Conditions: Schizophrenia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 152
Healthy volunteers: no

Brief summary:
This is a Phase 3, multicenter, 53-week, outpatient, open-label extension (OLE) study to evaluate the long-term safety, tolerability, and efficacy of KarXT in subjects with Diagnostic and Statistical Manual-Fifth Edition (DSM-5) schizophrenia who previously completed the treatment period of one of the two Phase 3 double-blind studies, KAR-007 or KAR-009. In this OLE study, all subjects will receive KarXT (a fixed combination of xanomeline 125 mg and trospium chloride 30 mg twice daily \[BID\]) for up to 52 weeks regardless of treatment assignment in the preceding Phase 3 acute study. The primary objective of the study is to assess the long-term safety and tolerability of KarXT in subjects with a DSM-5 diagnosis of schizophrenia. The secondary objective of this study is to assess the long-term efficacy and monitor trough concentrations of xanomeline and trospium after administration of KarXT.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Xanomeline and Trospium Chloride Capsules
Intervention descriptions: intervention 1: Oral xanomeline 50 mg/trospium chloride 20 mg BID on days 1-2 followed by xanomeline 100 mg/trospium chloride 20 mg BID on days 3-7. The dosage is increased to xanomeline 125 mg/trospium chloride 30 mg BID on days 8-364 unless the subject is experiencing adverse events from the xanomeline 100 mg/ trospium chloride 20 mg dose. Subjects who were increased to xanomeline 125 mg/trospium chloride 30 mg will have the option to return to xanomeline 100 mg/ trospium chloride 20 mg depending on clinical response and tolerability. Re-escalation to 125/30 BID or re-titration in cases in which the subject has been off KarXT for a longer period of time (at least a week) is allowed and will require a discussion between the principal investigator and the medical monitor.

Protocol document:
Prot_SAP_000.pdf: 
Official Title of Study: 
An Open-label Extension Study to Assess the Long-term Safety, Tolerability, and Efficacy of KarXT 
in Subjects With DSM-5 Schizophrenia 
NCT Number: NCT04659174 
Document Date (Date in which document was last revised): 11 Jan 2022 


KAR-008 
KarXT 
5.3.5.1 Clinical Study Report 
Karuna Therapeutics, Inc. 
 
Confidential 
Page 1 of 1 
 
16.1.1. 
Protocol and Protocol Amendments 
The original protocol, version 1.0, dated 24 August 2020, was amended 3 times. The changes in 
each amendment are summarized in Section 9.4.1. 
Protocols listed below are attached: 
Protocol Version 1.0, Original protocol, dated 24 August 2020 
Protocol Version 2.0, Protocol Amendment 1, dated 23 October 2020  
Protocol Version 3.0, Protocol Amendment 2, dated 30 June 2021 
Protocol Version 4.0, Protocol Amendment 3, dated 11 January 2022 
 
 
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1 
FINAL CLINICAL STUDY PROTOCOL  
 
Karuna Therapeutics 
Protocol Title: An Open-label Extension Study to Assess the Long-term Safety, 
Tolerability, and Efficacy of KarXT in Subjects with DSM-5 Schizophrenia 
 
Protocol Number: KAR-008 
 
IND Number: 
127471 
EudraCT Number: 
Not applicable 
Name of Investigational Product: 
KarXT 
Phase of Development: 
Phase 3 
Indication: 
Schizophrenia 
Sponsor: 
Karuna Therapeutics 
33 Arch Street 
Suite 3110 
Boston, MA 02110 
Tel: 
 
Email: 
 
Protocol Version:  
1.0 
Protocol Date: 
24 Aug 2020 
 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to Karuna Therapeutics. Any unauthorized 
copying or use of this document is prohibited. 
 
 
 
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PROTOCOL APPROVAL SIGNATURES
Protocol Title:
An Open-label Extension Study to Assess the Long-term Safety,
Tolerability, and Efficacy of KarXT in Subjects with DSM-5 
Schizophrenia
Protocol Number:
KAR-008
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Council for Harmonisation (ICH) guidelines for current Good 
Clinical Practice (GCP), and applicable regulatory requirements.
Sponsor Signatory
Karuna Therapeutics
Signature
Date (DD-Mmm-YYYY)
Karuna Therapeutics
Signature
Date (DD-Mmm-YYYY
Contract Research Organization Signatory 
Syneos Health
Signature
Date (DD-Mmm-YYYY)
Biostatistician
Kavanagh Statistical Consulting, LLC
Signature
Date (DD-Mmm-YYYY)
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INVESTIGATOR SIGNATURE PAGE
Protocol Title: 
An Open-label Extension Study to Assess the Long-term Safety, 
Tolerability, and Efficacy of KarXT in Subjects with DSM-5 
Schizophrenia 
Protocol Number: 
KAR-008 
Confidentiality and Current Good Clinical Practice (GCP)/E6(R2) Compliance Statement  
 
I, the undersigned, have reviewed this protocol (and amendments), including appendices, and I will 
conduct the study as described in compliance with this protocol (and amendments), and relevant 
International Council for Harmonisation (ICH) guidelines including GCP and applicable regulatory 
requirements. 
 
I am thoroughly familiar with the appropriate use of the KarXT, as described in this protocol and any 
other information provided by Karuna Therapeutics including, but not limited to, the current 
. 
 
Prior to initiating the trial, I will provide the independent ethics committee (IEC)/institutional review 
board (IRB) all items subject to review and will obtain a written and dated approval/favorable 
opinion. Once the protocol has been approved by the IEC/IRB, I will not modify this protocol without 
obtaining prior approval of Karuna Therapeutics and of the IEC/IRB. I will submit the protocol 
amendments and/or any informed consent form modifications to Karuna Therapeutics and the 
IEC/IRB, and approval will be obtained before any amendments are implemented. 
 
I ensure that all persons or party assisting me with the study are adequately qualified and informed 
about the Karuna Therapeutics KarXT and of their delegated study-related duties and functions as 
described in the protocol. I will supervise these delegated persons or parties in the conduct of this 
trial. 
 
I ensure that source documents and trial records that include all pertinent observations on each of the 
 
 
I understand that all information obtained during the conduct of the study with regard to the 
 
state of health will be regarded as confidential. No 
 names will be disclosed. All subjects will 
be identified by assigned numbers on all case report forms, laboratory samples, or source documents 
forwarded to the Sponsor. Clinical information may be reviewed by the Sponsor or its agents or 
regulatory agencies. Agreement must be obtained from the subject before disclosure of subject 
information to a third party. 
 
Information developed in this clinical study may be disclosed by Karuna Therapeutics to other 
clinical investigators, regulatory agencies, or other health authority or government agencies as 
required. 
<Name> 
 
<Title> 
Investigator Signature 
 
 
 
Date (DD-Mmm-YYYY) 
 
 
Institution 
 
 
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2 
SYNOPSIS 
Title of Study: 
An Open-label Extension Study to Assess the Long-term Safety, 
Tolerability, and Efficacy of KarXT in Subjects with DSM-5 Schizophrenia 
Protocol Number: 
KAR-008 
Investigators/Study Sites: 
Approximately 30 study sites in the United States and 10 study sites in 
Ukraine 
Phase of Development: 
Phase 3 
Objective(s): 
Primary Objective: 
The primary objective of the study is to assess the long-term safety and 
tolerability of KarXT in subjects with a Diagnostic and Statistical 
Manual-Fifth Edition (DSM-5) diagnosis of schizophrenia. 
Secondary Objective: 
The secondary objective of this study is to assess the long-term efficacy and 
monitor trough concentrations of xanomeline and trospium after 
administration of KarXT in adults with a DSM-5 diagnosis of 
schizophrenia: 
 
To evaluate the reduction in Positive and Negative Syndrome Scale 
(PANSS) total score 
 
To evaluate the reduction in PANSS positive score  
 
To evaluate the improvement in Clinical Global Impression-Severity 
(CGI-S) results  
 
To evaluate the reduction in PANSS negative score  
 
To evaluate the reduction in PANSS Marder Factor negative 
symptoms score 
 
To measure trough concentrations of xanomeline and trospium after 
administration of KarXT in adults who are acutely psychotic with a 
DSM-5 diagnosis of schizophrenia 
Exploratory Objective: 
The exploratory objectives of this study are 
 
To evaluate cognition with the Cambridge Neuropsychological Test 
Automated Battery (CANTAB) 
 
To evaluate prolactin levels after administration of KarXT 
 
To evaluate digital biomarkers of schizophrenia 
 
To evaluate ecological momentary assessment (EMA) in 
schizophrenia 
 
To evaluate cognitive insight 
Study Endpoint(s): 
Primary safety endpoint:  
The primary safety endpoint is the incidence of treatment-emergent adverse 
events (TEAEs) 
Secondary safety endpoints: 
The secondary safety endpoints of the study are: 
 
Incidence of serious TEAEs 
 
Incidence of TEAEs leading to withdrawal 
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Secondary efficacy endpoints:
The secondary efficacy endpoints of the study are: 
 
Change from baseline in PANSS total score at Week 52 
 
Change from baseline in PANSS positive score at Week 52 
 
Change from baseline in PANSS negative score at Week 52 
 
Change from baseline in PANSS Negative Marder Factor score at 
Week 52 
 
Change from baseline in CGI-S score at Week 52 
 
Percentage of PANSS responders (a 30% change in PANSS total 
score) at Week 52  
Other Endpoints:  
Safety endpoints: 
The other safety endpoints of the study are: 
 
Spontaneously reported cholinergic symptoms 
 
Change from baseline in Simpson-Angus Rating Scale (SAS) 
 
Change from baseline in Barnes Rating Scale for Akathisia 
(BARS) 
 
Change from baseline in Abnormal Involuntary Movement Scale 
(AIMS) 
 
Change from baseline in body weight, body mass index (BMI), 
waist circumference  
 
Change from baseline in orthostatic vital signs (supine and 
standing after 2 minutes): blood pressure (systolic and diastolic) 
and heart rate 
 
Change from baseline in clinical laboratory assessments 
(hematology, clinical chemistry, coagulation, urinalysis, and drug 
screen) 
 
Change from baseline in 12-lead electrocardiogram (ECG)  
 
Change from baseline in physical examination  
 
Suicidal ideation scale with the use of Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
Pharmacokinetic Endpoint: 
The pharmacokinetic endpoint of the study is measurement of trough 
plasma concentrations of xanomeline and trospium.  
Exploratory Endpoints: 
The exploratory endpoints of the study are:  
 
Change from baseline in cognition measuring core domains of 
impairment in schizophrenia using CANTAB 
 
Change from baseline in prolactin levels 
 
Observed digital biomarkers of schizophrenia 
 
Observed EMA data over time in schizophrenia 
 
Observed cognitive insight data over time 
Study Design: 
This is a Phase 3 multicenter, 53-week, outpatient, open-label extension 
(OLE) study to evaluate the long-term safety, tolerability, and efficacy of 
KarXT in subjects with DSM-5 schizophrenia who previously completed 
the treatment period of one of the two Phase 3 double-blind studies, 
KAR-007 or KAR-009. The study consists of a 52-week OLE treatment 
phase and a 7-day (±3 days) safety follow-up/end-of-study visit after the 
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last KarXT dose for subjects who complete the treatment phase and those 
who prematurely discontinue from the study.  
After written informed consent, subjects who have completed the KAR-007 
or KAR-009 Phase 3 acute study and received the last dose of the study 
drug in that trial will be rolled over in to the current OLE study. The 
assessments performed on Day 35 of Studies KAR-007 or KAR-009 will be 
considered as baseline assessments along with any additional assessments 
that will be performed on Day 1 of the current study. Consenting subjects 
who roll over into KAR-008 will have the previous blinded study 
medication discontinued and be dosed with a lead-in dose of open label 
KarXT the next day after completion of Visit 10 (Day 35) from the prior 
Study KAR-007 or KAR-009. The rollover is designed as above; a window 
extension is permitted but will need discussion with, and approval by, the 
medical monitor. 
Subjects who did not complete the full treatment period, or who early 
terminated Study KAR-007 or KAR-009, will not be eligible to enroll in 
this long-term extension study.  
A total of up to 350 subjects are planned to be enrolled in this study (aged 
18 to 65 years) across approximately 30 study sites in the United States and 
10 study sites in Ukraine. 
In this OLE study, all subjects will receive KarXT for up to 52 weeks. 
Regardless of treatment assignment in the preceding Phase 3 acute study 
(KAR-007 or KAR-009), all subjects will start on a lead-in dose of KarXT 
50/20 (50 mg xanomeline/20 mg trospium) 2 times per day (BID) for the 
first 2 days (Days 1 and 2), followed by KarXT 100/20 BID for the 
remainder of Week 1 (Days 3 to 7). On Day 8, dosing will be titrated 
upwards to KarXT 125/30 BID unless the subject is continuing to 
experience adverse events (AEs) from the previous dose of KarXT 100/20 
BID. All subjects who are increased to KarXT 125/30 BID, depending on 
tolerability, will have the option to return to KarXT 100/20 BID for the 
remainder of the treatment period. Re-escalation to 125/30 BID or 
re-titration in cases in which the subject has been off KarXT for a longer 
period of time (at least a week) is allowed and will require a discussion 
between the principal investigator and the medical monitor. Additional 
changes to KarXT dosing (e.g., temporary dose reductions) may be 
permitted as clinically indicated upon approval by the medical monitor.  
Beginning after Visit 5/Day 28, interim visits will be completed with 
flexibility between in-clinic visits, approximately once every 4 weeks. For 
interim visits, either a Home Health Care nurse or the study site staff will 
visit the subject to complete the scheduled visit. In addition to augment at-
home visits, the telemedicine visit can be used. When needed, the sites will 
have the option to schedule a subject for an in-clinic visit. 
A safety follow-up/end-of-study/early termination visit (Visit 30/Day 371 
±3 days) will be performed for all subjects after the last dose of KarXT. 
An Independent Safety Monitoring Committee will be responsible for 
periodically reviewing the safety data from this study and confirming that 
the study may continue. 
Number of Subjects: 
Inclusion Criteria:  
Individuals must meet all of the following criteria to be included in the 
study: 
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1. Subject is aged 18 to 65 years, inclusive. Exception: Subjects who 
turned 66 during KAR-007/009 participation will be eligible to 
continue in KAR-008. 
2. Subject is capable of providing informed consent.  
a. 
A signed informed consent form must be provided before any 
study assessments are performed. 
b. Subject must be fluent in (oral and written) English (United 
States only) or local language (Ukraine only) to consent. 
3. Subject has completed the treatment period on study drug (through 
Day 35 -2 days) of Studies KAR-007 or KAR-009.  
4. Subject resides in a stable living situation, in the opinion of the 
investigator. 
5. Subject has an identified, reliable informant/caregiver. An 
informant/caregiver is needed at the baseline visit as well as at the end 
of the study for relevant assessments. An informant/caregiver may not 
be necessary if the subject has been the patient of the investigator for 
 
