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The Ginkgo in Evaluation of Memory (GEM) study: Lessons learned for planning future dementia primary prevention trials
Symposia S4-02: Therapeutics and Therapeutic Strategies
P144 S4-01-06
USE OF NEUROIMAGING IN PREVENTIVE TRIALS
Peter J. Nestor, University of Cambridge, Cambridge, United Kingdom. Contact e-mail: [email protected] Although efficacy in disease-modifying trials can only be confirmed if patients fail to progress on clinical grounds, the rate of change in Alzheimer’s disease means that studies may require either very prolonged duration and/ or very large numbers to demonstrate such an effect_this, in turn, adding considerably to drug-development costs. This is particularly problematic in disease-modifying studies because, unlike symptomatic drug trials, in the short term, it is possible that adverse effects could spuriously drive cognitive performance downwards risking premature abandonment of potentially useful drugs. Imaging offers a surrogate marker for proof-ofconcept studies that can increase confidence to take drugs into latter-phase development. The presentation will discuss the potential benefits and limitations of structural, metabolic and ligand imaging for studies of this type. WEDNESDAY, JULY 15, 2009 SYMPOSIA S4-02 THERAPEUTICS AND THERAPEUTIC STRATEGIES S4-02-01
THE GINKGO IN EVALUATION OF MEMORY (GEM) STUDY: LESSONS LEARNED FOR PLANNING FUTURE DEMENTIA PRIMARY PREVENTION TRIALS
Jeff D. Williamson, Wake Forest University, Winston-Salem, NC, USA. Contact e-mail: [email protected] Background: Despite the very high contribution of dementia to age-related disability and institutionalization, there are few large, long-term clinical trials which can inform future primary dementia prevention trial design. The recently completed Ginkgo Evaluation of Memory Study (GEMS), a trial of the effectiveness of Ginkgo biloba in delaying the incidence of AD/all cause dementia, provides an ideal data set for use in refining and advancing clinical trial methods in the area of dementia prevention. Methods: A randomized, double-blind, placebo-controlled clinical trial conducted at 4 academic sites in the US. A total of 3,069 subjects age 75þ with normal cognition or MCI were randomized to either Ginkgo or placebo after extensive medical and neuropsychological screening. Assessments, including comorbidity incidence, medication compliance and cognitive function were performed every 6 months and incorporated proxy interviews, home visits, and telephone interviews. Results: Mean follow-up was extended to 6.2 years due to initially low dementia incidence rate and baseline mean age of participants was 79.1 years. A total of 523 persons developed dementia (246 placebo and 277 ginkgo) and there was no significant difference in the incidence of all-cause or Alzheimer’s type dementia between the treatment groups at the end of the trial. Participant visit and medication adherence was excellent and the primary outcome for 93.7 % of randomized participants was known at trial completion. We report data for both normal and MCI participants as well as review specific trial design features for promoting adherence, retention and outcome ascertainment. We present the methods incorporated to maximize adherence and retention, cognitive assessment, medication compliance. Additional GEMS results are presented to aid in future design and implementation of cost-effective dementia prevention trials. Conclusions: The GEMS results demonstrate the feasibility of successfully implementing dementia prevention trials in at-risk elderly cohorts. The GEMS experience will benefit future investigators seeking to design valid, cost-effective dementia prevention trials assessing medication effectiveness. S4-02-02
PHYSICAL ACTIVITY AND PREVENTION OF COGNITIVE DECLINE
Nicola T. Lautenschlager, The University of Melbourne, Melbourne, Australia. Contact e-mail: [email protected] Background: Several environmental factors are considered potential protective factors to delay or slow down cognitive decline and the onset of
Alzheimer’s Disease. One of those factors is regular physcial activity. Methods: This paper will give an overview on current hypotheses why physical activity should be able to protect brain function. It will highlight the ongoing discussion on what type, frequency and intensity of physical activity might be effective. Practical issues of the Fitness of the Ageing Brain Study (FABS) will be presented. FABS is a randomized controlled trial (RCT) with older volunteers, free of dementia, with mild cognitive impairment (MCI) or subjective memory complaints. This single-site trial was conducted in Perth, Australia and investigated whether a 6-month individualised home-based physical activity and behavioural intervention package can affect cognitive performance. Results: Whilst there is a growing body of literature to suggest that physical activity is a promising candidate for health promotion to protect brain function in older adults evidence from RCTs is still sparse and many practical questions remain unanswered. FABS included 170 volunteers who were assessed over a 18 months period. The Alzheimer’s Disease Assessment Scale (ADAS-Cog) was the main outcome measure and showed a significant difference between the intervention and the control group. Conclusions: The experience with the FABS trial suggests that older adults with MCI and memory complaints can successfully participate in a physical activity program designed to impact on cogntive function. The behavioural intervention component of the intervention seems crucial to achieve relevant changes in physical activity parameters. Large scale multi-site trials are needed to investigate whether this approach could be effective in reducing the risk of or delaying the onset of Alzheimer’s Disease. S4-02-03
