Trial Outcomes & Findings for A Study to Assess the Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Chinese Adult Subjects With DSM-5 Schizophrenia (NCT NCT05919823)

NCT ID: NCT05919823

Last Updated: 2025-12-17

Results Overview

PANSS Total Score is a clinical tool used to measure the severity of symptoms in individuals with schizophrenia. It includes 30 items divided into three subscales: Positive Symptoms (e.g., hallucinations, delusions) Negative Symptoms (e.g., social withdrawal, lack of motivation) General Psychopathology (e.g., anxiety, depression) Each item is rated from 1 (absent) to 7 (extreme), resulting in a total score range from 30 to 210. Higher PANSS Total Scores indicate more severe symptoms and worse clinical outcomes. Baseline is defined as last non-missing assessment prior to the first dose of study drug.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 202 participants
• Primary outcome timeframe: At Baseline and at Week 5 of the Double-Blind Period
• Results posted on: 2025-12-17

Participant Flow

Participants completed 5-week KarXT treatment in the double-blind period and signed ICF for the open-label extension period continued KarXT treatment to additional 12-week.

Participant milestones

Measure	Double-Blind Part: KarXT Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Double-Blind Period COMPLETED	79	78	0	0
Pre-Treatment Period STARTED	103	99	0	0
Pre-Treatment Period COMPLETED	102	98	0	0
Pre-Treatment Period NOT COMPLETED	1	1	0	0
Double-Blind Period STARTED	102	98	0	0
Double-Blind Period NOT COMPLETED	23	20	0	0
Open Label Period STARTED	0	0	38	28
Open Label Period COMPLETED	0	0	18	11
Open Label Period NOT COMPLETED	0	0	20	17

Reasons for withdrawal

Measure	Double-Blind Part: KarXT Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Pre-Treatment Period Screen failure	1	0	0	0
Pre-Treatment Period Protocol Violation	0	1	0	0
Double-Blind Period Adverse Event	8	9	0	0
Double-Blind Period Protocol Violation	2	1	0	0
Double-Blind Period Participant withdrew consent	11	7	0	0
Double-Blind Period Other reasons	2	3	0	0
Open Label Period Adverse Event	0	0	2	4
Open Label Period Lost to Follow-up	0	0	1	0
Open Label Period Protocol Violation	0	0	0	1
Open Label Period Participant withdrew consent	0	0	8	6
Open Label Period Death	0	0	0	1
Open Label Period Other reasons	0	0	9	5

Baseline Characteristics

A Study to Assess the Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Chinese Adult Subjects With DSM-5 Schizophrenia

Baseline characteristics by cohort

Measure	Double-Blind Part: KarXT n=103 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=99 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Total n=202 Participants Total of all reporting groups
Age, Continuous	37.3 Years STANDARD_DEVIATION 9.55 • n=6 Participants	36.9 Years STANDARD_DEVIATION 11.91 • n=5 Participants	—	—	37.1 Years STANDARD_DEVIATION 10.75 • n=488 Participants
Sex: Female, Male Female	56 Participants n=6 Participants	50 Participants n=5 Participants	—	—	106 Participants n=488 Participants
Sex: Female, Male Male	47 Participants n=6 Participants	49 Participants n=5 Participants	—	—	96 Participants n=488 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=6 Participants	0 Participants n=5 Participants	—	—	0 Participants n=488 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	103 Participants n=6 Participants	99 Participants n=5 Participants	—	—	202 Participants n=488 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=6 Participants	0 Participants n=5 Participants	—	—	0 Participants n=488 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=6 Participants	0 Participants n=5 Participants	—	—	0 Participants n=488 Participants
Race (NIH/OMB) Asian	103 Participants n=6 Participants	99 Participants n=5 Participants	—	—	202 Participants n=488 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=6 Participants	0 Participants n=5 Participants	—	—	0 Participants n=488 Participants
Race (NIH/OMB) Black or African American	0 Participants n=6 Participants	0 Participants n=5 Participants	—	—	0 Participants n=488 Participants
Race (NIH/OMB) White	0 Participants n=6 Participants	0 Participants n=5 Participants	—	—	0 Participants n=488 Participants
Race (NIH/OMB) More than one race	0 Participants n=6 Participants	0 Participants n=5 Participants	—	—	0 Participants n=488 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=6 Participants	0 Participants n=5 Participants	—	—	0 Participants n=488 Participants

PRIMARY outcome

Timeframe: At Baseline and at Week 5 of the Double-Blind Period

Population: All randomized participants who received at least one dose of study medicine and had baseline and least 1 post-baseline PANSS assessment in the double-blind period. Prespecified to be reported for the double-blind period only.

PANSS Total Score is a clinical tool used to measure the severity of symptoms in individuals with schizophrenia. It includes 30 items divided into three subscales:

Positive Symptoms (e.g., hallucinations, delusions) Negative Symptoms (e.g., social withdrawal, lack of motivation) General Psychopathology (e.g., anxiety, depression) Each item is rated from 1 (absent) to 7 (extreme), resulting in a total score range from 30 to 210.

Higher PANSS Total Scores indicate more severe symptoms and worse clinical outcomes.

Baseline is defined as last non-missing assessment prior to the first dose of study drug.

Outcome measures

Measure	Double-Blind Part: KarXT n=99 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=97 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Scores at Week 5 of the Double-Blind Period	-16.9 Score on a Scale Standard Error 2.122	-7.7 Score on a Scale Standard Error 2.074	—	—

SECONDARY outcome

Timeframe: At Baseline and at Week 5 of the Double-Blind Period

Population: All randomized participants who received at least one dose of study medicine and had baseline and least 1 post-baseline PANSS assessment in the double-blind period. Prespecified to be collected for the double-blind period only.

The PANSS Positive Symptom Score assesses the severity of positive symptoms in schizophrenia, such as hallucinations and delusions. It includes 7 items: delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. Each item is rated from 1 (absent) to 7 (extreme), for a total score range of 7 to 49. Higher scores indicate more severe symptoms and worse clinical outcomes.

Baseline is defined as last non-missing assessment prior to the first dose of study drug.

Outcome measures

Measure	Double-Blind Part: KarXT n=99 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=97 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Change From Baseline in Positive Symptom Score of the Positive and Negative Syndrome Scale (PANSS) at Week 5 of the Double-Blind Period	-6.5 Score on a Scale Standard Error 0.713	-4.6 Score on a Scale Standard Error 0.700	—	—

SECONDARY outcome

Timeframe: At Baseline and at Week 5 of the Double-Blind Period

Population: All randomized participants who received at least one dose of study medicine and had baseline and least 1 post-baseline PANSS assessment in the double-blind period. Prespecified to be reported for the double-blind period only.

