Mild Cognitive Impairment
Conditions
Keywords
Alzheimer's disease, hypertension medication, Mild Cognitive impairment, Amyloid Beta
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.
Interventions
DRUGPlacebo
A matched placebo will be given once daily for 12 months.
DRUGCandesartan
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.
Sponsors
National Institute on Aging (NIA)
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Hypotensive Episode | 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. |
| Number of Participants With Symptoms of Hypotension | 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. |
| Number of Participants With Hypotensive Episodes and Symptoms | Up to Month 12 | The number of participants with reported episodes hypotension as well as symptoms of hypotension. |
| Number of Participants With Elevated Serum Creatinine | 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. |
| Number of Participants With Hyperkalemia | 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. |
| Number of Participants Discontinuing Study Medication | Up to Month 12 | The number of participants who discontinued the study medication is presented here. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Augmentation Index (AI) | 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. |
| Hippocampal Volume | Baseline, Month 12 | Structural MRI images were acquired in order to assess hippocampal volume. Decreased hippocampal volume suggests neurodegenerative changes |
| Vasoreactivity | 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) |
| Global Standardized Uptake Value Ratio (SUVR) of (11)C-Pittsburgh Compound B ((11)C-PiB) | 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. |
| Global Standardized Uptake Value Ratio (SUVR) of [18F]T807 | 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. |
| Cerebrospinal Fluid (CSF) Total Tau Levels | 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. |
| EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) Toolbox Composite Score | 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. |
| Hopkins Verbal Learning Test (HVLT) Delayed Recall Score | 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. |
| Trail Making Test (TMT) Part B | 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. |
| Trail Making Test (TMT) Part B - A | 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. |
| Clinical Dementia Rating (CDR) Score | 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. |
| Cerebrospinal Fluid (CSF) of Tau Phosphorylated at Threonine 181 (p-tau181) Levels | 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. |
| Cerebrospinal Fluid (CSF) Amyloid Aβ42 Levels | 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. |
| Cerebrospinal Fluid (CSF) Amyloid Aβ40 Levels | 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. |
| Cerebrospinal Fluid (CSF) Amyloid Aβ42/Aβ40 Levels | Baseline, Month 12 | CSF Aβ42/Aβ40 levels were analyzed from CSF samples obtained via lumbar puncture. A lower ratio indicates worsening disease. |
| Pulse Wave Velocity (PWV) | 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. |
Countries
United States
Participant flow
Recruitment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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). | 38 |
| Placebo Participants receiving a placebo to match candesartan once a day orally for 12 months. | 39 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Candesartan |
|---|---|---|---|
| Age, Continuous | 69.5 years STANDARD_DEVIATION 8.5 | 68.1 years STANDARD_DEVIATION 8.5 | 66.7 years STANDARD_DEVIATION 8.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 75 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Montreal Cognitive Assessment (MoCA) Score | 20.7 score on a scale STANDARD_DEVIATION 2.7 | 20.8 score on a scale STANDARD_DEVIATION 3.3 | 20.9 score on a scale STANDARD_DEVIATION 3.9 |
| Number of Participants Taking Cholinesterase inhibitors or Memantine | 19 Participants | 37 Participants | 18 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 15 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 32 Participants | 62 Participants | 30 Participants |
| Region of Enrollment United States | 39 Participants | 77 Participants | 38 Participants |
| Sex: Female, Male Female | 25 Participants | 48 Participants | 23 Participants |
| Sex: Female, Male Male | 14 Participants | 29 Participants | 15 Participants |
| Sitting Diastolic Blood Pressure | 69.8 mmHg STANDARD_DEVIATION 10.1 | 68.8 mmHg STANDARD_DEVIATION 10.4 | 67.9 mmHg STANDARD_DEVIATION 9.9 |
| Sitting Heart Rate | 67.3 beats per minute STANDARD_DEVIATION 11.5 | 66.8 beats per minute STANDARD_DEVIATION 11.2 | 66.3 beats per minute STANDARD_DEVIATION 11.1 |
| Sitting Systolic Blood Pressure | 126.7 mmHg STANDARD_DEVIATION 13.2 | 125.4 mmHg STANDARD_DEVIATION 13.5 | 124.7 mmHg STANDARD_DEVIATION 13.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 38 | 0 / 39 |
| other Total, other adverse events | 20 / 38 | 17 / 39 |
| serious Total, serious adverse events | 0 / 38 | 0 / 39 |
Outcome results
Primary
Number of Participants Discontinuing Study Medication
The number of participants who discontinued the study medication is presented here.
