8  Safety evaluation

Safety analyses count subjects under the treatment actually received, so the group sizes below differ from the randomised group sizes in the study patients chapter for the subjects whose actual treatment differed from their planned treatment.

8.1 Extent of exposure

Table 14.3.5: Extent of exposure. Safety population.

Exposure	Placebo N = 861	Xanomeline Low Dose N = 961	Xanomeline High Dose N = 721
Exposure (days)	147.8 (62.1); 182.0 [0.0, 210.0]	85.9 (70.7); 62.5 [0.0, 212.0]	112.2 (65.5); 96.5 [15.0, 200.0]
Exposure category
0	1 (1.2%)	1 (1.0%)	0 (0%)
1 to 28	7 (8.1%)	28 (29%)	5 (6.9%)
29 to 84	11 (13%)	27 (28%)	29 (40%)
85 to 168	8 (9.3%)	15 (16%)	10 (14%)
>168	59 (69%)	25 (26%)	28 (39%)
1 Mean (SD); Median [Min, Max]; n (%)
Exposure is the total treatment duration in days, derived from the exposure analysis dataset. Category percentages use the number of safety-population subjects in each treatment group as denominator, so they sum to 100%.

8.2 Prior and concomitant medications

Table 14.3.6: Prior and concomitant medications by drug class and preferred term. Medications taken by at least 5% of subjects in any treatment group, safety population.

Drug class / preferred term	Placebo N = 861	Xanomeline Low Dose N = 961	Xanomeline High Dose N = 721
Any prior or concomitant medication	77 (90%)	86 (90%)	66 (92%)
Alimentary tract and metabolism	12 (14%)	12 (13%)	8 (11%)
Calcium	7 (8.1%)	6 (6.3%)	3 (4.2%)
Nizatidine	1 (1.2%)	1 (1.0%)	4 (5.6%)
Cardiovascular system	12 (14%)	13 (14%)	6 (8.3%)
Amlodipine	8 (9.3%)	1 (1.0%)	2 (2.8%)
Genito urinary system and sex hormones	6 (7.0%)	10 (10%)	5 (6.9%)
Estrogens conjugated	6 (7.0%)	10 (10%)	5 (6.9%)
Nervous system	23 (27%)	14 (15%)	8 (11%)
Acetylsalicylic acid	21 (24%)	11 (11%)	6 (8.3%)
Systemic hormonal preparations, excl.	2 (2.3%)	13 (14%)	8 (11%)
Hydrocortisone	2 (2.3%)	13 (14%)	8 (11%)
Uncoded	74 (86%)	82 (85%)	65 (90%)
Uncoded	74 (86%)	82 (85%)	65 (90%)
1 n (%)
Subjects taking more than one medication within a drug class or preferred term are counted once. Drug class is the ATC level 1 term; medications the pilot study left uncoded are reported under Uncoded. The overall row and the rows for each class count every subject with a qualifying record, including subjects whose only terms fall below the reporting threshold and are therefore not shown.

Concomitant medication use was extensive and comparable across the treatment groups, as expected in an elderly population.

8.3 Overview of adverse events

Table 14.3.1.1: Overview of treatment-emergent adverse events. Safety population.

Subjects with at least one event	Placebo N = 861	Xanomeline Low Dose N = 961	Xanomeline High Dose N = 721	Overall N = 2541
Any treatment-emergent adverse event (TEAE)	65 (76%)	84 (88%)	68 (94%)	217 (85%)
Any serious TEAE	0 (0%)	2 (2.1%)	1 (1.4%)	3 (1.2%)
Any severe TEAE	5 (5.8%)	16 (17%)	8 (11%)	29 (11%)
Any drug-related TEAE	43 (50%)	77 (80%)	64 (89%)	184 (72%)
Any TEAE leading to withdrawal	0 (0%)	0 (0%)	0 (0%)	0 (0%)
Any dermatologic TEAE	20 (23%)	39 (41%)	39 (54%)	98 (39%)
Any TEAE with fatal outcome	2 (2.3%)	1 (1.0%)	0 (0%)	3 (1.2%)
1 n (%)
Subjects are counted once in each row. A treatment-emergent adverse event started on or after the first dose of study drug.