The Positive and Negative Syndrome Scale (PANSS) Negative Symptom Score assesses the severity of negative symptoms in schizophrenia, such as emotional withdrawal and reduced motivation. It includes 7 items: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity, and stereotyped thinking. Each item is rated from 1 (absent) to 7 (extreme), for a total score range of 7 to 49. Higher scores indicate more severe symptoms and worse outcomes.

Baseline is defined as last non-missing assessment prior to the first dose of study drug.

Outcome measures

Measure	Double-Blind Part: KarXT n=99 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=97 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Change From Baseline in Negative Symptom Score of the Positive and Negative Syndrome Scale (PANSS) at Week 5 of the Double-Blind Period	-3.2 Score on a Scale Standard Error 0.664	-0.7 Score on a Scale Standard Error 0.648	—	—

SECONDARY outcome

Timeframe: At Baseline and at Week 5 of the Double-Blind Period

Population: All randomized participants who received at least one dose of study medicine and had baseline and least 1 post-baseline PANSS assessment in the double-blind period. Prespecified to be reported for the double-blind period only.

The Negative Marder Factor Score is subset of PANSS items used to evaluate negative symptoms based on a five-factor model. It includes 7 items: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, lack of spontaneity, motor retardation, and active social avoidance. Each item is rated from 1 to 7. Higher scores reflect greater severity of negative symptoms and poorer clinical outcomes. PANSS total score is the sum of all 30 items with a minimum score of 30 and a maximum score of 210. Higher scores indicate more severe symptoms. The PANSS Total Score is then the sum of the positive, negative, and general psychopathology symptom scores. Baseline is defined as last non-missing assessment prior to the first dose of study drug.

Outcome measures

Measure	Double-Blind Part: KarXT n=99 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=97 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Change From Baseline in Negative Marder Factor Score of the Positive and Negative Syndrome Scale (PANSS) at Week 5 of the Double-Blind Period	-3.1 Score on a Scale Standard Error 0.677	-0.5 Score on a Scale Standard Error 0.660	—	—

SECONDARY outcome

Timeframe: At Baseline and at Week 5 of the Double-Blind Period

Population: All randomized participants who received at least one dose of study medicine and had baseline and least 1 post-baseline CGI-S assessment in the double-blind period. Prespecified to be reported for the double-blind period only.

The CGI-S Score is a clinician-rated scale used to assess the severity of a patient's mental illness at a given time. It ranges from 1 (Normal, not at all ill) to 7 (Among the most extremely ill patients). The score reflects the clinician's overall impression based on observed symptoms, behavior, and functioning. Higher scores indicate greater illness severity and worse clinical status.

Baseline is defined as last non-missing assessment prior to the first dose of study drug.

Outcome measures

Measure	Double-Blind Part: KarXT n=99 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=97 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Change From Baseline in Clinical Global Impressions - Severity (CGI-S) Score at Week 5 of the Double-Blind Period	-0.9 Score on a Scale Standard Error 0.119	-0.5 Score on a Scale Standard Error 0.117	—	—

SECONDARY outcome

Timeframe: At Baseline and at Week 5 of the Double-Blind Period

Population: All randomized participants who received at least one dose of study medicine and had baseline and least 1 post-baseline PANSS assessment (≥30% Change) in the double-blind period. Prespecified to be reported for the double-blind period only.

PANSS Total Score is a clinical tool used to measure the severity of symptoms in individuals with schizophrenia. It includes 30 items divided into three subscales:

Positive Symptoms (e.g., hallucinations, delusions) Negative Symptoms (e.g., social withdrawal, lack of motivation) General Psychopathology (e.g., anxiety, depression) Each item is rated from 1 (absent) to 7 (extreme), resulting in a total score range from 30 to 210.

Higher PANSS Total Scores indicate more severe symptoms and worse clinical outcomes.

Baseline is defined as last non-missing assessment prior to the first dose of study drug.

Outcome measures

Measure	Double-Blind Part: KarXT n=76 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=76 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Percentage of PANSS Responders (≥30% Change in PANSS Total Score From Baseline) at Week 5 of the Double-Blind Period	42.1 Percentage of participants	26.3 Percentage of participants	—	—

SECONDARY outcome

Timeframe: At Baseline and at Week 12 of the Open-Label Period

Population: All participants who received at least one dose of study medicine in the open-label period and had study/open-label period baseline and least 1 post-baseline PANSS assessment in the Open-label Period. Prespecified to be reported for the open-label period only.

PANSS Total Score is a clinical tool used to measure the severity of symptoms in individuals with schizophrenia. It includes 30 items divided into three subscales:

Positive Symptoms (e.g., hallucinations, delusions) Negative Symptoms (e.g., social withdrawal, lack of motivation) General Psychopathology (e.g., anxiety, depression) Each item is rated from 1 (absent) to 7 (extreme), resulting in a total score range from 30 to 210.

Higher PANSS Total Scores indicate more severe symptoms and worse clinical outcomes.

Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

Outcome measures

Measure	Double-Blind Part: KarXT n=18 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=11 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Scores at Week 12 of the Open-Label Period Open-label period- baseline to Open-label period- Week 12	-2.7 Score on a Scale Standard Deviation 17.27	-6.1 Score on a Scale Standard Deviation 12.49	—	—
Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Scores at Week 12 of the Open-Label Period Study baseline to Open-label period- Week 12	-22.0 Score on a Scale Standard Deviation 21.67	-21.2 Score on a Scale Standard Deviation 19.76	—	—

SECONDARY outcome

Timeframe: At Baseline and at Week 12 of the Open-Label Period

Population: All participants who received at least one dose of study medicine in the open-label period and had study/open-label period baseline and least 1 post-baseline PANSS assessment in the Open-label Period. Prespecified to be reported for the open-label period only.

The PANSS Positive Symptom Score assesses the severity of positive symptoms in schizophrenia, such as hallucinations and delusions. It includes 7 items: delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. Each item is rated from 1 (absent) to 7 (extreme), for a total score range of 7 to 49. Higher scores indicate more severe symptoms and worse clinical outcomes.

Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

Outcome measures

Measure	Double-Blind Part: KarXT n=18 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=11 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Change From Baseline in Positive Symptom Score of the Positive and Negative Syndrome Scale (PANSS) at Week 12 of the Open-Label Period Study baseline to Open-label period - Week 12	-6.9 Score on a Scale Standard Deviation 6.09	-8.2 Score on a Scale Standard Deviation 6.65	—	—
Change From Baseline in Positive Symptom Score of the Positive and Negative Syndrome Scale (PANSS) at Week 12 of the Open-Label Period Open-label period- baseline to Open-label period- Week 12	-0.2 Score on a Scale Standard Deviation 5.31	-0.8 Score on a Scale Standard Deviation 4.64	—	—

SECONDARY outcome

Timeframe: At Baseline and at Week 12 of the Open-Label Period

Population: All participants who received at least one dose of study medicine in the open-label period and had study/open-label period baseline and least 1 post-baseline PANSS assessment in the Open-label Period. Prespecified to be reported for the open-label period only.

