Background

In randomized clinical trials (RCTs), monitoring adverse events (AEs) and serious AEs (SAEs) is critical. All Alzheimer's disease (AD) RCTs require participants to enroll with a study partner.

Objective

We examined AE reporting rates in mild-to-moderate AD trials and their associations with study partner type.

Methods

We estimated AE reporting rates using placebo data from seven independent RCTs conducted by the Alzheimer's Disease Cooperative Study. We assessed the heterogeneity of reporting rates as a function of visits using generalized estimating equations. In the primary analysis, we tested the hypotheses that the rates of reporting differed by study partner type and time they spent with the participant weekly using Poisson regression with robust variance estimation. In all regression models, log-transformed total patient years was included.

Results

The estimated reporting rates were 2.83 (95% CI: 2.66, 3.02), 1.18 (95% CI: 1.09, 1.28), 0.23 (95% CI: 0.19, 0.27), and 0.28 (95% CI: 0.24, 0.33) events per participant year for grade 1-3 AEs and SAEs, respectively. We estimated that greater number of visits per year was associated with increased reporting for grade 1-2 AEs and SAEs. We did not find evidence to suggest that AE reporting differed by study partner type or by time the study partner spent with the participant.

Conclusions

Study partner type and time the study partner spent with the participant did not appear to impact AE reporting. Estimated reporting rates may be useful to evaluate safety in future studies, particularly those with no control arm and similar visit frequencies.

Background

Dyadic enrollment of a participant and study partner is required in mild cognitive impairment (MCI) clinical trials, despite participants being functionally independent. Research examining how the study partner requirement impacts MCI trials remains limited.

Methods

Using the Alzheimer's Disease Cooperative Study donepezil and vitamin E MCI trial data, we quantified the proportions of enrolled spouse, adult child, and other dyads. We used multinomial regression to identify which baseline participant characteristics (age, sex, race and ethnicity, apolipoprotein E ε4 status, education, residence type) were associated with dyad type.

Results

Among 769 randomized dyads, 73% were spousal, 14% adult child, and 13% other dyads. Adjusting for multiple comparisons, underrepresented racial and ethnic background (eg, comparing Hispanic to non-Hispanic White participants: adult child vs. spouse odds ratio = 5.86; 95% confidence interval: 2.09, 16.5; other vs. spouse odds ratio = 4.95; 95% confidence interval: 1.83, 13.4), female sex, age, nonhouse residence, and apolipoprotein E ε4 noncarriage were each associated with a higher odds of having an adult child, as well as an other, study partner at enrollment.

Discussion

Increasing participation among nonspousal dyads may facilitate more inclusive and representative MCI trial samples.

Background

Missing data are a notable problem in Alzheimer's disease clinical trials. One cause of missing data is participant dropout. The Research Attitudes Questionnaire is a 7-item instrument that measures an individual's attitudes toward biomedical research, with higher scores indicating more favorable attitudes. The objective of this study was to describe the performance of the Research Attitudes Questionnaire over time and to examine whether Research Attitudes Questionnaire scores predict study dropout and other participant behaviors that affect trial integrity.

Methods

The Research Attitudes Questionnaire was collected at baseline and weeks 26 and 52 from each member of 119 participant/study partner dyads enrolled in a Phase 2, randomized, double-blind, placebo-controlled mild-to-moderate Alzheimer's disease clinical trial. Within-subject longitudinal analyses examined change in Research Attitudes Questionnaire scores over time in each population. Logistic regression analyses that controlled for trial arm and clustering in trial sites were used to assess whether baseline Research Attitudes Questionnaire scores predicted trial completion, study medication compliance, and enrollment in optional substudies.