Time frame: Up to Month 12
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Candesartan | Number of Participants Discontinuing Study Medication | 0 Participants |
| Placebo | Number of Participants Discontinuing Study Medication | 1 Participants |
Primary
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.
Time frame: Up to Month 12
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Candesartan | Number of Participants With a Hypotensive Episode | 16 Participants |
| Placebo | Number of Participants With a Hypotensive Episode | 4 Participants |
Primary
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.
Time frame: Up to Month 12
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Candesartan | Number of Participants With Elevated Serum Creatinine | 0 Participants |
| Placebo | Number of Participants With Elevated Serum Creatinine | 0 Participants |
Primary
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.
Time frame: Up to Month 12
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Candesartan | Number of Participants With Hyperkalemia | 0 Participants |
| Placebo | Number of Participants With Hyperkalemia | 1 Participants |
Primary
Number of Participants With Hypotensive Episodes and Symptoms
The number of participants with reported episodes hypotension as well as symptoms of hypotension.
Time frame: Up to Month 12
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Candesartan | Number of Participants With Hypotensive Episodes and Symptoms | 4 Participants |
| Placebo | Number of Participants With Hypotensive Episodes and Symptoms | 1 Participants |
Primary
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.
Time frame: Up to Month 12
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Candesartan | Number of Participants With Symptoms of Hypotension | 7 Participants |
| Placebo | Number of Participants With Symptoms of Hypotension | 10 Participants |
Secondary
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.
Time frame: Baseline, Month 12
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Candesartan | Augmentation Index (AI) | Baseline | 29.95 percentage of arterial stiffness |
| Candesartan | Augmentation Index (AI) | Month 12 | 28.36 percentage of arterial stiffness |
| Placebo | Augmentation Index (AI) | Baseline | 31.22 percentage of arterial stiffness |
| Placebo | Augmentation Index (AI) | Month 12 | 26.66 percentage of arterial stiffness |
Secondary
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.
Time frame: Baseline, Month 12
Population: This analysis includes participants who had CSF samples collected.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Candesartan | Cerebrospinal Fluid (CSF) Amyloid Aβ40 Levels | Baseline Aβ40 | 11624.00 pg/ml | Standard Error 625.86 |
| Candesartan | Cerebrospinal Fluid (CSF) Amyloid Aβ40 Levels | Month 12 Aβ40 | 11769.00 pg/ml | Standard Error 571.54 |
| Placebo | Cerebrospinal Fluid (CSF) Amyloid Aβ40 Levels | Baseline Aβ40 | 10802.00 pg/ml | Standard Error 623.82 |
| Placebo | Cerebrospinal Fluid (CSF) Amyloid Aβ40 Levels | Month 12 Aβ40 | 9735.00 pg/ml | Standard Error 573.74 |
Secondary
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.
Time frame: Baseline, Month 12
Population: This analysis includes participants who had CSF samples collected.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Candesartan | Cerebrospinal Fluid (CSF) Amyloid Aβ42/Aβ40 Levels | Baseline Aβ42/Aβ40 ratio | 0.049 Ratio | Standard Error 0.003 |
| Candesartan | Cerebrospinal Fluid (CSF) Amyloid Aβ42/Aβ40 Levels | Month 12 Aβ42/Aβ40 ratio | 0.050 Ratio | Standard Error 0.003 |
| Placebo | Cerebrospinal Fluid (CSF) Amyloid Aβ42/Aβ40 Levels | Baseline Aβ42/Aβ40 ratio | 0.052 Ratio | Standard Error 0.003 |
| Placebo | Cerebrospinal Fluid (CSF) Amyloid Aβ42/Aβ40 Levels | Month 12 Aβ42/Aβ40 ratio | 0.051 Ratio | Standard Error 0.003 |
Secondary
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.
Time frame: Baseline, Month 12
Population: This analysis includes participants who had CSF samples collected.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Candesartan | Cerebrospinal Fluid (CSF) Amyloid Aβ42 Levels | Baseline Aβ42 | 554.80 pg/ml | Standard Error 34.09 |
| Candesartan | Cerebrospinal Fluid (CSF) Amyloid Aβ42 Levels | Month 12 Aβ42 | 557.60 pg/ml | Standard Error 27.32 |
| Placebo | Cerebrospinal Fluid (CSF) Amyloid Aβ42 Levels | Baseline Aβ42 | 523.03 pg/ml | Standard Error 33.98 |
| Placebo | Cerebrospinal Fluid (CSF) Amyloid Aβ42 Levels | Month 12 Aβ42 | 476.32 pg/ml | Standard Error 27.43 |
Secondary
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.
