EMERGENT-1: A Study to Assess Safety and Efficacy of KarXT in Adult Patients With Schizophrenia

• Sponsor: Karuna Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03697252
• Collaborator: (none)
• Enrollment: 182
• Locations: 12
• Arms: 2
• Actual Duration (Months): 11.5
• Patients Per Site: 15.2
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

This is a Phase 2, randomized, double-blinded, placebo-controlled, inpatient study to examine the efficacy, safety, and tolerability profile of KarXT in adult subjects diagnosed with DSM-5 schizophrenia who are in an acute exacerbation phase. The primary objective of the study is to assess the efficacy of KarXT (a fixed combination of xanomeline and trospium chloride) (xanomeline 125 mg/trospium 30 mg twice daily [BID]) versus placebo in reducing Positive and Negative Syndrome Scale (PANSS) total scores in adult inpatients with a Diagnostic and Statistical Manual-Fifth Edition (DSM-5) diagnosis of schizophrenia. The secondary objectives of the study are to assess overall safety and tolerability of KarXT in adult inpatients with a DSM-5 diagnosis of schizophrenia.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: Xanomeline and Trospium Chloride Capsules; Drug: Placebo Capsules	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 182 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Double-blinded Study to Assess the Safety, Tolerability, and Efficacy of KarXT in Hospitalized Adults With DSM-5 Schizophrenia
• Actual Study Start Date: Sep 18, 2018
• Actual Primary Completion Date: Sep 4, 2019
• Actual Study Completion Date: Sep 4, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: KarXT	Drug: Xanomeline and Trospium Chloride Capsules; Xanomeline 50 mg/trospium 20 mg BID on days 1-2 followed by xanomeline 100 mg/trospium 20 mg BID on days 3-7. The dose is increased to xanomeline 125 mg/trospium 30 mg BID on days 8-34 unless the subject is experiencing adverse events from the xanomeline 100 mg/trospium 20 mg dose. Subjects who were increased to xanomeline 125 mg/trospium 30 mg will have the option to return to xanomeline 100 mg/trospium 20 mg depending on clinical response and tolerability. Dosing must not change after Visit 7 of the study (at 21 ± 2 days of dosing) and may be decreased for tolerability reasons no more than once during the study.; Other Names: KarXT
Placebo Comparator: Placebo	Drug: Placebo Capsules; Placebo Capsules

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 5 [Baseline and Week 5]

   The PANSS is a medical scale used for measuring symptom severity of participants with schizophrenia. The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. Participants were rated from 1 to 7 on each symptom scale. The total score is the sum of all scales with a minimum score of 30 and a maximum score of 210. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms.

Secondary Outcome Measures

1. Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Positive Score at Week 5 [Baseline and Week 5]

   The PANSS is a medical scale used for measuring symptom severity of participants with schizophrenia. The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. The positive symptoms in schizophrenia are the excess or distortion of normal functions such as hallucinations, delusions, grandiosity, and hostility. Participants were rated from 1 to 7 on each symptom scale, with a minimum score of 7 and a maximum score of 49. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms.

2. Number of Participants With Each Clinical Global Impression - Severity (CGI-S) Score at Baseline and 5 Weeks [Baseline and Week 5]

   The CGI-S modified asked the clinician 1 question: "Considering your total clinical experience, how mentally ill is the participant at this time?" The clinician's answer rated on the following 7-point scale: 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants.

3. Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Negative Score at Week 5 [Baseline and Week 5]

   The PANSS is a medical scale used for measuring symptom severity of participants with schizophrenia. The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. The negative symptoms in schizophrenia are the diminution or loss of normal functions. Participants were rated from 1 to 7 on each symptom scale, with a minimum score of 7 and a maximum score of 49. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms.

4. Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Marder Factor Score [Baseline and Week 5]

   The Marder Negative Factor score is derived from the PANSS and consists of the sum of 5 negative scales (N) and 2 general scales (G) (N1. Blunted affect; N2. Emotional withdrawal; N3. Poor rapport; N4. Passive/apathetic social withdrawal; N6. Lack of spontaneity; G7. Motor retardation; and G16. Active social avoidance), with a minimum score of 7 and a maximum score of 49.

