Vascular Cognitive Impairment no Dementia
Conditions
Brief summary
This is a 24-week randomized, double-blind, placebo-controlled parallel group design study involving Vascular cognitive impairment-no dementia (VCIND) patients to evaluate the efficacy and safety of oral NAC supplementation (2,400 mg daily) as an add-on therapy to improve cognitive function in patients undergoing cardiac rehabilitation (CR). The CR program consists of a harmonized aerobic and resistance training in a supervised group setting. Eligible patients will be randomized to receive NAC (four 600 mg capsules given as 2 capsules in the morning and 2 capsules in the evening) or matching placebo capsules. The initial NAC dosage will be 600mg/day (one 600mg capsule in the morning) for the first week, followed by 1,200 mg/day (one 600 mg capsule in the morning, one 600mg capsule in the evening) for the second week, followed by 1,800 mg/day (two 600mg capsules in the morning, one 600mg capsule in the evening) for third week, followed by 2,400mg/day (two 600mg capsules in the morning, two 600mg capsules in the evening) for the following 21 weeks.
Interventions
DRUGN Acetylcysteine
Patients will be randomized to receive N Acetylcysteine (NAC) (four 600 mg capsules given as 2 capsules in the morning and 2 capsules in the evening). The initial NAC dosage will be 600mg/day (one 600mg capsule in the morning) for the first week, followed by 1,200 mg/day (one 600 mg capsule in the morning, one 600mg capsule in the evening) for the second week, followed by 1,800 mg/day (two 600mg capsules in the morning, one 600mg capsule in the evening) for third week, followed by 2,400mg/day (two 600mg capsules in the morning, two 600mg capsules in the evening) for the following 21 weeks.
OTHERPlacebo oral capsule
Patients will receive four placebo capsules (lactose-based filler) given as 2 capsules in the morning and 2 capsules in the evening, which will be prepared to mimic the weight of the experimental capsules.The initial placebo dosage will be 600mg/day (one 600mg capsule in the morning) for the first week, followed by 1,200 mg/day (one 600 mg capsule in the morning, one 600mg capsule in the evening) for the second week, followed by 1,800 mg/day (two 600mg capsules in the morning, one 600mg capsule in the evening) for third week, followed by 2,400mg/day (two 600mg capsules in the morning, two 600mg capsules in the evening) for the following 21 weeks.
Sponsors
Sunnybrook Health Sciences Centre
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
55 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Males or females aged 55-80 years. * MoCA score of less than 28. * Modest deficits (1 SD below population norm) in executive function, memory, processing speed, or working memory based on the 60-minute battery recommended by the NINDS-CSN. * Speaks and understands English. * Enrollment in the Cardiac Rehabilitation program at the University Health Network Toronto Rehabilitation Institute.
Exclusion criteria
* A history of stroke * A history of epilepsy * Uncontrolled asthma (requiring hospitalization or ER visit in the last 3 months by patient report) * Uncontrolled diabetes (clinical determination) * Severe hypo/hypertension (clinical determination) * Uncontrolled hypercholesterolemia (clinical determination) * Presence of significant medical illnesses (Severely disturbed liver function, Severely disturbed kidney function, Severely disturbed lung function, HIV, HBV and/or HCV infection, Malignant tumors) * A current neurological condition (Parkinson's disease, Multiple sclerosis, Significant traumatic brain injury) * Major psychiatric condition (Current major depressive disorder, Schizophrenia, Bipolar disorder, Substance use disorder (alcohol abuse, heavy smoking (20 cigarettes or more/day)) * Contraindication to MRI or MRS (e.g. metal in body, pacemaker). * Contraindication to NAC (documented allergy) or allergy to lactose. * Daily Nitroglycerin use. * Bleeding disorders (e.g. hemophilia, Thrombotic Thrombocytopenic Purpura) and/or elective surgery within 30 days. * Volunteers who currently participate in another pharmacological study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Executive Function | 6 months | Differences in executive function composite z scores between experimental and placebo groups at 6 months. Executive function will be based on the trail test B, phonemic fluency, and semantic fluency found in the 60-minute battery recommended by the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network (NINDS-CSN) harmonized standards. A Z-score was computed based on published age-matched norms, and a composite Z-score was calculated. Higher z score represents better cognitive function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Processing Speed | 6 months | Differences in processing speed composite z scores between experimental and placebo groups at 6 months. Processing speed will be based on the symbol digit modalities test found in the 60-minute battery recommended by the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network (NINDS-CSN) harmonized standards. A z-score was computed based on published age-matched norms. Higher z-score represents better cognitive function. |
| Change in Memory | 6 months | Differences in memory composite z scores between experimental and placebo groups at 6 months. Memory will be based on the Hopkins Verbal Learning Test found in the 60-minute battery recommended by the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network (NINDS-CSN) harmonized standards. A z-score was computed based on published age-matched norms. Higher z-scores represent better cognitive function. |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| N-acetylcysteine Participants randomized into the N-acetylcysteine arm will be receiving N-acetylcysteine for 24 weeks.
