Ginkgo Biloba Prevention Trial in Older Individuals

This study has been completed.
Sponsor:
Collaborators:
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)
Information provided by (Responsible Party):
National Center for Complementary and Integrative Health (NCCIH)
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;   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
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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
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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 
Overall Participants Analyzed 
[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
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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  

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 
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
Statistical Test Type [2] Non-Inferiority or Equivalence
Statistical 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  

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 
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
Statistical Test Type [2] Non-Inferiority or Equivalence
Statistical 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
Statistical Test Type [2] Non-Inferiority or Equivalence
Statistical 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
Statistical Test Type [2] Non-Inferiority or Equivalence
Statistical 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
Statistical Test Type [2] Non-Inferiority or Equivalence
Statistical 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
Statistical Test Type [2] Non-Inferiority or Equivalence
Statistical 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
Statistical Test Type [2] Non-Inferiority or Equivalence
Statistical 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
Statistical Test Type [2] Non-Inferiority or Equivalence
Statistical 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
Statistical Test Type [2] Non-Inferiority or Equivalence
Statistical 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
Statistical Test Type [2] Non-Inferiority or Equivalence
Statistical 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
Statistical Test Type [2] Non-Inferiority or Equivalence
Statistical 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  

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 
Participants Analyzed 
[Units: Participants]
 1545   1524 
Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance. 
[Units: Z-score 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
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Mixed Models Analysis
P Value [4] .65
Treatment X Time interaction [5] -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] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[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.




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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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
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