Ginkgo biloba for the Prevention of Dementia and Alzheimer's Disease The Ginkgo Evaluation of Memory Study (GEMS)

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Ginkgo biloba for the Prevention of Dementia
and Alzheimer's DiseaseThe Ginkgo Evaluation
of Memory Study (GEMS)

• Steven T. DeKosky, MD
• for The GEMS Investigators
• Vice President and Dean
• University of Virginia School of Medicine
• Charlottesville, VA

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Rationale for GEMS

• Incidence of Alzheimer's doubles every five years
  past 65
• One third of Americans over the age of 85 suffer
  from some kind of dementia
• Long-term institutionalization of the patient,
  and financial and emotional devastation of the
  family
• Care of dementia patients gt 100 billion/year
• Currently no approved medication for prevention
  of dementia
• Laboratory and animal evidence that Ginkgo might
  work
• Powerful antioxidant effects
• In vitro effects against fibrillization of
  amyloid

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Ginkgo biloba

• One of the oldest known tree species (about 270
  million years old)
• Can live for over 1000 years
• Ginkgo is used in China as a traditional medicine
  for a range of conditions
• Memory enhancement
• Asthma
• Bronchitis
• Cardiac disease
• Medicinal extract is from the leaf
• It is one of the 10 best-selling herbal
  medications in the United States
• (2007 sales totaled over 107 million)

Source Luis Fernández García License
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Overview of GEMS

• Primary outcome Determine whether occurrence of
  dementia (any type) and Alzheimers disease
  specifically is lower for older people with
  normal memory treated with Ginkgo biloba compared
  with a placebo
• Design
• Randomized, double-blind, multi-center clinical
  trial
• 3,069 persons 75 years old with normal memory
  or very mild cognitive impairment (MCI 10)

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Secondary Outcomes

• All-cause mortality
• Combined CHD nonfatal MI, CHD death, coronary
  revascularization, hospitalized angina
• Combined CVD combined CHD, stroke, lower
  extremity revascularization, treated angina,
  fatal/ hospitalized/treated CHF, hospitalized or
  outpatient PAD
• General cognitive function (change over time)
• Physical function

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Secondary Objectives Subgroups

• Pre-specified
• Mild Cognitive Impairment
• Baseline CHD
• Apo-E genotype

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Safety Outcomes

• Hospitalization for bleeding
• Gastrointestinal
• Hemorrhagic Stroke

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The GEM Study Design
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Sites in GEMS

• 5 clinical sites in the United States, all
  Academic Medical Centers
• Johns Hopkins (Hagerstown, MD)
• University of California, Davis (Sacramento, CA)
• University of Pittsburgh, (Pittsburgh, PA)
• Wake Forest University
• Winston-Salem, NC
• Greensboro, NC

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GEM Study Coordination and Oversight
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Randomized Design of GEMS
Persons with Normal Memory Function or Mild
Cognitive Impairment (MCI)
Consent / Randomize (3,069)
Ginkgo biloba or Placebo

• Test every 6 months for
• New onset dementia of any type and Alzheimers
  disease specifically, and
• Other outcomes until death or end of study (up
  to 6.5 years).

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Inclusion Criteria for GEM Study

• Age/sex men and women aged gt 75 years
• English is usual language
• Willing to identify a proxy to help in memory
  assessment
• Cognitive Function Criteria
• Modified Mini-Mental State (3MS) score gt 80
• Normal score on the Dementia Questionnaire (DQ)
• Full Neuropsychological Battery consistent with
  either normal memory or MCI

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Major Exclusion Criteria

• Currently taking the anti-coagulant warfarin or
  have a history of bleeding disorders
• Taking medications for treatment of cognitive
  problems or dementia
• Participant unwilling to discontinue taking
  over-the-counter (OTC) Ginkgo biloba for the
  duration of the study
• History of or treatment for Parkinson's disease
• Congestive heart failure with disability
• Hospitalized for depression within the last year,
  or history of ECT
• Use of greater than 400-IU of vitamin E per day

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Sample Size Assumptions Statistical Methods

• Power 96 to detect 30 reduction, 86 to detect
  a 25 reduction in risk for primary outcome
• 2-sided a.05
• Analysis according to intent to treat
• Cumulative event rates Kaplan-Meier
• Differences between event curves - Log-rank tests
  Cox proportional hazards (PH) model