8.4 Adverse events by system organ class and preferred term

Table 14.3.1.2: Treatment-emergent adverse events by system organ class and preferred term. Events reported by at least 5% of subjects in any treatment group, safety population.

System organ class / preferred term	Placebo N = 861	Xanomeline Low Dose N = 961	Xanomeline High Dose N = 721
Any treatment-emergent adverse event	65 (76%)	84 (88%)	68 (94%)
Cardiac disorders	12 (14%)	14 (15%)	14 (19%)
Myocardial infarction	4 (4.7%)	2 (2.1%)	4 (5.6%)
Sinus bradycardia	2 (2.3%)	7 (7.3%)	8 (11%)
Gastrointestinal disorders	17 (20%)	15 (16%)	19 (26%)
Diarrhoea	9 (10%)	5 (5.2%)	3 (4.2%)
Nausea	3 (3.5%)	3 (3.1%)	6 (8.3%)
Salivary hypersecretion	0 (0%)	0 (0%)	4 (5.6%)
Vomiting	3 (3.5%)	4 (4.2%)	6 (8.3%)
General disorders and administration site conditions	21 (24%)	51 (53%)	36 (50%)
Application site dermatitis	5 (5.8%)	9 (9.4%)	7 (9.7%)
Application site erythema	3 (3.5%)	13 (14%)	14 (19%)
Application site irritation	3 (3.5%)	9 (9.4%)	9 (13%)
Application site pruritus	6 (7.0%)	23 (24%)	21 (29%)
Application site vesicles	1 (1.2%)	5 (5.2%)	5 (6.9%)
Fatigue	1 (1.2%)	5 (5.2%)	5 (6.9%)
Infections and infestations	16 (19%)	9 (9.4%)	13 (18%)
Nasopharyngitis	2 (2.3%)	4 (4.2%)	6 (8.3%)
Upper respiratory tract infection	6 (7.0%)	1 (1.0%)	3 (4.2%)
Nervous system disorders	8 (9.3%)	22 (23%)	23 (32%)
Dizziness	2 (2.3%)	9 (9.4%)	10 (14%)
Headache	3 (3.5%)	3 (3.1%)	5 (6.9%)
Syncope	0 (0%)	5 (5.2%)	2 (2.8%)
Respiratory, thoracic and mediastinal disorders	8 (9.3%)	9 (9.4%)	10 (14%)
Cough	1 (1.2%)	5 (5.2%)	5 (6.9%)
Skin and subcutaneous tissue disorders	20 (23%)	39 (41%)	39 (54%)
Blister	0 (0%)	5 (5.2%)	1 (1.4%)
Erythema	8 (9.3%)	14 (15%)	14 (19%)
Hyperhidrosis	2 (2.3%)	4 (4.2%)	8 (11%)
Pruritus	8 (9.3%)	21 (22%)	25 (35%)
Rash	5 (5.8%)	13 (14%)	8 (11%)
Skin irritation	3 (3.5%)	6 (6.3%)	5 (6.9%)
1 n (%)
Subjects reporting more than one event within a system organ class or preferred term are counted once. Percentages use the number of safety-population subjects in each treatment group as denominator. The overall row and the rows for each class count every subject with a qualifying record, including subjects whose only terms fall below the reporting threshold and are therefore not shown.

Application-site and other dermatologic events dominated the adverse event profile in both xanomeline groups. The pattern is consistent with the transdermal delivery system and with the primary endpoint result in Table 14.2.1.

8.5 Adverse events by maximum severity

Table 14.3.1.3: Treatment-emergent adverse events by maximum severity. Events reported by at least 5% of subjects in any treatment group, safety population.

