Dementia, Alzheimer's Disease
Conditions
Brief summary
This study will determine the effect of 240mg/day Ginkgo biloba in decreasing the incidence of dementia and specifically Alzheimer's disease (AD), slowing cognitive decline and functional disability, reducing incidence of cardiovascular disease, and decreasing total mortality.
Detailed description
Participants will be studied in a randomized trial of 240 mg of Ginkgo biloba as compared to placebo in healthy men and women, at least 75 years old. The trial will last approximately 8 years. The intervention will be considered unsuccessful in those participants who succumb to dementia, including Alzheimer's Disease and vascular dementia. There are four clinical centers: Pittsburgh, PA; Hagerstown, MD; Winston-Salem, NC; and Sacramento, CA; and a Coordinating Center at the University of Washington, Seattle. There will be a clinic visit every 6 months to determine morbidity, mortality and change in cognition that will include repeat of ADAS, CDR, and 10 battery neuropsychological evaluation and informant interview. The primary endpoint is dementia, specifically Alzheimer's disease, secondary endpoint will include the incidence of vascular disease, changes in cognitive function scores over time, total mortality and changes in functional status. The diagnosis of dementia will be based on neuropsychological testing, neurological exam, MRI, functional measurements, and review by a central adjudication committee and classified by DSM IV, NINCDS criteria and ADRTC criteria for vascular disease.
Interventions
DRUGGinkgo biloba
120mg twice a day
DRUGPlacebo
One pill twice daily
Sponsors
Office of Dietary Supplements (ODS)
National Institute of Neurological Disorders and Stroke (NINDS)
National Institute on Aging (NIA)
National Heart, Lung, and Blood Institute (NHLBI)
National Center for Complementary and Integrative Health (NCCIH)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
75 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Non-demented participants * Willing to participate in a seven-year follow-up trial of Ginkgo Biloba * English is their usual language * Willing informant who has frequent contact with the participant
Exclusion criteria
* Currently on anticoagulant therapy * Cancer diagnosed and treated within the past two years (except for skin cancer) * Participant with class III - IV congestive heart failure * Currently being treated with psychopharmacological drugs for depression * Hospitalized for depression within the last year * Taking Aricept (or similar agents) for cognitive problems or dementia * Baseline blood creatinine \>2 * Baseline SGGT is a marker of liver function (3 x normal\>or=90 IU) * Baseline hematocrit\<30 * Baseline white blood count\>or=15,000
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Incident Dementia | Brief neuropsychological testing every 6 months, detailed testing annually, average 6.1 years follow up | All cause dementia based on DSM-IV criteria as determined by an expert panel of clinicians using an adjudication process. A full neuropsychological battery was administered annually, or at 6 month visit if there was a diagnosis of dementia or initiation of medication for dementia by private physician, or change in Modified Mini Mental State Exam (3MSE), Clinical Dementia Rating (CDR), or Alzheimer Disease Assessment Scale (ADAS-Cog). Decline on tests scores based on an algorithm resulted in a neurological exam and brain imaging. These data were used in the adjudication process. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With the Indicated Cardiovascular Disease or Mortality | 6 months | Myocardial infarction (MI), angina, stroke (CVA), transient ischemic attack (TIA), combined coronary heart disease (CHD) (MI/angina), combined cerebrovascular (CVA/TIA), peripheral vascular disease, and mortality |
| Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance. | 6 months/annually | Rate of annual change by cognitive domain in standardized Z-score scale. Higher Z-scores indicate worse performance. Best score = -2.0 Z-score change per year (improvement); worse score = 2.0 Z-score change per year (decline). |
Countries
United States
Participant flow
Recruitment details
Recruitment occured between September 2000 through June 2002 primarily using mass mailings from targeted lists such as voter's registration and commercially available lists. Some sites chose to supplement this approach with newspaper, radio and television ads plus newsletter articles, posters and community presentations.
Pre-assignment details
After mailing brochures to potential participants, we conducted a telephone screening followed by an in-person clinic visit to finalize eligibility. Randomization was done at a second visit within close proximity to the screening visit.
Participants by arm
| Arm | Count |
|---|---|
| Ginkgo Biloba 120 mg twice daily, total 240 mg | 1,545 |
| Placebo Placebo 1 pill twice daily | 1,524 |
| Total | 3,069 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 97 | 98 |
Baseline characteristics
| Characteristic | Placebo | Ginkgo Biloba | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1524 Participants | 1545 Participants | 3069 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age Continuous | 79.1 years STANDARD_DEVIATION 3.3 | 79.1 years STANDARD_DEVIATION 3.3 | 79.1 years STANDARD_DEVIATION 3.3 |
| Region of Enrollment United States | 1524 participants | 1545 participants | 3069 participants |
| Sex: Female, Male Female | 716 Participants | 702 Participants | 1418 Participants |
| Sex: Female, Male Male | 808 Participants | 843 Participants | 1651 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1,504 / 1,545 | 1,469 / 1,524 |
| serious Total, serious adverse events | 1,000 / 1,545 | 961 / 1,524 |
Outcome results
Primary
Number of Participants With Incident Dementia
All cause dementia based on DSM-IV criteria as determined by an expert panel of clinicians using an adjudication process. A full neuropsychological battery was administered annually, or at 6 month visit if there was a diagnosis of dementia or initiation of medication for dementia by private physician, or change in Modified Mini Mental State Exam (3MSE), Clinical Dementia Rating (CDR), or Alzheimer Disease Assessment Scale (ADAS-Cog). Decline on tests scores based on an algorithm resulted in a neurological exam and brain imaging. These data were used in the adjudication process.