5. Percentage of Participants Who Were Clinical Global Impression - Severity of Illness (CGI-S) Responders [Week 5]

   The CGI-S modified asks the clinician 1 question: "Considering your total clinical experience, how mentally ill is the participant at this time?" The clinician's answer was rated on the following 7-point scale: 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants. A CGI-S responder is defined as a participant with a CGI-S scale equal to 1 or 2.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Subject is aged 18-60 years, inclusive, at screening

2. Subject has a primary diagnosis of schizophrenia established by a comprehensive psychiatric evaluation based on the DSM-5 (American Psychiatric Association 2013) criteria and confirmed by Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorder Studies (MINI) version 7.0.2.

3. Subject is experiencing an acute exacerbation or relapse of symptoms, with onset less than 2 months before screening

4. Positive and Negative Syndrome Scale total score between 80 and 120, inclusive, at screening

5. Score of ≥ 4 (moderate or greater) for ≥ 2 of the following Positive Scale (P) items at screening:

6. Item 1 (P1; delusions)

7. Item 2 (P2; conceptual disorganization)

8. Item 3 (P3; hallucinatory behavior)

9. Item 6 (P6; suspiciousness/persecution)

10. There should not be a change (improvement) in PANSS total score between screening and baseline of more than 20%

11. Subjects taking a depot antipsychotic could not have received a dose of medication for at least 1 and a half injection cycles before baseline (eg, 3 or more weeks off for a 2-week cycle)

12. Subject is capable of providing informed consent

13. A signed ICF must be provided before any study assessments are performed

14. Subject must be fluent (oral and written) in English in order to consent

15. Subject must have CGI-S score of ≥ 4 at screening and baseline visits

16. Body mass index must be ≥ 18 and ≤ 40 kg/m2

17. Both females of child bearing potential and males with partners of child bearing potential must be willing to use a double-barrier method of birth control (ie, any double combination of male or female condom with spermicidal gel, diaphragm, sponge, or cervical cap with spermicidal gel) during the study and for 7 days after the last dose of study drug.

18. Subject has an identified reliable informant

Exclusion Criteria:

1. Any primary DSM-5 disorder other than schizophrenia within 12 months before screening (confirmed using MINI version 7.0.2 at screening)

2. History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or oncologic disease or any other condition that, in the opinion of the investigator, would jeopardize the safety of the subject or the validity of the study results, to exclude patients with human immunodeficiency virus (HIV), cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma, and/or active hepatic viral infections based on the liver function test results.

3. History of or high risk of urinary retention, gastric retention, or narrow-angle glaucoma

4. History of irritable bowel syndrome (with or without constipation) or serious constipation requiring treatment within the last 6 months

5. Has a DSM-5 diagnosis of moderate to severe substance abuse disorder (except tobacco use disorder) within the 12 months before screening (confirmed using MINI version 7.0.2 at screening), or current abuse as determined by urine toxicology screen or alcohol test. A screening subject with mild substance abuse disorder within the 12 months before screening must be discussed and agreed upon with the medical monitor before he/she can be allowed into the study.

6. Clinically significant abnormal finding on the physical examination, medical history, ECG, or clinical laboratory results at screening

7. Pregnant, lactating, or less than 3 months postpartum. Sperm donation is not allowed for 90 days after the final dose of study drug

8. If, in the opinion of the investigator (and/or Sponsor), subject is unsuitable for enrollment in the study or subject has any finding that, in the view of the investigator (and/or Sponsor), may compromise the safety of the subject or affect their ability to adhere to the protocol visit schedule or fulfill visit requirements

9. Subject has had psychiatric hospitalization(s) for more than 30 days (cumulative) during the 90 days before screening

10. Subject has a history of treatment resistance to schizophrenia medications defined as failure to respond to 2 adequate courses of pharmacotherapy (a minimum of 4 weeks at an adequate dose per the label) or required clozapine within the last 12 months

