TSFAE04a:	Subjects With Treatment-emergent Adverse Events Leading to Permanent Discontinuation of Study Treatment by System Organ Class, Preferred Term, and [Subgroup]; Safety Analysis Set (Study jjcs - core)							
 	Active Study Agent 	Active Study Agent 	Active Study Agent 	 	Risk Difference (%) (95% CI) 	Risk Difference (%) (95% CI) 	
System Organ Class 	Xanomeline High Dose 	Xanomeline Low Dose 	Combined 	Placebo 	Xanomeline High Dose vs Placebo 	Xanomeline Low Dose vs Placebo 	
  Preferred Term, n (%) 	N=53 	N=73 	N=126 	N=59 	  	  	
Age Group: ≥18 to <65 years 	8 	5 	13 	7 	 	 	
 	  	  	  	  	  	  	
Subjects with ≥1 AE leading to discontinuation 	6 (75.0%) 	0 	6 (46.2%) 	1 (14.3%) 	60.7 (21.1, 100.0) 	-14.3 (-40.2, 11.6) 	
 	  	  	  	  	  	  	
General disorders and administration site conditions 	2 (25.0%) 	0 	2 (15.4%) 	0 	25.0 (-5.0, 55.0) 	0.0 (0.0, 0.0) 	
APPLICATION SITE PRURITUS 	2 (25.0%) 	0 	2 (15.4%) 	0 	25.0 (-5.0, 55.0) 	0.0 (0.0, 0.0) 	
 	 	 	 	 	 	 	
Skin and subcutaneous tissue disorders 	2 (25.0%) 	0 	2 (15.4%) 	1 (14.3%) 	10.7 (-28.9, 50.4) 	-14.3 (-40.2, 11.6) 	
ERYTHEMA 	1 (12.5%) 	0 	1 (7.7%) 	0 	12.5 (-10.4, 35.4) 	0.0 (0.0, 0.0) 	
PRURITUS 	1 (12.5%) 	0 	1 (7.7%) 	0 	12.5 (-10.4, 35.4) 	0.0 (0.0, 0.0) 	
DRUG ERUPTION 	0 	0 	0 	1 (14.3%) 	-14.3 (-40.2, 11.6) 	-14.3 (-40.2, 11.6) 	
 	 	 	 	 	 	 	
Gastrointestinal disorders 	1 (12.5%) 	0 	1 (7.7%) 	0 	12.5 (-10.4, 35.4) 	0.0 (0.0, 0.0) 	
SALIVARY HYPERSECRETION 	1 (12.5%) 	0 	1 (7.7%) 	0 	12.5 (-10.4, 35.4) 	0.0 (0.0, 0.0) 	
 	 	 	 	 	 	 	
Infections and infestations 	1 (12.5%) 	0 	1 (7.7%) 	0 	12.5 (-10.4, 35.4) 	0.0 (0.0, 0.0) 	
UPPER RESPIRATORY TRACT INFECTION 	1 (12.5%) 	0 	1 (7.7%) 	0 	12.5 (-10.4, 35.4) 	0.0 (0.0, 0.0) 	
 	 	 	 	 	 	 	
Nervous system disorders 	1 (12.5%) 	0 	1 (7.7%) 	0 	12.5 (-10.4, 35.4) 	0.0 (0.0, 0.0) 	
HEADACHE 	1 (12.5%) 	0 	1 (7.7%) 	0 	12.5 (-10.4, 35.4) 	0.0 (0.0, 0.0) 	
 	 	 	 	 	 	 	
Psychiatric disorders 	1 (12.5%) 	0 	1 (7.7%) 	0 	12.5 (-10.4, 35.4) 	0.0 (0.0, 0.0) 	
LISTLESS 	1 (12.5%) 	0 	1 (7.7%) 	0 	12.5 (-10.4, 35.4) 	0.0 (0.0, 0.0) 	
 	 	 	 	 	 	 	
Respiratory, thoracic and mediastinal disorders 	1 (12.5%) 	0 	1 (7.7%) 	0 	12.5 (-10.4, 35.4) 	0.0 (0.0, 0.0) 	
RESPIRATORY TRACT CONGESTION 	1 (12.5%) 	0 	1 (7.7%) 	0 	12.5 (-10.4, 35.4) 	0.0 (0.0, 0.0) 	
Age Group: ≥65 to <75 years 	16 	17 	33 	19 	 	 	
 	  	  	  	  	  	  	