System organ class / preferred term	Mild			Moderate			Severe
	Placebo N = 861	Xanomeline Low Dose N = 961	Xanomeline High Dose N = 721	Placebo N = 861	Xanomeline Low Dose N = 961	Xanomeline High Dose N = 721	Placebo N = 861	Xanomeline Low Dose N = 961	Xanomeline High Dose N = 721
Any treatment-emergent adverse event	58 (67%)	58 (60%)	60 (83%)	25 (29%)	54 (56%)	45 (63%)	5 (5.8%)	16 (17%)	8 (11%)
Cardiac disorders	9 (10%)	12 (13%)	8 (11%)	3 (3.5%)	5 (5.2%)	5 (6.9%)	2 (2.3%)	0 (0%)	1 (1.4%)
Myocardial infarction	1 (1.2%)	2 (2.1%)	3 (4.2%)	1 (1.2%)	0 (0%)	1 (1.4%)	2 (2.3%)	0 (0%)	0 (0%)
Sinus bradycardia	1 (1.2%)	6 (6.3%)	4 (5.6%)	1 (1.2%)	1 (1.0%)	4 (5.6%)
Gastrointestinal disorders	15 (17%)	10 (10%)	15 (21%)	2 (2.3%)	5 (5.2%)	3 (4.2%)	0 (0%)	0 (0%)	2 (2.8%)
Diarrhoea	9 (10%)	4 (4.2%)	2 (2.8%)	0 (0%)	1 (1.0%)	1 (1.4%)
Nausea	2 (2.3%)	2 (2.1%)	5 (6.9%)	1 (1.2%)	1 (1.0%)	0 (0%)	0 (0%)	0 (0%)	1 (1.4%)
Salivary hypersecretion	0 (0%)	0 (0%)	4 (5.6%)
Vomiting	2 (2.3%)	2 (2.1%)	5 (6.9%)	1 (1.2%)	2 (2.1%)	1 (1.4%)
General disorders and administration site conditions	18 (21%)	27 (28%)	25 (35%)	5 (5.8%)	23 (24%)	19 (26%)	0 (0%)	7 (7.3%)	0 (0%)
Application site dermatitis	5 (5.8%)	4 (4.2%)	2 (2.8%)	0 (0%)	4 (4.2%)	5 (6.9%)	0 (0%)	1 (1.0%)	0 (0%)
Application site erythema	3 (3.5%)	4 (4.2%)	9 (13%)	0 (0%)	7 (7.3%)	5 (6.9%)	0 (0%)	2 (2.1%)	0 (0%)
Application site irritation	1 (1.2%)	3 (3.1%)	3 (4.2%)	2 (2.3%)	3 (3.1%)	6 (8.3%)	0 (0%)	3 (3.1%)	0 (0%)
Application site pruritus	5 (5.8%)	13 (14%)	10 (14%)	1 (1.2%)	9 (9.4%)	11 (15%)	0 (0%)	1 (1.0%)	0 (0%)
Application site vesicles	1 (1.2%)	3 (3.1%)	2 (2.8%)	0 (0%)	2 (2.1%)	3 (4.2%)
Fatigue	1 (1.2%)	3 (3.1%)	5 (6.9%)	0 (0%)	2 (2.1%)	0 (0%)
Infections and infestations	12 (14%)	6 (6.3%)	10 (14%)	5 (5.8%)	2 (2.1%)	3 (4.2%)	0 (0%)	1 (1.0%)	0 (0%)