6. Women of childbearing potential (WOCBP) or men whose sexual 
partners are WOCBP must be sexually abstinent (in line with their 
preferred and usual lifestyle) or willing and able to use at least 1 highly 
effective method of contraception during the study and for at least 
7 days after the last dose of KarXT. Sperm donation is not allowed for 
90 days after the final dose of KarXT. A female subject is considered 
to be a WOCBP after menarche and until she is in a postmenopausal 
state for 12 consecutive months or is otherwise permanently sterile (for 
which acceptable methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy). For the definition and list 
of highly effective methods of contraception, see Appendix 1. 
Exclusion Criteria: 
Subjects will be excluded from the study if 1 or more of the following 
criteria is/are applicable: 
1. 
Risk for suicidal behavior during the study as determined by the 
-SSRS as confirmed by the 
following:  
a. 
Subject answers 
suicidal ideation with some intent to act, without specific 
plan) or Item 5 (active suicidal ideation with specific plan and 
intent) on the C-SSRS.  
b. Nonsuicidal self-injurious behavior is not exclusionary. 
2. 
Any clinically significant abnormality, including any finding(s) from 
the physical examination, vital signs, ECG, or laboratory test at the 
end-of-treatment visit of Studies KAR-007 or KAR-009 that the 
investigator, in consultation with the medical monitor, would consider 
to jeopardize the safety of the subject. 
3. 
Female subject is pregnant. 
4. 
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 
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safety of the subject or affect his/her ability to adhere to the protocol 
visit schedule or fulfill visit requirements. 
5. 
Subjects with extreme concerns relating to global pandemics such as 
coronavirus disease 2019 (COVID-19) that preclude study 
participation. 
6. 
Risk of violent or destructive behavior. 
7. 
Subjects participating in another investigational drug or device trial or 
planning on participating in another clinical trial during the course of 
the study. 
Planned Sample Size: 
A total of approximately 350 subjects (aged 18 to 65 years) are planned to 
be enrolled in this study.  
Investigational Therapy: 
1. Fixed dose KarXT 50/20 BID (50 mg xanomeline/20 mg trospium) 
oral (Days 1 to 2) 
2. Fixed dose KarXT 100/20 BID (100 mg xanomeline/20 mg trospium) 
oral (Days 3 to 7) 
3. Fixed dose KarXT 125/30 BID (125 mg xanomeline/30 mg trospium) 
oral (Days 8 to 364, if tolerated)  
Reference Therapy: 
Not applicable. 
Treatment Duration: 
Total study duration is up to 53 weeks, including a 52-week treatment 
phase and a 7-day follow-up/end-of-study phase. 
Safety assessments: 
Spontaneous AEs; serious AEs (SAEs) and AEs leading to discontinuation 
of the KarXT; cholinergic symptoms; SAS; BARS; AIMS; body weight; 
BMI; waist circumference; orthostatic vital signs; clinical laboratory 
assessments (hematology, clinical chemistry, coagulation, urinalysis, and 
drug screen); 12-lead ECG; physical examination; and C-SSRS will be 
evaluated throughout the study as scheduled. 
Efficacy assessments: 
PANSS total score, PANSS positive score, PANSS negative score, PANSS 
Negative Marder Factor score, and CGI-S score will be evaluated at 
scheduled visits. 
Pharmacokinetic assessment: 
Trough concentrations at scheduled visits. 
Exploratory assessments 
Cognition testing using CANTAB; prolactin levels; digital biomarkers of 
schizophrenia; EMA; and cognitive insight will be evaluated throughout the 
study as scheduled. 
Statistical Methods and 
Planned Analyses: 
Study Populations: 
Enrolled population: All subjects who have given informed consent for 
KAR-008. 
Safety population: All subjects who receive at least 1 dose of KarXT during 
the current study will be included in the safety population and will be used 
in the safety analysis. 
Modified ITT (mITT) population: All subjects who are enrolled, received at 
least 1 dose of KarXT during the current study, have a valid PANSS 
assessment at baseline of the acute study and at KAR-008 baseline will be 
included in the mITT population and will be used in the efficacy analysis. 
PK population: All subjects who have received at least 1 dose of KarXT 
and have at least 1 measurable plasma concentration in the current study 
will be included in the PK population. 
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The primary safety endpoint of the study is the incidence of TEAEs. 
Secondary safety endpoints are the incidence of serious TEAEs and the 
incidence of TEAEs leading to withdrawal of KarXT.  
The secondary efficacy endpoints are change from baseline to Week 52 in 
the PANSS positive score, PANSS negative score, PANSS Negative 
Marder Factor score, CGI-S score, and the percentage of PANSS 
responders at Week 52.  
The exploratory endpoints of the study are change from baseline in 
cognition (CANTAB), prolactin levels, digital biomarkers, EMA, and 
cognitive insight. 
Descriptive statistics will be used to provide an overview of the safety and 
efficacy results. For continuous parameters, descriptive statistics will 
include n, mean, median, standard deviation, minimum and maximum; For 
categorical parameters, the number and percentage of subjects in each 
category will be presented. The denominator for percentages will be based 
on the number of subjects appropriate for the purposes of analysis. No 
statistical hypothesis testing will be performed. 
 
 
 
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3
TABLE OF CONTENTS
1
FINAL CLINICAL STUDY PROTOCOL .......................................................................1
2
SYNOPSIS ........................................................................................................................4
3
TABLE OF CONTENTS ................................................................................................10
3.1
List of In-text Tables ..................................................................................................14
3.2
List of In-text Figures.................................................................................................15
4
LIST OF ABBREVIATIONS .........................................................................................16
5
INTRODUCTION...........................................................................................................19
5.1
Background on Schizophrenia....................................................................................19
5.2
Background on KarXT (Xanomeline Tartrate and Trospium Chloride)....................19
Nonclinical Studies ............................................................................................21
Completed Clinical Studies................................................................................24
5.3
Clinical Risks/Benefits of KarXT and Study Rationale.............................................32
6
STUDY OBJECTIVES AND ENDPOINTS ..................................................................34
6.1
Study Objectives.........................................................................................................34
Primary Objective ..............................................................................................34
Secondary Objective ..........................................................................................34
Exploratory Objective........................................................................................34
6.2
Study Endpoints..........................................................................................................34
Primary Safety Endpoint....................................................................................34
Secondary Endpoints..........................................................................................34
6.2.2.1
Safety Endpoints ..........................................................................................34
6.2.2.2
Efficacy Endpoints .......................................................................................35
Other Endpoints .................................................................................................35
6.2.3.1
Safety Endpoints ..........................................................................................35
6.2.3.2
Pharmacokinetic Endpoint ...........................................................................35
Exploratory Endpoints .......................................................................................35
7
INVESTIGATIONAL PLAN .........................................................................................36
7.1
Description of Overall Study Design and Plan...........................................................36
7.2
Discussion of Study Design........................................................................................39
7.3
End of Study...............................................................................................................39
7.4
Independent Safety Monitoring Committee ...............................................................40
8
SELECTION OF STUDY POPULATION.....................................................................41
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8.1
Inclusion Criteria........................................................................................................41
8.2
Exclusion Criteria.......................................................................................................41
8.3
Retesting for Eligibility ..............................................................................................42
8.4
Study Withdrawal, Removal, and Replacement of Subjects......................................42
Pregnancy...........................................................................................................44
8.5
Completion of the Study or Lost to Follow-up ..........................................................45
8.6
Study Termination......................................................................................................45
9
TREATMENTS...............................................................................................................46
9.1
Details of Study Treatments .......................................................................................46
Identity of Study Treatments..............................................................................46
Packaging and Labeling.....................................................................................47
KarXT Storage ...................................................................................................47
KarXT Retention................................................................................................47
9.2
Dosage Schedule ........................................................................................................47
Visit 1/Day 1 Dosing..........................................................................................47
Visit 2/Day 3 and/or Other Visits Occurring on Weekends/Holidays ...............48
Visit 3/Day 8 and Visit 4/Day 14 Dosing and PK considerations .....................48
9.3
Measures to Minimize Bias: Study Treatment Assignment.......................................48
Method of Study Treatment Assignment...........................................................48
Blinding48
9.4
Dosage Modification ..................................................................................................49
9.5
Treatment Accountability and Compliance................................................................49
9.6
Prior and Concomitant Therapy .................................................................................49
Prior and Concomitant Medications ..................................................................49
Concomitant Medications for Anxiety and/or Sleep Aid...................................50
10
STUDY PROCEDURES.................................................................................................51
10.1
Informed Consent .......................................................................................................58
10.2
Study Procedures........................................................................................................58
AiCure Adherence Technology .........................................................................58
11
SAFETY ASSESSMENTS .............................................................................................61
11.1
Demographics, Medical History, and Psychiatric History .........................................61
11.2
Vital Signs ..................................................................................................................61
11.3
Complete/Targeted Physical Examination .................................................................61
11.4
Weight, Height, Body Mass Index, and Waist Circumference ..................................62
11.5
Electrocardiograms.....................................................................................................62
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11.6
Laboratory Assessments.............................................................................................62
11.7
Adverse Events...........................................................................................................64
Adverse Events ..................................................................................................64
Adverse Events of Special Interest ....................................................................66
Serious Adverse Events .....................................................................................66
Serious Adverse Event Reporting......................................................................66
Drug-Induced Liver Injury.................................................................................67
Suspected Unexpected Serious Adverse Reactions ...........................................68
Pregnancy...........................................................................................................69
Overdose ............................................................................................................70
11.8
Simpson-Angus Rating Scale.....................................................................................71
11.9
Barnes Rating Scale for Akathisia..............................................................................71
11.10 Abnormal Involuntary Movement Scale ....................................................................71
11.11 Columbia-Suicide Severity Rating Scale ...................................................................71
11.12 Functional Constipation Inquiry.................................................................................71
12
EFFICACY ASSESSMENTS.........................................................................................73
12.1
Positive and Negative Syndrome Scale......................................................................73
12.2
Clinical Global Impression-Severity..........................................................................73
13
PHARMACOKINETICS ................................................................................................74
13.1
Pharmacokinetic Sampling.........................................................................................74
Blood Samples ...................................................................................................74
13.2
Pharmacokinetic Analytical Methodology.................................................................74
14
EXPLORATORY ASSESSMENTS...............................................................................75
14.1
Cognition Testing - Cambridge Neuropsychological Test Automated Battery .........75
14.2
Change in Prolactin ....................................................................................................75
14.3
Digital Biomarkers of Schizophrenia .........................................................................76
14.4
EMA Wellness Assessments......................................................................................76
Ecological Momentary Assessment...................................................................76
Insight into Cognitive Performance ...................................................................76
Data Collected on EMAW Platform ..................................................................77
15
STATISTICAL ANALYSIS...........................................................................................79
15.1
Determination of Sample Size....................................................................................79
15.2
Analysis Populations ..................................................................................................79
15.3
Safety Analysis...........................................................................................................79
15.4
Efficacy Analysis........................................................................................................80
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15.5
Pharmacokinetic Analysis ..........................................................................................80
15.6
Exploratory Analysis..................................................................................................80
15.7
Interim Analysis .........................................................................................................80
15.8
Handling of Missing Data ..........................................................................................81
16
STUDY MANAGEMENT..............................................................................................82
16.1
Approval and Consent ................................................................................................82
Regulatory Guidelines........................................................................................82
Institutional Review Board/Independent Ethics Committee..............................82
Informed Consent...............................................................................................82
16.2
Data Handling.............................................................................................................83
16.3
Source Documents......................................................................................................84
16.4
Record Retention........................................................................................................84
16.5
Monitoring..................................................................................................................85
16.6
Quality Control and Quality Assurance .....................................................................85
16.7
Protocol Amendment and Protocol Deviation............................................................85
Protocol Amendment .........................................................................................85
Protocol Deviations............................................................................................86
16.8
Ethical Considerations................................................................................................86
16.9
Financing and Insurance.............................................................................................86
16.10 Publication Policy/Disclosure of Data........................................................................86
17
REFERENCES................................................................................................................87
18
APPENDICES.................................................................................................................90
APPENDIX 1
CONTRACEPTION GUIDELINES............................................................91
APPENDIX 2
FUNCTIONAL CONSTIPATION INQUIRY ............................................93
APPENDIX 3.
ALTERNATIVE PROCEDURES DURING COVID-19 PANDEMIC-
RELATED PHYSICAL DISTANCING.........................................................................95
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3.1 
List of In-text Tables 
Table 1 
Study Design ...........................................................................................................38 
Table 2. Schedule of Assessments ........................................................................................52 
Table 3. Laboratory Assessments..........................................................................................63 
Table 4. Classification of Adverse Events by Intensity ........................................................65 
Table 5. Classification of Adverse Events by Relationship to KarXT..................................65 
Table 6. Cognitive Tests and Cognitive Domains Assessed by the Cambridge 
Neuropsychological Test Automated Battery .........................................................75 
 
 
 
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3.2 
List of In-text Figures 
Figure 1. Change from Baseline in PANSS Total Scores (KAR-004) ...................................28 
Figure 2. Change from Baseline in PANSS-Positive Scores (KAR-004) ..............................29 
Figure 3. Change from Baseline in CGI-S (KAR-004) ..........................................................30 
Figure 4. Change from Baseline in PANSS-Negative Scores (KAR-004).............................31 
 
 
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4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AD 
 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
alanine aminotransferase 
APD 
antipsychotic drug 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-12 
area under the plasma concentration-time curve from 0 to 12 hours 
AUC0-24 
area under the plasma concentration-time curve from 0 to 24 hours 
BACS 
Brief Assessment of Cognition in Schizophrenia 
BARS 
Barnes Akathisia Rating Scale 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global 
 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTS 
clinical trial subject 
DSM-5 
 
