Cognitive Aging
Conditions
Keywords
guanfacine, aging, cognitive aging, prefrontal cognitive function, executive function, prefrontal cortex
Brief summary
This proposal aims to determine whether low does of the alpha-2A-adrenoceptor agonist guanfacine can improve deficits in prefrontally-mediated cognitive functions in healthy elderly subjects.
Detailed description
Primary: * To determine whether low does of the α2A-adrenoceptor agonist guanfacine can improve deficits in prefrontally-mediated working memory and executive control functions, in healthy elderly subjects. Subjects will be randomly assigned to receive placebo or guanfacine at one of two dose levels: 0.1 mg, or 0.5 mg daily at bedtime in double-blind fashion for twelve weeks. Secondary: * To determine whether guanfacine can favorably influence global status and quality of life (QOL) in healthy elderly subjects. * To determine whether low-dose guanfacine is safe and well-tolerated in healthy elderly subjects.
Interventions
DRUGGuanfacine
Guanfacine 0.1 mg po qhs
DRUGPlacebo
Placebo po qhs
Sponsors
National Institute on Aging (NIA)
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
75 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Subjects enrolled will be nondemented, male and female individuals who meet the following inclusion criteria: * 75 years of age or older * Fluent in English * Stable medical condition for at least 4 weeks prior to Screening visit * Stable dose of non-excluded medications for at least 4 weeks prior to Screening visit
Exclusion criteria
* Dementia * Mild Cognitive Impairment (Amnestic MCI) * Clinically significant neurologic disease * Clinically significant or unstable medical conditions that would interfere with participation in the trial * Known hypersensitivity to guanfacine * History of alcohol or substance abuse or dependence within the past 5 years * Active major psychiatric disorders, including major depression * History of mental retardation * Significant abnormalities on clinical laboratories, ECG, or physical examination * Impairment of visual or auditory acuity sufficient to interfere with completion of study procedures * Education level \< 6 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean in the Prefrontal Executive Function Z-score (PEF6_6) | 12 weeks | The primary outcome measure (PEF6\_Z) is the mean of z-scores for 6 executive function tasks (CANTAB: Spatial Working Memory, Stockings of Cambridge, Intradimensiona/Extradimensional Shift, Paired Associates Learning; Stroop Color Word Score, Trail Making Test - B). The score is composed of six component scales coded as z scores that measures cognitive functioning in which higher scores represent better cognitive functioning; therefore, the least squares means listed here represent mean outcome changes from baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) | 12 weeks | The seven-point scale was collapsed into 3 groups and coded as a three-level ordinal scale of global status, representing ordered levels of worse (including minimally, moderately and markedly worse), unchanged, and improved (including minimally, moderately, and markedly improved) global status. |
| Quality of Life (SF-36 MCS) | 12 weeks | Quality of Life (QOL) was assessed using the SF-36 (36-Item Short-Form Health Survey; QualityMetric, Lincoln, RI), MCS subscale. The SF-36 is a self-administered general health-related quality of life scale with 36 items. The MCS subscale has been shown to be responsive in psychoactive drug trials. The score range is 0-100. Higher scores represent better mental health; therefore, the least squares means listed here represent mean outcome changes from baseline. |
Countries
United States
Participant flow
Pre-assignment details
154 subjects were screened, of which 135 were eligible. Of the 135 eligible, 12 withdrew consent and therefore 123 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Guanfacine 0.1 mg po Qhs Guanfacine: Guanfacine 0.1 mg po qhs | 41 |
| Guanfacine 0.5 mg po Qhs Guanfacine: Guanfacine 0.5 mg po qhs | 41 |
| Placebo po Qhs Placebo: Placebo po qhs | 41 |
| Total | 123 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 | 1 |
| Overall Study | Treatment Discontinued | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Guanfacine 0.1 mg po Qhs | Guanfacine 0.5 mg po Qhs | Placebo po Qhs | Total |
