 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).	0.00% 0/39 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).
General disorders Vasovagal syncope	2.6% 1/38 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).	0.00% 0/39 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).
Musculoskeletal and connective tissue disorders Joint pain	0.00% 0/38 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).	2.6% 1/39 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).
General disorders Runny nose	0.00% 0/38 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).	2.6% 1/39 • Information on adverse events was collected for the duration of each participant's study enrollment, from the time that individuals gave consent to participate through their final study visit (up to 12 months).

Additional Information

Ihab Hajjar, MD

University of Texas Southwestern

Phone: 214-645-9533

Email: ihabhajjar@emory.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place