EDC 
electronic data capture 
ECG 
electrocardiogram 
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination 
eCRF 
electronic case report form 
EMA 
Ecological Momentary Assessment 
EMAW 
Ecological Momentary Assessment Wellness 
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Abbreviation 
Definition 
EPS 
extrapyramidal symptoms 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability Accountability Act 
IB 
 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
IXRS 
interactive response system 
MCC 
microcrystalline cellulose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini International Neuropsychiatric Interview 
mITT 
modified intent-to-treat 
MMRM 
mixed model repeated measures 
OLE 
open-label extension 
PANSS 
Positive and Negative Syndrome Scale 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
SAS 
Simpson-Angus Rating Scale 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson Angus Scale 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TID 
thrice daily 
TK 
toxicokinetic 
Tmax 
time to maximum observed plasma concentration 
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Abbreviation 
Definition 
ULN 
upper limit of normal  
US 
United States 
VAS 
visual analog scale 
VCT 
Verified Clinical Trials 
VLMT 
Verbal Learning and Memory Test 
WOCBP 
women of child bearing potential 
 
 
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5 
INTRODUCTION 
5.1 
Background on Schizophrenia 
Schizophrenia is a long-term mental disorder involving a breakdown in the relation between 
thought, emotion, and behavior, and leads to faulty perception, inappropriate actions and 
feelings, withdrawal from reality and personal relationships into fantasy and delusion, and a 
sense of mental fragmentation. Symptoms include delusions, hallucination, disorganized speech 
or behavior, and impaired cognitive ability.[1] The prevalence of schizophrenia is between 0.6% 
and 1.9% in the United States population.[2] Moreover, a claims analysis has estimated that the 
annual prevalence of diagnosed schizophrenia in the United States (US) is 5.1 per 1000 lives.[3] 
It is found equally in males and females, with males usually having an earlier onset of 
symptoms.[4]  
Antipsychotic drugs (APDs) are the mainstay of treatment for schizophrenia.[5] All currently 
available antipsychotics act through blockage of all or subsets of dopamine receptors in the 
brain. First-generation APDs include chlorpromazine and haloperidol; treatment with these 
agents is marked by high rates of parkinsonian extrapyramidal symptoms (EPS) and tardive 
dyskinesia and they consequently have limited use today. The second-generation agents, that 
include risperidone, olanzapine, quetiapine, lurasidone, aripiprazole, and lumateperone, tend to 
have lower levels of EPS or tardive dyskinesia and are currently the most commonly prescribed 
APD class. However, the second-generation drugs also have problematic side effects that include 
significant weight gain, metabolic disturbances, sedation, and akathisia.[6, 7, 8] These side 
effects contribute to poor medication adherence resulting in frequent relapses and 
hospitalizations.[9, 10] Thus, there is a need for medications for schizophrenia which act through 
alternative mechanisms. 
Central muscarinic receptors have been hypothesized to be therapeutic treatments for 
schizophrenia based on several converging lines of evidence including both animal and human 
studies.[11, 12] There are 5 subtypes of muscarinic receptors (M1-M5). The therapeutic effect of 
central muscarinic receptor agonism is thought to be due to agonism of M1 and M4 receptors in 
the central nervous system (CNS).[13] However, compounds that agonize M1 and M4 receptors 
are often not specific enough not to also agonize M2 and M3 receptors outside of the CNS due to 
the highly conserved allosteric binding sites that the receptors share, leading to adverse events 
(AEs) related to activation of these peripheral receptors. Thus, any potential benefit of 
 [AD]) has 
been outweighed by the occurrence of AEs associated with peripheral cholinergic side effects 
(nausea, vomiting, diarrhea, sweating, and excess salivation). 
5.2 
Background on KarXT (Xanomeline Tartrate and Trospium Chloride) 
Xanomeline tartrate is a muscarinic-cholinergic receptor agonist. It has agonistic activity at all 
5 muscarinic receptors, but preferentially stimulates M1 and M4 receptors and binding to M1 and 
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M4 receptors in the CNS, which 
effects (Roth, unpublished data). A recent study reports that xanomeline is a very potent M4 
muscarinic agonist in vivo, measured by various second messenger assays.[14] Xanomeline also 
enters the brain rapidly achieving a brain to plasma ratio of greater than 10 making it an 
attractive CNS drug candidate.[15]  
Xanomeline does not have any direct binding activity on dopaminergic receptors, suggesting that 
its mechanism of action is unrelated to direct dopamine involvement. 
Previous double-blind, placebo-controlled clinical trials have provided strong evidence that 
xanomeline has clinically relevant antipsychotic efficacy. In a multicenter outpatient trial in AD 
(N = 343), 3 doses of xanomeline (up to 225 mg/day) and placebo were assessed for 
26 weeks.[16, 17] Significant dose-dependent improvements in psychotic symptoms relative to 
placebo were observed. Moreover, psychotic symptoms resolved quite rapidly in subjects who 
were symptomatic at baseline and a dose-dependent reduction in the emergence of psychotic 
symptoms versus placebo was also observed. In a completer analysis, cognitive improvement 
was also found suggesting longer treatment intervals may be necessary for cognitive 
enhancement.[16, 17] In a subsequent small (N = 20) double-blind, placebo-controlled inpatient 
trial in treatment-resistant subjects with schizophrenia, xanomeline (225 mg/day) demonstrated 
robust and relatively rapid improvement in psychosis compared to placebo. In addition, 
improvement in both negative symptoms and cognitive impairment was observed.[18] 
In both the AD and schizophrenia trials, as well as in previous healthy volunteer studies, 
dose-dependent 
sweating, and hypersalivation. These side effects were frequent and, at the higher doses of 
xanomeline, led 
profile curtailed further development of xanomeline as a single agent.  
It is believed that the procholinergic AEs associated with xanomeline are mediated by 
peripheral rather than central muscarinic receptors, which would 
make these AEs theoretically amenable to counteracting peripheral anticholinergic treatment. 
Trospium chloride is a peripherally acting muscarinic antagonist which binds to and antagonizes 
all 5 muscarinic receptor subtypes.[19] It is a commonly used generic drug approved for over 10 
years by the US Food and Drug Administration (FDA) and by European authorities to treat 
overactive bladder and is generally well tolerated.[19] Several human subject studies have 
demonstrated that trospium does not appreciably cross the blood-brain barrier, consistent with 
20]  
KarXT is a novel combination of xanomeline tartrate and trospium chloride. Karuna 
hypothesized that the addition of trospium would mitigate peripheral pro-cholinergic side effects 
(vomiting, nausea, diarrhea, sweating, and hyper-salivation) and thus provide a strategy to allow 
xanomeline to be administered and stimulate brain muscarinic receptors with a decreased side 
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effect burden. Phase 1 studies in healthy volunteers of this combination demonstrated that 
KarXT reduced these side effects by 46% compared to xanomeline alone.[21] Moreover, the 
remaining cholinergic AEs were generally mild to moderate in severity and transient in nature, 
often lasting a few hours without recurrence and were generally single-episode. In general, 
KarXT was well tolerated in healthy adult volunteers. These encouraging safety data prompted 
further work to assess KarXT for the treatment of schizophrenia and potentially other CNS 
disorders.
Karuna has recently completed an adequate and well-controlled, randomized, multi-center 
Phase 2, placebo-controlled, inpatient clinical trial of acute psychosis with schizophrenia in 
182 adult subjects (KAR-004). KarXT demonstrated a statistically significant and clinically 
meaningful 11.6 point mean reduction in total Positive and Negative Syndrome Scale (PANSS) 
at 5 weeks compared to placebo (p <0.0001), with statistical separation at each time point 
assessed (2, 4 and 5 weeks), and also demonstrated good overall safety and tolerability.
The purpose of the current study is to evaluate the long-term safety and tolerability of KarXT 
(xanomeline 125 mg/trospium 30 mg) administered twice daily (BID) in adult outpatients with 
-5) diagnosis of schizophrenia. 
Xanomeline is currently not approved or marketed in any country. Trospium is marketed in the 
US and other regions of the world for the treatment of overactive bladder.
Nonclinical Studies
The following is a summary of the important nonclinical safety and toxicology studies. More 
detailed information can be found in the KarXT 
The acute toxicity of xanomeline tartrate was evaluated in mice and rats. All animals were 
observed for 2 weeks for mortality and clinical signs of intolerance, and then necropsied for 
gross examinations. In-life findings attributed to the test article included excessive 
muscarinic-mediated pharmacology, such as excessive salivation, hypoactivity, ataxia, soft 
stools, exophthalmos, ocular discharge, tremors, and convulsions, with survivors typically 
appearing normal by Day 3 or Day 4. Gross findings at necropsy were generally unremarkable 
(eg, gas-distended or mucous-filled gastrointestinal [GI] tracts after oral dosing).
KarXT-301 was a 14-day, repeat dose study of KarXT in rats where relatively high doses of 
xanomeline and trospium were given, with either xanomeline alone or in combination with 
trospium. Seven groups of 10 rats/sex/group were administered either vehicle (reverse osmosis 
water), xanomeline alone at 37, 75, 150, or 300 mg/kg/day (split into BID doses, every 
12 hours), or xanomeline/trospium combination doses of 150/200 mg/kg/day or 
225/400 mg/kg/day, respectively (split into BID doses, every 12 hours). 
Satellite animals were included for the collection of plasma after the first and last doses for the 
determination of drug concentrations of each parent drug in support of toxicokinetic (TK) 
assessments.
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There was no target-organ toxicity revealed by clinical pathology or by gross or microscopic 
assessments. All intolerance could be attributed to recognized pharmacology of either test article. 
No dose-related ophthalmic observations were noted. Findings were not indicative of specific 
target organ toxicity. In short, no new hazard was identified.  
Clinical observations noted in most animals administered 300 mg/kg/day xanomeline included 
hypoactivity, clear oral discharge, dilated pupils, irregular or labored respiration, and rough 
haircoat, among other observations. These findings are generally consistent with the anticipated 
pharmacology of xanomeline.  
Three TK animals in the low-dose combination group died or were euthanized in extremis. It is 
unclear to what extent the combination treatment effects versus the different handling of these 
animals (including 3 plasma samplings per animal) contributed to these deaths. If gavage 
accidents were involved (as happened with some TK animals), then they were not detected at 
gross necropsy. There was no microscopic evidence of toxicity seen in any toxicity animals in 
this group or in the higher-dose combination group. 
Three toxicology and 3 TK animal deaths (total of 6) occurred in the high-dose combination 
group. Two toxicology animals had evidence of gavage accidents. For the third, the cause of 
death was undetermined, and a test article-related effect cannot be ruled out, but esophageal 
muscular degeneration/regeneration is indicated in some dosing-related trauma. If gavage 
accidents were involved, then they were not detected at gross necropsy. There was no evidence 
of target organ microscopic findings in GI tract or any other tissue of any animal, including the 
early death toxicity animals.  
A pharmacodynamics (PD)-mediated reduction in GI motility is consistent with the 
anti-muscarinic effects of trospium on intestinal musculature. Fecal retention, malabsorption, 
cessation of eating, dehydration, and rapid deterioration followed with continued dosing. 
Cessation of dosing in the high-dose combination animals that survived led to rapid recovery, 
implying the deleterious effects had been PD-related. No effects on food consumption were seen 
in any xanomeline-alone group. The lack of microscopic findings in the GI tract of any early 
death or surviving animal implies that the adverse effects were pharmacologically mediated 
rather than direct target organ toxicity. 
Twenty-eight Day Repeat-Dose Studies with Xanomeline in Rats and Monkeys: Rats were fed 
xanomeline tartrate at 0, 0.05, 0.1, or 0.2% daily and monkeys were fed xanomeline tartrate daily 
at 0, 5, 12.5, or 30 mg/kg. All animals survived until necropsy. Safety findings in rats included 
reduced body weight in the high-dose group, increases in gamma-glutamyl-transferase, 
cholesterol, and bilirubin, slight decreases in triglycerides, bile duct hyperplasia, higher serum 
potassium (males), and lower serum globulin (females). Findings in monkeys were dose-related 
and included signs of intolerance such as emesis, salivation, diarrhea, hypoactivity, weight loss, 
and treatment-related tachycardia in the high-dose animals. 
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Forty-Day Repeat Dose Study of KarXT in Rats (KarXT-302): Six groups of 15 rats/sex/group 
were given vehicle, xanomeline alone at 75 or 150 mg/kg/day, trospium alone at 100 mg/kg/day, 
or xanomeline/trospium combination at doses of 75/50 mg/kg/day or 150/100 mg/kg/day, with 
all doses split into BID doses. Satellite rats (TK animals) were included for collection of plasma 
after the first and last doses to determine concentrations of each drug. Dosing was initially 
planned to be 90 days, but was terminated after 40 days because of unexpected deaths in the TK 
animals. No target organ toxicity was seen. Safety findings included pharmacologically mediated 
constipation in the trospium alone and combination groups, and mild biliary hyperplasia in the 
high-dose xanomeline-alone and combination groups. There were 4 unscheduled deaths in TK 
animals; 2 in the high-dose xanomeline-alone group (150 g/kg/day) and 2 in the high-dose 
combination group (150 mg/kg/day xanomeline plus 100 mg/kg/day trospium). Both 
xanomeline-only animals had necropsy gross findings of a gavage accident and cause of death 
could not be determined. All toxicology animals survived to their scheduled sacrifice. The 
Sponsor considers that the volume depletion and trauma of multiple bleeds (3 per animal) 
followed by reduced absorption of fluids and nutrients secondary to reduced GI motility with 
continued BID dosing, explains the greater demise of TK animals relative to toxicity animals.  
Based on the results of the 90-day rat toxicology study, oral administration of trospium chloride 
and xanomeline tartrate alone or in combination to Crl:CD(SD) rats BID (12 hours ±60 minutes 
apart) at dosage levels of 25 and 50 mg/kg/dose trospium chloride, 37 and 75 mg/kg/dose 
xanomeline tartrate and a combination of 37/25, 75/25, and 75/50 mg/kg/dose xanomeline 
tartrate/trospium chloride for a minimum of 90 days resulted in minimal to moderate bile duct 
hyperplasia in the livers of the xanomeline tartrate and combination (xanomeline tartrate and 
trospium chloride) group males.  
Although there were no notable differences in the incidence of bile duct hyperplasia when 
comparing the single vs combination groups, there was an increased severity observed in the 
combination group males (specifically the 75/25 and 75/50 mg/kg/dose combination group 
males) when compared to the xanomeline tartrate group males at the terminal euthanasia. The 
bile duct hyperplasia was considered adverse in the high-dose xanomeline tartrate group males 
and in the 75/25 and 75/50 mg/kg/dose combination group males due to instances of moderate 
severity. Therefore, the no-observed-adverse-effect level was considered to be 50 mg/kg/dose for 
trospium chloride, 37 mg/kg/dose for xanomeline tartrate, and 37/25 mg/kg/dose for the 
combination of xanomeline tartrate/trospium chloride. At these doses for males, mean plasma 
AUC0-24 
 91.  
At these doses for females, mean plasma AUC0-24 
267,000 pg hr/mL for xanomeline, and 16,700 + 171,000 
 + xanomeline, 
respectively, on Day 91. The absence of bile duct hyperplasia in females cannot be explained 
from differences in drug exposure. At the recovery euthanasia, bile duct hyperplasia was still 
present, but was limited to minimal severity and there was a decreased incidence in both the 
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xanomeline tartrate and combination group males. There was also no notable difference in 
severity between the single vs combination groups at the recovery euthanasia. Given the 
decreased incidence/severity, in combination with the improved histologic appearance of bile 
ducts at the recovery euthanasia (ie, smaller/flattened epithelium, non-inflammatory, and an 
absence of portal bridging), changes at the recovery euthanasia were consistent with a partial 
resolution of bile duct hyperplasia. With an absence of correlating serum liver enzyme 
elevations, bile acid alterations or hepatocellular degeneration, necrosis or regeneration, and with 
the apparent reversibility following cessation of treatment, these findings appear to have been 
tolerable by the affected animals. Therefore, the maximum tolerated dose was considered to be 
50 mg/kg/dose for trospium chloride, 75 mg/kg/dose for xanomeline tartrate, and 
75/50 mg/kg/dose for the combination of xanomeline tartrate/trospium chloride. 
For males, corresponding mean plasma AUC0-24
822,000
respectively, on Day 91. For females, corresponding mean plasma AUC0-24 values were 
9230
950,000
rospium + xanomeline, respectively, on Day 91.
familiar exaggerations of systemic and CNS muscarinic effects that had previously been seen 
with xanomeline or trospium at high doses. Target organ findings with xanomeline alone were 
limited to biliary hyperplasia in the 28-day rat study but not the 28-day or 12-month monkey 
study, though similar findings were described in a 6-month monkey study. With KarXT, biliary 
hyperplasia was not observed in the 14-day rat study but was reported in the 40-day rat study. 
Notably, these hyperplastic findings are not thought to represent pre-neoplastic lesions, because 
they were of low severity; no fibrosis or associated hepatocellular changes, and no significant 
effects were seen on hepatobiliary-related serum chemistry.
Completed Clinical Studies
Refer to the IB for complete information regarding previous clinical studies conducted with 
xanomeline by Eli Lilly, and studies KAR-001, KAR-002, KAR-003 and KAR-004 conducted 
by Karuna Therapeutics using xanomeline with trospium.
To date, more than 750 subjects or volunteers have been exposed to xanomeline tartrate (oral 
formulation, either alone, in combination with trospium, or as the combination drug KarXT) in 
18 completed clinical studies conducted either by Eli Lilly or Karuna Therapeutics, some for as 
long as 3 years. In those studies, significant improvements in cognition and reduced psychotic 
symptoms were observed.
A study of xanomeline monotherapy in subjects with schizophrenia was reported in 2008.[18] In 
this pilot study, the effects of xanomeline were examined in 20 schizophrenia subjects utilizing a 
double-blind, placebo-controlled, 4-week study design. Subjects treated with xanomeline did 
significantly better than subjects in the placebo group on Brief Psychiatric Rating Scale total 
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scores and PANSS total scores (ie, 24-point change over placebo, p = 0.04). In the cognitive test 
battery, subjects in the xanomeline group showed improvements relative to placebo in some of 
the cognitive domains of verbal learning and short-term memory function. These studies 
demonstrated the potential for xanomeline as a treatment for psychosis and cognition across 
multiple subject populations.  
Study H2Q-EW-E001, conducted by Eli Lilly, had 36 male healthy volunteers in 4 groups of 9, 
who were administered escalating single doses of xanomeline tartrate in increments of 1, 5, 10, 
25, 50, 75, 100 and 150 mg. Each group took 2 ascending doses of xanomeline tartrate and 1 
dose of placebo in a single subject blind manner. There were no serious AEs (SAEs). Adverse 
events included watery diarrhea, nausea, dizziness, sweating, shivering, mild disorientation, 
increased blood pressure (BP), increase(s) in sitting and standing heart rate, slight increase in 
supine systolic BP, and postural hypotension. 
The clinical experience with KarXT initiated by Karuna Therapeutics to date includes 
3 completed Phase 1, clinical pharmacology studies in healthy volunteers (KAR-001, KAR-002, 
and KAR-003) and one completed Phase 2 study (KAR-004) in adult inpatients with DSM-5 
schizophrenia. 
The first study conducted by Karuna, KAR-001 was a Phase 1, double-blind, randomized, 
multiple-dose, pilot study comparing xanomeline administered alone to xanomeline administered 
in combination with trospium chloride in normal healthy volunteers. This study consisted of 
2 arms, in which xanomeline was administered three times daily (TID), alone, at a total daily 
dose of 225 mg in 1 arm, and the second arm received the same dose of xanomeline in 
combination with trospium chloride 20 mg administered BID, a total daily dose of 40 mg. 
Subjects were treated for 7 days. The goal was to determine whether this dosing regimen would 
reduce the cholinergic side effects of xanomeline by co-administration of the muscarinic 
antagonist, trospium. 
Overall, treatment with xanomeline 225 mg daily + trospium 40 mg daily administered over 
7 days was considered safe and well tolerated. The results of key and supportive endpoints 
showed a numerical reduction (although not statistically significant) in visual analog scale (VAS) 
scores for cholinergic events for the xanomeline + trospium treatment arm compared to the 
xanomeline-alone treatment arm. Specifically, consistent numerical reduction in VAS scores for 
the xanomeline + trospium treatment arm was observed for the supportive endpoints of 
maximum weekly individual VAS scores and mean daily maximum composite VAS scores.  
Results of the clinician-administered scales were supportive of a reduction in vomiting, feelings 
of nausea, excess salivation, and sweating that interfered with daily activities in the 
xanomeline + trospium treatment arm compared to the xanomeline-alone treatment arm. 
There were no meaningful differences between treatment groups in heart rate, resting BP, 
orthostatic BP or any electrocardiogram (ECG) parameters including QT. A small subset of 
subjects in both treatment arms had transient increases in heart rate and orthostatic BP changes 
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which may have contributed to syncope and postural dizziness in those subjects. Two subjects 
(both in the xanomeline-alone arm) experienced syncope. The incidence of orthostatic AEs in the 
KarXT group was approximately one-half that of subjects in the xanomeline-alone group. 
The most commonly reported treatment-emergent AEs (TEAEs) in KAR-
in either treatment arm) were hyperhidrosis, salivary hypersecretion, nausea, dizziness postural, 
and diarrhea. Subject incidences of these 5 TEAEs was higher in the xanomeline-alone treatment 
arm (61.8%) compared to the xanomeline + trospium treatment arm (34.3%).  
Overall, treatment with xanomeline 225 mg combined with trospium chloride 40 mg 
administered over 7 days was considered safe and well tolerated. The observed side effect profile 
was consistent with the known safety profile of xanomeline and trospium chloride. The incidence 
of TEAEs and cholinergic TEAEs was lower in the xanomeline + trospium treatment arm 
compared to the xanomeline-alone treatment arm. 
Study KAR-002 was a Phase 1, double-blind, randomized, multiple-dose adaptive design pilot 
study to evaluate the safety and tolerability of KarXT in normal healthy volunteers. Subjects 
received either 100 mg xanomeline + 20 mg trospium BID or placebo. The first cohort of this 
study was stopped after 1.5 days when the FDA put the program on hold due to a preliminary rat 
finding in the 14-day study. This study used a new formulation of KarXT in which xanomeline 
and trospium were combined into a single dose form and given BID. Safety findings included an 
increase in orthostatic complaints. Caution should be used in drawing conclusions from this 
study, as subjects did not have time to reach steady state plasma levels from dosing, as only 
3 doses were given. 
Study KAR-003 was a Phase 1, double-blind, randomized, multiple-dose, adaptive design, 
inpatient pilot study to evaluate the safety and tolerability of KarXT in normal healthy 
volunteers. The primary objective of this study was to assess the safety and tolerability of 7 days 
of daily administration of KarXT at various dose combinations, administered BID. Subjects 
received either KarXT or placebo (3:1 ratio). All subjects on KarXT received 2 days of 50 mg 
xanomeline + 20 mg trospium BID, and then increased to different doses for Days 3 to 7. This 
study also used the new formulation of KarXT in which xanomeline and trospium were 
combined into a single dosage form and given BID.  
There was a relatively high degree of variability in xanomeline and trospium exposures between 
individuals in all cohorts, which is consistent with previous results with KarXT, 
xanomeline-alone, and trospium-alone. Peak plasma concentrations were observed at a median 
time of 2.0 hours for xanomeline and 1.0 hour for trospium across all treatment groups and study 
days.  
Although there was insufficient data to draw a definitive conclusion regarding the impact of 
trospium on the pharmacokinetics (PK) and bioavailability of xanomeline, or the impact of 
xanomeline on the pharmacokinetics and bioavailability of trospium, the PK results suggest that 
neither drug had a meaningful impact on the PK behavior of the other drug. 
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During the 2-day lead-
completed dosing were dry mouth, nausea, and constipation. For the treatment groups that 
completed dosing, although the incidence of TEAEs was lower in the KarXT 100/20 BID 
(66.7%) group compared to KarXT 125/40 group (88.9%), the incidence of cholinergic TEAEs 
(nausea, vomiting, diarrhea, sweating, and excess salivation) was similar between the 2 groups. 
The most commonly reported TEAEs ( 20% of subjects in either treatment group) in these 
groups were dizziness, nausea, dry mouth, headache, vomiting, dyspepsia, somnolence, vision 
blurred, and dysuria. For the treatment groups that did not complete dosing (KarXT 150/20 BID 
group and KarXT 150/40 BID group), the cholinergic TEAEs were generally higher compared to 
the treatment groups that completed dosing.  
Overall, anticholinergic TEAEs appeared to occur primarily in the treatment groups that were 
dosed with 40 mg trospium BID (KarXT 150/40 BID and KarXT 125/40 BID groups), 
particularly when paired with 125 mg xanomeline BID, suggesting to consider slightly lowering 
the trospium dose from 40 mg BID in future studies. All TEAEs were mild or moderate in 
severity, and there were no SAEs or deaths. Treatment-emergent AEs were primarily cholinergic 
or orthostatic (and a few anticholinergic). Doses of 100 mg and 125 mg BID of xanomeline were 
well tolerated when paired with 20 mg and 40 mg BID of trospium, respectively. The safety and 
tolerability profile of KarXT 100/20 BID and KarXT 125/40 BID was acceptable and supports 
further evaluation at similar doses in future studies. Doses of KarXT 150/20 BID and 150/40 
BID were not well tolerated in this study. A pairing of 150 mg xanomeline with 40 mg trospium 
appeared to be better tolerated than 150/20, but some subjects still experienced tolerability 
issues. 
Study KAR-004 was a Phase 2 randomized, double-blinded study to assess the safety, 
tolerability, and efficacy of KarXT in adults with DSM-5 schizophrenia, hospitalized with acute 
psychosis. The primary objective of the study was to assess the efficacy of KarXT (125/30 BID) 
versus placebo in reducing PANSS total scores in adult inpatients with a DSM-5 diagnosis of 
schizophrenia. Subjects received either KarXT or placebo (1:1 ratio) for a treatment period of 
5 weeks. All subjects on KarXT received a lead-in dose of KarXT 50/20 BID for the first 2 days 
followed by KarXT 100/20 BID on Days 3 to 7. On Day 8, dosing was titrated upwards to 
KarXT 125/30 BID unless the subject was continuing to experience AEs from a previous dose 
increase of 100/20 BID. The clinical portion of this study was completed and the clinical study 
report is in progress. No new safety concerns have arisen during this study. 
The KAR-004 trial results are unambiguous regarding efficacy, where not only the primary 
outcome measure showed a robust separation from placebo, but the additional sensitivity and 
secondary outcome measures were consistently robust as well.  
KarXT demonstrated statistically significant and clinically meaningful mean reductions in total 
PANSS scores at 5 weeks compared to placebo (p <0.0001) in the modified intent-to-treat 
(mITT) population. The KarXT group showed an adjusted mean improvement of 17.40 points at 
Week 5 compared to an adjusted mean 5.85 point improvement in the placebo group for a 
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difference of 11.56 points in the total PANSS score (Figure 1). Substantial significant differences 
were also seen between KarXT and placebo at Weeks 2 and 4; moreover, the difference appeared 
to be widening with each successive time point. In addition, sensitivity analyses of the primary 
outcome measure all showed the same strong differences from placebo attesting to the robustness 
of the finding in Completer, last observation carried forward, and Per Protocol populations (all 
with p<0.0001). Also, analyses exploring missingness via imputation for missing data at random 
effect size observed in this trial was 0.75. 
Figure 1. 
Change from Baseline in PANSS Total Scores (KAR-004) 
 