The Positive and Negative Syndrome Scale (PANSS) Negative Symptom Score assesses the severity of negative symptoms in schizophrenia, such as emotional withdrawal and reduced motivation. It includes 7 items: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity, and stereotyped thinking. Each item is rated from 1 (absent) to 7 (extreme), for a total score range of 7 to 49. Higher scores indicate more severe symptoms and worse outcomes.

Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

Outcome measures

Measure	Double-Blind Part: KarXT n=18 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=11 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Change From Baseline in Negative Symptom Score of the Positive and Negative Syndrome Scale (PANSS) at Week 12 of the Open-Label Period Study baseline to Open-label period- Week 12	-4.3 Score on a Scale Standard Deviation 7.75	-3.0 Score on a Scale Standard Deviation 7.40	—	—
Change From Baseline in Negative Symptom Score of the Positive and Negative Syndrome Scale (PANSS) at Week 12 of the Open-Label Period Open-label period- baseline to Open-label period- Week 12	-0.4 Score on a Scale Standard Deviation 5.64	-1.4 Score on a Scale Standard Deviation 4.88	—	—

SECONDARY outcome

Timeframe: At Baseline and at Week 12 of the Open-Label Period

Population: All participants who received at least one dose of study medicine in the open-label period and had study/open-label period baseline and least 1 post-baseline PANSS assessment in the Open-label Period. Prespecified to be reported for the open-label period only.

The Negative Marder Factor Score is subset of PANSS items used to evaluate negative symptoms based on a five-factor model. It includes 7 items: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, lack of spontaneity, motor retardation, and active social avoidance. Each item is rated from 1 to 7. Higher scores reflect greater severity of negative symptoms and poorer clinical outcomes.

Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

Outcome measures

Measure	Double-Blind Part: KarXT n=18 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=11 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Change From Baseline in Negative Marder Factor Score of the Positive and Negative Syndrome Scale (PANSS) at Week 12 of the Open-Label Period Study baseline to Open-label period- Week 12	-3.9 Score on a Scale Standard Deviation 7.40	-3.0 Score on a Scale Standard Deviation 7.25	—	—
Change From Baseline in Negative Marder Factor Score of the Positive and Negative Syndrome Scale (PANSS) at Week 12 of the Open-Label Period Open-label period- baseline to Open-label period- Week 12	-0.2 Score on a Scale Standard Deviation 5.43	-0.8 Score on a Scale Standard Deviation 4.49	—	—

SECONDARY outcome

Timeframe: At Baseline and at Week 12 of the Open-Label Period

Population: All participants who received at least one dose of study medicine in the open-label period and had study/open-label period baseline and least 1 post-baseline CGI-S assessment in the Open-label Period. Prespecified to be reported for the open-label period only.

The CGI-S Score is a clinician-rated scale used to assess the severity of a patient's mental illness at a given time. It ranges from 1 (Normal, not at all ill) to 7 (Among the most extremely ill patients). The score reflects the clinician's overall impression based on observed symptoms, behavior, and functioning. Higher scores indicate greater illness severity and worse clinical status.

Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

Outcome measures

Measure	Double-Blind Part: KarXT n=18 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=11 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Change From Baseline in Clinical Global Impressions - Severity (CGI-S) Score at Week 12 of the Open-Label Period Study baseline to Open-label period- Week 12	-1.1 Score on a Scale Standard Deviation 1.06	-1.2 Score on a Scale Standard Deviation 0.98	—	—
Change From Baseline in Clinical Global Impressions - Severity (CGI-S) Score at Week 12 of the Open-Label Period Open-label period- baseline to Open-label period- Week 12	-0.1 Score on a Scale Standard Deviation 0.80	-0.5 Score on a Scale Standard Deviation 0.82	—	—

SECONDARY outcome

Timeframe: At Baseline and at Week 12 of the Open-Label Period

Population: All participants who received at least one dose of study medicine in the open-label period and had study/Open-label period baseline and least 1 post-baseline PANSS assessment in the Open-label Period. Prespecified to be reported for the open-label period only.

PANSS Total Score is a clinical tool used to measure the severity of symptoms in individuals with schizophrenia. It includes 30 items divided into three subscales:

Positive Symptoms (e.g., hallucinations, delusions) Negative Symptoms (e.g., social withdrawal, lack of motivation) General Psychopathology (e.g., anxiety, depression) Each item is rated from 1 (absent) to 7 (extreme), resulting in a total score range from 30 to 210.

Higher PANSS Total Scores indicate more severe symptoms and worse clinical outcomes.

Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

Outcome measures

Measure	Double-Blind Part: KarXT n=18 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=11 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Percentage of PANSS Responders (≥30% Change in PANSS Total Score From Baseline) at Week 12 of the Open-Label Period Study baseline to Open-label period- Week 12	66.7 Percentage of participants	45.5 Percentage of participants	—	—
Percentage of PANSS Responders (≥30% Change in PANSS Total Score From Baseline) at Week 12 of the Open-Label Period Open-label period- baseline to Open-label period- Week 12	16.7 Percentage of participants	27.3 Percentage of participants	—	—

SECONDARY outcome

Timeframe: From first dose until study completion (up to approximately 18 weeks)

Population: All treated participants in the double blind/open-label periods.

Adverse Event (AE):

An AE is any unfavorable and unintended sign, symptom, or disease that occurs in a participant during a clinical trial, regardless of whether it is related to the study treatment. This includes new conditions or worsening of pre-existing ones.

Serious Adverse Event (SAE):

An SAE is an AE that results in death, is life-threatening, requires hospitalization or prolongs existing hospitalization, causes persistent or significant disability/incapacity, or leads to a congenital anomaly/birth defect. Other events may be considered serious if they require medical intervention to prevent one of these outcomes.

Outcome measures

Measure	Double-Blind Part: KarXT n=102 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=98 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT n=38 Participants Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT n=28 Participants Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Leading to Study Drug Withdrawal Adverse events leading to drug withdrawal	8 Participants	9 Participants	2 Participants	4 Participants
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Leading to Study Drug Withdrawal Adverse events	97 Participants	90 Participants	33 Participants	28 Participants
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Leading to Study Drug Withdrawal Serious adverse events	0 Participants	3 Participants	0 Participants	3 Participants

SECONDARY outcome

Timeframe: From first dose until study completion (up to approximately 18 weeks)

Population: All treated participants in the double blind/open-label periods.

Orthostatic vital signs included blood pressure and heart rate. A participant having sustained orthostatic event is defined as the participant experienced at least one orthostatic event for at least 3 consecutive visits.

