The higher benefit of lecanemab in males compared to females in CLARITY AD is probably due to a real sex effect

Abstract

Introduction: The phase 3 trial CLARITY AD found lecanemab slowed cognitive decline by 27%. However, subgroup analyses indicated a significant 31% sex difference in the effect and suggested no or limited effectiveness in females. We used simulations constrained by the trial design to determine whether that difference reflects a pre-existing sex difference in Alzheimer's disease progression or was a random event.

Methods: Simulations were generated using linear mixed models of cognitive decline fit to data from Alzheimer's Disease Neuroimaging Initiative participants satisfying CLARITY AD inclusion criteria.

Results: The statistically non-significant 7.9% smaller cognitive decline rate in our cohort's males versus females does not explain CLARITY AD's 31% sex difference in lecanemab's effect. A ≥ 31% difference occurred randomly in only 12 of our 10,000 simulations (0.0012 probability).

Discussion: CLARITY AD's sex difference was probably not random. Lecanemab is likely less effective in females than males, but we cannot conclude the drug is ineffective in females.

Highlights: Lecanemab is more clinically effective in males than in females. Forest plots should only report subgroup-specific effects in well-powered subgroups. Trial simulations based on real data enable investigation of subgroup drug effects. We cannot conclude that lecanemab is clinically ineffective in females. A sex difference in lecanemab's efficacy could be linked to its action mechanism.

Keywords: Alzheimer's disease; Alzheimer's disease treatment; clinical trial; cognitive decline; data analysis; dementia; drug efficacy; forest plot; lecanemab; longitudinal data; mild cognitive impairment; phase 3 clinical trial; sex differences; simulation; statistical power; subgroup analysis.

FIGURE 1

Procedure for generating 10,000 clinical trial simulations constrained by the CLARITY AD design. First, ADNI participants who fit CLARITY AD inclusion criteria are selected to form our “simulation cohort.” We then fit the Equation 1 model to data from subsets of that cohort in Experiment 1 (only females and only males) and from the full cohort in Experiment 2. The model longitudinally tracks cohort‐ and participant‐level CDRSBΔbl scores. Next, to simulate a trial, we first randomly resample participants from our simulation cohort and then add noise to the baseline CDRSB score of each sampled participant. This process generates a cohort of synthetic participants—our “synthetic cohort”—for our simulated trial, for example where the sample size is equal to that specified in the CLARITY AD design. We then randomize those participants into “drug” and “placebo” groups. The synthetic cohort data are then input to the Equation 1 model that was originally fit to the simulation cohort. With noise added to the model parameters, Equation 1 is used to calculate CDRSBΔbl scores for each participant at a number of visits that matches the observation scheme of CLARITY AD, up to 18 months. A drug effect is simultaneously injected as a reduction in CDRSBΔbl slope for drug‐treated participants relative to placebo. Once the longitudinal CDRSBΔbl scores are generated (i.e., the trial data simulation is complete), the drug versus placebo group difference in CDRSBΔbl slope is extracted. The extracted slope difference is the observed drug effect size in the simulated trial. This process is repeated 10,000 times. Each simulated trial will have a different observed effect size because of the heterogeneity in natural cognitive decline trajectories in the trial's unique synthetic cohort. Finally, the observed effect sizes across the 10,000 simulations are plotted in a histogram, in which the mean observed drug versus placebo difference in slope is here indicated by the black dashed line. AD, Alzheimer's disease; ADNI, Alzheimer's Disease Neuroimaging Initiative; CDRSB, Clinical Dementia Rating Sum of Boxes; CDRSBΔbl, Clinical Dementia Rating Sum of Boxes change since baseline.

FIGURE 2

CDRSBΔbl trajectories for our simulation cohort participants selected from ADNI. Scores are tracked over number of years elapsed since a participant's baseline ADNI observation. A, Real individual trajectories for all simulation cohort participants, with overlaid female‐ and male‐specific group‐level trends estimated by Equation 1 indicated in red and blue, respectively, with confidence intervals. These two trends nearly overlap for the 18‐month period that corresponds to the CLARITY AD trial duration. There is no statistically significant sex difference in the estimated cognitive decline rate, as the confidence intervals on the slope values overlap between the two models (see Table 2). The models describing these trends were used in generating the Experiment 1 simulations. B, Real individual trajectories for all simulation cohort participants with the cohort‐level trend line estimated by Equation 1 indicated in green, with confidence interval. The model describing this trend was used in generating the Experiment 2 simulations. ADNI, Alzheimer's Disease Neuroimaging Initiative; CDRSBΔbl, Clinical Dementia Rating Sum of Boxes change since baseline

FIGURE 3

Histograms of simulated CDRSBΔbl slope differences for drug‐treated versus placebo groups (i.e., observed drug effect sizes) for simulated trials adhering to the CLARITY AD design parameters, but including only males (blue) or only females (red). Each histogram represents 10,000 simulations. The mean value for each distribution is indicated by a color‐coded dashed line. The small difference in means is statistically significant, as is the difference in variances. CDRSBΔbl, Clinical Dementia Rating Sum of Boxes change since baseline

FIGURE 4

Histogram of differences in CDRSBΔbl slope (here signifying differences in drug effect size) between two subgroups of randomly selected participants in 10,000 trial simulations constrained by the CLARITY AD design. The red dashed line indicates the value corresponding to the 31% difference between sex subgroups reported in CLARITY AD. The black dashed line corresponds to the preloaded known sex difference in drug effect from Experiment 1. Only 12 of 10,000 simulations (indicated in purple to the left of the red line) had a subgroup difference ≥ 31%. Even when a large difference is preloaded between subgroups, there is an extremely low probability of randomly observing a ≥ 31% difference in drug effect between subgroups. CDRSBΔbl, Clinical Dementia Rating Sum‐of‐Boxes change since baseline