Text blocks

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 Subject Disposition. Individual discontinued patients, with the date and the recorded reason for discontinuation, are listed in Section 16.2.1.

In summary, {{value:randomised-n}} patients were randomised and {{value:treated-n}} were treated. {{value:completed-n}} patients ({{value:completed-pct}}%) completed the study and {{value:discontinued-n}} discontinued prematurely. Of those treated, {{value:ae-any-n-total}} reported at least one adverse event, {{value:ae-excess-high-vs-placebo}} more in the high dose group than in the placebo group.

Every number in this paragraph is a named value: it is declared once in library/values/values.yaml, resolved by the pipeline against the committed Analysis Results Data, and cited here by name. The name is the unit of reuse — the same value can be quoted in the disposition narrative, the safety conclusions and a summary slide without any of them re-addressing the underlying ARD row, and the build fails if any of them drifts from it.

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 Demographic and Baseline Characteristics; 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 Extent of Exposure to Study Drug.

Treatment-emergent adverse events were reported by 217 of the 254 patients in the safety analysis set (85.4%), covering 1122 individual adverse event records.

The proportion of patients reporting at least one treatment-emergent adverse event rose with dose: 75.6% of patients receiving placebo, 87.5% receiving xanomeline low dose and 94.4% receiving xanomeline high dose. The same gradient was present, and more pronounced, for adverse events assessed by the investigator as related to study drug, reported by 43 patients (50.0%), 77 patients (80.2%) and 64 patients (88.9%) respectively.

Most events were of mild or moderate maximum severity. Severe events were reported by 5 patients (5.8%) receiving placebo, 16 patients (16.7%) receiving xanomeline low dose and 8 patients (11.1%) receiving xanomeline high dose; moderate events were reported by 129 patients (50.8%) overall.

Serious adverse events were uncommon in this study. They were reported by 3 patients (1.2%) overall: 0 receiving placebo, 2 receiving xanomeline low dose and 1 receiving xanomeline high dose. Adverse events with a fatal outcome were recorded for 3 patients, of whom 2 were receiving placebo. Deaths and serious adverse events are described in Section 12.3.

An overview of treatment-emergent adverse events is presented in Overview of Treatment-Emergent Adverse Events. Because exposure differed substantially between the groups (Section 12.1), the crude proportions above should be read alongside the exposure summary.

Treatment-emergent adverse events are summarised by system organ class and preferred term in Treatment-Emergent Adverse Events by System Organ Class and Preferred Term. The in-text display below is a thresholded rendering of the same analysis results, limited to preferred terms reported by at least five percent of patients in any treatment group.

The adverse event profile was dominated by local reactions to the transdermal system. General disorders and administration site conditions were the most frequently reported system organ class, affecting 51 of the 96 patients in the xanomeline low dose group (53.1%) and 50.0% of the high dose group, against 24.4% of patients receiving placebo. Skin and subcutaneous tissue disorders followed the same pattern with a clearer dose gradient: 23.3% receiving placebo, 40.6% in the low dose group and 54.2% in the high dose group.

At preferred-term level the picture is consistent. Pruritus was the single most common term, reported by 25 patients (34.7%) in the high dose group against 9.3% receiving placebo, and application site pruritus was reported by 21 patients (29.2%) against 7.0%. Erythema and application site erythema showed the same direction, reported by 19.4% and 19.4% of high dose patients respectively.

Outside the cutaneous and application site classes the pattern is less uniform. Nervous system disorders were reported by 31.9% of high dose patients and 9.3% of patients receiving placebo, the most common term being dizziness (21 patients overall). Gastrointestinal disorders showed no dose relationship — reported by 19.8% of patients receiving placebo and 26.4% of high dose patients — and diarrhoea, its most frequent term, was in fact reported more often on placebo (9 patients) than on high dose xanomeline (3 patients).

All treatment-emergent adverse events recorded during the study are listed by patient in Section 16.2.7. The listing gives, for each event, the patient identifier, treatment group, verbatim term, preferred term and system organ class, onset and resolution dates, maximum severity, seriousness, the investigator's assessment of relationship to study drug, the action taken with study drug and the outcome.

Serious adverse events, adverse events with a fatal outcome and adverse events leading to withdrawal of study drug are additionally presented in Listing of Serious Adverse Events.

Every listing carries the study number, the analysis set and the data cut-off date in its header, and identifies derived values in a conspicuous fashion, as required by ICH E3. Patient identifiers in listings intended for public disclosure are subject to the anonymisation approach described in the study's disclosure plan.

Adverse events with a fatal outcome were recorded for 3 of the 254 patients in the safety analysis set: 2 receiving placebo, 1 receiving xanomeline low dose and 0 receiving xanomeline high dose. Deaths were therefore not more frequent on active treatment, and with this number of events no inference about an effect of treatment on mortality is possible.