Outcome measures

Measure	Double-Blind Part: KarXT n=102 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=98 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT n=38 Participants Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT n=28 Participants Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Number of Participants With Orthostatic Vital Sign Events Orthostatic event at any visit	36 Participants	31 Participants	8 Participants	5 Participants
Number of Participants With Orthostatic Vital Sign Events A Decrease in Systolic Blood Pressure of ≥ 20 mmHg	21 Participants	10 Participants	2 Participants	2 Participants
Number of Participants With Orthostatic Vital Sign Events A Decrease in Diastolic Blood Pressure of ≥ 10 mmHg	16 Participants	16 Participants	4 Participants	5 Participants
Number of Participants With Orthostatic Vital Sign Events An Increase in Heart Rate of ≥ 30 bpm	9 Participants	12 Participants	2 Participants	0 Participants
Number of Participants With Orthostatic Vital Sign Events Sustained orthostatic events	3 Participants	2 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: At study baseline, Day 21 DB, Day 35 DB, open-label baseline, Day 14 OL, Day 84 OL, and end of study visit (up to approximately 18 weeks)

Population: All treated participants with baseline and at least one post baseline liver function assessment in the double blind/open-label periods.

ULN = upper limit of normal range.; DB = Double-blind period; OL = Open-label period. Hy's law is defined as an elevated alanine aminotransferase level (>3xULN) or an elevated aspartate aminotransferase (>3xULN) in combination with alkaline phosphatase <2xULN and elevated total bilirubin (>2 x ULN). Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

Outcome measures

Measure	Double-Blind Part: KarXT n=102 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=98 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT n=38 Participants Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT n=28 Participants Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Number of Participants With Elevated Liver Function Test Results Study Baseline - Alanine aminotransferase - >3XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Study Baseline - Alkaline phosphatase - >2XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Study Baseline - Gamma glutamyl transferase - >2XULN	1 Participants	1 Participants	1 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 21 DB - Aspartate Aminotransferase - >20XULN	0 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 21 DB - Alkaline phosphatase - >2XULN	0 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 21 DB - Bilirubin - >1.5XULN	0 Participants	2 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 21 DB - Bilirubin - >2XULN	0 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 35 DB - Alanine aminotransferase - >5XULN	0 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 35 DB - Alanine aminotransferase - >8XULN	0 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 35 DB - Alanine aminotransferase - >10XULN	0 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 35 DB - Aspartate Aminotransferase - >5XULN	0 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results End of study - Gamma glutamyl transferase - >2XULN	1 Participants	1 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results End of study - Hy's law cases	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Open-label baseline - Aspartate Aminotransferase - >8XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Open-label baseline - Aspartate Aminotransferase - >10XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Open-label baseline - Bilirubin - >2XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 14 OL - Aspartate Aminotransferase - >5XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 14 OL - Aspartate Aminotransferase - >8XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 84 - OL - Alanine aminotransferase - >3XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 84 - OL - Alanine aminotransferase - >8XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 84 - OL - Alanine aminotransferase - >20XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 84 - OL - Alkaline phosphatase - >2XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 84 - OL - Bilirubin - >1.5XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Study Baseline - Alanine aminotransferase - >5XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Study Baseline - Alanine aminotransferase - >8XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Study Baseline - Alanine aminotransferase - >10XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Study Baseline - Alanine aminotransferase - >20XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Study Baseline - Aspartate Aminotransferase - >3XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Study Baseline - Aspartate Aminotransferase - >5XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Study Baseline - Aspartate Aminotransferase - >8XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Study Baseline - Aspartate Aminotransferase - >10XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Study Baseline - Aspartate Aminotransferase - >20XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Study Baseline - Alkaline phosphatase - >1.5XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Study Baseline - Bilirubin - >1.5XULN	0 Participants	2 Participants	0 Participants	1 Participants
Number of Participants With Elevated Liver Function Test Results Study Baseline - Bilirubin - >2XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Study Baseline - Hy's law cases	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 21 DB - Alanine aminotransferase - >3XULN	5 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 21 DB - Alanine aminotransferase - >5XULN	2 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 21 DB - Alanine aminotransferase - >8XULN	1 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 21 DB - Alanine aminotransferase - >10XULN	0 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 21 DB - Alanine aminotransferase - >20XULN	0 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 21 DB - Aspartate Aminotransferase - >3XULN	1 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 21 DB - Aspartate Aminotransferase - >5XULN	1 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 21 DB- Aspartate Aminotransferase - >8XULN	1 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 21 DB - Aspartate Aminotransferase - >10XULN	1 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 21 DB - Alkaline phosphatase - >1.5XULN	2 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 21 DB - Gamma glutamyl transferase - >2XULN	9 Participants	1 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 21 DB - Hy's law cases	0 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 35 DB - Alanine aminotransferase - >3XULN	0 Participants	1 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 35 DB - Alanine aminotransferase - >20XULN	0 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 35 DB - Aspartate Aminotransferase - >3XULN	0 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 35 DB - Aspartate Aminotransferase - >8XULN	0 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 35 DB - Aspartate Aminotransferase - >10XULN	0 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 35 DB - Aspartate Aminotransferase - >20XULN	0 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 35 DB - Alkaline phosphatase - >1.5XULN	0 Participants	1 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 35 DB - Alkaline phosphatase - >2XULN	0 Participants	1 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 35 DB - Bilirubin - >1.5XULN	0 Participants	4 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 35 DB - Bilirubin - >2XULN	0 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 35 DB - Gamma glutamyl transferase - >2XULN	3 Participants	2 Participants	—	—
Number of Participants With Elevated Liver Function Test Results Day 35 DB - Hy's law cases	0 Participants	0 Participants	—	—
Number of Participants With Elevated Liver Function Test Results End of study - Alanine aminotransferase - >3XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results End of study - Alanine aminotransferase - >5XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results End of study - Alanine aminotransferase - >8XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results End of study - Alanine aminotransferase - >10XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results End of study - Alanine aminotransferase - >20XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results End of study - Aspartate Aminotransferase - >3XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results End of study - Aspartate Aminotransferase - >5XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results End of study - Aspartate Aminotransferase - >8XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results End of study - Aspartate Aminotransferase - >10XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results End of study - Aspartate Aminotransferase - >20XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results End of study - Alkaline phosphatase - >1.5XULN	0 Participants	1 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results End of study - Alkaline phosphatase - >2XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results End of study - Bilirubin - >1.5XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results End of study - Bilirubin - >2XULN	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Open-label baseline - Alanine aminotransferase - >3XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Open-label baseline - Alanine aminotransferase - >5XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Open-label baseline - Alanine aminotransferase - >8XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Open-label baseline - Alanine aminotransferase - >10XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Open-label baseline - Alanine aminotransferase - >20XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Open-label baseline - Aspartate Aminotransferase - >3XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Open-label baseline - Aspartate Aminotransferase - >5XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Open-label baseline - Aspartate Aminotransferase - >20XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Open-label baseline - Alkaline phosphatase - >1.5XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Open-label baseline - Alkaline phosphatase - >2XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Open-label baseline - Bilirubin - >1.5XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Open-label baseline - Gamma glutamyl transferase - >2XULN	—	—	1 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Open-label baseline - Hy's law cases	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 14 OL - Alanine aminotransferase - >3XULN	—	—	1 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 14 OL - Alanine aminotransferase - >5XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 14 OL - Alanine aminotransferase - >8XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 14 OL - Alanine aminotransferase - >10XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 14 OL - Alanine aminotransferase - >20XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 14 OL - Aspartate Aminotransferase - >3XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 14 OL - Aspartate Aminotransferase - >10XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 14 OL - Aspartate Aminotransferase - >20XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 14 OL - Alkaline phosphatase - >1.5XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 14 OL - Alkaline phosphatase - >2XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 14 OL - Bilirubin - >1.5XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 14 OL - Bilirubin - >2XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 14 OL - Gamma glutamyl transferase - >2XULN	—	—	1 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 14 OL - Hy's law cases	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 84 - OL - Alanine aminotransferase - >5XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 84 - OL - Alanine aminotransferase - >10XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 84 - OL - Aspartate Aminotransferase - >3XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 84 - OL - Aspartate Aminotransferase - >5XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 84 - OL - Aspartate Aminotransferase - >8XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 84 - OL - Aspartate Aminotransferase - >10XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 84 - OL - Aspartate Aminotransferase - >20XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 84 - OL - Alkaline phosphatase - >1.5XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 84 - OL - Bilirubin - >2XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 84 - OL - Gamma glutamyl transferase - >2XULN	—	—	0 Participants	0 Participants
Number of Participants With Elevated Liver Function Test Results Day 84 - OL - Hy's law cases	—	—	0 Participants	0 Participants

