Ginkgo Biloba Prevention Trial in Older Individuals

• Sponsor: National Center for Complementary and Integrative Health (NCCIH) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00010803
• Collaborator: Office of Dietary Supplements (ODS) (NIH), National Institute of Neurological Disorders and Stroke (NINDS) (NIH), National Institute on Aging (NIA) (NIH), National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 3,069
• Locations: 5
• Arms: 2
• Duration (Months): 129
• Patients Per Site: 613.8
• Patients Per Site Per Month: 4.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Dementia; Alzheimer's Disease	Drug: Ginkgo biloba; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3069 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: Ginkgo Biloba Prevention Trial in Older Individuals
• Study Start Date: Oct 1, 2000
• Actual Primary Completion Date: Apr 1, 2008
• Actual Study Completion Date: Jul 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo 1 pill twice a day	Drug: Placebo; One pill twice daily; Other Names: Identical appearance as Ginkgo biloba pill
Active Comparator: Ginkgo biloba Ginkgo biloba EGb761 120 mg twice daily	Drug: Ginkgo biloba; 120mg twice a day; Other Names: EGb761

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

2. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 75 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, Davis	Sacramento	California	United States	95817
2	Johns Hopkins University	Baltimore	Maryland	United States	21205
3	Wake Forest University School of Medicine	Winston-Salem	North Carolina	United States	27157-1063
4	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
5	University of Pittsburgh/University of Virginia	Charlottesville	Virginia	United States	22908

Sponsors and Collaborators

• National Center for Complementary and Integrative Health (NCCIH)
• 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)

Investigators

• Principal Investigator: Steven T. DeKosky, M.D., University of Pittsburgh, Department of Neurology

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here to learn more about The Ginkgo Evaluation of Memory Study

Publications

• DeKosky ST, Fitzpatrick A, Ives DG, Saxton J, Williamson J, Lopez OL, Burke G, Fried L, Kuller LH, Robbins J, Tracy R, Woolard N, Dunn L, Kronmal R, Nahin R, Furberg C; GEMS Investigators. The Ginkgo Evaluation of Memory (GEM) study: design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia. Contemp Clin Trials. 2006 Jun;27(3):238-53. Epub 2006 Apr 19.
• Fitzpatrick AL, Buchanan CK, Nahin RL, Dekosky ST, Atkinson HH, Carlson MC, Williamson JD; Ginkgo Evaluation of Memory (GEM) Study Investigators. Associations of gait speed and other measures of physical function with cognition in a healthy cohort of elderly persons. J Gerontol A Biol Sci Med Sci. 2007 Nov;62(11):1244-51.
• Fitzpatrick AL, Fried LP, Williamson J, Crowley P, Posey D, Kwong L, Bonk J, Moyer R, Chabot J, Kidoguchi L, Furberg CD, DeKosky ST; GEM Study Investigators. Recruitment of the elderly into a pharmacologic prevention trial: the Ginkgo Evaluation of Memory Study experience. Contemp Clin Trials. 2006 Dec;27(6):541-53. Epub 2006 Jul 4.
• Nahin RL, Fitzpatrick AL, Williamson JD, Burke GL, Dekosky ST, Furberg C; GEM Study Investigators. Use of herbal medicine and other dietary supplements in community-dwelling older people: Baseline data from the ginkgo evaluation of memory study. J Am Geriatr Soc. 2006 Nov;54(11):1725-35.
• Rosano C, Aizenstein H, Cochran J, Saxton J, De Kosky S, Newman AB, Kuller LH, Lopez OL, Carter CS. Functional neuroimaging indicators of successful executive control in the oldest old. Neuroimage. 2005 Dec;28(4):881-9. Epub 2005 Oct 12.
• Rosano C, Aizenstein HJ, Cochran JL, Saxton JA, De Kosky ST, Newman AB, Kuller LH, Lopez OL, Carter CS. Event-related functional magnetic resonance imaging investigation of executive control in very old individuals with mild cognitive impairment. Biol Psychiatry. 2005 Apr 1;57(7):761-7.
• Saxton J, Snitz BE, Lopez OL, Ives DG, Dunn LO, Fitzpatrick A, Carlson MC, Dekosky ST; GEM Study Investigators. Functional and cognitive criteria produce different rates of mild cognitive impairment and conversion to dementia. J Neurol Neurosurg Psychiatry. 2009 Jul;80(7):737-43. doi: 10.1136/jnnp.2008.160705. Epub 2009 Mar 11.
• Snitz BE, Saxton J, Lopez OL, Ives DG, Dunn LO, Rapp SR, Carlson MC, Fitzpatrick AL, Dekosky ST; GEM study Investigators. Identifying mild cognitive impairment at baseline in the Ginkgo Evaluation of Memory (GEM) study. Aging Ment Health. 2009 Mar;13(2):171-82. doi: 10.1080/13607860802380656.
• Williamson JD, Vellas B, Furberg C, Nahin R, Dekosky ST. Comparison of the design differences between the Ginkgo Evaluation of Memory study and the GuidAge study. J Nutr Health Aging. 2008 Jan;12(1):73S-9S.