11. Risk of violent or destructive behavior

12. Current involuntary hospitalization or incarceration

13. Participation in another clinical study in which the subject received an experimental or investigational drug agent within 3 months of screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Woodland International Research Group, LLC	Little Rock	Arkansas	United States	72211
2	Synergy East	Lemon Grove	California	United States	91945
3	Collaborative Neuroscience Network, LLC.	Long Beach	California	United States	90806
4	NRC Research Institute	Orange	California	United States	92868
5	Artemis Institute for Clinical Research	San Diego	California	United States	92103
6	Atlanta Center for Medical Research	Atlanta	Georgia	United States	30331
7	CBH Health, LLC	Gaithersburg	Maryland	United States	20877
8	Hassman Research Institute	Berlin	New Jersey	United States	08009
9	Midwest Clinical Research Center (and IP Shipment)	Dayton	Ohio	United States	45417
10	Community Clinical Research, Inc.	Austin	Texas	United States	78754
11	InSite Clinical Research, LLC	DeSoto	Texas	United States	75115
12	Pillar Clinical Research, LLC	Richardson	Texas	United States	75080

Sponsors and Collaborators

• Karuna Therapeutics

Investigators

• Study Director: Stephen Brannan, MD, Karuna Therapeutics

Study Documents (Full-Text)

• Study Protocol - Dec 13, 2018
• Statistical Analysis Plan - Dec 11, 2018

More Information

Publications

None provided.

• Responsible Party: Karuna Therapeutics
• ClinicalTrials.gov Identifier: NCT03697252
• Other Study ID Numbers: KAR-004
• First Posted: Oct 5, 2018
• Last Update Posted: Oct 26, 2020
• Last Verified: Oct 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Karuna Therapeutics: Schizophrenia
• Additional relevant MeSH terms: Schizophrenia; Xanomeline; Trospium chloride

Study Results

Participant Flow

Recruitment Details	The study was conducted in 12 study centers in North America.
Pre-assignment Detail	A total of 250 participants were screened, 182 were randomized, and 145 participants completed the study.

Arm/Group Title	KarXT	Placebo
Arm/Group Description	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 remainder of the treatment period.	Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.
Period Title: Overall Study
STARTED	90	92
COMPLETED	72	73
NOT COMPLETED	18	19

Baseline Characteristics

Arm/Group Title	KarXT	Placebo	Total
Arm/Group Description	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 remainder of the treatment period.	Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.	Total of all reporting groups
Overall Participants	90	92	182
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.4 (10.12)	41.6 (10.08)	42.5 (10.11)
Sex: Female, Male (Count of Participants)
Female	18 20%	24 26.1%	42 23.1%
Male	72 80%	68 73.9%	140 76.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 2.2%	2 2.2%	4 2.2%
Native Hawaiian or Other Pacific Islander	1 1.1%	1 1.1%	2 1.1%
Black or African American	67 74.4%	70 76.1%	137 75.3%
White	20 22.2%	17 18.5%	37 20.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	2 2.2%	2 1.1%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 5
Description	The PANSS is a medical scale used for measuring symptom severity of participants with schizophrenia. The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. Participants were rated from 1 to 7 on each symptom scale. The total score is the sum of all scales with a minimum score of 30 and a maximum score of 210. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms.
Time Frame	Baseline and Week 5

Outcome Measure Data

Analysis Population Description

The Modified Intent-to-Treat (MITT) population included all participants who were randomized, received at least one dose of study medication, and had a baseline and at least one post-baseline PANSS assessment. Here, the number of participants analyzed indicates participants who were evaluable for this measure at given time points for each group.

Arm/Group Title	KarXT	Placebo
Arm/Group Description	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 remainder of the treatment period.	Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.
Measure Participants	83	87
Least Squares Mean (Standard Error) [score on a scale]	-17.40 (1.749)	-5.85 (1.668)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KarXT, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-11.56
	Confidence Interval	(2-Sided) 95%; -16.07 to -7.05
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Statistics are from a mixed model for repeated measures (MMRM). The model includes the treatment group (KarXT or placebo), visit, and the interaction between the treatment group and visit as fixed factors, and baseline PANSS total score, site, age, and gender as covariates. An unstructured covariance matrix is used to model the correlation among repeated measurements and the denominator degrees of freedom are computed using the Kenward-Roger method.