Abbreviations: LS = least squares; mITT = modified intent-to-treat; PANSS = Positive and Negative Syndrome 
Scale; SEM = standard error of the mean. 
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A significant reduction in the secondary endpoint of PANSS-positive scores was observed 
(p<0.0001) at Week 5 as well as the 2 earlier time points (ie, Weeks 2 and 4; see Figure 2). 
Figure 2. 
Change from Baseline in PANSS-Positive Scores (KAR-004) 
 
Abbreviations: LS = least squares; mITT = modified intent-to-treat; PANSS = Positive and Negative Syndrome 
Scale; SEM = standard error of the mean. 
 
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As regards the Clinical Global Impression  Severity of Illness (CGI-S), subjects in the KarXT 
group overall significantly improved in ratings compared to placebo, with a p-value of <0.001 at 
Week 5. At Week 5, 8% of placebo subjects improved (decreased) their CGI-S ratings at least 
2 levels versus 28.9% of KarXT subjects (see Figure 3). 
Figure 3. 
Change from Baseline in CGI-S (KAR-004) 
 
Abbreviation: CGI-S = Clinical Global Impress
 
 
A statistically significant reduction in the secondary endpoint of PANSS-negative score was 
observed (p<0.001) at Week 5. Overall, the changes in the KarXT group were statistically 
significantly greater compared to the placebo group at Visits 6, 8, and 9 (p<0.001). The least 
square mean improvement for the placebo group was 1.32 points at Week 5 (Visit 9) and the 
mean improvement for the KarXT group was 3.85 points leading to a mean difference of 
2.53 points at Week 5 (Visit 9; see Figure 4). 
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Figure 4. 
Change from Baseline in PANSS-Negative Scores (KAR-004) 
 
Abbreviations: LS = least squares; mITT = modified intent-to-treat; PANSS = Positive and Negative Syndrome 
Scale; SEM = standard error of the mean. 
 
