Estimating attrition in mild-to-moderate Alzheimer’s disease and mild cognitive impairment clinical trials

Participant retention directly affects the validity and generalizability of clinical trial results. Greater than anticipated dropout can lead to failed futility analyses, extended or prematurely terminated trials, and invalid or biased results [1‐3]. Trials with greater than anticipated dropout are also at risk of being underpowered and unethical [4]. Guidelines from the American Academy of Neurology classify trial results with lower than 80% participant retention to be lower-quality evidence [5]. Accounting for anticipated dropout is critical to ensuring sufficient statistical power to detect an intervention effect if one exists [4, 6]. Research investigating how trial design features impact retention, however, remains limited. For example, limited information is available for expected attrition for trials of varying durations. There is a need for evidence-based retention estimates to guide trialists. To provide such estimates, we examined the impact of trial duration on study completion in mild-to-moderate Alzheimer’s disease (AD) and mild cognitive impairment (MCI) trials. AD is an active area of drug development and trials in this area face unique challenges in participant retention [7].

Using the AlzForum and ClinicalTrials.gov databases, we reviewed phase II and phase III placebo-controlled trials conducted between 1995 and 2022 (Table 1). We included parallel design trials with results available on ClinicalTrials.gov or in a peer-reviewed publication and excluded trials that terminated before completion. Trials with primary outcome measures that could add heterogeneity to our estimates (i.e., depression, sleep disturbance, agitation, psychosis) were excluded. We also excluded randomized withdrawal trials, crossover design studies, and trials with a primary outcome of time to conversion. When trials had a range of possible follow-up durations, we used the average reported duration. Trials with two cohorts of different trial durations were included as separate data points. We assessed only the double-blind phase of a study. We categorized trials into MCI or mild-to-moderate AD. The MCI analyses included studies that enrolled participants with MCI (based exclusively on clinical and cognitive diagnostic criteria) or “prodromal AD” (diagnostic criteria for MCI plus a biomarker for AD). Mild-to-moderate AD analyses included trials enrolling participants with “early AD” (frequently including mild dementia and MCI with a biomarker for AD), “mild AD dementia,” and “mild-to-moderate AD dementia” (typically based on diagnostic criteria and scores on the Mini-Mental State Exam).

One hundred twenty-five mild-to-moderate AD and twelve MCI trials met the criteria for inclusion in this study. Three mild-to-moderate AD trials did not report differences in completion by treatment arms. We found that 21 mild-to-moderate AD trials and 1 MCI trial demonstrated greater dropout in the treatment arm (Fig. 1). No trials were observed to have greater dropout in the placebo arm.

Trials with longer study duration had lower retention (Fig. 2). Using binomial regression with robust variance estimates to account for within-trial correlation, we estimated that a 6-month increase in trial duration was associated with a 27% decrease in the odds of trial completion (OR = 0.73; 95% CI 0.66, 0.81; p < 0.001) among mild-to-moderate AD trials and a 55% decrease (OR = 0.45; 95% CI 0.36, 0.57; p < 0.001) among MCI trials. In regression models including participants in both treatment and placebo groups, completion rates for 6-, 12-, and 18-month trials were estimated to be 82.6%, 77.5%, and 71.4% for mild-to-moderate AD trials and 91.7%, 83.3%, and 69.3% for MCI trials, respectively. In models including only participants in placebo groups, the completion rates for 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. In exploratory analyses, we observed fairly consistent associations between trial duration and completion rates for subgroups of mild-to-moderate AD trials (sample size prevented subgroup analyses in MCI trials). Rates were similar for phase II (n = 84; OR = 0.72; 95% CI 0.59, 0.88; p = 0.002) and phase III (n = 39; OR = 0.74; 95% CI 0.66, 0.83; p < 0.001) trials; for disease-modifying (n = 89; OR = 0.77; 95% CI 0.69, 0.87; p < 0.001) and symptomatic (n = 35; OR = 0.42; 95% CI 0.15, 1.22; p = 0.1094) trials; and for single-site (n = 17; OR = 0.81; 95% CI 0.60, 1.08; p = 0.153) and multi-site (n = 107; OR = 0.73; 95% CI 0.66, 0.81; p < 0.001) trials (Additional file 1: Fig. S1).

In this analysis of MCI and mild-to-moderate AD trials, we found that participant retention was negatively associated with trial duration. The proportions 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. Trials with a duration greater than 6 months that incorporate common attrition estimates of 10% per year or 20% overall, therefore, may be at risk of being underpowered. This is concerning, since AD trials have increased in length over time [8].

While trials in both diagnostic groups presented similar patterns of attrition with increasing duration, mild-to-moderate AD trials were estimated to have lower completion estimates at 6- and 12-months while MCI trials were estimated to have lower completion rates at 18 months. Age may be a risk factor for participant dropout [9, 10], and participants in the mild-to-moderate AD trials are likely to be older than those in MCI trials [11]. AD is also a progressive disease. Previous examinations of data from NIH-funded Alzheimer’s Disease Research Centers (ADRC) identified worsening cognitive impairment as a risk factor for dropout [12]. This may be most relevant in longer MCI trials, where cognitive decline may be accompanied by the onset of functional impairment.

AD trial participants must co-enroll with a study partner [7]. Longer trials bring an added burden for dyads and may require more careful planning and resources to reduce modifiable barriers to trial completion [13]. For example, a previous study observed an association between the number of retention tactics used at NIH-funded ADRCs and rates of retention at 1 and 2 years [14]. Trials that require longer participation may also benefit from adjusting other study design features like reducing/replacing high-burden assessments (e.g., lumbar puncture) and increasing motivating factors such as returning test results [15] and even financial bonuses for trial completion [16].

While our study underscores the association between trial duration and retention, trial duration decisions are complex. For example, financial considerations may influence duration decisions [17]. Trials with objectives related to pharmacodynamics and pharmacokinetics may require shorter durations. Trials that enroll participants at earlier stages of the disease (e.g., MCI or early AD) may observe less change over time, therefore requiring longer durations [18, 19]. Our results suggest relatively similar associations between duration and retention between MCI and dementia trials. Symptomatic agents may produce measurable effects more rapidly, requiring shorter durations, while disease-modifying treatments may require a longer duration to detect measurable attenuation of AD progression [18]. Though the association with duration was similar between symptomatic and disease-modifying trials here, we note that symptomatic trials were heavily skewed toward shorter durations. We also found similar associations between phase II and phase III trials and between single- and multi-site trials. Overall, trial duration should not be determined based on anticipated retention rates; however, our findings suggest that duration does impact retention and can provide valuable insights into projected retention rates for investigators during the design stage.

While decisions related to expected trial attrition are guided by several factors, these estimates may assist investigators in designing trials and suggest that attrition is associated with trial duration and may frequently exceed protocolized expectations.