Nasopharyngitis	1 (1.2%)	3 (3.1%)	5 (6.9%)	1 (1.2%)	0 (0%)	1 (1.4%)	0 (0%)	1 (1.0%)	0 (0%)
Upper respiratory tract infection	4 (4.7%)	1 (1.0%)	2 (2.8%)	2 (2.3%)	0 (0%)	1 (1.4%)
Nervous system disorders	6 (7.0%)	14 (15%)	17 (24%)	2 (2.3%)	9 (9.4%)	7 (9.7%)	0 (0%)	3 (3.1%)	4 (5.6%)
Dizziness	2 (2.3%)	6 (6.3%)	6 (8.3%)	0 (0%)	3 (3.1%)	3 (4.2%)	0 (0%)	0 (0%)	1 (1.4%)
Headache	3 (3.5%)	2 (2.1%)	4 (5.6%)	0 (0%)	0 (0%)	1 (1.4%)	0 (0%)	1 (1.0%)	0 (0%)
Syncope	0 (0%)	1 (1.0%)	0 (0%)	0 (0%)	2 (2.1%)	1 (1.4%)	0 (0%)	2 (2.1%)	1 (1.4%)
Respiratory, thoracic and mediastinal disorders	7 (8.1%)	7 (7.3%)	8 (11%)	1 (1.2%)	3 (3.1%)	2 (2.8%)
Cough	1 (1.2%)	3 (3.1%)	3 (4.2%)	0 (0%)	2 (2.1%)	2 (2.8%)
Skin and subcutaneous tissue disorders	15 (17%)	16 (17%)	32 (44%)	8 (9.3%)	24 (25%)	15 (21%)	0 (0%)	4 (4.2%)	1 (1.4%)
Blister	0 (0%)	1 (1.0%)	1 (1.4%)	0 (0%)	3 (3.1%)	0 (0%)	0 (0%)	1 (1.0%)	0 (0%)
Erythema	4 (4.7%)	6 (6.3%)	10 (14%)	4 (4.7%)	8 (8.3%)	4 (5.6%)
Hyperhidrosis	2 (2.3%)	1 (1.0%)	8 (11%)	0 (0%)	3 (3.1%)	0 (0%)
Pruritus	7 (8.1%)	9 (9.4%)	16 (22%)	1 (1.2%)	11 (11%)	9 (13%)	0 (0%)	1 (1.0%)	0 (0%)
Rash	2 (2.3%)	9 (9.4%)	5 (6.9%)	3 (3.5%)	3 (3.1%)	2 (2.8%)	0 (0%)	1 (1.0%)	1 (1.4%)
Skin irritation	2 (2.3%)	2 (2.1%)	3 (4.2%)	1 (1.2%)	3 (3.1%)	2 (2.8%)	0 (0%)	1 (1.0%)	0 (0%)
1 n (%)
Subjects reporting more than one event within a preferred term are counted once, under the highest severity reported for that term. Percentages use the number of safety-population subjects in each treatment group as denominator. The overall row and the rows for each class count every subject with a qualifying record, including subjects whose only terms fall below the reporting threshold and are therefore not shown.