2. Secondary Outcome

Title	Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Positive Score at Week 5
Description	The PANSS is a medical scale used for measuring symptom severity of participants with schizophrenia. The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. The positive symptoms in schizophrenia are the excess or distortion of normal functions such as hallucinations, delusions, grandiosity, and hostility. Participants were rated from 1 to 7 on each symptom scale, with a minimum score of 7 and a maximum score of 49. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms.
Time Frame	Baseline and Week 5

Outcome Measure Data

Analysis Population Description

The Modified Intent-to-Treat (MITT) population included all participants who were randomized, received at least one dose of study medication, and had a baseline and at least one post-baseline PANSS assessment. Here, the number of participants analyzed indicates participants who were evaluable for this measure at given time points for each group.

Arm/Group Title	KarXT	Placebo
Arm/Group Description	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 remainder of the treatment period.	Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.
Measure Participants	83	87
Least Squares Mean (Standard Error) [score on a scale]	-5.62 (0.601)	-2.38 (0.573)

3. Secondary Outcome

Title	Number of Participants With Each Clinical Global Impression - Severity (CGI-S) Score at Baseline and 5 Weeks
Description	The CGI-S modified asked the clinician 1 question: "Considering your total clinical experience, how mentally ill is the participant at this time?" The clinician's answer rated on the following 7-point scale: 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants.
Time Frame	Baseline and Week 5

Outcome Measure Data

Analysis Population Description

The MITT population included all participants who were randomized, received at least one dose of study medication, and had a baseline and at least one post-baseline PANSS assessment. Here, the number of participants analyzed indicates participants who were evaluable for this measure at given time points for each group.

Arm/Group Title	KarXT	Placebo
Arm/Group Description	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 remainder of the treatment period.	Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.
Measure Participants	83	87
Baseline: Score = 1	0 0%	0 0%
Week 5: Score = 1	1 1.1%	0 0%
Baseline: Score = 2	0 0%	0 0%
Week 5: Score = 2	3 3.3%	1 1.1%
Baseline: Score = 3	0 0%	0 0%
Week 5: Score = 3	23 25.6%	7 7.6%
Baseline: Score = 4	13 14.4%	17 18.5%
Week 5: Score = 4	21 23.3%	21 22.8%
Baseline: Score = 5	60 66.7%	60 65.2%
Week 5: Score = 5	21 23.3%	38 41.3%
Baseline: Score = 6	10 11.1%	9 9.8%
Week 5: Score = 6	2 2.2%	4 4.3%
Baseline: Score = 7	0 0%	1 1.1%
Week 5: Score = 7	1 1.1%	2 2.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KarXT, Placebo
	Comments	Comparison of KarXT and Placebo at Week 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

Title	Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Negative Score at Week 5
Description	The PANSS is a medical scale used for measuring symptom severity of participants with schizophrenia. The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. The negative symptoms in schizophrenia are the diminution or loss of normal functions. Participants were rated from 1 to 7 on each symptom scale, with a minimum score of 7 and a maximum score of 49. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms.
Time Frame	Baseline and Week 5

Outcome Measure Data

Analysis Population Description

The MITT population included all participants who were randomized, received at least one dose of study medication, and had a baseline and at least one post-baseline PANSS assessment. Here, the number of participants analyzed indicates participants who were evaluable for this measure at given time points for each group.

