Ginkgo Biloba Prevention Trial in Older Individuals

This study has been completed.
Sponsor:
Collaborators:
Information provided by (Responsible Party):
National Center for Complementary and Alternative Medicine (NCCAM)
ClinicalTrials.gov Identifier:
NCT00010803
First received: February 2, 2001
Last updated: March 11, 2013
Last verified: March 2013
Results First Received: March 27, 2009  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Prevention
Conditions: Dementia
Alzheimer's Disease
Interventions: Drug: Ginkgo biloba
Drug: Placebo

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups
  Description
Ginkgo Biloba EGb 761 Ginkgo biloba 120 mg twice daily
Placebo Placebo twice daily

Participant Flow:   Overall Study
    Ginkgo Biloba     Placebo  
STARTED     1545 [1]   1524 [1]
COMPLETED     1448 [2]   1426 [2]
NOT COMPLETED     97     98  
Withdrawal by Subject                 97                 98  
[1] Randomized
[2] Reached endpoint of dementia, death or completion



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Ginkgo Biloba 120 mg twice daily, total 240 mg
Placebo Placebo 1 pill twice daily
Total Total of all reporting groups

Baseline Measures
    Ginkgo Biloba     Placebo     Total  
Number of Participants  
[units: participants]
  1545     1524     3069  
Age  
[units: participants]
     
<=18 years     0     0     0  
Between 18 and 65 years     0     0     0  
>=65 years     1545     1524     3069  
Age  
[units: years]
Mean ± Standard Deviation
  79.1  ± 3.3     79.1  ± 3.3     79.1  ± 3.3  
Gender  
[units: participants]
     
Female     702     716     1418  
Male     843     808     1651  
Region of Enrollment  
[units: participants]
     
United States     1545     1524     3069  



  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Number of Participants With Incident Dementia   [ Time Frame: Brief neuropsychological testing every 6 months, detailed testing annually, average 6.1 years follow up ]

Measure Type Primary
Measure Title Number of Participants With Incident Dementia
Measure Description 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  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Subjects developing incident dementia during trial in each group, intention to treat (ITT).

Reporting Groups
  Description
Ginkgo Biloba 120 mg twice daily, total 240 mg
Placebo Placebo 1 pill twice a day

Measured Values
    Ginkgo Biloba     Placebo  
Number of Participants Analyzed  
[units: participants]
  1545     1524  
Number of Participants With Incident Dementia  
[units: Participants]
  277     246  


Statistical Analysis 1 for Number of Participants With Incident Dementia
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Log Rank
P Value [4] 0.21
Hazard Ratio (HR) [5] 1.12
95% Confidence Interval ( 0.94 to 1.33 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Previously provided
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Time to dementia in Ginkgo vs placebo groups. The Cox proportional hazards model was used to compute hazard ratios and log-rank tests.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  No text entered.



2.  Secondary:   Number of Participants With the Indicated Cardiovascular Disease or Mortality   [ Time Frame: 6 months ]

Measure Type Secondary
Measure Title Number of Participants With the Indicated Cardiovascular Disease or Mortality
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Total cohort of 3069 based on same design as primary outcome, ITT.

Reporting Groups
  Description
Ginkgo Biloba 120 mg twice daily, total 240 mg
Placebo Placebo 1 pill twice a day

Measured Values
    Ginkgo Biloba     Placebo  
Number of Participants Analyzed  
[units: participants]
  1545     1524  
Number of Participants With the Indicated Cardiovascular Disease or Mortality  
[units: Participants]
   
Total Mortality     197     188  
Atherosclerotic CHD Mortality     45     42  
Incident MI     68     60  
Incident Angina     66     76  
Incident CHD (MI &/or angina)     107     110  
Incident CHF     112     122  
Incident Stroke     73     59  
Incident TIA     27     31  
Incident CVD (stroke &/or TIA)     99     88  
Total CHD and CVD     157     154  