Subjects with ≥1 AE leading to discontinuation 	7 (43.8%) 	3 (17.6%) 	10 (30.3%) 	6 (31.6%) 	12.2 (-19.9, 44.2) 	-13.9 (-41.6, 13.7) 	
 	  	  	  	  	  	  	
General disorders and administration site conditions 	2 (12.5%) 	1 (5.9%) 	3 (9.1%) 	1 (5.3%) 	7.2 (-11.8, 26.3) 	0.6 (-14.4, 15.6) 	
APPLICATION SITE IRRITATION 	1 (6.2%) 	0 	1 (3.0%) 	0 	6.2 (-5.6, 18.1) 	0.0 (0.0, 0.0) 	
APPLICATION SITE PRURITUS 	0 	1 (5.9%) 	1 (3.0%) 	0 	0.0 (0.0, 0.0) 	5.9 (-5.3, 17.1) 	
FATIGUE 	1 (6.2%) 	0 	1 (3.0%) 	0 	6.2 (-5.6, 18.1) 	0.0 (0.0, 0.0) 	
APPLICATION SITE ERYTHEMA 	0 	0 	0 	1 (5.3%) 	-5.3 (-15.3, 4.8) 	-5.3 (-15.3, 4.8) 	
 	 	 	 	 	 	 	
Skin and subcutaneous tissue disorders 	3 (18.8%) 	0 	3 (9.1%) 	1 (5.3%) 	13.5 (-8.1, 35.1) 	-5.3 (-15.3, 4.8) 	
ERYTHEMA 	1 (6.2%) 	0 	1 (3.0%) 	0 	6.2 (-5.6, 18.1) 	0.0 (0.0, 0.0) 	
PRURITUS 	1 (6.2%) 	0 	1 (3.0%) 	0 	6.2 (-5.6, 18.1) 	0.0 (0.0, 0.0) 	
RASH 	1 (6.2%) 	0 	1 (3.0%) 	1 (5.3%) 	1.0 (-14.6, 16.5) 	-5.3 (-15.3, 4.8) 	
SKIN IRRITATION 	1 (6.2%) 	0 	1 (3.0%) 	0 	6.2 (-5.6, 18.1) 	0.0 (0.0, 0.0) 	
 	 	 	 	 	 	 	
Respiratory, thoracic and mediastinal disorders 	1 (6.2%) 	1 (5.9%) 	2 (6.1%) 	1 (5.3%) 	1.0 (-14.6, 16.5) 	0.6 (-14.4, 15.6) 	
ALLERGIC GRANULOMATOUS ANGIITIS 	1 (6.2%) 	0 	1 (3.0%) 	0 	6.2 (-5.6, 18.1) 	0.0 (0.0, 0.0) 	
DYSPHONIA 	0 	1 (5.9%) 	1 (3.0%) 	0 	0.0 (0.0, 0.0) 	5.9 (-5.3, 17.1) 	
NASAL CONGESTION 	1 (6.2%) 	0 	1 (3.0%) 	0 	6.2 (-5.6, 18.1) 	0.0 (0.0, 0.0) 	
POSTNASAL DRIP 	0 	0 	0 	1 (5.3%) 	-5.3 (-15.3, 4.8) 	-5.3 (-15.3, 4.8) 	
 	 	 	 	 	 	 	
Gastrointestinal disorders 	0 	1 (5.9%) 	1 (3.0%) 	0 	0.0 (0.0, 0.0) 	5.9 (-5.3, 17.1) 	
DIARRHOEA 	0 	1 (5.9%) 	1 (3.0%) 	0 	0.0 (0.0, 0.0) 	5.9 (-5.3, 17.1) 	
VOMITING 	0 	1 (5.9%) 	1 (3.0%) 	0 	0.0 (0.0, 0.0) 	5.9 (-5.3, 17.1) 	
 	 	 	 	 	 	 	
Investigations 	0 	1 (5.9%) 	1 (3.0%) 	2 (10.5%) 	-10.5 (-24.3, 3.3) 	-4.6 (-22.4, 13.1) 	
WEIGHT DECREASED 	0 	1 (5.9%) 	1 (3.0%) 	0 	0.0 (0.0, 0.0) 	5.9 (-5.3, 17.1) 	
BLOOD CREATINE PHOSPHOKINASE INCREASED 	0 	0 	0 	1 (5.3%) 	-5.3 (-15.3, 4.8) 	-5.3 (-15.3, 4.8) 	
ELECTROCARDIOGRAM T WAVE AMPLITUDE DECREASED 	0 	0 	0 	1 (5.3%) 	-5.3 (-15.3, 4.8) 	-5.3 (-15.3, 4.8) 	
 	 	 	 	 	 	 	