Time frame: Baseline, Month 12
Population: This analysis includes participants who had CSF samples collected.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Candesartan | Cerebrospinal Fluid (CSF) of Tau Phosphorylated at Threonine 181 (p-tau181) Levels | Baseline p-tau | 100.29 pg/ml | Standard Error 9.09 |
| Candesartan | Cerebrospinal Fluid (CSF) of Tau Phosphorylated at Threonine 181 (p-tau181) Levels | Month 12 p-tau | 88.52 pg/ml | Standard Error 8.58 |
| Placebo | Cerebrospinal Fluid (CSF) of Tau Phosphorylated at Threonine 181 (p-tau181) Levels | Baseline p-tau | 81.58 pg/ml | Standard Error 9.07 |
| Placebo | Cerebrospinal Fluid (CSF) of Tau Phosphorylated at Threonine 181 (p-tau181) Levels | Month 12 p-tau | 68.49 pg/ml | Standard Error 8.59 |
Secondary
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.
Time frame: Baseline, Month 12
Population: This analysis includes participants who had CSF samples collected.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Candesartan | Cerebrospinal Fluid (CSF) Total Tau Levels | Baseline Total Tau | 638.31 Picograms per milliliter (pg/ml) | Standard Error 53.61 |
| Candesartan | Cerebrospinal Fluid (CSF) Total Tau Levels | Month 12 Total Tau | 571.96 Picograms per milliliter (pg/ml) | Standard Error 52.89 |
| Placebo | Cerebrospinal Fluid (CSF) Total Tau Levels | Baseline Total Tau | 529.04 Picograms per milliliter (pg/ml) | Standard Error 53.5 |
| Placebo | Cerebrospinal Fluid (CSF) Total Tau Levels | Month 12 Total Tau | 441.25 Picograms per milliliter (pg/ml) | Standard Error 53.02 |
Secondary
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.
Time frame: Baseline, Month 12
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Candesartan | Clinical Dementia Rating (CDR) Score | Baseline | 1.86 score on a scale | Standard Error 0.15 |
| Candesartan | Clinical Dementia Rating (CDR) Score | Month 12 | 2.18 score on a scale | Standard Error 0.28 |
| Placebo | Clinical Dementia Rating (CDR) Score | Month 12 | 2.21 score on a scale | Standard Error 0.27 |
| Placebo | Clinical Dementia Rating (CDR) Score | Baseline | 1.85 score on a scale | Standard Error 0.14 |
Secondary
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.
Time frame: Baseline, Month 6, Month 12
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Candesartan | 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 |
| Candesartan | 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 |
| Candesartan | 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 |
| Placebo | EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) Toolbox Composite Score | Baseline | -0.05 score on a scale | Standard Error 0.11 |
| Placebo | EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) Toolbox Composite Score | Month 6 | 0.04 score on a scale | Standard Error 0.14 |
| Placebo | EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) Toolbox Composite Score | Month 12 | -0.06 score on a scale | Standard Error 0.14 |
Secondary
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.
Time frame: Baseline, 12 Months
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Candesartan | Global Standardized Uptake Value Ratio (SUVR) of (11)C-Pittsburgh Compound B ((11)C-PiB) | Baseline | 1.32 Ratio of target and reference regions |
| Candesartan | 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 |
| Placebo | Global Standardized Uptake Value Ratio (SUVR) of (11)C-Pittsburgh Compound B ((11)C-PiB) | Baseline | 1.42 Ratio of target and reference regions |
| Placebo | Global Standardized Uptake Value Ratio (SUVR) of (11)C-Pittsburgh Compound B ((11)C-PiB) | Month 12 | 1.46 Ratio of target and reference regions |
Secondary
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.