The overall safety/tolerability data were also fairly unambiguous; among the highlights:  
 The overall discontinuation rate on KarXT was 20%, similar to placebo (21%). The number 
of discontinuations due to TEAEs was equal in the KarXT and placebo arms (N = 2 in each 
group) 
 The dose escalation rate on KarXT was high and similar to placebo: 
o 91% of KarXT subjects escalated to 125/30 KarXT (vs 97% on placebo) 
o 4% percent de-escalated back to 100/20 KarXT dose (vs 1% on placebo) 
 The overall TEAE rate on KarXT was 54% vs 43% on placebo: 
o The most common TEAEs were constipation, nausea, dry mouth, dyspepsia, and 
vomiting. None of these TEAEs were severe and none led to discontinuations 
o One SAE occurred in the study (the subject was on KarXT): the subject discontinued 
treatment and subsequently sought hospital care for worsening psychosis, meeting the 
regulatory definition of an SAE.   
o No syncope or mean changes in BP were seen 
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o A 5.5 bpm peak mean placebo adjusted resting heart rate increase with a downward 
trend after Week 2 was seen 
o One subject (on KarXT) was discontinued due to an elevated gamma-glutamyl 
transpeptidase (GGT) 
o There were no new safety findings associated with KarXT that have not been observed 
with either xanomeline alone or trospium alone in previous trials 
 KarXT did not show evidence of many of the kinds of AEs that often occur in currently 
available antipsychotics for the treatment of schizophrenia  
 The rates of the following AEs were similar for KarXT and placebo: somnolence, weight 
gain, and EPS 
Two randomized, double-blind, placebo-controlled Phase 3 trials (KAR-007 and KAR-009) are 
planned in which the subjects will be exposed to either KarXT or placebo (1:1) for a period of up 
to 5 weeks. Subjects who complete either of these 2 studies will be eligible to roll over into this 
long-term open-label study. 
5.3 
Clinical Risks/Benefits of KarXT and Study Rationale 
The risks and benefits of KarXT in humans are not fully known. KarXT is a fixed dose 
combination of xanomeline and trospium.  
The available clinical trial data indicate that KarXT has robust efficacy and a favorable safety 
profile that appears unique compared to all available APDs. Most of these clinical data were 
setting. Treatment with KarXT is not associated with weight gain, sedation, or meaningful EPS 
changes. In contrast, these serious side-effects pose a significant risk with other APD treatments 
for schizophrenia and can lead to discontinuation of treatment and significant morbidity. A Phase 
2 registration quality pivotal trial in 182 subjects met the primary endpoint with the PANSS total 
score showing a 11.6 point mean improvement compared to placebo with a highly significant 
(p < 0.0001) separation from placebo (-17.4 KarXT vs. -5.9 placebo) at Week 5. KarXT, as 
compared to placebo, demonstrated highly significant reduction in PANSS total scores 
(p < 0.0001) at all post randomization time points (Weeks 2, 4 and, 5) with a calculated effects 
at all post randomization time points for PANSS positive symptom subscores, PANSS negative 
symptom subscores, PANSS Marder Factor negative symptom subscores, and CGI-S scores. 
Over 750 subjects or volunteers have been exposed to xanomeline tartrate (oral formulation; 
either alone, in combination with trospium, or as the combination drug KarXT) in clinical 
studies. These early clinical studies, as well as nonclinical pharmacology and toxicology studies, 
have not revealed any specific contraindications to the use of xanomeline. The most common 
side effects/symptoms are the cholinergic related effects: nausea, vomiting, excess salivation, 
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excess sweating, and diarrhea. In addition, subjects treated with xanomeline alone have reported 
both syncope and orthostatic dizziness. The addition of trospium decreases the peripheral 
cholinergic effect of xanomeline creating a better tolerated therapy. In addition, a titration phase 
also increases the tolerability of KarXT. 
Trospium chloride has been marketed in the US for 12 years. The most frequently reported AEs 
reported in pivotal trials were dry mouth, constipation, abdominal pain, headache, urinary 
retention, and abnormal vision and accommodation. For additional information, the package 
insert for trospium chloride tablets for oral use can be found in the IB. 
In a Phase 2 (KAR-004) clinical study, KarXT (100/20 and 125/30) significantly reduced the 
symptoms of schizophrenia in subjects with acute psychosis after treatment for 28 days. KarXT 
also showed an acceptable safety profile with the most common TEAEs being constipation, 
nausea, dry mouth, dyspepsia, and vomiting. All the reported TEAEs were mild or moderate in 
intensity. One SAE (psychotic disorder) was reported by a single subject and no deaths were 
reported in the study. KarXT was generally well-tolerated and found to be safe in this patient 
population. 
KarXT represents a novel approach to the treatment of patients with schizophrenia that will 
provide an important and meaningful alternative to current therapies. The current tolerability and 
AE profile and the efficacy of KarXT justify further development of KarXT in this patient 
population by advancing to Phase 3 trials. Two such Phase 3 trials (KAR-007 and KAR-009) are 
planned where the subjects will receive the study drug (KarXT or placebo) for 5 weeks.  
In the current study, regardless of treatment assignment in the preceding Phase 3 study 
(KAR-007 or KAR-009), all subjects will receive KarXT for a period of approximately 52 weeks 
with the primary objective of assessing the long-term safety and tolerability profile of KarXT in 
an out-patient setting. All subjects will start with a lead-in dose of KarXT 50/20 BID for Days 1 
to 2 and then the dose will be titrated to 100/20 BID for Days 3 to 7, allowing the subject to 
adjust to KarXT before receiving a higher dose of 125/30 BID starting on Day 8, unless the 
subject is continuing to experience AEs from the previous dose increase of KarXT 100/20 BID. 
All subjects who are increased to KarXT 125/30 BID, depending on tolerability, will have the 
option to return to KarXT 100/20 BID for the remainder of the treatment period. Re-escalation to 
125/30 BID or re-titration in cases where subject has been off the KarXT for a longer period of 
time is allowed and will require a discussion between the principal investigator (PI) and the 
medical monitor. 
Dosing will occur every 12 ±4.5 hours each day, during waking hours. KarXT should be dosed 
on an empty stomach: ie, at least 1 hour before a meal or 2 to 3 hours after a meal.  
The current study is designed to demonstrate that long-term treatment with KarXT in adult 
schizophrenia subjects is safe and tolerable.  
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6
STUDY OBJECTIVES AND ENDPOINTS
6.1
Study Objectives
Primary Objective
The primary objective of the study is to assess the long-term safety and tolerability of KarXT in 
subjects with a DSM-5 diagnosis of schizophrenia.
Secondary Objective
The secondary objective of this study is to assess the long-term efficacy and monitor trough 
concentrations of xanomeline and trospium after administration of KarXT in adults with a DSM-
5 diagnosis of schizophrenia:
To evaluate the reduction in PANSS total score
To evaluate the reduction of PANSS positive score 
To evaluate the improvement in Clinical Global Impression Severity (CGI-S) results 
To evaluate the reduction of PANSS negative score 
To evaluate the reduction of PANSS Marder Factor negative symptoms score
To measure trough concentrations of xanomeline and trospium after administration of 
KarXT in adults who are acutely psychotic with a DSM-5 diagnosis of schizophrenia
Exploratory Objective
The exploratory objectives of this study are:
To evaluate cognition with the Cambridge Neuropsychological Test Automated Battery 
(CANTAB)
To evaluate prolactin levels after administration of KarXT
To evaluate digital biomarkers of schizophrenia
To evaluate Ecological momentary assessment (EMA) in schizophrenia
To evaluate cognitive insight
6.2
Study Endpoints
Primary Safety Endpoint
The primary safety endpoint of this study is the incidence of treatment-emergent AEs (TEAE).
Secondary Endpoints
6.2.2.1
Safety Endpoints
The secondary safety endpoints of this study are: 
Incidence of serious TEAEs
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Incidence of TEAEs leading to withdrawal
6.2.2.2
Efficacy Endpoints
The secondary efficacy endpoints of this study are:
Change from baseline in PANSS total score at Week 52
Change from baseline in PANSS positive score at Week 52
Change from baseline in PANSS negative score at Week 52
Change from baseline in PANSS Negative Marder Factor score at Week 52
Change from baseline in CGI-S score at Week 52
Percentage of PANSS responders (a 30% change in PANSS total score) at Week 52
Other Endpoints
6.2.3.1
Safety Endpoints
Spontaneously reported cholinergic symptoms
Change from baseline in Simpson-Angus Rating Scale (SAS)
Change from baseline in Barnes Rating Scale for Akathisia (BARS)
Change from baseline in Abnormal Involuntary Movement Scale (AIMS)
Change from baseline in body weight, body mass index (BMI), waist circumference 
Change from baseline in orthostatic vital signs (supine and standing after 2 minutes): BP 
(systolic and diastolic) and heart rate
Change from baseline in clinical laboratory assessments (hematology, clinical chemistry, 
coagulation, urinalysis, and drug screen)
Change from baseline in 12-lead ECG 
Change from baseline in physical examination 
Suicidal ideation scale with the use of Columbia-Suicide Severity Rating Scale (C-SSRS)
6.2.3.2
Pharmacokinetic Endpoint
The PK endpoint of this study is to measurement of trough plasma concentrations of xanomeline 
and trospium.
Exploratory Endpoints
The exploratory endpoints of this study are: 
Change from baseline in cognition measuring core domains of impairment in 
schizophrenia using CANTAB
Change from baseline in prolactin levels
Observed digital biomarkers of schizophrenia 
Observed EMA data over time in schizophrenia
Observed cognitive insight data over time
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7 
INVESTIGATIONAL PLAN 
7.1 
Description of Overall Study Design and Plan 
This is a Phase 3 multicenter, 53-week, outpatient, open-label extension (OLE) study to evaluate 
the long-term safety, tolerability, and efficacy of KarXT in subjects with DSM-5 schizophrenia 
who previously completed the treatment period of one of the two Phase 3 double-blind studies, 
KAR-007 or KAR-009. The study consists of a 52-week OLE treatment phase and a 7-day 
(±3 days) follow-up/end-of-study (EOS) visit after the last KarXT dose for subjects who 
complete the treatment phase and those who prematurely discontinue from the study.  
After written informed consent, subjects who have completed either the KAR-007 or KAR-009 
Phase 3 acute study and received the last dose of the study drug in that trial will be rolled over in 
to the current OLE study. The assessments performed on Day 35 of Studies KAR-007 or 
KAR-009 will be considered as baseline assessments along with any additional assessments that 
will be performed on Day 1 of the current study. Consenting subjects who roll over into 
KAR-008 will be dosed with a lead-in dose of open-label KarXT the next day after completion 
of Visit 10 (Day 35) from the prior Studies KAR-007 or KAR-009. The rollover is designed as 
above; a window extension is permitted but will need discussion with, and approval by, the 
medical monitor. 
Subjects who did not complete the full treatment period, or who early terminated Studies 
KAR-007 or KAR-009, will not be eligible to enroll in this long-term extension study.   
A total of up to 350 subjects are planned to be enrolled in this study (aged 18 to 65 years) across 
approximately 30 study sites in the United States and 10 study sites in Ukraine.  
In this OLE study, all subjects will receive KarXT for up to 52 weeks. Regardless of treatment 
assignment in the preceding Phase 3 acute study (KAR-007 or KAR-009), all subjects will start 
on a lead-in dose of KarXT 50/20 BID for the first 2 days (Days 1 and 2), followed by 
KarXT 100/20 BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing will be titrated 
upwards to KarXT 125/30 BID unless the subject is continuing to experience AEs from the 
previous dose of KarXT 100/20 BID. All subjects who are increased to KarXT 125/30 BID, 
depending on tolerability, will have the option to return to KarXT 100/20 BID for the remainder 
of the treatment period. Re-escalation to 125/30 BID or re-titration in cases in which the subject 
has been off KarXT for a longer period of time (at least a week) is allowed and will require a 
discussion between the PI and the medical monitor. Additional changes to KarXT dosing (e.g., 
temporary dose reductions) may be permitted as clinically indicated upon approval by the 
medical monitor. 
Beginning after Visit 5/Day 28, interim visits will be completed with flexibility between the 
in-clinic visits, approximately once every 4 weeks For interim visits, either a Home Health Care 
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nurse or the study site staff will visit the subject to complete the scheduled visit. In addition to 
augment at-home visits, the telemedicine visit can be used. When needed, the sites will have the 
option to schedule a subject for an in-clinic visit. 
All subjects will have structured diagnostic interview sessions and questionnaires administered 
throughout the study (see Schedule of Assessments Table 2). Analyses of change from baseline 
in diagnostic measures will be performed. 
Safety will be assessed through spontaneous AEs; SAEs and AEs leading to discontinuation of 
KarXT; cholinergic symptoms; SAS; BARS; AIMS; body weight; BMI; waist circumference; 
orthostatic vital signs; clinical laboratory assessments (hematology, clinical chemistry, 
coagulation, urinalysis, and drug screen), 12-lead ECG; physical examination; and C-SSRS will 
be evaluated throughout the study as scheduled. Section 11 provides complete details on these 
safety assessments. 
Efficacy will be assessed through PANSS total score, PANSS-positive score, PANSS-negative 
score, PANSS Negative Marder Factor score, and CGI-S score at scheduled visits. Refer to 
Section 12 for more details. 
Details on PK assessments are provided in Section 13 and include monitoring of trough 
concentrations at scheduled visits. 
Exploratory assessments include cognition testing using CANTAB; digital biomarkers of 
schizophrenia; EMA; and cognitive insight, which will be evaluated at scheduled visits. See 
Section 14 for more details. 
A safety follow-up/end of study/ET visit (Visit 30/Day 371 ±3 days) will be performed for all 
subjects after the last dose of KarXT. 
An Independent Safety Monitoring Committee (ISMC) will be responsible for periodically 
reviewing the safety data from this study and confirming that the study may continue. 
Table 1 presents the study design. 
 
