Marina Ritchie

Background: Amid recent approvals, early Alzheimer’s disease (AD) remains an active area of treatment development, but research on the utility of recruitment incentives in early AD trials remains limited. We examined how trial design features impact enrollment decisions among Mild Cognitive Impairment (MCI) patients and their family members.Method: We performed a conjoint analysis experiment to compare early AD patients’ preferences for trial features. Individuals with MCI were asked to rate their willingness to participate in a series of trial scenarios (using a 7‐point ordered scale) that varied in four pre‐selected factors, each with two levels. Three trial incentives were included: 1) active‐control design with participants randomized to an investigational anti‐amyloid therapy or aducanumab (vs. placebo control), 2) tau PET disclosure (vs. no return of tau PET results), and 3) remote study partner participation (vs. required in‐person study partner participation). We included one negative control (5% vs. 25% risk of brain swelling). We used a generalized estimating equations (GEE) model to account for within‐subject correlation and to assess the utility of the differing factor levels. An exchangeable working correlation structure was used for parameter estimation, and robust variance estimates for model coefficient estimates were used for final inference.Result: Among 26 patients with MCI (mean [SD] age 78.3 [8.2], 31% female, 85% non‐Hispanic White), returning tau PET results had the highest utility (est: 0.47; CI: 0.13, 0.81; p = 0.007). Trials with the option for remote study partner participation showed a similar trend in utility (est: 0.29; CI: ‐0.05, 0.63; p = 0.097). Trials with active‐controlled design (est: 0.01; CI: ‐0.33, 0.35; p = 0.956 did not demonstrate significant utility and trials with higher risk of brain swelling had a negative utility (est: ‐0.64; CI: ‐0.99, ‐0.30; p<0.001) (Figure 1).Conclusion: These findings suggest that returning biomarker results may have a greater impact on participant enrollment decisions than would use of active‐controlled designs or providing the option for study partners to participate remotely.

Background: Participant retention is a key determinant for a successful clinical trial. In Alzheimer’s disease (AD) trials, participants are typically required to enroll with a study partner, which adds barriers to retention. Previous analyses of North American trial data found that most study partners were spouses and that such dyads had higher study completion rates than other study partner types. We sought to determine whether these findings could be confirmed in additional trials conducted across broader geographic regions.Method: Our post‐hoc analyses used data from two phase II trials of semorinemab, Tauriel (prodromal‐to‐mild AD; NCT03289143) and Lauriet (mild‐to‐moderate AD; NCT03828747), we examined the proportion of participants completing the trials by study partner type (Domestic Partner vs. Other) and geographical region (North America and Europe). We fit logistic regression models to assess whether participant retention differed by study partner type in the two trials (separately and combined) and adjusted the models for region, study partner type, participant age, sex, education, APOE4 status, and study partner sex. We considered potential effect modification by region by including an interaction term between study partner type and region. We conducted sensitivity analyses excluding participants who discontinued based on adverse events or death.Result: We observed effect modification by region in the association between study partner type and retention (Tauriel: p = 0.011, Lauriet: p = 0.015; combined: p = 0.003). In Europe, Other study partner types had significantly lower odds of trial completion compared to domestic partners in Tauriel (OR: 0.21; CI: 0.06, 0.74) and in the combined analysis (OR: 0.28; CI: 0.11, 0.65). While not statistically significant, we observed similar trends in Lauriet (OR: 0.36; CI: 0.10, 1.22). No clear differences in retention were observed across study partner types in North America for either trial.Conclusion: Data from the two semorinemab trials suggest that there may be regional differences in the impact of study partner type on retention. Further studies are needed to assess the generalizability of these findings, with an emphasis on cohorts with more representative samples of non‐spousal dyads.

