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Randomized Controlled Trial
. 2023 Apr 3;6(4):e237230.
doi: 10.1001/jamanetworkopen.2023.7230.

Lecanemab for Patients With Early Alzheimer Disease: Bayesian Analysis of a Phase 2b Dose-Finding Randomized Clinical Trial

Donald A Berry  1 , Shobha Dhadda  2 , Michio Kanekiyo  2 , David Li  2 , Chad J Swanson  2 , Michael Irizarry  2 , Lynn D Kramer  2 , Scott M Berry  1
Affiliations
Randomized Controlled Trial

Lecanemab for Patients With Early Alzheimer Disease: Bayesian Analysis of a Phase 2b Dose-Finding Randomized Clinical Trial

Donald A Berry et al. JAMA Netw Open. .

Abstract

Importance: Bayesian clinical trial designs are increasingly common; given their promotion by the US Food and Drug Administration, the future use of the bayesian approach will only continue to increase. Innovations possible when using the bayesian approach improve the efficiency of drug development and the accuracy of clinical trials, especially in the context of substantial data missingness.

Objective: To explain the foundations, interpretations, and scientific justification of the bayesian approach in the setting of lecanemab trial 201, a bayesian-designed phase 2 dose-finding trial; to demonstrate the efficiency of using a bayesian design; and to show how it accommodates innovations in the prospective design and also treatment-dependent types of missing data.

Design, setting, and participants: This study was a bayesian analysis of a clinical trial comparing the efficacy of 5 lecanemab 201 dosages for treatment of early Alzheimer disease. The goal of the lecanemab 201 trial was to identify the effective dose 90 (ED90), the dose achieving at least 90% of the maximum effectiveness of doses considered in the trial. This study assessed the bayesian adaptive randomization used, in which patients were preferentially assigned to doses that would give more information about the ED90 and its efficacy.

Interventions: Patients in the lecanemab 201 trial were adaptively randomized to 1 of 5 dose regimens or placebo.

Main outcomes and measures: The primary end point of lecanemab 201 was the Alzheimer Disease Composite Clinical Score (ADCOMS) at 12 months with continued treatment and follow-up out to 18 months.

Results: A total 854 patients were included in trial treatment: 238 were in the placebo group (median age, 72 years [range, 50-89 years]; 137 female [58%]) and 587 were assigned to a lecanemab 201 treatment group (median age, 72 years [range, 50-90 years]; 272 female [46%]). The bayesian approach improved the efficiency of a clinical trial by prospectively adapting to the trial's interim results. By the trial's end more patients had been assigned to the better-performing doses: 253 (30%) and 161 (19%) patients to 10 mg/kg monthly and 10 mg/kg biweekly vs 51 (6%), 52 (6%), and 92 (11%) patients to 5 mg/kg monthly, 2.5 mg/kg biweekly, and 5 mg/kg biweekly, respectively. The trial identified 10 mg/kg biweekly as the ED90. The change in ADCOMS of the ED90 vs placebo was -0.037 at 12 months and -0.047 at 18 months. The bayesian posterior probability that the ED90 was superior to placebo was 97.5% at 12 months and 97.7% at 18 months. The respective probabilities of super-superiority were 63.8% and 76.0%. The primary analysis of the randomized bayesian lecanemab 201 trial found in the context of missing data that the most effective dose of lecanemab nearly doubles its estimated efficacy at 18 months of follow-up in comparison with restricting analysis to patients who completed the full 18 months of the trial.

Conclusions and relevance: Innovations associated with the bayesian approach can improve the efficiency of drug development and the accuracy of clinical trials, even in the context of substantial data missingness.

Trial registration: ClinicalTrials.gov Identifier: NCT01767311.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr D. Berry reported coownership of Berry Consultants LLC, a company that designs bayesian clinical trials for pharmaceutical and medical device companies, National Institutes of Health cooperative groups, patient advocacy groups, and international consortia; he reported research funding from Eisai Pharmaceuticals during the conduct of the study. Dr Dhadda reported employment with Eisai Inc outside the submitted work. Mr Kanekiyo reported employment at Eisai Inc. Dr Li reported employment with Eisai Inc. Dr Irizarry reported employment with Eisai Inc during the conduct of the study. Dr Kramer reported service as a corporate officer with Eisai Inc outside the submitted work; he reported employment with Eisai Inc. Dr S. Berry reported part ownership of Berry Consultants, who received funding for design and analysis work for this trial from Eisai Inc during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Final Results by Dose Cohort for the Final 12-Month and 18-Month Analyses
In panels B and E, whiskers indicate 95% probability intervals for the bayesian model. In panels C and F, the probability that each dose is the ED90 sums to 1. Probability that the benefit on Alzheimer Disease Composite Clinical Score (ADCOMS) is greater than the super-superiority threshold (SST) is also indicated for each dose, with probabilities not constrained to sum to 1. The super-superiority and futility boundaries refer to the probability of being greater than the SST (Pr(>SST)). If the Pr(>SST) for the most likely ED90 exceeds the success boundary, this would indicate that the analysis would recommend going to phase 3. If Pr(>SST) for the most likely ED90 is below the futility boundary, then the analysis would recommend stopping accrual (if still accruing) and not going to phase 3. The third plot on the rightmost panel, Pr(>PBO), is the probability that the dose’s benefit on ADCOMS is greater than that on placebo.
Figure 2.
Figure 2.. Posterior Probabilities Over Time Since Randomization
The super-superiority and futility boundaries refer to the probability of being greater than the super-superiority threshold (Pr(>SST)). If Pr(>SST) for the most likely ED90 exceeds the super-superiority boundary (95%) at analysis 4 or later, then analysis would recommend going to phase 3. If the Pr(>SST) for the most likely ED90 is below the futility boundary (5% for first 3 analyses and 7.5% thereafter), then analysis would recommend stopping accrual (if still accruing) and not going to phase 3. Pr(>PBO) is the probability that the dose’s benefit on Alzheimer Disease Composite Clinical Score is greater than that on placebo. Pr(>PBO) played no role in the design of the trial.
Figure 3.
Figure 3.. Final Posterior Distributions of the Benefit in Alzheimer Disease Composite Clinical Score (ADCOMS) for Dose 10 mg/kg Biweekly, the Most Likely Effective Dose (ED90), at 12 and 18 Months
SST indicates super-superiority threshold. Benefits of the ED90 dose were compared with placebo results.
Figure 4.
Figure 4.. Box-Whisker Plots Demonstrating Differential Effects of Multiple Imputing Values by Dose Group for Patients Who Dropped Out Before 18 Months
In panel A, a comparison of the change from baseline in ADCOMS over time from randomization to 18 months for patients receiving placebo and 10 mg/kg biweekly suggests different reasons that patients dropped out. Dose 10 mg/kg biweekly had greater rates of administrative missingness and patients on placebo who went missing had greater levels of disease progression. In panel B, the status of all completers is shown as a horizontal black line with the box-whisker plots showing the distributions of those patients with missing values based on 10 000 imputations. The mean of the 10 000 imputed sample means of patients with imputed values is the horizontal black line within the orange box. The green box-whisker plot shows the 10 000 combined means of the completer and the imputed means. The mean in the box-whisker plot for patients in the placebo group is greater than the mean for completers, while the opposite is true for dose group 10 mg/kg biweekly. This shows the importance of bayesian modeling. The bayesian comparison of dose 10 mg/kg biweekly with placebo shows almost double the advantage as compared with restricting the sample to patients completing treatment.
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