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Table 1 
Study Design 
 
Period: 
Open-Label Extension Treatmenta 
End of 
Treatment 
EOS/ET/UNS 
Day: 
Day 1 
Day 3 
+1 day 
Day 8 
±1 day 
Day 14 
±2 days 
Day 28b 
±3 days 
Day 56 
±3 days 
Days 84 
to 350 
±3 days 
Day 364 ±3 
days 
Day 371 ±3 
days 
Visit: 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5b 
Visit 7 
Visits 9 
to 28 
Visit 29 
Visit 30 
Xanomeline/ 
trospium 
(KarXT)*: 
50/20 BID 
100/20 
BID 
125/30 
BID 
(Option: 
100/20 
BID)c 
125/30 
BID 
(Option: 
100/20 
BID)c,d 
125/30 
BID 
(Option: 
100/20 
BID)c,d 
125/30 
BID 
(Option: 
100/20 
BID)c,d 
125/30 
BID 
(Option: 
100/20 
BID)c,d 
125/30 BID 
(Option: 
100/20 
BID)c,d 
N/A 
Comment(s): 
2-day lead-
in dose 
Upward 
titration 
of dose 
Upward 
titration 
of dose 
 
7 (±3) days 
after the last 
dose or for ET 
from the study 
or UNS 
Abbreviations: BID = twice daily; EOS = end of study; ET = early termination; N/A = not applicable; PI = principal investigator; UNS = unscheduled. 
* All the KarXT doses are in mg. 
a. 
Visits 1, 2, 3, 4, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, and 30 are in-clinic/on-site visits. Visits 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, and 28 are 
interim visits. 
b. 
Beginning after Visit 5/Day 28, interim visits will be completed with flexibility between in-clinic visits, approximately once every 4 weeks.  
c. 
All subjects who are increased to KarXT 125/30, depending on tolerability, will have the option to return to KarXT 100/20 BID for the remainder of the 
treatment period.  
d. 
Re-escalation to 125/30 BID or re-titration in cases where subject has been off KarXT for a longer period of time (at least a week) is allowed and will 
require a discussion between the PI and the medical monitor. Additional changes to KarXT dosing (e.g., temporary dose reductions) may be permitted as 
clinically indicated upon approval by the medical monitor. 
 
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7.2 
Discussion of Study Design 
The KarXT clinical development program includes this open-label extension study to evaluate 
the long-term safety, tolerability, and efficacy data for KarXT in subjects with schizophrenia 
who participated in either of the 2 Phase 3 double-blind clinical studies and completed the 
treatment period without any tolerability/safety issues. 
This study will allow subjects that were randomized into a preceding Phase 3 study (KAR-007 or 
KAR-009) to reinstitute (or initiate treatment if a placebo subject) KarXT therapy. Subjects will 
receive KarXT (with the same lead-in dose of KarXT 50/20 BID), regardless of treatment 
assignment from the preceding Phase 3 study. Thus, subjects who received placebo during the 
preceding Phase 3 study who may not have demonstrated clinical benefit, nonetheless, may be 
considered appropriate for the current study, as all subjects will receive KarXT.  
The dosing plan for this study has been established and follows the earlier studies. All eligible 
subjects will receive the same lead-in doses of KarXT (KarXT 50/20 BID). Dosing will be 
titrated to 100/20 BID on Day 3 and further titrated to 125/30 BID on Day 8, unless the subject 
continues to experience AE(s) from the previous dose increase of KarXT.  
During the study, all subjects who are increased to the highest dose of KarXT, depending on 
tolerability, will have the option to return to the next lower dose of KarXT (100/20 BID) for the 
remainder of the treatment period. Re-escalation to 125/30 BID or re-titration in cases where 
subject has been off KarXT for a longer period of time (at least a week) is allowed and will 
require a discussion between the PI and the medical monitor.  
Beginning after Visit 5/Day 28 (approximately 1 month of KarXT treatment), interim visits will 
be completed every 4 weeks between the in-clinic visits, to allow for subject safety monitoring 
and IP dispensing and accountability. For interim visits, either a Home Health Care nurse or the 
study site staff will visit the subject to complete the scheduled visit. In addition to augment at-
home visits, the telemedicine visit can be used. When needed, the sites will have the option to 
schedule a subject for an in-clinic visit. 
A 52-week treatment phase is considered to be sufficient to demonstrate the long-term safety and 
tolerability of KarXT. A sample size of approximately 350 subjects is also determined to be an 
appropriate number of evaluable subjects to assess the long-term safety of KarXT administration. 
Section 5.2 details the nonclinical and clinical background information available on KarXT, 
including dose rationale.  
7.3 
End of Study  
A subject will have fulfilled the requirements for study completion if/when the subject has 
completed the study treatment, including the EOS visit or the last scheduled visit as indicated in 
the Schedule of Assessments (Table 2) in accordance with the protocol. 
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7.4 
Independent Safety Monitoring Committee 
For the purpose of this study, the ISMC is an independent group of individuals with pertinent 
expertise that reviews on a regular basis accumulating safety data from the clinical study. This 
committee will be responsible, on a periodic basis, for confirming the safety of KarXT 
throughout the study, with particular focus on assessing for any new or long-term toxicities that 
might be involved with KarXT. 
The reviews will allow a comparison of event rates and detection of safety signals, and to 
identify important safety information. The ISMC charter will contain the details of the types of 
data to be reviewed, the defined triggers for review, the minimum frequency of meetings (timed, 
if no triggers), and the communication plan for disseminating review recommendations. 
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8 
SELECTION OF STUDY POPULATION 
Section 7.1 provides information regarding the number of subjects planned to be enrolled. 
8.1 
Inclusion Criteria 
Individuals must meet all of the following criteria to be included in the study: 
1. Subject is aged 18 to 65 years, inclusive. Exception: Subjects who turned 66 during 
KAR-007/009 participation will be eligible to continue in KAR-008. 
2. Subject is capable of providing informed consent. 
a. A signed informed consent form must be provided before any study assessments 
are performed. 
b. Subject must be fluent in (oral and written) English (United States only) or local 
language (Ukraine only) to consent. 
3. Subject has completed the treatment period on study drug (through Day 35 -2 days) of 
Studies KAR-007 or KAR-009.  
4. Subject resides in a stable living situation, in the opinion of the investigator. 
5. Subject has an identified, reliable informant/caregiver. An informant/caregiver is needed 
at the baseline visit as well as at the end of the study for relevant assessments. An 
informant/caregiver may not be necessary if the subject has been the patient of the 
 
6. Women of childbearing potential (WOCBP) or men whose sexual partners are WOCBP 
must be sexually abstinent (in line with their preferred and usual lifestyle) or willing and 
able to use at least 1 highly effective method of contraception during the study and for at 
least 7 days after the last dose of KarXT. Sperm donation is not allowed for 90 days after 
the final dose of KarXT. A female subject is considered to be a WOCBP after menarche 
and until she is in a postmenopausal state for 12 consecutive months or is otherwise 
permanently sterile (for which acceptable methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy) [22]. For the definition and list of highly 
effective methods of contraception, see APPENDIX 1. 
8.2 
Exclusion Criteria 
Subjects will be excluded from the study if 1 or more of the following criteria is/are applicable: 
1. 
al 
assessment and C-SSRS as confirmed by the following:  
a. Subject answers Y
some intent to act, without specific plan) or Item 5 (active suicidal ideation with 
specific plan and intent) on the C-SSRS assessment. 
b. Nonsuicidal self-injurious behavior is not exclusionary. 
2. Any clinically significant abnormality including any finding(s) from the physical 
examination, vital signs, ECG, or laboratory test at the end-of-treatment visit of Studies 
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KAR-007 or KAR-009 that the investigator, in consultation with the medical monitor, 
would consider to jeopardize the safety of the subject. 
3. Female subject is pregnant. 
4. 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 his/her ability to adhere to 
the protocol visit schedule or fulfill visit requirements. 
5. Subjects with extreme concerns relating to global pandemics such as coronavirus disease 
2019 (COVID-19) that preclude study participation. 
6. Risk of violent or destructive behavior. 
7. Subjects participating in another investigational drug or device trial or planning on 
participating in another clinical trial during the course of the study. 
8.3 
Retesting for Eligibility 
Subjects who are willing to participate in the study but who do not meet all the requirements for 
safety laboratory assessments performed on Day 35 -2 days of Studies KAR-007 or KAR-009 
and therefore do not enroll, may be retested (retesting for elevated LFTs is not allowed) upon 
approval of the medical monitor on a case-by-case basis. However, these subjects will be dosed 
on Day 1 and will be retested as needed upon availability of the laboratory test results. Any 
abnormal lab values deemed to be clinically significant by the PI should be reported as AEs and 
dosing changes made as appropriate. Such subjects may be allowed to be retested up to 1 time. 
When re-testing within the same end of treatment procedure of Studies KAR-007 or KAR-009, 
only the exclusionary laboratory tests will be repeated once, in case the exclusionary laboratory 
result is not due to a pathological condition and is occasional.  
8.4 
Study Withdrawal, Removal, and Replacement of Subjects 
If a subject discontinues study treatment and is withdrawn from the study for any reason, the 
study site must immediately notify the medical monitor. The date and the reason for study 
discontinuation must be recorded on the electronic case report form (eCRF). Subjects who 
complete or discontinue early from the study will be asked to return to the study site within 
7 (±3) days of the last administration of KarXT to complete EOS assessments as indicated in the 
Schedule of Assessments (Table 2). 
In the event that a subject discontinues prematurely from the study because of a 
treatment-emergent AE (TEAE) or serious TEAE, the TEAE or serious TEAE will be followed 
up until it resolves (returns to normal or baseline values) or stabilizes, or until it is judged by the 
investigator to no longer be clinically significant. 
Once a subject is withdrawn from the study, the subject may not re-enter the study. 
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A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons 
including, but not limited to, the following: 
 progressive disease 
 unacceptable toxicity or AE 
 subject withdrawal of consent: at any time, a subject's participation in the study may be 
terminated at his/her request or on the basis of the 
clinical judgment; the 
reason for subject withdrawal will be noted on the eCRF 
 intercurrent illness: a condition, injury, or disease unrelated to the primary diagnosis that 
became apparent during treatment and necessitated the subject s termination from the 
study 
 general or specific changes in the subject's condition that renders him/her ineligible for 
further treatment according to the inclusion/exclusion criteria (eg, subject has need for a 
medication prohibited by the protocol) 
 subject fails to adhere to the protocol requirements (eg, drug noncompliance [if a subject 
is off KarXT for >5 consecutive days])  
 violation of entry criteria, ie, enrolled subjects who are later discovered not to meet 
eligibility criteria 
 development of suicidal or assaultive behavior 
 alcohol or illegal drug use 
 pregnancy, as indicated in Section 11.7.7. Any female study subject or female partner of 
the male subject becomes pregnant while participating in the study and is willing and able 
to consent to pregnancy follow-up, will be followed until her pregnancy reaches term. 
 
 
Subjects who withdraw from the study will be encouraged to complete the same final evaluations 
as subjects completing the study according to this protocol, particularly safety evaluations. The 
aim is to record data in the same way as for subjects who completed the study. 
Reasonable efforts will be made to contact subjects who are lost to follow-up. A subject will be 
considered lost to follow-up if he or she repeatedly fails to return for scheduled visits and is 
unable to be contacted by the study center. These efforts m
file. Subjects with AEs ongoing at end of study will be followed until the AE is resolved or the 
subject is considered to be in stable condition. 
The Sponsor has the right to terminate the study at any time in case of SAEs or if special 
circumstances concerning the KarXT become known, making further treatment of subjects 
impossible. In this event, the investigator(s) will be informed of the reason for study termination. 
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Pregnancy
No evidence of mutagenicity, or treatment effects on reproduction, fertility, or fetal parameters 
have been demonstrated in animals following administration of xanomeline, but there are no 
adequate and well-controlled studies in pregnant women (FDA Pregnancy Category B). Animal 
reproduction studies of trospium chloride have shown an adverse effect on the fetus, but 
potential benefits may warrant the use of the drug in pregnant women despite the risk (FDA 
Pregnancy Category C).
Therefore, WOCBP in this study must be willing to use a highly effective method of birth 
control (see APPENDIX 1 for a list of acceptable highly effective methods of contraception) 
during the study and for 7 days after the last dose of KarXT. WOCBP will have a urine
pregnancy test on Day 1 (before receiving KarXT) and thereafter, as designated at other 
scheduled visits (Table 2). In case of positive urine pregnancy test result, a serum pregnancy test 
should be performed to confirm the result.
Pregnant women are excluded from this study because the effects of KarXT on the developing 
human fetus are unknown with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment 
of the mother with KarXT, women who become pregnant must discontinue KarXT immediately.
The effects of KarXT on sperm are unknown. Male subjects whose sexual partners are WOCBP 
must agree to use a highly effective method of birth control (see APPENDIX 1 for a list of 
acceptable highly effective methods of contraception) and must not impregnate a sexual partner 
during or for 90 days after the last dose of KarXT. They must also agree to refrain from sperm 
donation for 90 days after the last dose of KarXT.
WOCBP will be instructed that known or suspected pregnancy occurring during the study should 
be confirmed and reported to the investigator. If a female subject becomes pregnant, the 
investigator must withdraw her from the study without delay. The subject must not receive any 
further doses of the KarXT. The investigator must notify the Sponsor or the designee of any 
female subject or female partner of a male subject that becomes pregnant while participating in 
the study. If the female subject or the female partner of the male subject is willing and able to 
consent to pregnancy follow-up, she will be followed until her pregnancy reaches term. Only 
those procedures that would not expose the pregnant female patient to undue risk will be 
performed. See Section 11.7.7 for further reporting and monitoring details.
Full details of the pregnancy will be recorded on the withdrawal page (exit form) of the eCRF, or 
a Pregnancy Reporting Form will be completed if the subject has completed the study. 
Notification of the pregnancy should be submitted via the Pregnancy Reporting Form within 
24 hours of knowledge of the pregnancy. Pregnancy is not to be considered an AE; however, it 
must be reported using the same procedure as described for reporting SAEs, Section 11.7.4.
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8.5 
Completion of the Study or Lost to Follow-up 
The study will be completed when all subjects have completed their study-related procedures in 
accordance with the protocol. 
Every reasonable effort will be made to contact subjects who are lost to follow-up to obtain EOS 
information. Details regarding follow-up efforts are to be documented in the 
records/source documentation. 
8.6 
Study Termination 
The availability of any new adverse safety information related to KarXT may result in stopping 
the study. An investigator, Sponsor, or Institutional Ethics Committee (IEC)/Institutional Review 
Board (IRB) may take such actions. If the study is terminated for safety reasons, subjects will be 
notified immediately and assured that appropriate treatment and follow-up will be available. If an 
investigator terminates the study, the Sponsor, subjects, and IEC/IRB will be informed about the 
reason for such action. Similarly, if the Sponsor terminates the study, it will inform the 
investigators, the IEC/IRB, and the subjects of the reason for such an action. Similar 
notifications will be sent by the IEC/IRB if it takes such an action. 
 