• Responsible Party: National Center for Complementary and Integrative Health (NCCIH)
• ClinicalTrials.gov Identifier: NCT00010803
• Other Study ID Numbers: U01 AT000162-01M; NCT00004535
• First Posted: Feb 5, 2001
• Last Update Posted: Mar 14, 2013
• Last Verified: Mar 1, 2013

• Additional relevant MeSH terms: Alzheimer Disease

Study Results

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 Detail	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.

Arm/Group Title	Ginkgo Biloba	Placebo
Arm/Group Description	EGb 761 Ginkgo biloba 120 mg twice daily	Placebo twice daily
Period Title: Overall Study
STARTED	1545	1524
COMPLETED	1448	1426
NOT COMPLETED	97	98

Baseline Characteristics

Arm/Group Title	Ginkgo Biloba	Placebo	Total
Arm/Group Description	120 mg twice daily, total 240 mg	Placebo 1 pill twice daily	Total of all reporting groups
Overall Participants	1545	1524	3069
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	1545 100%	1524 100%	3069 100%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	79.1 (3.3)	79.1 (3.3)	79.1 (3.3)
Sex: Female, Male (Count of Participants)
Female	702 45.4%	716 47%	1418 46.2%
Male	843 54.6%	808 53%	1651 53.8%
Region of Enrollment (participants) [Number]
United States	1545 100%	1524 100%	3069 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Incident Dementia
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

Outcome Measure Data

Analysis Population Description

Subjects developing incident dementia during trial in each group, intention to treat (ITT).

Arm/Group Title	Ginkgo Biloba	Placebo
Arm/Group Description	120 mg twice daily, total 240 mg	Placebo 1 pill twice a day
Measure Participants	1545	1524
Number [Participants]	277 17.9%	246 16.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ginkgo Biloba, Placebo
	Comments	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.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Previously provided
Statistical Test of Hypothesis	p-Value	0.21
	Comments
	Method	Log Rank
	Comments	Time to dementia in Ginkgo vs placebo groups. The Cox proportional hazards model was used to compute hazard ratios and log-rank tests.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; 0.94 to 1.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants With the Indicated Cardiovascular Disease or Mortality
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

Outcome Measure Data

Analysis Population Description

Total cohort of 3069 based on same design as primary outcome, ITT.