Background: Clinical outcome assessments (COAs) that measure functional capacities are key tools to evaluate efficacy in Alzheimer’s disease (AD) clinical trials. The Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS‐ADL) scale is frequently used to assess changes in both basic and instrumental activities of daily living, but there is no clear consensus on what magnitude of change on this scale may be considered clinically meaningful. To address this question, we conducted anchor‐based analyses (as recommended by the FDA) to explore meaningful within‐patient/participant change thresholds on the ADCS‐ADL.Methods: Our anchor‐based analyses (and supportive distribution‐based analyses) used data from two phase 2 semorinemab trials, Tauriel (NCT03289143; early AD) and Lauriet (NCT03828747; mild‐to‐moderate AD). The Caregiver Global Impression of Change‐Alzheimer’s Disease (CaGI‐Alz), a caregiver‐reported measure on subjective change in participant function, served as the anchoring scale. To determine if anchor‐based analyses were appropriate, we first examined correlations between the ADCS‐ADL change scores and CaGI‐Alz ratings at Weeks 25 and 49 for both trials, along with Week 61 for Lauriet, and Week 73 for Tauriel. To determine meaningful change thresholds, we analyzed the mean changes on the ADCS‐ADL for participants rated as performing “somewhat worse” on CaGI‐Alz. Those rated as demonstrating“no‐change” were used for comparison.Results: Correlations between the ADCS‐ADL and the CaGI‐Alz scales were consistently stronger at Week 49 and later time points (Table 1). For those rated as “somewhat worse,” mean decline on the ADCS‐ADL ranged from approximately 5 to 8 points across time points, and uniformly exceeded distribution‐based thresholds. Larger declines on the ADCS‐ADL were associated with “somewhat worse” ratings in patients in Lauriet (mild‐to‐moderate AD) compared to Tauriel (early AD) and at later time points in both trials (Table 2). Patients rated as “no change” by the caregiver experienced some decline on the ADCS‐ADL, although generally less than the declines seen in those rated “somewhat worse.”Conclusion: The anchor‐ and distribution‐based approaches suggest that clinically meaningful change on the ADCS‐ADL may be greater than the 2 points that has previously been postulated (Dysken et al., 2014). Higher change thresholds may be required to reflect meaningful changes perceptible to caregivers.

Many cognitively unimpaired older adults are interested in learning their Alzheimer’s disease (AD) biomarker status, but little is known about motiva

INTRODUCTION: Amid recent approvals, early Alzheimer's disease (AD) remains an active area of treatment development.METHODS: We performed a conjoint experiment to compare preferences among 26 patients with mild cognitive impairment for four trial features including designs incorporating active aducanumab‐control (vs. placebo), returning tau positron emission tomography (PET) results (vs. no disclosure), remote study partner participation (vs. in person), and increased risk of brain swelling (vs. lower risk). We used a generalized estimating equation to model the utility of factor levels.RESULTS: Returning tau PET results had the highest utility (est: 0.47; 95% confidence interval [CI]: 0.13, 0.81; P = 0.007); remote study partner participation showed a similar trend (est: 0.29; 95% CI: −0.05, 0.63; P = 0.097). Trials with active‐controlled design (est: 0.01; 95% CI: −0.33, 0.35; P = 0.956) did not demonstrate utility and higher risk of brain swelling had negative utility (est: −0.64; 95% CI: −0.99, −0.30; P < 0.001).DISCUSSION: Returning additional biomarker results may increase willingness to enroll in early AD trials.Highlights: We compared mild cognitive impairment participant preferences for four trial design features. Returning tau positron emission tomography results had the highest utility. Remote study partner participation showed a positive, albeit non‐significant, trend. No utility was observed for an active aducanumab‐control design.

The recent FDA approval of amyloid-lowering drugs is changing the landscape of Alzheimer disease (AD) clinical practice. Previously, apolipoprotein E (APOE) genetic testing was not recommended in the care of people with AD because of limited clinical utility. With the advent of amyloid-lowering drugs, APOE genotype will play an important role in guiding treatment recommendations. Recent clinical trials have reported strong associations between APOE genotype and the safety and possibly the efficacy of amyloid-lowering drugs. Therefore, a clinical workflow that includes biomarker and genetic testing should be implemented to provide patients with the opportunity to make informed decisions and instruct safety monitoring for clinicians. Pretest consent, education, and counseling will be an essential aspect of this process for patients and their family members to understand the implications of these tests and their results. Given that the approved amyloid-lowering drugs are indicated for patients with mild cognitive impairment or mild dementia with biomarker evidence of AD, biomarker testing should be performed before genetic testing and genetic testing should only be performed in patients interested in treatment with amyloid-lowering drugs. It is also important to consider other implications of genetic testing, including burden on and need for additional training for clinicians, the role of additional providers, and the potential challenges for patients and families.

INTRODUCTION: Trialists need a thorough understanding of whether reactions to Alzheimer's disease (AD) biomarker information differ among racial and ethnic groups in preclinical AD trials.METHODS: We used data from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease Study to analyze cognitively unimpaired participants’ responses on the Impact of Event Scale (IES) 24 to 72 hours after amyloid disclosure. We fit a linear regression model to test whether mean IES scores differed among participants from specific racial and ethnic groups. We considered potential effect modification by amyloid status.RESULTS: Reactions to disclosure did not significantly differ among participant groups based on self‐reported race and ethnicity. Although the results were not significant when stratified by amyloid status, all racial and ethnic groups except for participants self‐reporting Hispanic/Latino ethnicity were observed to have higher mean IES in the elevated amyloid group.DISCUSSION: These results support continued use of current disclosure methods in preclinical AD trials.