8.6 Adverse events by relationship to study drug

Table 14.3.1.4: Treatment-emergent adverse events by relationship to study drug. Events reported by at least 5% of subjects in any treatment group, safety population.

System organ class / preferred term	Related			Not related
	Placebo N = 861	Xanomeline Low Dose N = 961	Xanomeline High Dose N = 721	Placebo N = 861	Xanomeline Low Dose N = 961	Xanomeline High Dose N = 721
Any treatment-emergent adverse event	43 (50%)	77 (80%)	64 (89%)	50 (58%)	48 (50%)	46 (64%)
Cardiac disorders	6 (7.0%)	8 (8.3%)	3 (4.2%)	6 (7.0%)	8 (8.3%)	11 (15%)
Myocardial infarction	2 (2.3%)	1 (1.0%)	1 (1.4%)	2 (2.3%)	1 (1.0%)	3 (4.2%)
Sinus bradycardia	2 (2.3%)	2 (2.1%)	0 (0%)	0 (0%)	5 (5.2%)	8 (11%)
Gastrointestinal disorders	4 (4.7%)	8 (8.3%)	9 (13%)	13 (15%)	7 (7.3%)	10 (14%)
Diarrhoea	3 (3.5%)	3 (3.1%)	1 (1.4%)	6 (7.0%)	2 (2.1%)	2 (2.8%)
Nausea	0 (0%)	3 (3.1%)	3 (4.2%)	3 (3.5%)	0 (0%)	3 (4.2%)
Salivary hypersecretion	0 (0%)	0 (0%)	3 (4.2%)	0 (0%)	0 (0%)	1 (1.4%)
Vomiting	0 (0%)	3 (3.1%)	2 (2.8%)	3 (3.5%)	1 (1.0%)	4 (5.6%)
General disorders and administration site conditions	18 (21%)	45 (47%)	33 (46%)	4 (4.7%)	11 (11%)	8 (11%)
Application site dermatitis	5 (5.8%)	9 (9.4%)	7 (9.7%)
Application site erythema	3 (3.5%)	13 (14%)	14 (19%)
Application site irritation	3 (3.5%)	9 (9.4%)	9 (13%)
Application site pruritus	6 (7.0%)	23 (24%)	21 (29%)
Application site vesicles	1 (1.2%)	5 (5.2%)	5 (6.9%)
Fatigue	1 (1.2%)	2 (2.1%)	4 (5.6%)	0 (0%)	3 (3.1%)	1 (1.4%)
Nervous system disorders	4 (4.7%)	14 (15%)	13 (18%)	5 (5.8%)	9 (9.4%)	14 (19%)
Dizziness	2 (2.3%)	7 (7.3%)	5 (6.9%)	0 (0%)	2 (2.1%)	5 (6.9%)
Headache	1 (1.2%)	1 (1.0%)	1 (1.4%)	2 (2.3%)	2 (2.1%)	4 (5.6%)
Syncope	0 (0%)	5 (5.2%)	2 (2.8%)
Skin and subcutaneous tissue disorders	16 (19%)	37 (39%)	38 (53%)	7 (8.1%)	4 (4.2%)	4 (5.6%)
Blister	0 (0%)	5 (5.2%)	1 (1.4%)
Erythema	8 (9.3%)	13 (14%)	14 (19%)	0 (0%)	1 (1.0%)	0 (0%)
Hyperhidrosis	1 (1.2%)	4 (4.2%)	8 (11%)	1 (1.2%)	0 (0%)	0 (0%)
Pruritus	7 (8.1%)	20 (21%)	25 (35%)	1 (1.2%)	1 (1.0%)	0 (0%)
Rash	3 (3.5%)	11 (11%)	6 (8.3%)	2 (2.3%)	2 (2.1%)	2 (2.8%)
Skin irritation	2 (2.3%)	6 (6.3%)	5 (6.9%)	1 (1.2%)	0 (0%)	0 (0%)
Infections and infestations				16 (19%)	9 (9.4%)	13 (18%)
Nasopharyngitis				2 (2.3%)	4 (4.2%)	6 (8.3%)
Upper respiratory tract infection				6 (7.0%)	1 (1.0%)	3 (4.2%)
Respiratory, thoracic and mediastinal disorders				6 (7.0%)	9 (9.4%)	10 (14%)
Cough				1 (1.2%)	5 (5.2%)	5 (6.9%)
1 n (%)
Subjects reporting more than one event within a preferred term are counted once, as related if any event for that term was investigator-assessed as related. Percentages use the number of safety-population subjects in each treatment group as denominator. The overall row and the rows for each class count every subject with a qualifying record, including subjects whose only terms fall below the reporting threshold and are therefore not shown.

8.7 Serious adverse events and deaths

Table 14.3.1.5: Serious treatment-emergent adverse events. Safety population.

Preferred term	Placebo N = 861	Xanomeline Low Dose N = 961	Xanomeline High Dose N = 721
Any serious treatment-emergent adverse event	0 (0%)	2 (2.1%)	1 (1.4%)
Partial seizures with secondary generalisation	0 (0%)	0 (0%)	1 (1.4%)
Syncope	0 (0%)	2 (2.1%)	0 (0%)
1 n (%)
Seriousness was assessed by the investigator according to the protocol definition.

Subject-level detail for every serious event is listed in Listing 16.2.7.1.

8.7.1 Narratives

ICH E3 requires a narrative for every death, every other serious adverse event, and any other adverse event judged to be of special interest. Narratives are written from the source documents rather than from the analysis datasets, so they cannot be generated from the data in this demonstration. One narrative is reproduced below to show the structure; the remainder would follow the same shape, one per event.

Subject 01-701-XXXX, placebo, serious adverse event. A subject in the placebo group experienced a serious adverse event during the treatment period. The event began on the study day recorded in Listing 16.2.7.1, was assessed by the investigator as not related to study drug, and resolved. Study drug was not withdrawn and the subject continued in the study.

The subject identifier and the clinical content of this narrative are placeholders and are not drawn from the source data.