Vascular disorders 	1 (6.2%) 	0 	1 (3.0%) 	0 	6.2 (-5.6, 18.1) 	0.0 (0.0, 0.0) 	
WOUND HAEMORRHAGE 	1 (6.2%) 	0 	1 (3.0%) 	0 	6.2 (-5.6, 18.1) 	0.0 (0.0, 0.0) 	
 	 	 	 	 	 	 	
Metabolism and nutrition disorders 	0 	0 	0 	1 (5.3%) 	-5.3 (-15.3, 4.8) 	-5.3 (-15.3, 4.8) 	
DECREASED APPETITE 	0 	0 	0 	1 (5.3%) 	-5.3 (-15.3, 4.8) 	-5.3 (-15.3, 4.8) 	
 	 	 	 	 	 	 	
Musculoskeletal and connective tissue disorders 	0 	0 	0 	1 (5.3%) 	-5.3 (-15.3, 4.8) 	-5.3 (-15.3, 4.8) 	
SHOULDER PAIN 	0 	0 	0 	1 (5.3%) 	-5.3 (-15.3, 4.8) 	-5.3 (-15.3, 4.8) 	
 	 	 	 	 	 	 	
Nervous system disorders 	0 	0 	0 	1 (5.3%) 	-5.3 (-15.3, 4.8) 	-5.3 (-15.3, 4.8) 	
PARKINSON'S DISEASE 	0 	0 	0 	1 (5.3%) 	-5.3 (-15.3, 4.8) 	-5.3 (-15.3, 4.8) 	
 	 	 	 	 	 	 	
Psychiatric disorders 	0 	0 	0 	1 (5.3%) 	-5.3 (-15.3, 4.8) 	-5.3 (-15.3, 4.8) 	
DISORIENTATION 	0 	0 	0 	1 (5.3%) 	-5.3 (-15.3, 4.8) 	-5.3 (-15.3, 4.8) 	
Age Group: ≥75 years 	29 	51 	80 	33 	 	 	
 	  	  	  	  	  	  	
Subjects with ≥1 AE leading to discontinuation 	10 (34.5%) 	17 (33.3%) 	27 (33.8%) 	11 (33.3%) 	1.1 (-22.5, 24.8) 	0.0 (-20.6, 20.6) 	
 	  	  	  	  	  	  	
General disorders and administration site conditions 	2 (6.9%) 	7 (13.7%) 	9 (11.2%) 	3 (9.1%) 	-2.2 (-15.7, 11.3) 	4.6 (-9.0, 18.3) 	
APPLICATION SITE IRRITATION 	0 	3 (5.9%) 	3 (3.8%) 	0 	0.0 (0.0, 0.0) 	5.9 (-0.6, 12.3) 	
APPLICATION SITE PRURITUS 	0 	3 (5.9%) 	3 (3.8%) 	0 	0.0 (0.0, 0.0) 	5.9 (-0.6, 12.3) 	
APPLICATION SITE DERMATITIS 	1 (3.4%) 	0 	1 (1.2%) 	1 (3.0%) 	0.4 (-8.4, 9.3) 	-3.0 (-8.9, 2.8) 	
APPLICATION SITE ERYTHEMA 	0 	1 (2.0%) 	1 (1.2%) 	0 	0.0 (0.0, 0.0) 	2.0 (-1.8, 5.8) 	
ASTHENIA 	0 	1 (2.0%) 	1 (1.2%) 	0 	0.0 (0.0, 0.0) 	2.0 (-1.8, 5.8) 	
CHEST PAIN 	1 (3.4%) 	0 	1 (1.2%) 	0 	3.4 (-3.2, 10.1) 	0.0 (0.0, 0.0) 	
ULCER 	0 	1 (2.0%) 	1 (1.2%) 	0 	0.0 (0.0, 0.0) 	2.0 (-1.8, 5.8) 	
APPLICATION SITE INDURATION 	0 	0 	0 	1 (3.0%) 	-3.0 (-8.9, 2.8) 	-3.0 (-8.9, 2.8) 	
APPLICATION SITE REACTION 	0 	0 	0 	1 (3.0%) 	-3.0 (-8.9, 2.8) 	-3.0 (-8.9, 2.8) 	
OEDEMA PERIPHERAL 	0 	0 	0 	1 (3.0%) 	-3.0 (-8.9, 2.8) 	-3.0 (-8.9, 2.8) 	
 	 	 	 	 	 	 	