TREATMENT EFFECTS OF NSAIDS RELATED TO STAGE OFALZHEIMER PATHOGENESIS: LESSONS FROM ADAPT
John C. S. Breitner, VA Puget Sound HCS, University of Washington, Seattle, WA, USA. Contact e-mail: [email protected] Background: Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) is inversely associated with subsequent incidence of Alzheimer’s dementia (AD) in many observational studies. However, clinical trials have shown no benefit, and possible harm, from NSAIDs given to patients with established or prodromal AD. Methods: The randomized, placebo-controlled Alzheimer’s Disease Anti-inflammatory Prevention Trial was designed to test the hypotheses that the NSAIDs naproxen and celecoxib could prevent AD in cognitively healthy elderly persons. Because of safety concerns, the treatments were stopped after a followup interval averaging two years. Subjects were then followed for two more years. Furthermore, 118 volunteers donated cerebrospinal fluid (CSF) between 22 - 44 months following treatment termination. Results: At treatment termination, 24 cases of incident AD had developed among 2,250 enrollees. Contrary to hypothesis, interim analyses at that time found increased incidence of AD in participants assigned to either NSAID. In the follow-up interval another 40 AD onsets were detected. The trial’s primary intent-to-treat analyses now showed no overall disproportion in AD events by treatment group, but there were substantial differences in treatment effects during empirically defined earlier vs. later periods of observation (P ¼ 0.01). Earlier, AD incidence was increased in groups assigned to either NSAID, and notably so for 54 individuals who had a mild cognitive syndrome at enrollment. The later hazard ratio for naproxen-assigned participants was 0.44 (95% CI 0.19 - 1.03). After exclusion of individuals with baseline cognitive syndromes, the naproxen hazard ratio was 0.33 (95% CI 0.11 - 0.98). A neuroprotective effect of naproxen was also evident in CSF measures of the AD biomarkers tau and A-beta-42. The tau / A-beta ratio was reduced by almost half in the group originally assigned to naproxen (P ¼ 0.02), and this effect was unabated 42 months following treatment termination. Conclusions: These findings are more complex than those originally envisioned. They suggest that NSAIDs can accelerate AD pathogenesis in those who already have relatively advanced disease, but may protect against this process in those with healthier brains. In any case, they constitute the first observations of a pharmacological intervention that demonstrably modifies AD pathogenesis in humans.
P144 S4-01-06
USE OF NEUROIMAGING IN PREVENTIVE TRIALS
Peter J. Nestor, University of Cambridge, Cambridge, United Kingdom. Contact e-mail: [email protected] Although efficacy in disease-modifying trials can only be confirmed if patients fail to progress on clinical grounds, the rate of change in Alzheimer’s disease means that studies may require either very prolonged duration and/ or very large numbers to demonstrate such an effect_this, in turn, adding considerably to drug-development costs. This is particularly problematic in disease-modifying studies because, unlike symptomatic drug trials, in the short term, it is possible that adverse effects could spuriously drive cognitive performance downwards risking premature abandonment of potentially useful drugs. Imaging offers a surrogate marker for proof-ofconcept studies that can increase confidence to take drugs into latter-phase development. The presentation will discuss the potential benefits and limitations of structural, metabolic and ligand imaging for studies of this type. WEDNESDAY, JULY 15, 2009 SYMPOSIA S4-02 THERAPEUTICS AND THERAPEUTIC STRATEGIES S4-02-01
THE GINKGO IN EVALUATION OF MEMORY (GEM) STUDY: LESSONS LEARNED FOR PLANNING FUTURE DEMENTIA PRIMARY PREVENTION TRIALS
Jeff D. Williamson, Wake Forest University, Winston-Salem, NC, USA. Contact e-mail: [email protected] Background: Despite the very high contribution of dementia to age-related disability and institutionalization, there are few large, long-term clinical trials which can inform future primary dementia prevention trial design. The recently completed Ginkgo Evaluation of Memory Study (GEMS), a trial of the effectiveness of Ginkgo biloba in delaying the incidence of AD/all cause dementia, provides an ideal data set for use in refining and advancing clinical trial methods in the area of dementia prevention. Methods: A randomized, double-blind, placebo-controlled clinical trial conducted at 4 academic sites in the US. A total of 3,069 subjects age 75þ with normal cognition or MCI were randomized to either Ginkgo or placebo after extensive medical and neuropsychological screening. Assessments, including comorbidity incidence, medication compliance and cognitive function were performed every 6 months and incorporated proxy interviews, home visits, and telephone interviews. Results: Mean follow-up was extended to 6.2 years due to initially low dementia incidence rate and baseline mean age of participants was 79.1 years. A total of 523 persons developed dementia (246 placebo and 277 ginkgo) and there was no significant difference in the incidence of all-cause or Alzheimer’s type dementia between the treatment groups