8.8 Laboratory evaluations

Table 14.3.4.1: Shift from baseline to worst post-baseline category. Alanine aminotransferase, safety population.

Characteristic	Low			Normal			High
	Placebo N = 01	Xanomeline Low Dose N = 11	Xanomeline High Dose N = 01	Placebo N = 801	Xanomeline Low Dose N = 891	Xanomeline High Dose N = 681	Placebo N = 41	Xanomeline Low Dose N = 31	Xanomeline High Dose N = 41
Worst post-baseline category
Low	0 (NA%)	0 (0%)	0 (NA%)	1 (1.3%)	5 (5.6%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)
Normal	0 (NA%)	1 (100%)	0 (NA%)	73 (91%)	76 (85%)	61 (90%)	1 (25%)	0 (0%)	0 (0%)
High	0 (NA%)	0 (0%)	0 (NA%)	6 (7.5%)	8 (9.0%)	7 (10%)	3 (75%)	3 (100%)	4 (100%)
1 n (%)
Categories are relative to the reference range of the reporting laboratory. The worst post-baseline category is high if any post-baseline value was high, otherwise low if any value was low. Percentages use the number of subjects in each baseline category and treatment group as denominator, so they sum to 100% within each baseline category.

Table 14.3.4.2: Shift from baseline to worst post-baseline category. Aspartate aminotransferase, safety population.

Characteristic	Normal			High
	Placebo N = 781	Xanomeline Low Dose N = 851	Xanomeline High Dose N = 691	Placebo N = 61	Xanomeline Low Dose N = 81	Xanomeline High Dose N = 31
Worst post-baseline category
Low	0 (0%)	0 (0%)	1 (1.4%)	0 (0%)	0 (0%)	0 (0%)
Normal	70 (90%)	76 (89%)	63 (91%)	2 (33%)	3 (38%)	1 (33%)
High	8 (10%)	9 (11%)	5 (7.2%)	4 (67%)	5 (63%)	2 (67%)
1 n (%)
Categories are relative to the reference range of the reporting laboratory. The worst post-baseline category is high if any post-baseline value was high, otherwise low if any value was low. Percentages use the number of subjects in each baseline category and treatment group as denominator, so they sum to 100% within each baseline category.

Table 14.3.4.3: Shift from baseline to worst post-baseline category. Bilirubin, safety population.

Characteristic	Normal			High
	Placebo N = 821	Xanomeline Low Dose N = 891	Xanomeline High Dose N = 691	Placebo N = 21	Xanomeline Low Dose N = 31	Xanomeline High Dose N = 31
Worst post-baseline category
Low	0 (0%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)
Normal	78 (95%)	88 (99%)	67 (97%)	0 (0%)	2 (67%)	0 (0%)
High	4 (4.9%)	1 (1.1%)	2 (2.9%)	2 (100%)	1 (33%)	3 (100%)
1 n (%)
Categories are relative to the reference range of the reporting laboratory. The worst post-baseline category is high if any post-baseline value was high, otherwise low if any value was low. Percentages use the number of subjects in each baseline category and treatment group as denominator, so they sum to 100% within each baseline category.

Table 14.3.4.4: Shift from baseline to worst post-baseline category. Creatinine, safety population.

Characteristic	Low			Normal			High
	Placebo N = 21	Xanomeline Low Dose N = 01	Xanomeline High Dose N = 11	Placebo N = 811	Xanomeline Low Dose N = 881	Xanomeline High Dose N = 661	Placebo N = 11	Xanomeline Low Dose N = 51	Xanomeline High Dose N = 51
Worst post-baseline category
Low	1 (50%)	0 (NA%)	1 (100%)	1 (1.2%)	1 (1.1%)	2 (3.0%)	0 (0%)	0 (0%)	0 (0%)
Normal	1 (50%)	0 (NA%)	0 (0%)	72 (89%)	82 (93%)	56 (85%)	0 (0%)	0 (0%)	0 (0%)
High	0 (0%)	0 (NA%)	0 (0%)	8 (9.9%)	5 (5.7%)	8 (12%)	1 (100%)	5 (100%)	5 (100%)
1 n (%)
Categories are relative to the reference range of the reporting laboratory. The worst post-baseline category is high if any post-baseline value was high, otherwise low if any value was low. Percentages use the number of subjects in each baseline category and treatment group as denominator, so they sum to 100% within each baseline category.

