Of the 769 subjects randomized into the trial, 214 incident dementias were observed, 325 subjects completed the 36 month trial without converting to dementia, and 230 (30%) did not complete the closed-label phase of the trial. Of the 230 non-completers, 17 subjects died, 47 were discontinued by site clinicians due to adverse events, 105 withdrew consent during the trial, 55 discontinued treatment and ultimately withdrew consent during the trial, and six moved or otherwise refused further contact. Study discontinuation occurred within the first six months for 117 subjects and within the first year for 172 subjects. Over four-fifths of those lost (193, 83.9%) dropped by month 18, with 9.6%, 5.7%, and 0.9% dropping in each of the remaining six month intervals. Overall, the mean length in study was 23.2 months (standard deviation (sd) 13.4), with subjects who discontinued completing an average of 9.5 months (sd 8.9) of follow-up, compared to 18.4 months (sd 9.1) for incident dementia cases and 36.0 (sd 0.4) for those who completed the closed-label portion of the trial without converting to dementia.
Baseline characteristics by discontinuation status are presented in . Subjects who dropped were different from those who continued in the study on several demographic measures. In univariate analyses, risk of study discontinuation was higher among females (HR: 1.36, p=0.020), among non-white subjects compared to white, non-Hispanic subjects (HR: 2.12, p<0.001), and among those with less than high school education (HR: 1.51, p=0.047). Rates of study discontinuation were highest at commercial sites (43.8%), and lowest at ADCs (23.0%, p<0.001). University-affiliated sites had slightly higher rates of study discontinuation compared to ADCs (28.5%, p=0.150). Subjects who were married had lower rates of study discontinuation than their unmarried counterparts (27.0% vs 39.8%, p=0.001). Only one clinical measure was a statistically significant predictor of study discontinuation in the univariate analysis: subjects with a Ham-D score of ≥6 to 12 were more likely to discontinue than subjects scoring < 6 (HR: 1.6, p=0.004). Subjects in the donepezil arm were more likely to discontinue than subjects in the placebo arm (HR: 2.2, p<0.001).
Univariate Comparisons of Baseline Measures with Study Discontinuation (SD).
Per our pre-specified model building algorithm, covariates selected for the final multivariate model based on a univariate log-rank test p-value < 0.1 were treatment arm, site classification, marital status/informant relationship, education, gender, race/ethnicity, and HAM-D score. Age was not significantly related to study discontinuation at the p<0.1 level, but was forced into the model. Of potential pairwise interactions, only the gender by marital status term was statistically significant (likelihood ratio test p-value < 0.0001); this interaction was added to the model using married men as the referent gender by marital status category. The two measures with univariate p-values between 0.1 and 0.15, the Beck Informant Depression Scale and the primary language indicator, were added separately to the model and tested for significance. Neither significantly improved the model (likelihood ratio test p-values > 0.3), nor did their inclusion modify coefficients of covariates already in the model by more that 15%, and therefore these terms were not included in the final model. Proportional hazards assumptions were not rejected for any terms in the model (p>0.3).
The final multivariate model is presented in . Hazard ratios and p-values in the full multivariate model are largely consist with those observe in the univariate analyses, although in the final model we observe that the effect of marital status on discontinuation is present only within men (HR=2.24, p=0.001 for unmarried versus married men). The gender effect remains, but individual terms in the final model comparing married and unmarried women to the referent married men category are not statistically significant because of the reduced per comparison sample size. If these two female categories are pooled, the gender effect is statistically significant (HR=1.34, p=0.044 for women versus married men).
Multivariate Cox Proportional Hazards Model of Time to Study Discontinuation*.
When we reran the model censoring subjects who died rather than counting them as study discontinuation events, the coefficients and p-values for all of the statistically significant predictors in were not appreciably changed except for the HAM-D term, which was attenuated and no longer a significant predictor of study discontinuation (HR 1.21, p=0.27). When we reran the model further censoring both deaths and other serious adverse events, the coefficients for all of the significant predictors were not appreciably changed, although in this model the p-value for the education less than high school term became only marginally statistically significant (p-value changing from 0.02 to 0.07 after censoring of deaths and other serious adverse events).
The final disposition of study subjects is summarized by type of clinical recruitment site in . Subjects recruited by commercial sites were less likely to convert to dementia, and more likely to die or discontinue compared to non-commercial sites. Reasons for voluntary study discontinuation by type of clinical recruitment site are summarized in . “Caregiver unwilling or unable to participate” was the most commonly sited reason, scored by 35 of 160 caregivers (22%). There were no significant differences in the frequency of reasons by site type, although there was a trend toward subjects recruited by commercial sites discontinuing because of concern that the treatment medication was not effective (p = 0.07) and a trend toward subjects recruited by non-commercial sites discontinuing because of travel requirements (p = 0.06).
Final Disposition of Study Subjects, by Clinical Site Type.
Reasons for Voluntary Study Discontinuation, by Clinical Site Type.