In this study of GBE as a primary prevention for cognitive decline, we examined the feasibility of randomizing and following a cohort of seniors at high risk for cognitive decline (the oldest old) in a standard clinical trial for up to 42-months using a non-prescription medication. Importantly, subjects did not exhibit unusual levels of dropout with only 29 deaths (24.5%) and 10 non-mortality related dropouts (8.5%) during the 42-month study. This may reflect the relatively healthy nature of this volunteer sample of the oldest old. However, they did have common stable medical conditions such as heart disease and hypertension. Although not formally recorded as part of the study, we generally observed that many subjects were highly motivated and pleased to contribute to science and to “feel useful” at an advanced age.
Observed excess bleeding-related complications associated with Ginkgo have been reported.19
There were no observed excess bleeding-related complications in this study, but we did observe more strokes (6 cases) and TIA (1 case) in the GBE group. The stroke cases except one were not hemorrhagic, were generally not severe (only two subjects required institutional long-term care), and there were no deaths. The increased stroke risk will require further close scrutiny in other GBE prevention trials.
The absence of a protective effect of GBE against progression to CDR = 0.5 in this pilot study is potentially related to the limited statistical power of this relatively small number of participants and short duration of follow-up. However, we obtained a consistent, independent signal of a possible protective effect in that the delayed recall scores (which were independent of the CDR assessment) showed the same trend. Based on the data from this trial we estimate that we would need at least 300 subjects followed for the same period of time with similar proportions of death, dropout, and cognitive decline as in the current study to obtain 80% power to detect the significant effect of GBE, given a true hazard ratio of 0.5 (i.e., GBE group has 50% reduction in risk of progression to CDR = 0.5). Given a true hazard ratio of 0.8 (i.e., GBE group has 20% reduction in the risk of progression to CDR = 0.5), we would need over 2,800 subjects to attain 80% power. Obtaining this sample size may require a large sampling frame from which to draw the sample and could limit larger study feasibility. Our method was originally focused on a single metropolitan population, mail-based sampling approach using existing driving and voter registration lists containing over 10,000 oldest old (over 30,000 people over the age of 84 live in this area). Because of budgetary constraints, no special advertising or recruitment methods were used, which would likely increase the number of subjects who would participate. In general, studies of this size are conducted as multicenter efforts. Ongoing larger GBE trials20,21
are powered using much larger samples on the assumption that the transition rates to cognitive impairment are low (especially in younger elderly) and the efficacy of GBE may be modest. Our data suggest that these other studies should be able to definitively establish a brain protective effect of GBE assuming that such variables as the dosing and the nature of the population samples enrolled (i.e., these other studies have a younger elderly population under treatment) are not major determinants of efficacy.
The results of the primary outcome of interest (conversion to CDR 0.5) did not appear to be affected by a number of variables that have been suggested to influence the susceptibility to dementia including sex, education, chronic medical illnesses, and apolipoprotein E genotype. In the covariate analyses only depression score and treatment group were significant. The mean depression scores were very low with no subject qualifying for clinically significant depression and thus the practical significance of this observation is uncertain.
Given the finding of an effect on efficacy based on medication adherence, we were particularly interested in conducting careful exploratory studies based on statistical models with the medication adherence level as a control variable. This was because medication management ability is highly associated with cognitive functioning among the elderly.22-26
This poses a unique problem for dementia prevention studies because 1) participants are usually non-institutionalized elderly volunteers and their medication adherence cannot be fully controlled, 2) those with subclinical dementia might experience a decline in medication adherence prior to the clinical manifestation of the disease, and 3) depression which was shown to be a premorbid condition or a risk factor of dementia27
could also affect medication adherence.28-30
That is, lower adherence would decrease the benefit of GBE, but a lower adherence level is associated with declining cognitive abilities. Thus, it is difficult to evaluate the efficacy of the active agent. Additionally, the potentially very high correlation between study outcome and average medication adherence level during the follow-up, for example, would mask the effect of preventive agents on the outcome. How to best examine efficacy of an active agent in the face of potential development of memory decline that impairs treatment adherence in dementia prevention studies is an important challenge. If the duration of surveil-lance prior to developing dementia was sufficiently long, one could take the average medication adherence levels at least several years prior to the dementia incidence, assuming that subjects were free from subclinical stage disease during these years. It will be important in future prevention trials to incorporate such considerations into the design and analysis strategies of these studies.
Under all circumstances methods to facilitate and increase adherence in dementia prevention trials will be critical. One simple goal is, where possible, to use once a day dosing. The optimal dosing regimen for GBE is not known.6
In our study, we used three times a day dosing and found the overall mean medication adherence level defined as the average percentage of pills taken during the first 6 months was 84%. Over 68% of study participants met our criteria for being adherent (80% or higher and 110% or lower based on pill counts) during the first 6 months regardless of whether they were taking active drug or placebo. This is very similar to three times a day dosing adherence rates found in a systematic review of 57 studies of medication adherence in younger populations using electronic monitors.31
Although age has not been a significant correlate of adherence in other analyses,32
our study extends the age range well beyond that in most of the earlier studies and further demonstrates the feasibility of conducting trials in the oldest old.
The suggestive results of a protective effect of GBE found in our study needs to be confirmed by ongoing larger prevention studies such as the Ginkgo Evaluation of Memory study in the US21
and the European GuidAge study.20
To our knowledge, our study is the first to report the results of a dementia prevention RCT among oldest old subjects. The results suggest that this population should not be excluded because of preconceived notions of frailty, poor adherence, or confounding medical problems, but to the contrary, may be a highly informative group to study especially in initial early phase II prevention designs because of their higher susceptibility to dementia and growing relevance to the demographics of those most affected with dementia. More stroke and TIA cases were observed among the GBE group, which requires further study in other GBE prevention trials.