Arm/Group Title	Ginkgo Biloba	Placebo
Arm/Group Description	120 mg twice daily, total 240 mg	Placebo 1 pill twice a day
Measure Participants	1545	1524
Total Mortality	197 12.8%	188 12.3%
Atherosclerotic CHD Mortality	45 2.9%	42 2.8%
Incident MI	68 4.4%	60 3.9%
Incident Angina	66 4.3%	76 5%
Incident CHD (MI &/or angina)	107 6.9%	110 7.2%
Incident CHF	112 7.2%	122 8%
Incident Stroke	73 4.7%	59 3.9%
Incident TIA	27 1.7%	31 2%
Incident CVD (stroke &/or TIA)	99 6.4%	88 5.8%
Total CHD and CVD	157 10.2%	154 10.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ginkgo Biloba, Placebo
	Comments	Total Mortality
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Previously provided
Statistical Test of Hypothesis	p-Value	0.70
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.85 to 1.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ginkgo Biloba, Placebo
	Comments	Atherosclerotic CHD mortality
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Previously provided
Statistical Test of Hypothesis	p-Value	0.78
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 0.70 to 1.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ginkgo Biloba, Placebo
	Comments	Incident Myocardial Infarction
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Previously provided
Statistical Test of Hypothesis	p-Value	0.54
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; 0.79 to 1.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ginkgo Biloba, Placebo
	Comments	Incident Angina
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Previously Provided
Statistical Test of Hypothesis	p-Value	0.32
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Ginkgo Biloba, Placebo
	Comments	Incident CHD
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Previously provided
Statistical Test of Hypothesis	p-Value	0.66
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.72 to 1.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Ginkgo Biloba, Placebo
	Comments	Incident CHF
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Previously Provided
Statistical Test of Hypothesis	p-Value	0.48
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.71 to 1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Ginkgo Biloba, Placebo
	Comments	Incident Stroke
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Previously provided
Statistical Test of Hypothesis	p-Value	0.25
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.52 to 1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Ginkgo Biloba, Placebo
	Comments	Incident TIA
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Previously provided
Statistical Test of Hypothesis	p-Value	0.59
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.52 to 1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Ginkgo Biloba, Placebo
	Comments	Incident CVD
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Previously provided
Statistical Test of Hypothesis	p-Value	0.42
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Ginkgo Biloba, Placebo
	Comments	Total CHD and CVD combined
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Previously provided
Statistical Test of Hypothesis	p-Value	0.98
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; 0.80 to 1.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Progression of Cognitive Decline in Standardized Z-score Scale. Higher Z-scores Indicate Worse Performance.
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

Outcome Measure Data

Analysis Population Description

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/Group Title	Ginkgo Biloba	Placebo
Arm/Group Description	120 mg twice daily, total 240 mg	Placebo 1 pill twice a day
Measure Participants	1545	1524
Global Cognition (mean Z-score of 5 domains)	0.069	0.071
Memory (mean Z-score of 2 memory tests)	0.043	0.041
Attention (mean Z-score of 2 attention tests)	0.043	0.048
Visuospatial Abilities (mean Z-score of 2 tests)	0.107	0.118
Language (mean Z-score of 2 language tests)	0.045	0.041
Executive Functions (mean Z-score of 2 tests)	0.092	0.089

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ginkgo Biloba, Placebo
	Comments	Linear mixed models comparing rates of change in global cognition scores (z-scores) by treatment group
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.65
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Treatment X Time interaction
	Estimated Value	-0.002
	Confidence Interval	(2-Sided) 95%; -0.009 to 0.005
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse event data were collected every six months at testing visits, and at interim 3 month adherence phone calls.
Arm/Group Title	Ginkgo Biloba		Placebo
Arm/Group Description	EGb 761 Ginkgo biloba 120 mg twice daily		Placebo twice daily
All Cause Mortality
	Ginkgo Biloba		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ginkgo Biloba		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1000/1545 (64.7%)		961/1524 (63.1%)
General disorders
Death	197/1545 (12.8%)	197	188/1524 (12.3%)	188
Bleeding	138/1545 (8.9%)	171	140/1524 (9.2%)	178
All other SAEs	374/1545 (24.2%)	1627	358/1524 (23.5%)	1647
Vascular disorders
Stroke	80/1545 (5.2%)	88	71/1524 (4.7%)	82
Other (Not Including Serious) Adverse Events
	Ginkgo Biloba		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1504/1545 (97.3%)		1469/1524 (96.4%)
General disorders
non-hospitalized self-reported symptom	0/1545 (0%)	0	0/1524 (0%)	0
All adverse events	1504/1545 (97.3%)	1504	1469/1524 (96.4%)	1469
Self-reported non-hospitalized symptom collected every 6 months	1504/1545 (97.3%)	1504	1469/1524 (96.4%)	1469

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.