at the end of the trial. Participant visit and medication adherence was excellent and the primary outcome for 93.7 % of randomized participants was known at trial completion. We report data for both normal and MCI participants as well as review specific trial design features for promoting adherence, retention and outcome ascertainment. We present the methods incorporated to maximize adherence and retention, cognitive assessment, medication compliance. Additional GEMS results are presented to aid in future design and implementation of cost-effective dementia prevention trials. Conclusions: The GEMS results demonstrate the feasibility of successfully implementing dementia prevention trials in at-risk elderly cohorts. The GEMS experience will benefit future investigators seeking to design valid, cost-effective dementia prevention trials assessing medication effectiveness. S4-02-02
PHYSICAL ACTIVITY AND PREVENTION OF COGNITIVE DECLINE
Nicola T. Lautenschlager, The University of Melbourne, Melbourne, Australia. Contact e-mail: [email protected] Background: Several environmental factors are considered potential protective factors to delay or slow down cognitive decline and the onset of
Alzheimer’s Disease. One of those factors is regular physcial activity. Methods: This paper will give an overview on current hypotheses why physical activity should be able to protect brain function. It will highlight the ongoing discussion on what type, frequency and intensity of physical activity might be effective. Practical issues of the Fitness of the Ageing Brain Study (FABS) will be presented. FABS is a randomized controlled trial (RCT) with older volunteers, free of dementia, with mild cognitive impairment (MCI) or subjective memory complaints. This single-site trial was conducted in Perth, Australia and investigated whether a 6-month individualised home-based physical activity and behavioural intervention package can affect cognitive performance. Results: Whilst there is a growing body of literature to suggest that physical activity is a promising candidate for health promotion to protect brain function in older adults evidence from RCTs is still sparse and many practical questions remain unanswered. FABS included 170 volunteers who were assessed over a 18 months period. The Alzheimer’s Disease Assessment Scale (ADAS-Cog) was the main outcome measure and showed a significant difference between the intervention and the control group. Conclusions: The experience with the FABS trial suggests that older adults with MCI and memory complaints can successfully participate in a physical activity program designed to impact on cogntive function. The behavioural intervention component of the intervention seems crucial to achieve relevant changes in physical activity parameters. Large scale multi-site trials are needed to investigate whether this approach could be effective in reducing the risk of or delaying the onset of Alzheimer’s Disease. S4-02-03
TREATMENT EFFECTS OF NSAIDS RELATED TO STAGE OFALZHEIMER PATHOGENESIS: LESSONS FROM ADAPT
John C. S. Breitner, VA Puget Sound HCS, University of Washington, Seattle, WA, USA. Contact e-mail: [email protected] Background: Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) is inversely associated with subsequent incidence of Alzheimer’s dementia (AD) in many observational studies. However, clinical trials have shown no benefit, and possible harm, from NSAIDs given to patients with established or prodromal AD. Methods: The randomized, placebo-controlled Alzheimer’s Disease Anti-inflammatory Prevention Trial was designed to test the hypotheses that the NSAIDs naproxen and celecoxib could prevent AD in cognitively healthy elderly persons. Because of safety concerns, the treatments were stopped after a followup interval averaging two years. Subjects were then followed for two more years. Furthermore, 118 volunteers donated cerebrospinal fluid (CSF) between 22 - 44 months following treatment termination. Results: At treatment termination, 24 cases of incident AD had developed among 2,250 enrollees. Contrary to hypothesis, interim analyses at that time found increased incidence of AD in participants assigned to either NSAID. In the follow-up interval another 40 AD onsets were detected. The trial’s primary intent-to-treat analyses now showed no overall disproportion in AD events by treatment group, but there were substantial differences in treatment effects during empirically defined earlier vs. later periods of observation (P ¼ 0.01). Earlier, AD incidence was increased in groups assigned to either NSAID, and notably so for 54 individuals who had a mild cognitive syndrome at enrollment. The later hazard ratio for naproxen-assigned participants was 0.44 (95% CI 0.19 - 1.03). After exclusion of individuals with baseline cognitive syndromes, the naproxen hazard ratio was 0.33 (95% CI 0.11 - 0.98). A neuroprotective effect of naproxen was also evident in CSF measures of the AD biomarkers tau and A-beta-42. The tau / A-beta ratio was reduced by almost half in the group originally assigned to naproxen (P ¼ 0.02), and this effect was unabated 42 months following treatment termination. Conclusions: These findings are more complex than those originally envisioned. They suggest that NSAIDs can accelerate AD pathogenesis in those who already have relatively advanced disease, but may protect against this process in those with healthier brains. In any case, they constitute the first observations of a pharmacological intervention that demonstrably modifies AD pathogenesis in humans.