This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with the International Council for Harmonisation Guideline for Good Clinical Practice (ICH E6) and the applicable regulatory requirements of the jurisdictions in which the study was conducted.

The protocol, the protocol amendments, the patient information sheet and the informed consent form were reviewed and approved by the responsible independent ethics committee or institutional review board at each participating centre before any patient was screened. Substantial amendments were submitted for review and approved before implementation, except where an immediate change was necessary to eliminate a hazard to patients.

Written informed consent was obtained from every patient, or from the patient's legally acceptable representative where the patient was not competent to consent, before any study-specific procedure was performed. Because the study enrolled patients with mild to moderate Alzheimer's disease, the consent process explicitly provided for assessment of decisional capacity and, where capacity was impaired, for consent by a legally acceptable representative together with the assent of the patient.

Patients and their representatives were informed of the objectives of the study, of the investigational nature of the treatment, of the reasonably foreseeable risks and inconveniences, and of their right to withdraw from the study at any time without penalty or loss of benefits to which they were otherwise entitled. A copy of the signed consent form was provided to each patient or representative. The patient information sheet and the sample consent form are provided in Section 16.1.3.

This was a randomised, double-blind, placebo-controlled, parallel-group study of the Xanomeline Transdermal Therapeutic System (TTS) in patients with mild to moderate Alzheimer's disease. Patients who satisfied all entry criteria at screening were randomised in equal allocation to one of three treatment groups — placebo, xanomeline low dose, or xanomeline high dose — and treated for the planned treatment period defined in the protocol, followed by an end-of-study evaluation.

A total of 254 patients were randomised and treated: 86 to placebo, 96 to xanomeline low dose and 72 to xanomeline high dose. Patients who were screened but not randomised are excluded from all analyses presented in this report; the derivation of the analysis populations is described in Section 11.1.

Study drug was supplied as a transdermal patch applied once daily. The blind was maintained by supplying placebo and active patches of identical appearance, and by withholding the randomisation code from investigators, patients and study personnel involved in the conduct of the study until database lock. The randomisation scheme and codes are provided in Section 16.1.7.

No changes were made to the conduct of the study after the first patient was randomised, other than those recorded in the protocol amendments provided in Section 16.1.1.

The analyses presented in this report follow the statistical analysis plan. Every analysis was executed from version-controlled specifications, and each regeneration of a display is recorded as a numbered iteration with the specification hash, the input dataset hashes and the software environment that produced it. Any analysis performed after the statistical analysis plan was finalised is identified as post hoc where it appears. The complete documentation of statistical methods, including the specification and environment provenance for every display in this report, is provided in Section 16.1.9.

Of the 254 patients randomised and treated, 110 (43.3%) completed the study and 144 (56.7%) discontinued prematurely.

Completion was substantially lower in both xanomeline groups than in the placebo group. 58 of the 86 patients randomised to placebo (67.4%) completed the study, compared with 25 of 96 (26.0%) in the xanomeline low dose group and 27 of 72 (37.5%) in the xanomeline high dose group. Premature discontinuation was therefore about twice as frequent in the xanomeline groups as in the placebo group, and this imbalance is the dominant feature of study conduct.

Death was recorded as the reason for discontinuation in 3 patients: 2 receiving placebo, 1 receiving xanomeline low dose and 0 receiving xanomeline high dose. The remaining 141 discontinuations are recorded in the analysis dataset as other or not specified, so no further breakdown of discontinuation reason is available from these data; the adverse event profile that plausibly accounts for the imbalance is described in Section 12.2.

Patient disposition is summarised in 14.1.1. Individual discontinued patients, with the date and the recorded reason for discontinuation, are listed in Section 16.2.1.

The safety analysis set comprised all patients who were randomised and received at least one dose of study medication. It included 254 patients: 86 in the placebo group, 96 in the xanomeline low dose group and 72 in the xanomeline high dose group. All safety analyses in this report, and every display referenced from Section 12, are based on this analysis set, and each display identifies its analysis set in the header in accordance with ICH E3.

Patients who were screened but not randomised are excluded from every analysis set. Analysis-set membership is derived in a documented, version-controlled data preparation step rather than assumed from the source data; that derivation, and the environment that executed it, are recorded in Section 16.1.9.

No efficacy analysis set is defined for this report. The public ADaM package used as the data source for this demonstration contains no efficacy analysis dataset for this study, so the efficacy sections and the corresponding post-text displays in Section 14.2 are intentionally not populated. Patients excluded from any analysis population would be listed in Section 16.2.3.

Demographic and baseline characteristics were comparable across the three treatment groups in the safety analysis set of 254 patients.

The study population was elderly, as expected for a mild to moderate Alzheimer's disease population. Mean age overall was 75.1 years (SD 8.25), with a median of 77 years and a range of 51 to 89 years. Mean age was 75.2 years in the placebo group, 76.0 years in the xanomeline low dose group and 73.8 years in the xanomeline high dose group.

Women accounted for 143 patients (56.3%) overall, and the proportion of women ranged from 48.6% in the xanomeline high dose group to 61.6% in the placebo group. The population was predominantly white (230 patients, 90.6%), with 23 patients reported as Black or African American. The limited racial diversity of the population should be considered when generalising the findings of this study.

Demographic and baseline characteristics are summarised in 14.1.2; individual demographic data are listed in Section 16.2.4.

Exposure to study drug was longest in the placebo group and shortest in the xanomeline low dose group, a direct consequence of the discontinuation pattern described in Section 10.1. The imbalance must be taken into account when interpreting crude adverse event frequencies.

Mean duration of exposure was 147.8 days (SD 62.13) in the placebo group, 85.9 days (SD 70.66) in the xanomeline low dose group and 112.2 days (SD 65.52) in the xanomeline high dose group. The corresponding medians were 182.0, 62.5 and 96.5 days. Individual exposure ranged from 0 to 212 days across the safety analysis set.

Cumulative exposure thresholds show the same pattern. At least 30 days of exposure was achieved by 78 patients (90.7%) receiving placebo, 65 (67.7%) receiving xanomeline low dose and 67 (93.1%) receiving xanomeline high dose. Long-term exposure of at least 180 days was reached by 55 patients (64.0%) in the placebo group, against 25 (26.0%) and 26 (36.1%) in the low and high dose groups respectively — so fewer than half as many xanomeline patients as placebo patients reached the long-term exposure threshold.

Extent of exposure, including total and average daily dose, is summarised in 14.3.1.1.