SECONDARY outcome

Timeframe: At study baseline, Day 21 DB, Day 35 DB, open-label baseline, Day 14 OL, Day 84 OL, and end of study visit (up to approximately 18 weeks)

Population: All treated participants with baseline and at least one post-baseline result in the double blind/open-label periods.

ULN = Upper limit of normal; DB = Double-blind period; OL = Open-label period. Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

Outcome measures

Measure	Double-Blind Part: KarXT n=102 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=98 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT n=38 Participants Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT n=28 Participants Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Number of Participants With Elevated Metabolic Syndrome Parameters End of study - Total Cholesterol > ULN	5 Participants	4 Participants	4 Participants	1 Participants
Number of Participants With Elevated Metabolic Syndrome Parameters End of study - Triglycerides > ULN	8 Participants	14 Participants	2 Participants	4 Participants
Number of Participants With Elevated Metabolic Syndrome Parameters Open-label baseline - Glucose > ULN	—	—	6 Participants	3 Participants
Number of Participants With Elevated Metabolic Syndrome Parameters Open-label baseline - Total Cholesterol > ULN	—	—	1 Participants	2 Participants
Number of Participants With Elevated Metabolic Syndrome Parameters Open-label baseline - Triglycerides > ULN	—	—	9 Participants	6 Participants
Number of Participants With Elevated Metabolic Syndrome Parameters Day 14 OL - Glucose > ULN	—	—	5 Participants	5 Participants
Number of Participants With Elevated Metabolic Syndrome Parameters Day 14 OL - Total Cholesterol > ULN	—	—	3 Participants	2 Participants
Number of Participants With Elevated Metabolic Syndrome Parameters Day 14 OL - Triglycerides > ULN	—	—	8 Participants	3 Participants
Number of Participants With Elevated Metabolic Syndrome Parameters Day 84 OL - Glucose > ULN	—	—	1 Participants	2 Participants
Number of Participants With Elevated Metabolic Syndrome Parameters Day 84 OL - Total Cholesterol > ULN	—	—	2 Participants	1 Participants
Number of Participants With Elevated Metabolic Syndrome Parameters Day 84 OL - Triglycerides > ULN	—	—	2 Participants	2 Participants
Number of Participants With Elevated Metabolic Syndrome Parameters Day 21 DB - Total Cholesterol > ULN	7 Participants	6 Participants	—	—
Number of Participants With Elevated Metabolic Syndrome Parameters Day 21 DB - Triglycerides > ULN	19 Participants	22 Participants	—	—
Number of Participants With Elevated Metabolic Syndrome Parameters Day 35 DB - Triglycerides > ULN	18 Participants	25 Participants	—	—
Number of Participants With Elevated Metabolic Syndrome Parameters End of study - Glucose > ULN	6 Participants	7 Participants	1 Participants	3 Participants
Number of Participants With Elevated Metabolic Syndrome Parameters Day 35 DB - Glucose > ULN	12 Participants	12 Participants	—	—
Number of Participants With Elevated Metabolic Syndrome Parameters Day 35 DB - Total Cholesterol > ULN	7 Participants	8 Participants	—	—
Number of Participants With Elevated Metabolic Syndrome Parameters Study baseline - Glucose > ULN	14 Participants	18 Participants	6 Participants	8 Participants
Number of Participants With Elevated Metabolic Syndrome Parameters Study baseline - Total Cholesterol > ULN	19 Participants	11 Participants	6 Participants	5 Participants
Number of Participants With Elevated Metabolic Syndrome Parameters Study baseline - Triglycerides > ULN	18 Participants	20 Participants	5 Participants	8 Participants
Number of Participants With Elevated Metabolic Syndrome Parameters Day 21 DB - Glucose > ULN	10 Participants	8 Participants	—	—

SECONDARY outcome

Timeframe: At study baseline and up to study completion (up to approximately 18 weeks)

Population: All treated participants with available baseline and at least one post-baseline ECG result in the double blind/open-label periods.

Anytime post-baseline includes all assessments from the first dose of study drug until end of study visit in double-blind/open-label part, including unscheduled assessments. Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

Outcome measures

Measure	Double-Blind Part: KarXT n=102 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=98 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT n=38 Participants Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT n=28 Participants Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Number of Participants With Abnormal Electrocardiogram (ECG) Results Anytime post baseline - QTcF > 500 msec	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Electrocardiogram (ECG) Results Anytime post baseline - QTcF Increase > 30 msec from study baseline	17 Participants	21 Participants	4 Participants	6 Participants
Number of Participants With Abnormal Electrocardiogram (ECG) Results Anytime post baseline - PR ≥ 250 msec	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Electrocardiogram (ECG) Results Baseline - QTcF > 450 msec	3 Participants	0 Participants	3 Participants	0 Participants
Number of Participants With Abnormal Electrocardiogram (ECG) Results Baseline - QTcF > 500 msec	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Electrocardiogram (ECG) Results Baseline - QRS Interval ≥ 150 msec	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Electrocardiogram (ECG) Results Anytime post baseline - QTcF > 480 msec	0 Participants	0 Participants	1 Participants	0 Participants
Number of Participants With Abnormal Electrocardiogram (ECG) Results Anytime post baseline - QRS Interval ≥ 150 msec	1 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Electrocardiogram (ECG) Results Baseline - QTcF > 480 msec	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Electrocardiogram (ECG) Results Baseline - PR ≥ 250 msec	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Electrocardiogram (ECG) Results Anytime post baseline - QTcF > 450 msec	2 Participants	2 Participants	1 Participants	0 Participants
Number of Participants With Abnormal Electrocardiogram (ECG) Results Anytime post baseline - QTcF Increase > 60 msec from study baseline	2 Participants	0 Participants	0 Participants	2 Participants
Number of Participants With Abnormal Electrocardiogram (ECG) Results Anytime post baseline - QTcF Increase > 30 msec from open-label baseline	—	—	4 Participants	6 Participants
Number of Participants With Abnormal Electrocardiogram (ECG) Results Anytime post baseline - QTcF Increase > 60 msec from open-label baseline	—	—	1 Participants	0 Participants