Statistical Analysis 1 for Number of Participants With the Indicated Cardiovascular Disease or Mortality
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Log Rank
P Value [4] 0.70
Hazard Ratio (HR) [5] 1.04
95% Confidence Interval ( 0.85 to 1.27 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Total Mortality
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Previously provided
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Number of Participants With the Indicated Cardiovascular Disease or Mortality
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Log Rank
P Value [4] 0.78
Hazard Ratio (HR) [5] 1.06
95% Confidence Interval ( 0.70 to 1.62 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Atherosclerotic CHD mortality
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Previously provided
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for Number of Participants With the Indicated Cardiovascular Disease or Mortality
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Log Rank
P Value [4] 0.54
Hazard Ratio (HR) [5] 1.12
95% Confidence Interval ( 0.79 to 1.58 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Incident Myocardial Infarction
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Previously provided
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 4 for Number of Participants With the Indicated Cardiovascular Disease or Mortality
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Log Rank
P Value [4] 0.32
Hazard Ratio (HR) [5] 0.84
95% Confidence Interval ( 0.61 to 1.18 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Incident Angina
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Previously Provided
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 5 for Number of Participants With the Indicated Cardiovascular Disease or Mortality
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Log Rank
P Value [4] 0.66
Hazard Ratio (HR) [5] 0.94
95% Confidence Interval ( 0.72 to 1.23 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Incident CHD
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Previously provided
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 6 for Number of Participants With the Indicated Cardiovascular Disease or Mortality
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Log Rank
P Value [4] 0.48
Hazard Ratio (HR) [5] 0.91
95% Confidence Interval ( 0.71 to 1.18 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Incident CHF
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Previously Provided
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 7 for Number of Participants With the Indicated Cardiovascular Disease or Mortality
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Log Rank
P Value [4] 0.25
Hazard Ratio (HR) [5] 0.87
95% Confidence Interval ( 0.52 to 1.45 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Incident Stroke
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Previously provided
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 8 for Number of Participants With the Indicated Cardiovascular Disease or Mortality
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Log Rank
P Value [4] 0.59
Hazard Ratio (HR) [5] 0.87
95% Confidence Interval ( 0.52 to 1.45 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Incident TIA
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Previously provided
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 9 for Number of Participants With the Indicated Cardiovascular Disease or Mortality
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Log Rank
P Value [4] 0.42
Cox Proportional Hazard [5] 1.12
95% Confidence Interval ( 0.84 to 1.50 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Incident CVD
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Previously provided
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  No text entered.

Statistical Analysis 10 for Number of Participants With the Indicated Cardiovascular Disease or Mortality
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Log Rank
P Value [4] 0.98
Hazard Ratio (HR) [5] 1.00
95% Confidence Interval ( 0.80 to 1.25 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Total CHD and CVD combined
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Previously provided
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  No text entered.



3.  Secondary:   Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance.   [ Time Frame: 6 months/annually ]

Measure Type Secondary
Measure Title Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance.
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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

Reporting Groups
  Description
Ginkgo Biloba 120 mg twice daily, total 240 mg
Placebo Placebo 1 pill twice a day

Measured Values
    Ginkgo Biloba     Placebo  
Number of Participants Analyzed  
[units: participants]
  1545     1524  
Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance.  
[units: Z-scoreĀ units]
Mean ( 95% Confidence Interval )
   
Global Cognition (mean Z-score of 5 domains)     0.069  
  ( 0.064 to 0.074 )  
  0.071  
  ( 0.065 to 0.076 )  
Memory (mean Z-score of 2 memory tests)     0.043  
  ( 0.034 to 0.051 )  
  0.041  
  ( 0.032 to 0.050 )  
Attention (mean Z-score of 2 attention tests)     0.043  
  ( 0.037 to 0.050 )  
  0.048  
  ( 0.041 to 0.054 )  
Visuospatial Abilities (mean Z-score of 2 tests)     0.107  
  ( 0.097 to 0.117 )  
  0.118  
  ( 0.108 to 0.128 )  
Language (mean Z-score of 2 language tests)     0.045  
  ( 0.037 to 0.054 )  
  0.041  
  ( 0.033 to 0.048 )  
Executive Functions (mean Z-score of 2 tests)     0.092  
  ( 0.086 to 0.099 )  
  0.089  
  ( 0.082 to 0.096 )  


Statistical Analysis 1 for Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance.
Groups [1] All groups
Method [2] Mixed Models Analysis
P Value [3] .65
Treatment X Time interaction [4] -0.002
95% Confidence Interval ( -0.009 to 0.005 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Linear mixed models comparing rates of change in global cognition scores (z-scores) by treatment group
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information