7  Primary and secondary endpoints

7.1 Primary endpoint: time to first dermatologic event

Table 14.2.1: Time to first dermatologic treatment-emergent adverse event. Intention-to-treat population.
Treatment group Subjects Subjects with an event Median time to event (days) Hazard ratio (95% CI) p-value
Placebo 86 20 (23.3%) Not reached Reference
Xanomeline Low Dose 84 39 (46.4%) 80 (55, NA) 2.98 (1.73, 5.13) <0.001
Xanomeline High Dose 84 39 (46.4%) 89 (50, NA) 3.34 (1.94, 5.75) <0.001
Medians and confidence intervals are Kaplan-Meier estimates. Hazard ratios come from a Cox proportional hazards model with planned treatment as the only covariate and placebo as the reference group. A median is reported as not reached where fewer than half the subjects in the group had an event.

0% 20% 40% 60% 0 50 100 150 200 Days since first dose Cumulative incidence Placebo Xanomeline Low Dose Xanomeline High Dose 86 70 56 50 0 84 40 22 17 0 84 36 17 16 0 Xanomeline High Dose Xanomeline Low Dose Placebo At Risk

Figure 14.2.1: Cumulative incidence of the first dermatologic treatment-emergent adverse event, intention-to-treat population.

Both xanomeline groups reached a higher cumulative incidence of dermatologic events than placebo, and the separation appeared within the first weeks of treatment. The hazard ratios in Table 14.2.1 quantify that difference; the confidence intervals exclude one for both dose groups.

2 subjects have a last date known to be alive that precedes their first dose in the source data, and are censored at day 1 rather than excluded, which is the behaviour of admiral::derive_param_tte(). They enter the risk set for the first day only, so their influence on the estimates is negligible without being nil.

7.1.1 Supportive analysis: per-protocol population

Table 14.2.1.1: Time to first dermatologic treatment-emergent adverse event (supportive analysis). Per-protocol population.
Treatment group Subjects Subjects with an event Median time to event (days) Hazard ratio (95% CI) p-value
Placebo 58 11 (19.0%) Not reached Reference
Xanomeline Low Dose 25 10 (40.0%) Not reached 2.65 (1.12, 6.23) 0.026
Xanomeline High Dose 27 15 (55.6%) 174 (46, NA) 3.87 (1.77, 8.43) <0.001
Medians and confidence intervals are Kaplan-Meier estimates. Hazard ratios come from a Cox proportional hazards model with planned treatment as the only covariate and placebo as the reference group. The per-protocol population is restricted to safety-population subjects who completed the study.

The per-protocol result in Table 14.2.1.1 is consistent in direction and magnitude with the intention-to-treat result in Table 14.2.1, supporting the primary conclusion.

7.1.2 Subgroup analysis

Overall Sex Age group 1 3 10 All subjects Male Female >64 18-64 Hazard ratio (95% CI), xanomeline (any dose) vs placebo

Figure 14.2.2: Hazard ratio for the primary endpoint by age group and sex, intention-to-treat population.

The treatment effect on the primary endpoint was consistent across sex and age-group subgroups, with no confidence interval crossing the line of no effect.

7.2 Secondary endpoint: change in systolic blood pressure

Table 14.2.2: Change from baseline in supine systolic blood pressure at week 24. Safety population.
Treatment group n LS mean change (SE) 95% CI Difference versus placebo (95% CI) p-value
Placebo 59 -2.02 (1.88) (-5.75, 1.71) Reference
Xanomeline Low Dose 25 -0.99 (2.90) (-6.74, 4.76) 1.03 (-5.83, 7.90) 0.77
Xanomeline High Dose 28 -5.47 (2.73) (-10.89, -0.05) -3.45 (-10.02, 3.13) 0.30
Least-squares means from an analysis of covariance model with actual treatment group as a factor and the baseline value as a covariate. n is the number of subjects with both a baseline and a week 24 supine value; no values are imputed. Vital signs are measured in three postures, each with its own baseline; the model uses the supine measurement, so each subject contributes one observation.

125 130 135 140 Week 2 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Systolic Blood Pressure (mmHg) (mean and standard error) Placebo Xanomeline Low Dose Xanomeline High Dose

Figure 14.2.3: Mean supine systolic blood pressure by visit and treatment group, safety population.

Mean systolic blood pressure remained stable across the treatment period in all three groups. The differences from placebo at week 24 were small and their confidence intervals included zero, so no treatment effect on systolic blood pressure was demonstrated.