Background: Participant retention is a key factor that affects clinical trial integrity. Trial protocols estimate attrition as a function of sample size calculations. Alzheimer’s disease (AD) is an area of active treatment development. We aimed to quantify the association between trial duration and completion rates and provide guidance for estimating attrition in AD trial protocols. Methods: Using the Alzforum and ClinicalTrials.gov databases, we analyzed retention data from 125 mild-to-moderate AD and 12 mild cognitive impairment (MCI) clinical trials. We compared the rates of completion between trial arms (active vs. control) and ran regression models to test the hypothesis that trials with longer study duration have lower trial completion using all available data and restricting to placebo data. Our primary outcome was the odds of trial completion for a 6-month increase in trial duration. From the regression model, we estimated the proportion of participants completing 6-, 12-, and 18-month trials. Results: We found that 21 (17%) mild-to-moderate AD trials and 1 (8%) MCI trial demonstrated greater dropout in treatment compared to placebo arms. For every 6-month increase in trial duration, there was a 27% decrease in the odds of trial completion (OR = 0.73; 95% CI 0.66, 0.81; p < 0.001) among participants in mild-to-moderate AD trials and a 55% decrease (OR = 0.45; 95% CI 0.36, 0.57; p < 0.001) among participants in MCI trials. The proportion of participants in the placebo group completing 6-, 12-, and 18-month trials were estimated to be 85.2%, 80.0%, and 73.3% for mild-to-moderate AD trials and 91.9%, 84.2%, and 71.3% for MCI trials, respectively. Conclusions: Longer duration trials may be underpowered to demonstrate estimated treatment effects and may suffer from a greater risk of bias than do shorter trials.

Timely accrual of a representative sample is a key factor in whether Alzheimer’s disease (AD) clinical trials successfully answer the scientific questions under study. Studies in other fields have observed that, over time, recruitment to trials has become increasingly reliant on larger numbers of sites, with declines in the average per-site recruitment rate. Here, we examined the trends in recruitment over a 20-year period of NIH-funded AD clinical trials conducted by the Alzheimer’s Disease Cooperative Study (ADCS), a temporally consistent network of sites devoted to interventional research. We performed retrospective analyses of eleven ADCS randomized clinical trials. To examine the recruitment planning, we calculated the expected number of participants to be enrolled per site for each trial. To examine the actual trial recruitment rates, we quantified the number of participants enrolled per site per month. No effects of time were observed on recruitment planning or overall recruitment rates across trials. No trial achieved an overall recruitment rate greater than one subject per site per month. We observed the fastest recruitment rates in trials with no competition and the slowest in trials that overlapped in time. The highest recruitment rates were consistently seen early within trials and declined over the course of studies. Trial recruitment projections should plan for fewer than one participant randomized per site per month and consider the number of other AD trials being conducted concurrently.

Background: Participant retention directly affects the validity and generalizability of clinical trial results. Investigators need information about expected attrition when planning trials of varying durations.Method: Using the Alzforum and clinicaltrials.gov databases we reviewed 351 phase 2 and 3 placebo‐controlled trials conducted since 1998. Eighty‐six mild‐to‐moderate Alzheimer’s disease (AD) and eleven Mild Cognitive Impairment (MCI) trials met criteria for inclusion in this study. We first assessed the frequency with which trial arms differed in overall retention. When trials included more than one active arm, we combined those arms into a single group. To model associations between trial duration and retention, we used binomial regression.Result: Figure 1 illustrates differences in the observed proportion of participants completing in each trial between active and placebo arms for mild‐to‐moderate AD (Figure 1A) and MCI trials (Figure 1B). For each trial, a 95% confidence interval for the true difference between arms is provided. Since there was no consistent difference between arms, subsequent analyses combined active and placebo arms. Figure 2 illustrates the completion rate by trial duration for mild‐to‐moderate AD (Figure 2A) and MCI trials (Figure 2B). A local smoother along with uncertainty regions is added for visual aid. In general, trials with longer study duration had lower retention rates. Using binomial regression with robust variance estimates to account for within‐trial correlation, we estimated that a 6‐month increase in trial duration is associated with a 34% decrease in the odds of trial completion (OR=0.66; 95% CI: 0.58, 0.75; p<0.001) among mild‐to‐moderate AD trials and a 20% decrease (OR=0.80; 95% CI: 0.68, 0.93; p=0.004) among MCI trials. From the binomial regression model, the proportion of participants completing 6, 12, and 18‐month trials were estimated to be 82.9%, 76.3%, and 68.0% for mild‐to‐moderate AD trials and 82.6%, 79.1%, and 75.2% for MCI trials, respectively.Conclusion: While decisions related to expected trial attrition are guided by several factors, these estimates may assist investigators designing trials and suggest that trial attrition is frequent and related to trial duration.