Results

Participants and study partners endorsed statistically similar ratings on the Research Attitudes Questionnaire that were stable over time. Participants with baseline Research Attitudes Questionnaire scores above 28.5 were 4.7 (95% confidence interval = 1.01 to 21.95) times as likely to complete the trial compared to those with lower scores. Applying the same cutoff, baseline study partner Research Attitudes Questionnaire scores were similarly able to predict study completion (odds ratio = 4.2, 95% confidence interval = 1.71 to 10.32). Using a score cutoff of 27.5, higher participant Research Attitudes Questionnaire scores predicted study medication compliance (odds ratio = 5.85, 95% confidence interval = 1.34 to 25.54). No relationship was observed between Research Attitudes Questionnaire score and participation in optional substudies.

Conclusion

This brief instrument that measures research attitudes may identify participants at risk for behaviors that cause missing data.

Context

Several reports from small clinical trials have suggested that estrogen replacement therapy may be useful for the treatment of Alzheimer disease (AD) in women.

Objective

To determine whether estrogen replacement therapy affects global, cognitive, or functional decline in women with mild to moderate AD.

Design

The Alzheimer's Disease Cooperative Study, a randomized, double-blind, placebo-controlled clinical trial conducted between October 1995 and January 1999.

Setting

Thirty-two study sites in the United States.

Participants

A total of 120 women with mild to moderate AD and a Mini-Mental State Examination score between 12 and 28 who had had a hysterectomy.

Interventions

Participants were randomized to estrogen, 0.625 mg/d (n = 42), or 1.25 mg/d (n = 39), or to identically appearing placebo (n = 39). One subject withdrew after randomization but before receiving medication; 97 subjects completed the trial.

Main outcome measures

The primary outcome measure was change on the Clinical Global Impression of Change (CGIC) 7-point scale, analyzed by intent to treat; secondary outcome measures included other global measures as well as measures of mood, specific cognitive domains (memory, attention, and language), motor function, and activities of daily living; compared by the combined estrogen groups vs the placebo group at 2, 6, 12, and 15 months of follow-up.

Results

The CGIC score for estrogen vs placebo was 5.1 vs 5.0 (P = .43); 80% of participants taking estrogen vs 74% of participants taking placebo worsened (P = .48). Secondary outcome measures also showed no significant differences, with the exception of the Clinical Dementia Rating Scale, which suggested worsening among patients taking estrogen (mean posttreatment change in score for estrogen, 0.5 vs 0.2 for placebo; P = .01).

Conclusions

Estrogen replacement therapy for 1 year did not slow disease progression nor did it improve global, cognitive, or functional outcomes in women with mild to moderate AD. The study does not support the role of estrogen for the treatment of this disease. The potential role of estrogen in the prevention of AD, however, requires further research.

Objective

A randomized, placebo-controlled, double-blind, multicenter 52-week phase 2 trial of resveratrol in individuals with mild to moderate Alzheimer disease (AD) examined its safety and tolerability and effects on biomarker (plasma Aβ40 and Aβ42, CSF Aβ40, Aβ42, tau, and phospho-tau 181) and volumetric MRI outcomes (primary outcomes) and clinical outcomes (secondary outcomes).

Methods

Participants (n = 119) were randomized to placebo or resveratrol 500 mg orally once daily (with dose escalation by 500-mg increments every 13 weeks, ending with 1,000 mg twice daily). Brain MRI and CSF collection were performed at baseline and after completion of treatment. Detailed pharmacokinetics were performed on a subset (n = 15) at baseline and weeks 13, 26, 39, and 52.

Results

Resveratrol and its major metabolites were measurable in plasma and CSF. The most common adverse events were nausea, diarrhea, and weight loss. CSF Aβ40 and plasma Aβ40 levels declined more in the placebo group than the resveratrol-treated group, resulting in a significant difference at week 52. Brain volume loss was increased by resveratrol treatment compared to placebo.

Conclusions

Resveratrol was safe and well-tolerated. Resveratrol and its major metabolites penetrated the blood-brain barrier to have CNS effects. Further studies are required to interpret the biomarker changes associated with resveratrol treatment.

Classification of evidence

This study provides Class II evidence that for patients with AD resveratrol is safe, well-tolerated, and alters some AD biomarker trajectories. The study is rated Class II because more than 2 primary outcomes were designated.