Time frame: Brief neuropsychological testing every 6 months, detailed testing annually, average 6.1 years follow up
Population: Subjects developing incident dementia during trial in each group, intention to treat (ITT).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ginkgo Biloba | Number of Participants With Incident Dementia | 277 Participants |
| Placebo | Number of Participants With Incident Dementia | 246 Participants |
Comparison: The null hypothesis is that the instantaneous hazard rate for Ginkgo biloba and placebo are the same. Assumptions were based on 4%/yr dementia and 6%/yr mortality and dropout combined. A sample size of 3000 with an average follow up of 5 years resulted in 96% power to detecting a 30% reduction in the rate of dementia at a 2-sided significance level of 0.5.p-value: 0.2195% CI: [0.94, 1.33]Log Rank
Secondary
Number of Participants With the Indicated Cardiovascular Disease or Mortality
Myocardial infarction (MI), angina, stroke (CVA), transient ischemic attack (TIA), combined coronary heart disease (CHD) (MI/angina), combined cerebrovascular (CVA/TIA), peripheral vascular disease, and mortality
Time frame: 6 months
Population: Total cohort of 3069 based on same design as primary outcome, ITT.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ginkgo Biloba | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Total Mortality | 197 Participants |
| Ginkgo Biloba | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Atherosclerotic CHD Mortality | 45 Participants |
| Ginkgo Biloba | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Incident MI | 68 Participants |
| Ginkgo Biloba | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Incident Angina | 66 Participants |
| Ginkgo Biloba | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Incident CHD (MI &/or angina) | 107 Participants |
| Ginkgo Biloba | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Incident CHF | 112 Participants |
| Ginkgo Biloba | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Incident Stroke | 73 Participants |
| Ginkgo Biloba | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Incident TIA | 27 Participants |
| Ginkgo Biloba | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Incident CVD (stroke &/or TIA) | 99 Participants |
| Ginkgo Biloba | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Total CHD and CVD | 157 Participants |
| Placebo | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Incident TIA | 31 Participants |
| Placebo | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Total Mortality | 188 Participants |
| Placebo | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Incident CHF | 122 Participants |
| Placebo | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Atherosclerotic CHD Mortality | 42 Participants |
| Placebo | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Total CHD and CVD | 154 Participants |
| Placebo | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Incident MI | 60 Participants |
| Placebo | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Incident Stroke | 59 Participants |
| Placebo | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Incident Angina | 76 Participants |
| Placebo | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Incident CVD (stroke &/or TIA) | 88 Participants |
| Placebo | Number of Participants With the Indicated Cardiovascular Disease or Mortality | Incident CHD (MI &/or angina) | 110 Participants |
Comparison: Total Mortalityp-value: 0.795% CI: [0.85, 1.27]Log Rank
Comparison: Atherosclerotic CHD mortalityp-value: 0.7895% CI: [0.7, 1.62]Log Rank
Comparison: Incident Myocardial Infarctionp-value: 0.5495% CI: [0.79, 1.58]Log Rank
Comparison: Incident Anginap-value: 0.3295% CI: [0.61, 1.18]Log Rank
Comparison: Incident CHDp-value: 0.6695% CI: [0.72, 1.23]Log Rank
Comparison: Incident CHFp-value: 0.4895% CI: [0.71, 1.18]Log Rank
Comparison: Incident Strokep-value: 0.2595% CI: [0.52, 1.45]Log Rank
Comparison: Incident TIAp-value: 0.5995% CI: [0.52, 1.45]Log Rank
Comparison: Incident CVDp-value: 0.4295% CI: [0.84, 1.5]Log Rank
Comparison: Total CHD and CVD combinedp-value: 0.9895% CI: [0.8, 1.25]Log Rank
Secondary
Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance.
Rate of annual change by cognitive domain in standardized Z-score scale. Higher Z-scores indicate worse performance. Best score = -2.0 Z-score change per year (improvement); worse score = 2.0 Z-score change per year (decline).
Time frame: 6 months/annually
Population: Final test scores were imputed for participants who did not have a cognitive exam during the year before death (n=234) or dropout (n=154) or during the month before censoring for dementia (n=70). Factors in imputed model included treatment group, demographic and health history variables, study site, and other cognitive scores. Higher Z-scores worse
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Ginkgo Biloba | Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance. | Global Cognition (mean Z-score of 5 domains) | 0.069 Z-score units |
| Ginkgo Biloba | Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance. | Memory (mean Z-score of 2 memory tests) | 0.043 Z-score units |
| Ginkgo Biloba | Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance. | Attention (mean Z-score of 2 attention tests) | 0.043 Z-score units |
| Ginkgo Biloba | Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance. | Visuospatial Abilities (mean Z-score of 2 tests) | 0.107 Z-score units |
| Ginkgo Biloba | Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance. | Language (mean Z-score of 2 language tests) | 0.045 Z-score units |
| Ginkgo Biloba | Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance. | Executive Functions (mean Z-score of 2 tests) | 0.092 Z-score units |
| Placebo | Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance. | Language (mean Z-score of 2 language tests) | 0.041 Z-score units |
| Placebo | Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance. | Global Cognition (mean Z-score of 5 domains) | 0.071 Z-score units |
| Placebo | Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance. | Visuospatial Abilities (mean Z-score of 2 tests) | 0.118 Z-score units |
| Placebo | Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance. | Memory (mean Z-score of 2 memory tests) | 0.041 Z-score units |
| Placebo | Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance. | Executive Functions (mean Z-score of 2 tests) | 0.089 Z-score units |
| Placebo | Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance. | Attention (mean Z-score of 2 attention tests) | 0.048 Z-score units |
Comparison: Linear mixed models comparing rates of change in global cognition scores (z-scores) by treatment groupp-value: 0.6595% CI: [-0.009, 0.005]Mixed Models Analysis