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9
TREATMENTS
9.1
Details of Study Treatments
KarXT is formulated as hard hydroxypropyl methylcellulose oral capsules containing 2 distinct 
populations of drug beads, 1 of which is loaded with xanomeline tartrate and the other of which 
is loaded with trospium chloride. Each capsule contains the free base equivalent of xanomeline 
and trospium according to the desired dosage strength. In addition to the active ingredients, the 
drug beads contain microcrystalline cellulose (MCC). The beads are not coated and are 
formulated for immediate release of the active ingredients.
Identity of Study Treatments
Active study agents for treatment group will be size 0, Swedish orange, opaque, and 
hydroxypropyl methylcellulose hard capsules. For the 2-day lead-in period (Days 1 and 2), 
subjects will receive capsule strength KarXT 50/20 BID, followed by 2 capsules of KarXT 
50/10 mg BID or a dosage of 100/20 mg BID for a total daily dose of 200/40 mg for the 
remainder of Week 1 (Days 3 to 7). At the beginning of Week 2, dosing may be increased to 
2 capsules of KarXT 62.5/15 mg or a dosage of 125/30 mg BID for a total daily dose of 
250/60 mg, depending on tolerability. Investigators have the option to return a subject to KarXT 
100/20 mg BID for the remainder of the treatment period. Re-escalation to 125/30 BID or 
re-titration in cases where subject has been off KarXT for a longer period of time (at least a 
week) is allowed and will require a discussion between the PI and the medical monitor.
Note: In these cases of dose reduction, re-escalation or re-titration, additional PK samples will be 
collected at 8 and 14 days post dose reduction, re-escalation, or re-titration in accordance with 
the Visits 3 and 4 schedules, respectively, and the original PK sampling schedule will be 
followed thereafter.
KarXT 50/10 mg is composed of 44.4% xanomeline tartrate, 5.8% trospium chloride, excipients 
37.59% MCC, 11.5% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a size 0, 
Swedish orange, hydroxypropyl methylcellulose hard capsule.
KarXT 50/20 mg is composed of 33.4% xanomeline tartrate, 8.7% trospium chloride, excipients 
39.8% MCC, 17.3% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a size 0, Swedish 
orange, hydroxypropyl methylcellulose hard capsule.
KarXT 62.5/15 mg is composed of 41.7% xanomeline tartrate, 6.5% trospium chloride, 
excipients 38.1% MCC, 12.9% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a 
size 0, Swedish orange, hydroxypropyl methylcellulose hard capsule.
All investigational agents are to be stored according to requirements.
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Packaging and Labeling
The study packaging and labeling will be performed by Corealis Pharma, located in Laval, 
Quebec, Canada and Catalent Pharma Solutions, located in Winchester, Kentucky (labelling for 
the US sites), and Catalent Pharma Solutions, located in Philadelphia, Pennsylvania (labelling for 
Ukrainian sites). All packaging and labeling operations will be performed according to Good 
Manufacturing Practice for Medicinal Products and the relevant regulatory requirements.
Bulk supply bottles are labeled with the name of the drug, recommended storage conditions, the 
name and address of the manufacturer and the Investigational Use Statement (for the US sites: 
Limite
and for the 
).
Further details on labeling of investigational product will be provided in the Pharmacy Manual.
Subjects will be provided an automated medication dispenser which will be prefilled with 
medication at scheduled intervals. Full details on study medication dispensing can be found in 
the Pharmacy Manual. 
KarXT Storage
Prior to dispensing KarXT to the subjects, it must be stored at controlled room temperature
15°C-25°C.
KarXT Retention
KarXT must be retained until completion or termination of the study, and written authorization 
from the Sponsor has been received. All unused and used KarXT must be destroyed at the site or 
has provided written authorization prior to return or destruction, and that appropriate records of 
the disposal are documented and maintained. No used or unused KarXT may be disposed until 
fully accounted for by the study monitor.
9.2
Dosage Schedule
Subjects who roll over into KAR-008 will be dosed on the next day after completion of Visit 10 
(Day 35) in Study KAR-007 or KAR-009. The first dose of the KarXT will be administered in 
the morning of Day 1 and the last dose will be administered in the evening of Day 364 (±3 days). 
KarXT should be administered daily BID on an empty stomach (ie, at least 1 hour before a meal)
or 2 to 3 hours after a meal. Some considerations for dosing and PK blood withdrawals are 
provided in the subsections below.
Visit 1/Day 1 Dosing
The first dose will be administered in the morning and the evening dose will be 
administered at 12 (±4.5) hours after the morning dose.
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All subjects must be administered 4 doses of the KarXT 50/20 before dose escalation to 
KarXT 100/20 BID.
Visit 2/Day 3 and/or Other Visits Occurring on Weekends/Holidays
When Day 3 occurs on a weekend, it is expected that the complete Visit 2 will be 
performed, and the subject
dose will be escalated on Day 3.
If completion of the visit is not possible on Day 3, the +1-day visit window may be used. 
In this instance, the dose will not be up-titrated until the study visit occurs. In all cases, 
the subject must have had at least 4 doses of KarXT 50/20 before escalating to 
KarXT 100/20.
This may result in only 4 days of the KarXT 100/20 dose at Visit 3/Day 8, which is 
acceptable.
All the subjects must be administered 8 doses of the KarXT 100/20 before dose escalation 
to KarXT 125/30 BID.
Visit 3/Day 8 and Visit 4/Day 14 Dosing and PK considerations
If dose escalation to the KarXT 125/30 level is confirmed by investigator order on 
Visit 3/Day 8, that dose is to be administered in the morning (after the pre-dose PK blood 
draw) (Table 2).
If the use of visit windows becomes necessary, PK sampling must accompany the actual 
day of uptitration for Visit 3/Day 8. 
On Days 8 and 14, 3 PK samples will be collected at pre-dose in the morning, 1 hour 
(+5 min), and 2 hours (+10 min) postdose. 
Note: In case of dose reduction, re-escalation, or re-titration, additional PK samples will be 
collected at 8 and 14 days post dose reduction, re-escalation, or re-titration in accordance with 
the Visits 3 and 4 schedules, respectively, and the original PK sampling schedule will be 
followed thereafter.
9.3
Measures to Minimize Bias: Study Treatment Assignment
Method of Study Treatment Assignment
The 9-digit Subject Number previously assigned to the subject in the Study KAR-007/KAR-009 
will continue to be used in the current Study KAR-008. This number will be associated with the 
subject throughout the current study.
Blinding
This is an open-label study; therefore, blinding is not applicable.
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9.4
Dosage Modification
Subjects will self-administer the KarXT as described in Section 7.1 and in accordance with the 
Schedule of Assessments (Table 2). The KarXT doses were selected based on the previous 
preclinical and clinical studies (see Section 5.2). Per the protocol, subjects will be evaluated for 
dose adjustments starting at Visit 3 through the remainder of the treatment period (see 
Section 9.1.1). 
9.5
Treatment Accountability and Compliance
The pharmacist or other designated individual will maintain records of study treatment delivered 
to the study site, the inventory at the study site, the distribution to each subject, and the return of 
materials to the Sponsor or designee for storage or disposal. These records should include dates, 
quantities, batch/serial numbers, expiration dates, temperature log, and unique code numbers 
assigned to the product and study subjects.
Administration of KarXT will be supervised by study site personnel (during in-clinic visits) and
by a digital compliance tool to ensure compliance (AiCure technology). Also, KarXT will be 
dispensed using MedReady time-controlled dispensing device, which dispenses KarXT at 
scheduled intervals. Subjects will be advised to return the MedReady device to the site staff at 
each in-clinic visit for drug accountability and refilling.
For interim visits, the empty or unused dosettes will be collected by the Home Health Care nurse 
and/or site staff. In case a Home Health Care nurse performs the interim visit, he/she will 
perform a preliminary drug accountability before shipping the empty or unused dosettes to the 
study site for final accountability check. Full details can be found in the Pharmacy Manual.
Investigators will maintain records that adequately document that the subjects were provided 
with the correct study treatment supply and reconcile the usage of the study drug. Investigational 
product will not be returned to the Sponsor or designee until accountability has been fully 
monitored through the end of the study. KarXT accountability will be assessed periodically by 
the assigned study monitor.
9.6
Prior and Concomitant Therapy
Prior and Concomitant Medications
Subjects will be asked to confirm all prior medications taken up to 6 months before the current 
study (and recorded from the lead-in study), up to the time of the first dose of study medication 
on Day 1. All prior medications will be recorded on the eCRF.
Restricted prior therapies are provided below.
All medications and other treatments taken by the subject during the study, including those 
treatments initiated before the start of the study, must be recorded on the eCRF.
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During the study (ie, from the time of enrollment at baseline visit [Day 1] until study completion
[EOS/ET]), subjects will refrain from the use of any new concomitant medications without the 
specific prior approval of the investigator. The administration of any other concomitant 
medications during the study period is prohibited without the prior approval of the investigator 
unless its use is deemed necessary in a medical emergency. Any medication or therapy that is 
taken by or administered to the subject during the course of the study must be recorded in the 
eCRF. The entry must include the dose, regimen, route, indication, and dates of use.
All the subjects enrolled in to the study must not take the below mentioned prohibited 
medications for the duration of the study.
Oral antipsychotic medications, monoamine oxidase inhibitors, mood stabilizers (ie, 
lithium), anticonvulsants (eg, lamotrigine, Depakote), tricyclic antidepressants (eg, 
imipramine, desipramine), selective serotonin reuptake inhibitors, or any other 
psychoactive medications except for anxiolytics that were taken on an as needed basis 
(eg, lorazepam, chloral hydrate). 
Long acting injectable antipsychotics (including INVEGA TRINZA®). 
Note: Please direct questions relating to prohibited medications to the medical monitor.
Concomitant Medications for Anxiety and/or Sleep Aid
Subjects are allowed to take benzodiazepines (up to 6 mg lorazepam/day or equivalent) for 
anxiety, agitation, and insomnia. Subjects may also use non-benzodiazepine medications 
(eg, zolpidem, zaleplon) as a sleep aid. Study sites must record the use of concomitant
medications in the eCRF and 
source document. Note: Cognition testing should not be 
done within 8 hours of receiving a benzodiazepine or sleep medication.
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10 STUDY PROCEDURES 
Table 2 outlines the timing of procedures and assessments to be performed throughout the study. 
Section 11.6 specifies laboratory assessment samples to be obtained. See Sections 11, 12, 13, and 
14 for additional details regarding efficacy, safety, PK, and exploratory assessments, 
respectively. 
See APPENDIX 3 for alterative procedures during COVID-19 pandemic-related physical 
distancing. 
If a subject tests positive for COVID-19 during the study, he/she may be quarantined as needed 
and any scheduled visits should be rescheduled or alternative procedures (see APPENDIX 3) be 
followed at the discretion of the investigator. If the subject requires hospitalization, an SAE 
should be reported and the subject should be followed up as outlined in Section 11.7.4. 
  
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Table 2. 
Schedule of Assessments  
DAY 
(± 3d, unless otherwise noted) 
1 
3 
(+1d) 
8 
(± 1d) 
14 
(± 2d) 
28 
42 
56 
70 
84 
98 
102 
116 
130 
154 
168 
WEEK 
1 
 
 
2 
4a 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
TYPE OF VISIT Clinic Clinic Clinic Clinic Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic 
Interim 
Clinic 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject eligibility verification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (WOCBP 
only)b 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Urine drugs of abuse and alcohol 
testingc 
 
 
 
 
 
 
 
 
Review of inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, body weight, BMI, waist 
circumferenced 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Complete physical examinatione 
X** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical examinationf 
Spontaneous AEsg 
 
 
 
 
 
X 
 
Review of concomitant 
medicationsh 
 
 
 
 
 
X 
 
Vital signs: BP and HRi 
 
 
 
 
 
 
 
Resting ECG (12-lead)j 
X** 
 
 
X 
 
 
 
 
 
 
X 
Blood samples for clinical 
laboratory testsk 
X** 
 
 
X 
X 
 
 
X 
 
 
X 
COVID-19 testingl 
X 
 
 
X 
 
 
 
 
 
 
X 
Blood sample for prolactinm 
X** 
 
 
X 
 
 
 
 
 
 
X 
Functional constipation inquiryn 
X** 
 
 
 
 
 
 
Interim clinical observationso 
 
Determination of dose titration 
 
PK blood drawp 
PANSSq 
C-SSRSr 
**
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DAY 
(± 3d, unless otherwise noted) 
1 
3 
(+1d) 
8 
(± 1d) 
14 
(± 2d) 
28 
42 
56 
70 
84 
98 
102 
116 
130 
154 
168 
WEEK 
1 
 
 
2 
4a 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
TYPE OF VISIT Clinic Clinic Clinic Clinic Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic 
Interim 
Clinic 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGI-S scale 
Cognition testings 
**
SAS 
BARS 
AIMS 
AiCure registration and training 
KarXT dispensed and compliance 
evaluatedt 
EMA registration and training 
EMAu 
Cognitive insightv 
Digital biomarkersw 
 
 
 
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Table 2 
Schedule of Assessments (Continued from Visits 16 to 30) 
DAY 
(± 3d, unless 
otherwise noted) 
182 
196 
210 
224 
238 
252 
266 
280 
294 
308 
322 
336 
350 
364 
371 
WEEK 26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52 
53 
VISIT 16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
(EOT) 
30 
(EOS/ET/UNS*) 
TYPE OF VISIT Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic InterimClinic Interim 
Clinic 
Clinic 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(WOCBP only)b 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Urine drugs of abuse 
and alcohol testingc 
Height, body weight, 
BMI, waist 
circumferenced 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Complete physical 
examinatione 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Spontaneous AEsg 
Review of concomitant 
medicationsh 
Vital signs: BP and 
HRi 
Resting ECG (12-lead)j 
 
 
 
 
 
X 
 
 
 
Blood samples for 
clinical laboratory 
testsk 
 
 
 
 
 
X 
 
 
 
COVID-19 testingl 
 
 
 
 
 
X 
 
 
 
Blood sample for 
prolactinm 
 
 
 
 
 
X 
 
 
 