Serious adverse events were reported by 3 patients (1.2%) overall: 0 patients (0.0%) receiving placebo, 2 patients (2.1%) receiving xanomeline low dose and 1 patients (1.4%) receiving xanomeline high dose. The between-group differences in serious adverse events are far smaller than the differences in overall adverse event frequency reported in Section 12.2.1, and the events reported were of a kind consistent with the comorbidity expected in an elderly population.

Adverse events of severe maximum intensity — reported here as other significant adverse events — were more frequent on active treatment: 16 patients (16.7%) in the low dose group and 8 patients (11.1%) in the high dose group, compared with 5 patients (5.8%) receiving placebo.

Individual serious adverse events, with the patient identifier, treatment group, system organ class, preferred term, severity, relationship to study drug, onset and resolution study day and outcome, are presented in Listing of Serious Adverse Events. Narratives for these patients are provided in Section 12.3.2.

Xanomeline transdermal therapeutic system was associated with a dose-related increase in treatment-emergent adverse events. At least one treatment-emergent adverse event was reported by 94.4% of patients in the high dose group and 87.5% in the low dose group, compared with 75.6% receiving placebo, and events assessed as related to study drug followed the same gradient (50.0%, 80.2% and 88.9% respectively).

The excess was concentrated in local, cutaneous events. Skin and subcutaneous tissue disorders alone were reported by 54.2% of high dose patients against 23.3% receiving placebo, and general disorders and administration site conditions by 50.0% against 24.4%, with pruritus and erythema at and beyond the application site the dominant preferred terms.

Study discontinuation was correspondingly higher on active treatment: 74.0% of low dose patients and 62.5% of high dose patients discontinued prematurely, against 32.6% receiving placebo. The analysis dataset does not record a reason for the great majority of these discontinuations, so the contribution of adverse events to them cannot be quantified from these data — but the consequence for exposure is unambiguous: mean treatment duration was 147.8 days on placebo against 85.9 and 112.2 days on low and high dose xanomeline.

Serious adverse events and deaths did not follow this pattern. Serious adverse events were reported by 3 patients (1.2%) in the whole safety analysis set, and adverse events with a fatal outcome by 3 patients, of whom 2 were receiving placebo. The safety signal in this study is therefore one of local tolerability rather than of systemic serious toxicity. That conclusion is bounded by exposure: placebo patients accumulated substantially more time on study drug, so the crude proportions above understate rather than overstate the tolerability difference, and they say little about safety beyond the exposure actually achieved in the xanomeline groups.

No efficacy data are analysed in this report, so no benefit-risk conclusion is drawn.

This study evaluated the safety and tolerability of the xanomeline transdermal therapeutic system in an elderly population with mild to moderate Alzheimer's disease. 254 patients were randomised and treated, with a mean age of 75.1 years and a range of 51 to 89 years. Demographic and baseline characteristics were comparable across the treatment groups, so the differences described below are unlikely to be explained by baseline imbalance.

The most consequential finding is a tolerability limitation rather than a safety signal in the conventional sense. Only 26.0% of patients in the xanomeline low dose group and 37.5% in the high dose group completed the study, against 67.4% receiving placebo — 71 and 45 premature discontinuations respectively, against 28 on placebo. The consequence is visible in exposure: mean treatment duration fell from 147.8 days on placebo to 85.9 days on low dose xanomeline, and exposure of at least 180 days was reached by only 26.0% of low dose patients and 36.1% of high dose patients, compared with 64.0% of placebo patients.

The adverse events that accompany this pattern are local and cutaneous, as would be expected of a transdermal formulation. General disorders and administration site conditions were reported by 50.0% of high dose patients against 24.4% receiving placebo, and skin and subcutaneous tissue disorders by 54.2% against 23.3%, with pruritus and erythema the dominant preferred terms. Systemic events tell a different story. Nervous system disorders separated less sharply (31.9% against 9.3%), serious adverse events were reported by only 3 patients across the whole safety analysis set, and adverse events with a fatal outcome occurred in 3 patients, of whom 2 were receiving placebo.

Three limitations bound the interpretation of these results. First, the imbalance in exposure means crude adverse event proportions are not directly comparable between groups: patients receiving placebo had substantially more time in which to report events, so the observed excess in the xanomeline groups is a conservative rather than an inflated description of the difference. Second, the analysis dataset records no reason for the great majority of discontinuations, so the causal link between the cutaneous events and the withdrawals — although strongly suggested by their joint distribution — cannot be established from these data alone; the patient narratives in Section 12.3.2 and the listings in Section 16.2.1 are the appropriate place to examine it. Third, the population was elderly and predominantly white (90.6%), which limits generalisability, and no efficacy data are analysed in this report, so nothing here speaks to whether the tolerability burden is offset by clinical benefit.

Within those bounds, the conclusion supported by these data is that the xanomeline transdermal therapeutic system at the doses studied is associated with a high rate of local cutaneous and application site reactions and with markedly reduced treatment persistence, without an accompanying increase in serious adverse events or deaths. A formulation or titration strategy that reduces application site reactions would be the logical prerequisite to any further evaluation of this route of administration in this population.

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.