Nervous system disorders 	3 (10.3%) 	4 (7.8%) 	7 (8.8%) 	0 	10.3 (-0.7, 21.4) 	7.8 (0.5, 15.2) 	
DIZZINESS 	1 (3.4%) 	3 (5.9%) 	4 (5.0%) 	0 	3.4 (-3.2, 10.1) 	5.9 (-0.6, 12.3) 	
SYNCOPE 	1 (3.4%) 	1 (2.0%) 	2 (2.5%) 	0 	3.4 (-3.2, 10.1) 	2.0 (-1.8, 5.8) 	
HEADACHE 	1 (3.4%) 	0 	1 (1.2%) 	0 	3.4 (-3.2, 10.1) 	0.0 (0.0, 0.0) 	
 	 	 	 	 	 	 	
Skin and subcutaneous tissue disorders 	2 (6.9%) 	3 (5.9%) 	5 (6.2%) 	3 (9.1%) 	-2.2 (-15.7, 11.3) 	-3.2 (-15.0, 8.5) 	
BLISTER 	0 	1 (2.0%) 	1 (1.2%) 	0 	0.0 (0.0, 0.0) 	2.0 (-1.8, 5.8) 	
PRURITUS 	0 	1 (2.0%) 	1 (1.2%) 	0 	0.0 (0.0, 0.0) 	2.0 (-1.8, 5.8) 	
RASH 	1 (3.4%) 	0 	1 (1.2%) 	0 	3.4 (-3.2, 10.1) 	0.0 (0.0, 0.0) 	
RASH PRURITIC 	1 (3.4%) 	0 	1 (1.2%) 	0 	3.4 (-3.2, 10.1) 	0.0 (0.0, 0.0) 	
SKIN IRRITATION 	0 	1 (2.0%) 	1 (1.2%) 	1 (3.0%) 	-3.0 (-8.9, 2.8) 	-1.1 (-8.0, 5.9) 	
ERYTHEMA 	0 	0 	0 	1 (3.0%) 	-3.0 (-8.9, 2.8) 	-3.0 (-8.9, 2.8) 	
HYPERHIDROSIS 	0 	0 	0 	1 (3.0%) 	-3.0 (-8.9, 2.8) 	-3.0 (-8.9, 2.8) 	
 	 	 	 	 	 	 	
Cardiac disorders 	1 (3.4%) 	1 (2.0%) 	2 (2.5%) 	0 	3.4 (-3.2, 10.1) 	2.0 (-1.8, 5.8) 	
MYOCARDIAL INFARCTION 	1 (3.4%) 	0 	1 (1.2%) 	0 	3.4 (-3.2, 10.1) 	0.0 (0.0, 0.0) 	
PALPITATIONS 	0 	1 (2.0%) 	1 (1.2%) 	0 	0.0 (0.0, 0.0) 	2.0 (-1.8, 5.8) 	
 	 	 	 	 	 	 	
Infections and infestations 	1 (3.4%) 	1 (2.0%) 	2 (2.5%) 	5 (15.2%) 	-11.7 (-25.6, 2.2) 	-13.2 (-26.0, -0.4) 	
NASOPHARYNGITIS 	1 (3.4%) 	1 (2.0%) 	2 (2.5%) 	1 (3.0%) 	0.4 (-8.4, 9.3) 	-1.1 (-8.0, 5.9) 	
LOCALISED INFECTION 	0 	0 	0 	1 (3.0%) 	-3.0 (-8.9, 2.8) 	-3.0 (-8.9, 2.8) 	
UPPER RESPIRATORY TRACT INFECTION 	0 	0 	0 	2 (6.1%) 	-6.1 (-14.2, 2.1) 	-6.1 (-14.2, 2.1) 	
URINARY TRACT INFECTION 	0 	0 	0 	1 (3.0%) 	-3.0 (-8.9, 2.8) 	-3.0 (-8.9, 2.8) 	
 	 	 	 	 	 	 	