SECONDARY outcome

Timeframe: From first dose to study completion (up to approximately 18 weeks)

Population: All treated participants in the double blind/open-label periods with baseline and at least one post-baseline assessment.

The C-SSRS is a clinician- or self-administered questionnaire assessing suicidal ideation and behavior. It rates ideation severity from 1 (wish to be dead) to 5 (active suicidal ideation with specific plan and intent). It also records the presence or absence of suicidal behaviors, including actual, interrupted, or aborted attempts, and preparatory acts. The highest level of ideation or most severe behavior reported is used to determine suicide risk; higher ideation scores or any suicidal behavior indicate greater risk. Baseline is the last non-missing assessment before first study drug dose.

Outcome measures

Measure	Double-Blind Part: KarXT n=101 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=97 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT n=38 Participants Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT n=27 Participants Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Number of Participants With Suicidal Ideation as Defined by a Columbia-Suicide Severity Rating Scale (C-SSRS) Ideation Score of 1 or Greater Post-Baseline Suicidal ideation - Wish to be Dead	5 Participants	4 Participants	1 Participants	3 Participants
Number of Participants With Suicidal Ideation as Defined by a Columbia-Suicide Severity Rating Scale (C-SSRS) Ideation Score of 1 or Greater Post-Baseline Suicidal ideation - Non-Specific Active Suicidal Thoughts	6 Participants	3 Participants	1 Participants	1 Participants
Number of Participants With Suicidal Ideation as Defined by a Columbia-Suicide Severity Rating Scale (C-SSRS) Ideation Score of 1 or Greater Post-Baseline SI - Active Suicidal Ideation with any Methods without Intent to Act	1 Participants	2 Participants	0 Participants	1 Participants
Number of Participants With Suicidal Ideation as Defined by a Columbia-Suicide Severity Rating Scale (C-SSRS) Ideation Score of 1 or Greater Post-Baseline SI - Active Suicidal Ideation with Some Intent to Act without Specific Plan	1 Participants	1 Participants	0 Participants	1 Participants
Number of Participants With Suicidal Ideation as Defined by a Columbia-Suicide Severity Rating Scale (C-SSRS) Ideation Score of 1 or Greater Post-Baseline Suicidal ideation (SI) - Any Suicidal Ideation	7 Participants	4 Participants	1 Participants	3 Participants
Number of Participants With Suicidal Ideation as Defined by a Columbia-Suicide Severity Rating Scale (C-SSRS) Ideation Score of 1 or Greater Post-Baseline Suicidal ideation - Active Suicidal Ideation with Specific Plan and Intent	1 Participants	0 Participants	0 Participants	1 Participants

SECONDARY outcome

Timeframe: At study baseline, open-label baseline, and up to study completion (up to approximately 18 weeks)

Population: All treated participants in the double blind/open-label periods with baseline and at least one post-baseline assessment.

Treatment-emergent parkinsonism is defined as Simpson-Angus Scale total score >3 with a baseline score ≤3. Treatment-emergent akathisia is defined as Barnes Akathisia Rating Scale global clinical assessment score >2 with a baseline score ≤2. Treatment-emergent dyskinesia is defined as any Abnormal Involuntary Movement Scale (AIMS) item 1-7 score ≥3 with a baseline score <3 for the item, or score ≥2 on two or more of AIMS items 1-7 with baseline <2 for the items. Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

Outcome measures

Measure	Double-Blind Part: KarXT n=102 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=98 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT n=38 Participants Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT n=28 Participants Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Number of Participants With Clinically Meaningful Changes in Simpson-Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), and Abnormal Involuntary Movement Scale (AIMS) Results Treatment-Emergent Akathisia with respect to study baseline	2 Participants	3 Participants	0 Participants	0 Participants
Number of Participants With Clinically Meaningful Changes in Simpson-Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), and Abnormal Involuntary Movement Scale (AIMS) Results Treatment-Emergent Parkinsonism with respect to study baseline	3 Participants	2 Participants	1 Participants	1 Participants
Number of Participants With Clinically Meaningful Changes in Simpson-Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), and Abnormal Involuntary Movement Scale (AIMS) Results Treatment-Emergent Dyskinesia with respect to study baseline	0 Participants	2 Participants	0 Participants	1 Participants
Number of Participants With Clinically Meaningful Changes in Simpson-Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), and Abnormal Involuntary Movement Scale (AIMS) Results Treatment-Emergent Parkinsonism with respect to open-label baseline	—	—	2 Participants	0 Participants
Number of Participants With Clinically Meaningful Changes in Simpson-Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), and Abnormal Involuntary Movement Scale (AIMS) Results Treatment-Emergent Akathisia with respect to open-label baseline	—	—	0 Participants	0 Participants
Number of Participants With Clinically Meaningful Changes in Simpson-Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), and Abnormal Involuntary Movement Scale (AIMS) Results Treatment-Emergent Dyskinesia with respects to open-label baseline	—	—	0 Participants	1 Participants

SECONDARY outcome

Timeframe: At study baseline, Day 35 DB, open-label baseline, Day 84 OL, and end of study visit (up to approximately 18 weeks)

Population: All treated participants in the double blind/open-label periods with baseline and at least one post-baseline assessment.

Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

Outcome measures

Measure	Double-Blind Part: KarXT n=80 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=80 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT n=21 Participants Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT n=19 Participants Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Change From Baseline in Body Weight End of study change from study baseline	-2.773 Kg Standard Deviation 3.1119	-0.646 Kg Standard Deviation 3.3921	-2.533 Kg Standard Deviation 6.4198	-4.995 Kg Standard Deviation 5.2225
Change From Baseline in Body Weight End of study change from open-label baseline	—	—	-1.462 Kg Standard Deviation 5.1589	-2.850 Kg Standard Deviation 3.2432
Change From Baseline in Body Weight Day 35 change from study baseline	-2.125 Kg Standard Deviation 2.9596	-1.184 Kg Standard Deviation 3.1079	—	—
Change From Baseline in Body Weight Day 84 change from study baseline	—	—	-2.889 Kg Standard Deviation 6.7846	-6.955 Kg Standard Deviation 5.0021
Change From Baseline in Body Weight Day 84 change from open-label baseline	—	—	-1.222 Kg Standard Deviation 5.2847	-4.182 Kg Standard Deviation 2.9634

SECONDARY outcome

Timeframe: At study baseline, Day 35 DB, open-label baseline, Day 84 OL, and end of study visit (up to approximately 18 weeks)

Population: All treated participants in the double blind/open-label periods with baseline and at least one post-baseline assessment.

Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

Outcome measures

Measure	Double-Blind Part: KarXT n=80 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=79 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT n=21 Participants Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT n=19 Participants Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Change From Baseline in Body Mass Index (BMI) Day 35/Week 5 Change from Study baseline	-0.79 Kg/m2 Standard Deviation 1.106	-0.43 Kg/m2 Standard Deviation 1.135	—	—
Change From Baseline in Body Mass Index (BMI) Day 84/Week 12 Change from Study baseline	—	—	-1.10 Kg/m2 Standard Deviation 2.692	-2.61 Kg/m2 Standard Deviation 1.983
Change From Baseline in Body Mass Index (BMI) Day 84/Week 12 Change from open-label baseline	—	—	-0.46 Kg/m2 Standard Deviation 2.121	1.59 Kg/m2 Standard Deviation 1.276
Change From Baseline in Body Mass Index (BMI) End of Study Change from Study baseline	-1.01 Kg/m2 Standard Deviation 1.133	-0.22 Kg/m2 Standard Deviation 1.193	-0.92 Kg/m2 Standard Deviation 2.499	-1.83 Kg/m2 Standard Deviation 1.930
Change From Baseline in Body Mass Index (BMI) End of Study Change from open-label baseline	—	—	-0.52 Kg/m2 Standard Deviation 2.046	-1.05 Kg/m2 Standard Deviation 1.224

SECONDARY outcome

Timeframe: At study baseline, Day 35 DB, open-label baseline, Day 84 OL, and end of study visit (up to approximately 18 months)

Population: All treated participants in the double blind/open-label periods with baseline and at least one post-baseline assessment.

Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

Outcome measures

Measure	Double-Blind Part: KarXT n=80 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=80 Participants Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT n=21 Participants Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT n=19 Participants Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Change From Baseline in Waist Circumference Day 35/Week 5 Change from Study baseline	-2.27 cm Standard Deviation 4.070	-1.01 cm Standard Deviation 3.269	—	—
Change From Baseline in Waist Circumference Day 84/Week 12 Change from Study baseline	—	—	-3.96 cm Standard Deviation 8.288	-4.82 cm Standard Deviation 6.416
Change From Baseline in Waist Circumference Day 84/Week 12 Change from open-label baseline	—	—	-1.88 cm Standard Deviation 7.198	-2.27 cm Standard Deviation 4.671
Change From Baseline in Waist Circumference End of Study Change from Study baseline	-3.40 cm Standard Deviation 4.155	-1.34 cm Standard Deviation 4.167	-4.69 cm Standard Deviation 8.183	-3.39 cm Standard Deviation 5.345
Change From Baseline in Waist Circumference End of Study Change from open-label baseline	—	—	-3.12 cm Standard Deviation 6.874	-2.45 cm Standard Deviation 2.543

SECONDARY outcome

Timeframe: On Day 28 of the Double-Blind Period

Population: All treated participants who received at least one dose of study medicine in the double-blind period and who have available PK data. Prespecified to be reported for the Double-Blind Period only. participants who received treatment are not mutually exclusive

AUC₀-12 (Area Under the Concentration-Time Curve from time zero to 12 hours) is the total amount of drug in the blood measured from the time the drug is given (time zero) up to 12 hours after dosing.

Outcome measures

Measure	Double-Blind Part: KarXT n=42 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Area Under the Concentration-Time Curve (AUC0-12) of Xanomeline and Trospium - Double-Blind Period Day 28 - Xanomeline 100/20	93200 pg*h/mL Geometric Coefficient of Variation 89.9	—	—	—
Area Under the Concentration-Time Curve (AUC0-12) of Xanomeline and Trospium - Double-Blind Period Day 28 - Xanomeline 125/30	87100 pg*h/mL Geometric Coefficient of Variation 75.9	—	—	—
Area Under the Concentration-Time Curve (AUC0-12) of Xanomeline and Trospium - Double-Blind Period Day 28 - Trospium 100/20	48600 pg*h/mL Geometric Coefficient of Variation 70.4	—	—	—
Area Under the Concentration-Time Curve (AUC0-12) of Xanomeline and Trospium - Double-Blind Period Day 28 - Trospium 125/30	47900 pg*h/mL Geometric Coefficient of Variation 81.9	—	—	—

SECONDARY outcome

Timeframe: On Day 28 of the Double-Blind Period

Population: All treated participants who received at least one dose of study medicine in the double-blind period and who have available PK data. Prespecified to be reported for the Double-Blind Period only. Participants who received treatment are not mutually exclusive

Cmax is the highest concentration of a drug measured in the blood after it is given.

Outcome measures

Measure	Double-Blind Part: KarXT n=45 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Maximum Observed Plasma Concentration (Cmax) of Xanomeline and Trospium - Double-Blind Period Day 28 - Xanomeline 100/20	16000 pg/mL Geometric Coefficient of Variation 129.1	—	—	—
Maximum Observed Plasma Concentration (Cmax) of Xanomeline and Trospium - Double-Blind Period Day 28 - Xanomeline 125/30	15900 pg/mL Geometric Coefficient of Variation 95.9	—	—	—
Maximum Observed Plasma Concentration (Cmax) of Xanomeline and Trospium - Double-Blind Period Day 28 - Trospium 100/20	11100 pg/mL Geometric Coefficient of Variation 139.7	—	—	—
Maximum Observed Plasma Concentration (Cmax) of Xanomeline and Trospium - Double-Blind Period Day 28 - Trospium 125/30	9330 pg/mL Geometric Coefficient of Variation 99.3	—	—	—

SECONDARY outcome

Timeframe: On Day 28 of the Double-Blind Period

Population: All treated participants who received at least one dose of study medicine in the double-blind period and who have available PK data. Prespecified to be reported for the Double-Blind Period only. participants who received treatment are not mutually exclusive

Tmax is the amount of time it takes to reach that highest concentration (Cmax) after the drug is given.