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GEMS Visit Components

• 2-hour cognitive assessment (w/proxy)
• Depression assessment
• Medical history including CVD
• Medication update (prescription OTC)
• Functional testing (walking speed)
• Blood draw for serum marker and genetic testing

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GEMS Cognitive Test Battery
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Eligibility Screening Strategies
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GEMS Design Dementia Outcome Ascertainment

• Incident dementia based on
• 1. Neuropsychological testing
• 2. Neurological exam
• 3. MRI
• 4. Review and final diagnosis according to
  standardized definitions and by panel of experts
  in dementia diagnosis

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GEMS ResultsBaseline Characteristics
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GEMS Results Baseline Characteristics
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GEMS ResultsCumulative adherence to assigned
study tablets by follow-up visit (excluding
death and incident dementia)
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GEMS Results Cumulative Dementia Rates by
Treatment
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GEMS ResultsHazard Ratios for Cox Regression
Analyses All Dementia and Subtypes of Dementia
comparing Ginkgo to placebo
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GEMS ResultsHazard Ratios for All Dementia and
Subtypes of Dementia Those at Baseline with
Normal Cognition and MCI
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GEMS ResultsAdverse Events
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Overall Conclusion
Ginkgo biloba at 120 mg twice a day is not
effective in reducing the overall incidence of
dementia or Alzheimers disease in older adults.
Neither is Ginkgo biloba effective in preventing
dementia in persons with mild cognitive
impairment.
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The GEM Study Other Conclusions

• Ginkgo biloba is not effective at reducing the
  incidence of coronary heart disease in persons
  over age 75
• Ginkgo biloba is not effective at reducing the
  incidence of stroke persons over age 75
• Ginkgo biloba is not effective at reducing
  mortality in persons over age 75

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The GEM Study Other Conclusions

• Ginkgo biloba at 120 mg twice a day does not
  increase the risk for bleeding in persons over
  age 75
• True for persons taking or not taking aspirin
• Effect of Ginkgo biloba on bleeding for persons
  taking warfarin is still not known

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The GEM Study Other Conclusions

• Large numbers of elderly volunteers can be
  maintained in research studies for prevention
  trials
• A variety of models can be attempted to shorten
  the time of study
• Shorter evaluations/larger N
• Less stringent cognitive criteria at baseline
  (tradeoff is advance of disease and possible
  effects of drugs earlier)
• Aggressive use of biomarkers to determine at risk
  subjects, increase incidence rates, observe
  biomarker change to determine use as surrogate

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The GEM Study Future Plans

• Use current information to
• Improve ability to identify people sooner who are
  at risk for Alzheimers disease
• Evaluate whether Ginkgo biloba may improve
  walking ability, depression, cancer risk, etc.
• Additional testing of some GEM Study volunteers
• Help understanding of changes in brain function
  with age and memory decline
• Includes brain MRI Scans, limited new memory
  testing (FDG and PiB-PET scans for Pittsburgh
  volunteers)

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The GEM Study Recommendations

• Ginkgo biloba should not be used for the
  prevention of memory loss, Alzheimers disease,
  heart disease or stroke in older people
• Research like GEMS is critically important if our
  nation is to implement the most cost-effective
  use of scarce Medicare dollars

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Principal Investigators and Functions

• Cognitive Diagnostic Center (University of
  Pittsburgh)
• ST DeKosky MD PI
• J Saxton PhD
• O Lopez MD
• Beth Snitz, PhD
• Clinical diagnoses, dementia ascertainment,
  consensus conference
• Clinical Coordinating Center (Wake Forest)
• C Furberg, PI
• J Williamson, CoPI
• intervention adherence, adverse effects, IRB
  issues, training, performance monitoring and QC
• MRI Center (Pitt)
• Carolyn Meltzer, MD, PhD

• Data Coordinating Center (Univ. Washington)
• R. Kronmal, PhD PI
• A Fitzpatrick, PhD
• data management, statistical analyses,
  randomization, tracking participants
• Clinical Field Centers
• L Fried MD and Michelle Carlson (Johns Hopkins)
• G Burke MD PI (Wake Forest)
• L Kuller MD PI (Pitt)
• J Robbins MD PI (UC-Davis)
• Evaluation and follow-up
• of subjects
• Blood laboratory (Univ. Vermont)
• R Tracy PhD PI