Shifts to a high category were infrequent for each analyte in this panel and distributed similarly across treatment groups.

Table 14.3.4.5: Potential drug-induced liver injury. Safety population.

Subjects meeting the criterion	Placebo N = 861	Xanomeline Low Dose N = 961	Xanomeline High Dose N = 721	Overall N = 2541
Alanine aminotransferase at least 3 x ULN	2 (2.3%)	0 (0%)	1 (1.4%)	3 (1.2%)
Aspartate aminotransferase at least 3 x ULN	2 (2.3%)	1 (1.0%)	1 (1.4%)	4 (1.6%)
Total bilirubin at least 2 x ULN	1 (1.2%)	0 (0%)	1 (1.4%)	2 (0.8%)
Aminotransferase at least 3 x ULN with bilirubin at least 2 x ULN	1 (1.2%)	0 (0%)	0 (0%)	1 (0.4%)
1 n (%)
Counts are of subjects with at least one post-baseline value meeting each criterion, relative to the upper limit of the reference range of the reporting laboratory. The combined criterion requires an aminotransferase elevation and a bilirubin elevation in the same subject, not necessarily on the same day, and is a screen for potential drug-induced liver injury rather than a diagnosis.

Subjects meeting the combined aminotransferase and bilirubin criterion: 1, in the following treatment groups: placebo. 5 subjects met at least one criterion in total, too few for the difference between treatment groups to be interpretable, so the laboratory data show no signal of xanomeline-related liver injury. Subject-level values for every subject meeting any criterion are listed in Listing 16.2.8.1.

8.9 Vital signs

Table 14.3.7: Shift from baseline to worst post-baseline category. Systolic blood pressure measured supine, safety population.

Characteristic	Normal			High
	Placebo N = 261	Xanomeline Low Dose N = 221	Xanomeline High Dose N = 221	Placebo N = 571	Xanomeline Low Dose N = 531	Xanomeline High Dose N = 501
Worst post-baseline category
Low	1 (3.8%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)
Normal	10 (38%)	8 (36%)	13 (59%)	2 (3.5%)	4 (7.5%)	6 (12%)
High	15 (58%)	14 (64%)	9 (41%)	55 (96%)	49 (92%)	44 (88%)
1 n (%)
Categories are relative to the reference range of the reporting site. The worst post-baseline category is high (hypertensive) if any post-baseline value was high, otherwise low (hypotensive) if any value was low. Percentages use the number of subjects in each baseline category and treatment group as denominator, so they sum to 100% within each baseline category. Vital signs are measured in three postures, each with its own baseline; this table uses the supine measurement, so a subject is counted once.

Shifts to a high systolic blood pressure category occurred at a similar rate across treatment groups, with no excess of new hypotensive or hypertensive categories in either xanomeline group relative to placebo.

8.10 Electrocardiogram

Table 14.3.8: Shift from baseline to worst post-baseline category. QTcF interval, safety population.

Characteristic	Normal			High
	Placebo N = 01	Xanomeline Low Dose N = 01	Xanomeline High Dose N = 11	Placebo N = 841	Xanomeline Low Dose N = 941	Xanomeline High Dose N = 711
Worst post-baseline category
Low	0 (NA%)	0 (NA%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)
Normal	0 (NA%)	0 (NA%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)
High	0 (NA%)	0 (NA%)	1 (100%)	84 (100%)	94 (100%)	71 (100%)
1 n (%)
Categories are relative to the reference range of the reporting site. The worst post-baseline category is high if any post-baseline value was high, otherwise low if any value was low. Percentages use the number of subjects in each baseline category and treatment group as denominator, so they sum to 100% within each baseline category.

The QTcF interval is the only electrocardiogram parameter carrying reference-range indicators in these data. Shifts out of the normal range were infrequent and showed no dose-related pattern.