The flow diagram for all participants randomized to either placebo (n=1524) or G biloba (n=1545) is shown in the . There was no difference between treatment groups in the number of participants who did not contribute longitudinal neuropsychological data (180 G biloba and 198 placebo participants; P=.25). Median follow-up time was 6.1 years (maximum, 7.3 years). Cumulative study drug adherence did not differ between assigned treatments, with 60.3% of all active participants taking their assigned study medications at the end of the trial. The percentage of participants who were nonadherent at each visit ranged from 3% to 8.5% throughout the study. Participants were considered nonadherent at the time of a scheduled visit if any of the following criteria were met: (1) they refused further participation in the study; (2) they took less than 50% of the study pills for 2 consecutive visits; or (3) they missed 2 consecutive visits or consecutively missed 1 visit and took less than 50% of pills at 1 visit.
Flow of Participants Through the Ginkgo Evaluation of Memory Study and Longitudinal Cognitive Decline Analysis
The mean age at randomization was 79.1 years (range, 72-96 years), and 54% of participants were men (). Self-reported race was 95.5% white (n=2930), 2.9% African American (n=90), 0.9% Asian/Pacific Islander (n=28), and 0.7% other (n=21). Education was reported as 12 or fewer years by 36.0% of participants (n=1104) and 16 years or more by 38.0% (n=1190). The treatment groups did not differ with respect to age, sex, years of education, MCI status at baseline, or APOE*E4 status. The placebo group performed better than the G biloba group on the California Verbal Learning Test delayed recall (P=.04), WAIS-R Block Design (P=.007), and Stroop interference (P=.02) tests at baseline; scores on the other 7 neuropsychological tests and the 3MSE and ADAS-Cog did not differ by treatment group. Although relatively few were enrolled, the placebo group had more African Americans than the G biloba group (3.5% vs 2.3%; P=.05).
Baseline Characteristics of Study Participants by Study Drug Assignment
shows the primary results of the analysis for cognitive decline. On average, test performance was worse with increasing time since randomization. Average scores did not differ by treatment group. The G biloba
and placebo groups did not differ in rates of cognitive change for the global cognition score or any of the cognitive domains, as indicated by the treatment×time coefficient, which represents the average annual difference in slopes between treatment groups. We found no significant effect modification by age, sex, race, APOE
status, education, or MCI status at baseline (P
>.05). The eTable
(available at http://www.jama.com
) presents full model estimates. shows estimated annual rates of change for all individual neuropsychological test scores in their original scales. Mean scores for representative neuropsychological tests in their original scales are shown in eFigure 1
. While the actual values reflect the different reasons for administering the tests (for diagnostic purposes to year 4, then routinely), the lack of differences between treatment groups is apparent.
Results of Linear Mixed Models for Each Cognitive Domain and Global Cognitiona
Annual Rates of Change for Individual Neuropsychological Test Scores by Study Drug Assignmenta
Neuropsychological tests were given only for diagnostic reasons up to approximately year 4. However, the 3MSE and ADAS-Cog were administered throughout the study, so these results were analyzed as well. Estimated annual rates of 3MSE change among participants without MCI at baseline were −0.25 (95% confidence interval [CI], −0.31 to −0.20) and −0.27 (95% CI, −0.32 to −0.22) points per year in the placebo and G biloba
groups, respectively (P
=.71 for difference by treatment). Those with MCI at baseline scored lower initially and declined more quickly, with annual rates of change of −0.44 (95% CI, −0.57 to −0.31) and −0.59 (95% CI, −0.71 to −0.47) in the placebo and G biloba
groups, respectively. Observed 3MSE mean scores are shown in eFigure 2
. A test for modification of the association of treatment with decline by MCI status was suggestive (P
=.06), but stratified analyses found no effect of treatment on rate of change in either those with (P
=.48) or without (P
=.96) MCI at baseline. Similar analyses of ADAS-Cog data showed no association of treatment with rate of change (P
=.97). The annual rate of ADAS-Cog change was 0.13 (95% CI, 0.10-0.16) for participants without MCI at baseline and 0.32 (95% CI, 0.27-0.38) for those with MCI at baseline regardless of treatment group. Observed ADAS-Cog mean scores are shown in eFigure 3
In a secondary analysis, the baseline was shifted to study year 6, thereby excluding the period when neuropsychological evaluations were administered only as part of diagnosis (to participants who had positive results on the screening tests). Results of this secondary analysis were consistent with the primary analysis results; rates of cognitive change for all domains and for the global score did not differ by treatment group (all P>.50).
The adverse event profiles for the G biloba
and placebo groups were similar and the rates of serious adverse events, including mortality and incidence of coronary heart disease, stroke of any type, and major bleeding, did not differ significantly. Complete rates of adverse and serious adverse events were published previously.1