Arm/Group Title	KarXT	Placebo
Arm/Group Description	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 remainder of the treatment period.	Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.
Measure Participants	83	87
Least Squares Mean (Standard Error) [score on a scale]	-3.18 (0.481)	-0.90 (0.454)

5. Secondary Outcome

Title	Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Marder Factor Score
Description	The Marder Negative Factor score is derived from the PANSS and consists of the sum of 5 negative scales (N) and 2 general scales (G) (N1. Blunted affect; N2. Emotional withdrawal; N3. Poor rapport; N4. Passive/apathetic social withdrawal; N6. Lack of spontaneity; G7. Motor retardation; and G16. Active social avoidance), with a minimum score of 7 and a maximum score of 49.
Time Frame	Baseline and Week 5

Outcome Measure Data

Analysis Population Description

The MITT population included all participants who were randomized, received at least one dose of study medication, and had a baseline and at least one post-baseline PANSS assessment. Here, the number of participants analyzed indicates participants who were evaluable for this measure at given time points for each group.

Arm/Group Title	KarXT	Placebo
Arm/Group Description	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 remainder of the treatment period.	Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.
Measure Participants	83	87
Least Squares Mean (Standard Error) [score on a scale]	-3.85 (0.520)	-1.32 (0.492)

6. Secondary Outcome

Title	Percentage of Participants Who Were Clinical Global Impression - Severity of Illness (CGI-S) Responders
Description	The CGI-S modified asks the clinician 1 question: "Considering your total clinical experience, how mentally ill is the participant at this time?" The clinician's answer was rated on the following 7-point scale: 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants. A CGI-S responder is defined as a participant with a CGI-S scale equal to 1 or 2.
Time Frame	Week 5

Outcome Measure Data

Analysis Population Description

The MITT population included all participants who were randomized, received at least one dose of study medication, and had a baseline and at least one post-baseline PANSS assessment. Here, the number of participants analyzed indicates participants who were evaluable for this measure at given time points for each group.

Arm/Group Title	KarXT	Placebo
Arm/Group Description	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 remainder of the treatment period.	Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.
Measure Participants	72	73
Number [percentage of participants]	5.6 6.2%	1.4 1.5%

Adverse Events

Time Frame	From the start of study drug administration up to Week 5
Adverse Event Reporting Description	The Safety population included all participants who received at least one dose of study medication.
Arm/Group Title	KarXT		Placebo
Arm/Group Description	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 remainder of the treatment period.		Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.
All Cause Mortality
	KarXT		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/89 (0%)		0/90 (0%)
Serious Adverse Events
	KarXT		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/89 (1.1%)		0/90 (0%)
Psychiatric disorders
Psychotic disorder	1/89 (1.1%)	1	0/90 (0%)	0
Other (Not Including Serious) Adverse Events
	KarXT		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	48/89 (53.9%)		39/90 (43.3%)
Cardiac disorders
Tachycardia	3/89 (3.4%)	3	2/90 (2.2%)	2
Gastrointestinal disorders
Constipation	15/89 (16.9%)	16	3/90 (3.3%)	3
Nausea	15/89 (16.9%)	15	4/90 (4.4%)	4
Dry mouth	8/89 (9%)	8	1/90 (1.1%)	1
Dyspepsia	8/89 (9%)	11	4/90 (4.4%)	4
Vomiting	8/89 (9%)	8	4/90 (4.4%)	4
Diarrhoea	2/89 (2.2%)	3	4/90 (4.4%)	4
Investigations
Weight increased	3/89 (3.4%)	3	4/90 (4.4%)	4
Gamma-Glutamyltransferase increased	2/89 (2.2%)	2	0/90 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	2/89 (2.2%)	2	0/90 (0%)	0
Nervous system disorders
Headache	6/89 (6.7%)	7	5/90 (5.6%)	5
Somnolence	5/89 (5.6%)	5	4/90 (4.4%)	4
Akathisia	3/89 (3.4%)	3	0/90 (0%)	0
Dizziness	3/89 (3.4%)	3	3/90 (3.3%)	3
Sedation	2/89 (2.2%)	2	2/90 (2.2%)	2
Psychiatric disorders
Agitation	2/89 (2.2%)	2	1/90 (1.1%)	1
Insomnia	2/89 (2.2%)	2	2/90 (2.2%)	2
Skin and subcutaneous tissue disorders
Hyperhidrosis	2/89 (2.2%)	2	1/90 (1.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.