N Acetylcysteine: Patients will be randomized to receive N Acetylcysteine (NAC) (four 600 mg capsules given as 2 capsules in the morning and 2 capsules in the evening). The initial NAC dosage will be 600mg/day (one 600mg capsule in the morning) for the first week, followed by 1,200 mg/day (one 600 mg capsule in the morning, one 600mg capsule in the evening) for the second week, followed by 1,800 mg/day (two 600mg capsules in the morning, one 600mg capsule in the evening) for third week, followed by 2,400mg/day (two 600mg capsules in the morning, two 600mg capsules in the evening) for the following 21 weeks. | 29 |
| Placebo Participants randomized into the placebo arm will be receiving placebo for 24 weeks.
Placebo oral capsule: Patients will receive four placebo capsules (lactose-based filler) given as 2 capsules in the morning and 2 capsules in the evening, which will be prepared to mimic the weight of the experimental capsules.The initial placebo dosage will be 600mg/day (one 600mg capsule in the morning) for the first week, followed by 1,200 mg/day (one 600 mg capsule in the morning, one 600mg capsule in the evening) for the second week, followed by 1,800 mg/day (two 600mg capsules in the morning, one 600mg capsule in the evening) for third week, followed by 2,400mg/day (two 600mg capsules in the morning, two 600mg capsules in the evening) for the following 21 weeks. | 30 |
| Total | 59 |
Baseline characteristics
| Characteristic | N-acetylcysteine | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 67.1 years STANDARD_DEVIATION 8 | 68.0 years STANDARD_DEVIATION 7.5 | 67.6 years STANDARD_DEVIATION 7.7 |
| Executive Function | -0.54 z-score STANDARD_DEVIATION 0.68 | -0.48 z-score STANDARD_DEVIATION 0.48 | -0.52 z-score STANDARD_DEVIATION 0.58 |
| Race/Ethnicity, Customized Ethnicity Arab/Middle Eastern | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Ethnicity Asian/South Asian | 5 Participants | 7 Participants | 12 Participants |
| Race/Ethnicity, Customized Ethnicity Black/African American | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Ethnicity Caucasian/European | 19 Participants | 21 Participants | 40 Participants |
| Race/Ethnicity, Customized Ethnicity Other (mixed) | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Canada | 29 Participants | 30 Participants | 59 Participants |
| Sex: Female, Male Female | 12 Participants | 6 Participants | 18 Participants |
| Sex: Female, Male Male | 17 Participants | 24 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 30 |
| other Total, other adverse events | 21 / 29 | 20 / 30 |
| serious Total, serious adverse events | 0 / 29 | 0 / 30 |
Outcome results
Primary
Change in Executive Function
Differences in executive function composite z scores between experimental and placebo groups at 6 months. Executive function will be based on the trail test B, phonemic fluency, and semantic fluency found in the 60-minute battery recommended by the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network (NINDS-CSN) harmonized standards. A Z-score was computed based on published age-matched norms, and a composite Z-score was calculated. Higher z score represents better cognitive function.
Time frame: 6 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine | Change in Executive Function | 0.32 z-score |
| Placebo | Change in Executive Function | 0.36 z-score |
Secondary
Change in Memory
Differences in memory composite z scores between experimental and placebo groups at 6 months. Memory will be based on the Hopkins Verbal Learning Test found in the 60-minute battery recommended by the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network (NINDS-CSN) harmonized standards. A z-score was computed based on published age-matched norms. Higher z-scores represent better cognitive function.
Time frame: 6 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine | Change in Memory | 0.03 z-score |
| Placebo | Change in Memory | -0.10 z-score |
Secondary
Change in Processing Speed
Differences in processing speed composite z scores between experimental and placebo groups at 6 months. Processing speed will be based on the symbol digit modalities test found in the 60-minute battery recommended by the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network (NINDS-CSN) harmonized standards. A z-score was computed based on published age-matched norms. Higher z-score represents better cognitive function.
Time frame: 6 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine | Change in Processing Speed | 0.03 Z-score |
| Placebo | Change in Processing Speed | 0.17 Z-score |