Time frame: Baseline, 12 Months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Candesartan | Global Standardized Uptake Value Ratio (SUVR) of [18F]T807 | Baseline | 1.33 Ratio of target and reference regions | Standard Error 0.05 |
| Candesartan | Global Standardized Uptake Value Ratio (SUVR) of [18F]T807 | Month 12 | 1.34 Ratio of target and reference regions | Standard Error 0.06 |
| Placebo | Global Standardized Uptake Value Ratio (SUVR) of [18F]T807 | Baseline | 1.36 Ratio of target and reference regions | Standard Error 0.04 |
| Placebo | Global Standardized Uptake Value Ratio (SUVR) of [18F]T807 | Month 12 | 1.34 Ratio of target and reference regions | Standard Error 0.05 |
Secondary
Hippocampal Volume
Structural MRI images were acquired in order to assess hippocampal volume. Decreased hippocampal volume suggests neurodegenerative changes
Time frame: Baseline, Month 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Candesartan | Hippocampal Volume | Baseline | 6949.82 mm^3 | Standard Error 151.66 |
| Candesartan | Hippocampal Volume | Month 12 | 6761.12 mm^3 | Standard Error 151.42 |
| Placebo | Hippocampal Volume | Baseline | 6662.21 mm^3 | Standard Error 151.49 |
| Placebo | Hippocampal Volume | Month 12 | 6521.30 mm^3 | Standard Error 152.14 |
Secondary
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.
Time frame: Baseline, Month 6, Month 12
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Candesartan | Hopkins Verbal Learning Test (HVLT) Delayed Recall Score | Baseline | 4.83 number of words recalled | Standard Error 0.53 |
| Candesartan | Hopkins Verbal Learning Test (HVLT) Delayed Recall Score | Month 6 | 5.40 number of words recalled | Standard Error 0.52 |
| Candesartan | Hopkins Verbal Learning Test (HVLT) Delayed Recall Score | Month 12 | 5.10 number of words recalled | Standard Error 0.52 |
| Placebo | Hopkins Verbal Learning Test (HVLT) Delayed Recall Score | Baseline | 5.29 number of words recalled | Standard Error 0.52 |
| Placebo | Hopkins Verbal Learning Test (HVLT) Delayed Recall Score | Month 6 | 5.08 number of words recalled | Standard Error 0.51 |
| Placebo | Hopkins Verbal Learning Test (HVLT) Delayed Recall Score | Month 12 | 5.39 number of words recalled | Standard Error 0.51 |
Secondary
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.
Time frame: Baseline, Month 12
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Candesartan | Pulse Wave Velocity (PWV) | Baseline | 7.81 m/s |
| Candesartan | Pulse Wave Velocity (PWV) | Month 12 | 7.71 m/s |
| Placebo | Pulse Wave Velocity (PWV) | Baseline | 8.73 m/s |
| Placebo | Pulse Wave Velocity (PWV) | Month 12 | 8.14 m/s |
Secondary
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.
Time frame: Baseline, Month 6, Month 12
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Candesartan | Trail Making Test (TMT) Part B | Baseline | 149.44 seconds | Standard Error 14 |
| Candesartan | Trail Making Test (TMT) Part B | Month 6 | 122.04 seconds | Standard Error 13.49 |
| Candesartan | Trail Making Test (TMT) Part B | Month 12 | 148.06 seconds | Standard Error 16.01 |
| Placebo | Trail Making Test (TMT) Part B | Baseline | 142.93 seconds | Standard Error 13.88 |
| Placebo | Trail Making Test (TMT) Part B | Month 6 | 152.91 seconds | Standard Error 13.35 |
| Placebo | Trail Making Test (TMT) Part B | Month 12 | 152.96 seconds | Standard Error 15.65 |
Secondary
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.
Time frame: Baseline, Month 6, Month 12
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Candesartan | Trail Making Test (TMT) Part B - A | Baseline | 108.08 seconds | Standard Error 14.06 |
| Candesartan | Trail Making Test (TMT) Part B - A | Month 6 | 81.59 seconds | Standard Error 11.56 |
| Candesartan | Trail Making Test (TMT) Part B - A | Month 12 | 103.64 seconds | Standard Error 13.9 |
| Placebo | Trail Making Test (TMT) Part B - A | Baseline | 91.56 seconds | Standard Error 13.87 |
| Placebo | Trail Making Test (TMT) Part B - A | Month 6 | 102.38 seconds | Standard Error 11.45 |
| Placebo | Trail Making Test (TMT) Part B - A | Month 12 | 103.50 seconds | Standard Error 13.52 |
Secondary
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)
Time frame: Month 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Candesartan | Vasoreactivity | 0.27 (ml/100g/min)/mmHg |
| Placebo | Vasoreactivity | -0.17 (ml/100g/min)/mmHg |