Outcome measures

Measure	Double-Blind Part: KarXT n=45 Participants Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Time to Cmax (Tmax) of Xanomeline and Trospium - Double-Blind Period Day 28 - Xanomeline 100/20	1.70 Hours Interval 0.0 to 11.97	—	—	—
Time to Cmax (Tmax) of Xanomeline and Trospium - Double-Blind Period Day 28 - Xanomeline 125/30	1.93 Hours Interval 0.0 to 11.95	—	—	—
Time to Cmax (Tmax) of Xanomeline and Trospium - Double-Blind Period Day 28 - Trospium 100/20	0.56 Hours Interval 0.0 to 11.9	—	—	—
Time to Cmax (Tmax) of Xanomeline and Trospium - Double-Blind Period Day 28 - Trospium 125/30	0.97 Hours Interval 0.42 to 2.07	—	—	—

Adverse Events

Double-Blind Part: KarXT

Serious events: 0 serious events

Other events: 97 other events

Deaths: 0 deaths

Double-Blind Part: Placebo

Serious events: 3 serious events

Other events: 90 other events

Deaths: 0 deaths

Open-Label Part: KarXT/KarXT

Serious events: 0 serious events

Other events: 33 other events

Deaths: 0 deaths

Open-Label Part: Placebo/KarXT

Serious events: 3 serious events

Other events: 28 other events

Deaths: 1 deaths

Serious adverse events

Measure	Double-Blind Part: KarXT n=102 participants at risk Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the Participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All Participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=98 participants at risk Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT n=38 participants at risk Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the Participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All Participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT n=28 participants at risk Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the Participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All Participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Injury, poisoning and procedural complications Spinal compression fracture	0.00% 0/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	1.0% 1/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Psychiatric disorders Completed suicide	0.00% 0/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	3.6% 1/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Psychiatric disorders Schizophrenia	0.00% 0/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.0% 2/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	7.1% 2/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Psychiatric disorders Suicidal ideation	0.00% 0/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	3.6% 1/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.

Other adverse events

Measure	Double-Blind Part: KarXT n=102 participants at risk Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the Participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All Participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the first 3 week of the treatment period.	Double-Blind Part: Placebo n=98 participants at risk Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Open-Label Part: KarXT/KarXT n=38 participants at risk Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the Participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All Participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.	Open-Label Part: Placebo/KarXT n=28 participants at risk Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the Participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All Participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Blood and lymphatic system disorders Anaemia	0.98% 1/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	3.1% 3/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.6% 1/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	7.1% 2/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Cardiac disorders Postural orthostatic tachycardia syndrome	7.8% 8/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	11.2% 11/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	5.3% 2/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Cardiac disorders Sinus bradycardia	0.00% 0/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	4.1% 4/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	7.1% 2/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Cardiac disorders Sinus tachycardia	16.7% 17/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.0% 2/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	10.7% 3/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Cardiac disorders Tachycardia	19.6% 20/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.0% 2/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	5.3% 2/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	10.7% 3/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Endocrine disorders Hyperprolactinaemia	3.9% 4/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	9.2% 9/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	10.5% 4/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	10.7% 3/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Gastrointestinal disorders Abdominal discomfort	3.9% 4/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.0% 2/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	7.1% 2/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Gastrointestinal disorders Constipation	31.4% 32/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	20.4% 20/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	15.8% 6/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	28.6% 8/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Gastrointestinal disorders Diarrhoea	11.8% 12/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	3.1% 3/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	5.3% 2/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	14.3% 4/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Gastrointestinal disorders Dry mouth	2.9% 3/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	4.1% 4/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	7.1% 2/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Gastrointestinal disorders Nausea	37.3% 38/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	5.1% 5/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	13.2% 5/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	50.0% 14/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Gastrointestinal disorders Retching	0.00% 0/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	5.3% 2/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Gastrointestinal disorders Vomiting	47.1% 48/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.0% 2/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	26.3% 10/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	71.4% 20/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Infections and infestations Nasopharyngitis	4.9% 5/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	8.2% 8/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.6% 1/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Infections and infestations Upper respiratory tract infection	3.9% 4/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	6.1% 6/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	7.9% 3/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	7.1% 2/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Investigations Alanine aminotransferase increased	8.8% 9/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	4.1% 4/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	5.3% 2/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	3.6% 1/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Investigations Aspartate aminotransferase increased	6.9% 7/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.0% 2/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.6% 1/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Investigations Blood bilirubin increased	0.98% 1/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	6.1% 6/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Investigations Blood pressure increased	12.7% 13/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	4.1% 4/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	5.3% 2/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	7.1% 2/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Investigations Blood pressure orthostatic decreased	12.7% 13/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	9.2% 9/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	5.3% 2/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	7.1% 2/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Investigations Blood prolactin increased	3.9% 4/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	7.1% 7/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Investigations Electrocardiogram T wave abnormal	6.9% 7/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	5.1% 5/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.6% 1/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	7.1% 2/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Investigations Heart rate increased	5.9% 6/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.0% 2/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.6% 1/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	14.3% 4/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Investigations Protein urine present	2.0% 2/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	1.0% 1/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	7.9% 3/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Investigations Weight decreased	20.6% 21/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	16.3% 16/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	28.9% 11/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	35.7% 10/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Metabolism and nutrition disorders Decreased appetite	7.8% 8/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	4.1% 4/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.6% 1/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	25.0% 7/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Metabolism and nutrition disorders Hyperlipidaemia	2.0% 2/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	1.0% 1/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.6% 1/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	7.1% 2/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Metabolism and nutrition disorders Hyperuricaemia	2.9% 3/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	5.1% 5/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	3.6% 1/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Metabolism and nutrition disorders Hypokalaemia	7.8% 8/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	8.2% 8/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	5.3% 2/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	3.6% 1/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Metabolism and nutrition disorders Hyponatraemia	2.9% 3/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	7.9% 3/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	3.6% 1/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Nervous system disorders Dizziness	19.6% 20/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	5.1% 5/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.6% 1/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	10.7% 3/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Nervous system disorders Headache	8.8% 9/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.0% 2/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	3.6% 1/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Psychiatric disorders Impulsive behaviour	0.98% 1/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	8.2% 8/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	5.3% 2/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	7.1% 2/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Psychiatric disorders Insomnia	5.9% 6/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	5.1% 5/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.6% 1/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	7.1% 2/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Psychiatric disorders Schizophrenia	8.8% 9/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	11.2% 11/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	5.3% 2/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	10.7% 3/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	2.0% 2/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	7.9% 3/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Vascular disorders Hypertension	7.8% 8/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.0% 2/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	0.00% 0/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	10.7% 3/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Vascular disorders Orthostatic hypotension	15.7% 16/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	14.3% 14/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	10.5% 4/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	10.7% 3/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Infections and infestations Urinary tract infection	2.0% 2/102 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.0% 2/98 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	2.6% 1/38 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.	7.1% 2/28 • Double-blind part: From the start of study drug administration up to week 5. Open-label extension part: From the start of study drug administration up to week 12 The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.

Additional Information

Bristol-Myers Squibb Study Director

Bristol-Myers Squibb

Phone: 1-855-907-3286

Email: Clinical.Trials@bms.com

Results disclosure agreements

• Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
• Publication restrictions are in place

Restriction type: OTHER