Injury, poisoning and procedural complications 	1 (3.4%) 	1 (2.0%) 	2 (2.5%) 	0 	3.4 (-3.2, 10.1) 	2.0 (-1.8, 5.8) 	
CONTUSION 	1 (3.4%) 	1 (2.0%) 	2 (2.5%) 	0 	3.4 (-3.2, 10.1) 	2.0 (-1.8, 5.8) 	
 	 	 	 	 	 	 	
Gastrointestinal disorders 	0 	1 (2.0%) 	1 (1.2%) 	2 (6.1%) 	-6.1 (-14.2, 2.1) 	-4.1 (-13.1, 4.9) 	
DIARRHOEA 	0 	1 (2.0%) 	1 (1.2%) 	1 (3.0%) 	-3.0 (-8.9, 2.8) 	-1.1 (-8.0, 5.9) 	
HIATUS HERNIA 	0 	0 	0 	1 (3.0%) 	-3.0 (-8.9, 2.8) 	-3.0 (-8.9, 2.8) 	
 	 	 	 	 	 	 	
Psychiatric disorders 	1 (3.4%) 	0 	1 (1.2%) 	0 	3.4 (-3.2, 10.1) 	0.0 (0.0, 0.0) 	
DELIRIUM 	1 (3.4%) 	0 	1 (1.2%) 	0 	3.4 (-3.2, 10.1) 	0.0 (0.0, 0.0) 	
 	 	 	 	 	 	 	
Renal and urinary disorders 	0 	1 (2.0%) 	1 (1.2%) 	0 	0.0 (0.0, 0.0) 	2.0 (-1.8, 5.8) 	
INCONTINENCE 	0 	1 (2.0%) 	1 (1.2%) 	0 	0.0 (0.0, 0.0) 	2.0 (-1.8, 5.8) 	
 	 	 	 	 	 	 	
Respiratory, thoracic and mediastinal disorders 	0 	1 (2.0%) 	1 (1.2%) 	0 	0.0 (0.0, 0.0) 	2.0 (-1.8, 5.8) 	
DYSPNOEA 	0 	1 (2.0%) 	1 (1.2%) 	0 	0.0 (0.0, 0.0) 	2.0 (-1.8, 5.8) 	
 	 	 	 	 	 	 	
Eye disorders 	0 	0 	0 	1 (3.0%) 	-3.0 (-8.9, 2.8) 	-3.0 (-8.9, 2.8) 	
EYE PRURITUS 	0 	0 	0 	1 (3.0%) 	-3.0 (-8.9, 2.8) 	-3.0 (-8.9, 2.8) 	
 	 	 	 	 	 	 	
Investigations 	0 	0 	0 	1 (3.0%) 	-3.0 (-8.9, 2.8) 	-3.0 (-8.9, 2.8) 	
CYSTOSCOPY 	0 	0 	0 	1 (3.0%) 	-3.0 (-8.9, 2.8) 	-3.0 (-8.9, 2.8) 	
 	 	 	 	 	 	 	
Surgical and medical procedures 	0 	0 	0 	1 (3.0%) 	-3.0 (-8.9, 2.8) 	-3.0 (-8.9, 2.8) 	
CATARACT OPERATION 	0 	0 	0 	1 (3.0%) 	-3.0 (-8.9, 2.8) 	-3.0 (-8.9, 2.8) 	

Note: Subjects are counted only once for any given event, regardless of the number of times they actually experienced the event. 	
Note: Subjects are counted only once for any given event, regardless of the number of times they actually experienced the event.	
Note: Subjects are counted only once for any given event, regardless of the number of times they actually experienced the event.	
Note: Subjects are counted only once for any given event, regardless of the number of times they actually experienced the event.	
Note: Subjects are counted only once for any given event, regardless of the number of times they actually experienced the event.	
Note: Subjects are counted only once for any given event, regardless of the number of times they actually experienced the event.	
Note: Subjects are counted only once for any given event, regardless of the number of times they actually experienced the event.	
Note: Adverse events are coded using MedDRA version 26.0. 	: Adverse events are coded using MedDRA version 26.	: Adverse events are coded using MedDRA version 26.	: Adverse events are coded using MedDRA version 26.	: Adverse events are coded using MedDRA version 26.	: Adverse events are coded using MedDRA version 26.	: Adverse events are coded using MedDRA version 26.