|---|---|---|---|---|
| Age, Continuous | 80.0 years STANDARD_DEVIATION 4 | 80.1 years STANDARD_DEVIATION 4 | 80.5 years STANDARD_DEVIATION 4 | 80.2 years STANDARD_DEVIATION 4 |
| Sex: Female, Male Female | 19 Participants | 18 Participants | 17 Participants | 54 Participants |
| Sex: Female, Male Male | 22 Participants | 23 Participants | 24 Participants | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 25 / 41 | 32 / 41 | 34 / 41 |
| serious Total, serious adverse events | 2 / 41 | 1 / 41 | 2 / 41 |
Outcome results
Primary
Mean in the Prefrontal Executive Function Z-score (PEF6_6)
The primary outcome measure (PEF6\_Z) is the mean of z-scores for 6 executive function tasks (CANTAB: Spatial Working Memory, Stockings of Cambridge, Intradimensiona/Extradimensional Shift, Paired Associates Learning; Stroop Color Word Score, Trail Making Test - B). The score is composed of six component scales coded as z scores that measures cognitive functioning in which higher scores represent better cognitive functioning; therefore, the least squares means listed here represent mean outcome changes from baseline
Time frame: 12 weeks
Population: 119 of the 123 trial participants had outcome data recorded at 12 weeks follow-up.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine 0.1 mg | Mean in the Prefrontal Executive Function Z-score (PEF6_6) | 0.121 Z-score | Standard Error 0.056 |
| Guanfacine 0.5 mg | Mean in the Prefrontal Executive Function Z-score (PEF6_6) | 0.213 Z-score | Standard Error 0.056 |
| Placebo | Mean in the Prefrontal Executive Function Z-score (PEF6_6) | 0.270 Z-score | Standard Error 0.056 |
p-value: 0.06Regression, Linear
p-value: 0.47Regression, Linear
Secondary
Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC)
The seven-point scale was collapsed into 3 groups and coded as a three-level ordinal scale of global status, representing ordered levels of worse (including minimally, moderately and markedly worse), unchanged, and improved (including minimally, moderately, and markedly improved) global status.
Time frame: 12 weeks
Population: 119 of the 123 trial participants had outcome data recorded at 12 weeks of follow-up
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Guanfacine 0.1 mg | Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) | No Change | 20 participants |
| Guanfacine 0.1 mg | Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) | Worse | 4 participants |
| Guanfacine 0.1 mg | Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) | Improved | 16 participants |
| Guanfacine 0.5 mg | Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) | No Change | 22 participants |
| Guanfacine 0.5 mg | Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) | Worse | 2 participants |
| Guanfacine 0.5 mg | Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) | Improved | 15 participants |
| Placebo | Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) | Worse | 3 participants |
| Placebo | Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) | Improved | 12 participants |
| Placebo | Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) | No Change | 25 participants |
p-value: 0.67Regression, Logistic
p-value: 0.46Regression, Logistic
Secondary
Quality of Life (SF-36 MCS)
Quality of Life (QOL) was assessed using the SF-36 (36-Item Short-Form Health Survey; QualityMetric, Lincoln, RI), MCS subscale. The SF-36 is a self-administered general health-related quality of life scale with 36 items. The MCS subscale has been shown to be responsive in psychoactive drug trials. The score range is 0-100. Higher scores represent better mental health; therefore, the least squares means listed here represent mean outcome changes from baseline.
Time frame: 12 weeks
Population: 119 of the 123 trial participants had outcome data recorded at 12 weeks of follow up
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine 0.1 mg | Quality of Life (SF-36 MCS) | -0.618 units on a scale | Standard Error 0.825 |
| Guanfacine 0.5 mg | Quality of Life (SF-36 MCS) | -0.960 units on a scale | Standard Error 0.835 |
| Placebo | Quality of Life (SF-36 MCS) | -0.083 units on a scale | Standard Error 0.829 |
p-value: 0.65Regression, Linear
p-value: 0.46Regression, Linear