Functional constipation 
inquiryn 
Interim clinical 
observationso 
PK blood drawp 
PANSSq 
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DAY 
(± 3d, unless 
otherwise noted) 
182 
196 
210 
224 
238 
252 
266 
280 
294 
308 
322 
336 
350 
364 
371 
WEEK 26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52 
53 
VISIT 16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
(EOT) 
30 
(EOS/ET/UNS*) 
TYPE OF VISIT Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim 
Clinic 
Clinic 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRSr 
CGI-S scale 
Cognition testings 
SAS 
BARS 
AIMS 
KarXT dispensed and 
compliance evaluatedt 
EMAu 
Cognitive insightv 
Digital biomarkersw 
Abbreviations: AE = adverse event; AIMS = Abnormal Involuntary Movement scale; BARS = Barnes Akathisia Rating Scale; BL = baseline; BMI = body 
mass index; BP = blood pressure; CGI-
-19 = coronavirus disease of 2019; C-SSRS = Columbia-
Suicide Severity Rating Scale; d = day; ECG = electrocardiogram; EMAW = EMA Wellness; EOS = end of study; EOT = end of treatment; ET = early 
termination; HR = heart rate; PANSS = Positive and Negative Syndrome Scale; PK = pharmacokinetic; QTcF = QT interval corrected by Fridericia; 
SAS = Simpson-Angus Rating Scale; UNS = unscheduled visit. 
Note: See APPENDIX 3 for optional modifications to the schedule of assessments during a pandemic period when local or governmental guidelines impose 
physical distancing restrictions. 
* Other assessments as needed. 
** Results are recorded from Day 35 visit of Study KAR-007/KAR-009 except for cognition testing for which the results are recorded from Day 32 visit of 
Study KAR-007/KAR-009. 
a. 
Beginning after Visit 5/Day 28, interim visits will be completed every 2 weeks with flexibility between the in-clinic visits, which will occur every 
month. For interim visits, either a Home Health Care nurse or the study site staff will visit the subject to complete the scheduled visit, in addition to the 
telemedicine visit. Also when needed, the sites will have the option to schedule a subject for an in-clinic visit. 
b. 
A urine pregnancy test for WOCBP should be performed at scheduled visits. In case of positive urine pregnancy test result, the sample should be sent to 
central laboratory for further investigation. 
c. 
A National Institute on Drug Abuse-5 (NIDA-5) urine drug screen (cannabinoids or marijuana, phencyclidine, amphetamines, opiates, and cocaine) and 
test for alcohol (breathalyzer or blood alcohol level) will be performed at scheduled visits. 
d. 
Height is recorded from Study KAR-007/KAR-009. 
e. 
A complete physical examination includes body temperature (°C), general appearance, head/eyes/ears/nose/throat (HEENT), examination of thorax and, 
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assessment of cardiac, musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited neurological examination. 
f. 
A targeted physical examination includes at a minimum body temperature, a check of general appearance, as well as examination of organ systems that 
are relevant to t
nclude 
symptom-driven physical examinations which will be performed as clinically indicated at any study visit. 
g. 
A part of interim clinical observations. For interim visits, spontaneous AEs will be reviewed by telemedicine over telephone or through video chat. 
Adverse events as reported by subjects or observed by clinical staff and occurs after dosing. One PK blood sample may be drawn if a 
relevant/significant AE (based on medical judgment) is reported during a scheduled visit or if there is a dose titration or a relevant/significant AE 
reported during an unscheduled visit (no multiple draws). 
h. 
For interim visits, concomitant medications will be reviewed by telemedicine over telephone or through video chat if the Home Health Care nurse 
performs the visit. 
i. 
Vital signs measurements should be taken at scheduled in-clinic visits, while the subject is supine and standing after 2 minutes. BP includes systolic and 
diastolic BP and is to be taken in the same arm for the duration of the study. During clinic visits, beginning with Day 1, orthostatic vital signs should 
occur 2 (±1) hours after morning dosing whenever possible.  
j. 
ECG will be obtained within 1 to 2 hours post morning dose. ECG at all scheduled visits will be performed before blood withdrawal for any safety 
laboratory tests and/or PK analysis. ECGs will be transmitted electronically to a central reader for determination of ventricular rate (bpm), PR (msec), 
QRS (msec), QT (msec), QTcF (msec) measurements, and any other results. 
k. 
Refer to Section 11.6 for individual laboratory tests. 
l. 
Optional COVID-
 If a subject tests positive for COVID-19 
during the study, he/she may be quarantined and any scheduled visits should be rescheduled at the discretion of the investigator. If the subject requires 
hospitalization, an SAE should be reported and the subject should be followed up as per Section 11.7.4. 
m. 
Blood sample for prolactin should be collected in the morning predose at scheduled visits. 
n. 
Functional constipation inquiry: At specified visit, subjects will be asked whether they have experienced constipation (per the ROME III criteria and 
Bristol Stool Form Scale; see APPENDIX 2) since the last visit and if yes, whether the constipation required intervention. If the subject answers yes, 
sites are instructed to ask subjects to provide event date and ensure the event is documented as an AE and treatment is documented as concomitant 
medication.  
o. 
Interim clinical observations include: collection of vital signs, review of spontaneous AEs and concomitant medications. These assessments will be 
performed by a Home Health Care nurse and/or telemedicine over telephone or through video chat. 
p. 
PK blood samples will be collected in the morning before dosing on Days 8, 14, 84, 168 and 364. On Days 8 and 14, three PK samples will be collected 
at pre-dose in the morning, 1 hour (+5 min), and 2 hours (+10 min) postdose. For Days 84, 168, and 364, a single sample before the morning dose will 
be collected. Note: In cases of dose reduction, re-escalation or re-titration, additional PK samples will be collected at 8 and 14 days post dose reduction, 
re-escalation, or re-titration in accordance with the Visits 3 and 4 schedules, respectively, and the original PK sampling schedule will be followed 
thereafter. 
q. 
It is recommended, if at all possible, that the PANSS assessment should be performed before all the other scale assessments for all visits at which it is 
performed. The PANSS assessment includes the Marder Factor. 
r. 
The 
 should be used for C-SSRS administration. At the Unscheduled visit, the C-SSRS should be performed to monitor subjects 
for suicidality. 
s. 
Cognition testing is performed using CANTAB. Cognition testing should not be done within 8 hours of receiving a benzodiazepine or sleep medication. 
Cognition testing at Visit 30 will only be performed if the visit is a result of Early Termination of a subject. 
t. 
See Pharmacy Manual for details on KarXT dispensing and compliance evaluation.  
u. 
EMA will be completed by the subject at home on a cellular device 3 times per day for 7 days every 28 days, beginning on Day 29. An abbreviated 
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version of the assessment will be utilized on Days 4-6 and 15-17 to familiarize subjects with the process.  
v. 
Cognitive insight will be completed by the subject at home on a cellular device 1 time per day for 3 days every 28 days beginning on Day 32. Refer to 
Study Operational Manual for details. 
w. 
Digital biomarkers of schizophrenia will be calculated through completion of a smartphone-based assessment daily by the subject for 3 days collected 
initially on Days 4-6, 9-11, and 15-17. Subsequently subjects will complete assessments daily for 3 days every 28 days, beginning on Day 29. 
 
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10.1 Informed Consent
Informed consent forms must be approved for use by the reviewing Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB). Before performing any study-related 
procedures, the investigator (or designee) will obtain written informed consent from the subject
and/or caregiver.
10.2 Study Procedures
Assessments and their timing are to be performed as outlined in the Schedule of Assessments 
(Table 2). Section 11.6 specifies laboratory assessment samples to be obtained. 
Assessments and procedures scheduled at a visit where KarXT is administered should be 
performed before administration of treatment unless otherwise indicated in the Schedule of 
Assessments (Table 2).
Safety assessments are described in Section 11 and include spontaneous AEs; SAEs and AEs 
leading to discontinuation of the KarXT; cholinergic symptoms; SAS; BARS; AIMS; body 
weight; BMI; waist circumference; orthostatic vital signs; ECG; clinical laboratory assessments 
(hematology, clinical chemistry, coagulation, urinalysis, and drug screen); physical examination; 
and C-SSRS.
Efficacy assessments are described in Section 12 and include PANSS and CGI-S scores.
PK assessments are described in Section 13 and include monitoring of trough concentrations of 
xanomeline and trospium.
Exploratory assessments are described in Section 14 and include cognition testing using 
CANTAB; prolactin levels; digital biomarkers of schizophrenia; EMA; and cognition insight.
The investigator may, at his/her discretion, arrange for a subject to have an unscheduled 
assessment, especially in the case of AEs that require follow-up or are considered by the 
investigator to be possibly related to the use of KarXT. The unscheduled visit page in the eCRF 
must be completed. The assessments and procedures that may be performed during an 
unscheduled visit are outlined in the Schedule of Assessments (Table 2). Additional assessments 
can be performed as needed, at the discretion of the investigator, and following discussion with 
the medical monitor.
Study discontinuation procedures are described in Section 8.4 and Section 8.6.
AiCure Adherence Technology
This study will employ a medication adherence monitoring platform (herein after referred to as 
Platform) for all subjects in the study. The Platform uses artificial intelligence on smartphones to 
confirm medication ingestion. In addition, built-in reminders and a communication system allow 
real-time intervention in case of drug interruptions. 
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Use of this Platform will in no way supersede or replace the physician and/or prescribed 
medication protocol of the subjects. Because the Platform does not change the medication 
protocol of the subjects, but rather encourages adherence to the predefined protocol, use of this 
Platform presents minimal risk to the subjects. Use of the Platform will be required for all 
subjects in the study. 
The monitoring Platform requires that all subjects take each dose of the medication while using a 
smartphone. Participants will download the AiCure application on their personal smartphone 
device; for participants who do not have a smartphone or do not wish to use their personal 
smartphone, site personnel will provide the participant with one of the preloaded backup 
provisioned devices. 
When at home, study subjects will receive a medication reminder at a time within a predefined 
window. This notification reminds subjects to take their medication dose while using the 
Platform. Subjects will follow a series of prescribed steps in front of the front-facing webcam to 
visually confirm their ingestion of the medication. The application on the smartphone will make 
an automated determination of whether the subject has properly taken their medication at the 
prescribed time. There is no need for a healthcare provider to review the administration, nor 
would a healthcare provider need to be available at the time the subject takes their medication. 
The amount of guidance that the device provides to the subject is automatically reduced as the 
subject becomes more proficient at using the application. 
Digital Biomarker Assessment: 
During the study, the AiCure Platform will also present additional material to subjects on their 
smartphone and record and analyze their responses. The material will be presented to subjects in 
one of two ways. In the first, material will be presented to subjects, and will include 
questionnaires provided at regular intervals during the study. Images may also be shown to 
subjects, and they will be asked to describe each image in a few sentences to the camera of the 
smartphone. This Digital Biomarker Assessment will only be conducted in some countries 
participating in the trial. 
Data Collected on the AiCure Platform: 
After the device confirms proper medication ingestion, video recordings will be encrypted and 
transmitted to a secure centralized location for further analysis, including testing for duplicate 
enrollment. Video and audio recordings from the Digital Biomarker assessments will be 
encrypted and transmitted in a similar manner. The captured data and video is reviewable 
through a roles and rules restricted system ensuring privacy of the information. The system is 
compliant with applicable US and European data privacy laws, including General Data 
Protection Regulation (GDPR) (EU) 2016/679 the Health Insurance Portability and 
Accountability Act (HIPAA), which protects the privacy and security of healthcare information. 
Phone numbers of the patients may also be collected and stored in an encrypted manner. Storing 
the phone numbers will allow for direct communication with patients, including automated 
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messaging from the Platform device and contact by healthcare providers or other monitoring 
personnel. At no time is the phone number visible to healthcare providers or monitoring 
personnel. Individuals outside the clinical sites will not be provided with patient names, nor will 
they be given access to patient medical records. 
The Platform may provide significant benefits to study subjects as well as to the other 
stakeholders in the trial. Subjects will benefit from rapid and tailored intervention in case of 
non-adherence (drug interruptions) without having to visit the clinic for unscheduled visits. 
Healthcare providers will have access to real-time and continuous adherence data without having 
to rely on self-reported data or frequent study visits by patients. Subjects who regularly fail to 
take their medication will be contacted by healthcare providers or other study monitoring 
personnel for retraining. 
 
 
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11 SAFETY ASSESSMENTS 
Safety assessments (spontaneous AEs; SAEs and AEs leading to discontinuation of the KarXT; 
cholinergic symptoms; SAS; BARS; AIMS; body weight; BMI; waist circumference; orthostatic 
vital signs; ECG; clinical laboratory assessments [hematology, clinical chemistry, coagulation, 
urinalysis, and drug screen]; physical examination; and C-SSRS) will be performed at 
protocol-specified visits, as specified in the Schedule of Assessments (Table 2).  
11.1 Demographics, Medical History, and Psychiatric History 
Demographic data, and medical and psychiatric history will be recorded from the Phase 3, 
double-blind, acute study (KAR-007/KAR-009).  
Illnesses first occurring or detected during the study and/or worsening of a concomitant illness 
during the study are to be documented as AEs on the eCRF in accordance with Section 11.7. All 
changes not present at baseline or described in the past medical history and identified as 
clinically noteworthy must be recorded as AEs. 
11.2 Vital Signs 
Orthostatic vital signs (systolic and diastolic BP and heart rate measurements) will be evaluated 
at the in-clinic visits indicated in the Schedule of Assessments (Table 2). All vital signs will be 
measured supine and standing after 2 minutes. Blood pressure measurements are to be taken in 
the same arm for the duration of the study. During treatment, beginning with Day 1, orthostatic 
vital signs should occur 2 (±1) hours after morning dosing, whenever possible. 
Vital sign measurements will be repeated if clinically significant or machine/equipment errors 
occur. Out-of-range BP, or heart rate measurements w
discretion. Any confirmed, clinically significant vital sign measurements must be recorded as 
AEs. 
11.3 Complete/Targeted Physical Examination 
A complete physical examination (body temperature, general appearance, 
head/eyes/ears/nose/throat [HEENT], examination of thorax and abdomen, assessment of 
cardiac, musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited 
neurological examination) will be performed at visits as specified in Table 2. Physical 
examinations will be performed by a physician. 
A targeted physical examination includes at a minimum body temperature, a check of general 
appearance, as well as examination of organ systems that are relevant to the investigator, based 
e. 
These also include symptom-driven physical examinations which will be performed as clinically 
indicated at any study visit. 
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11.4 Weight, Height, Body Mass Index, and Waist Circumference 
Height measurement will be recorded from the lead-in Study KAR-007 or KAR-009, weight, and 
waist circumference measurements will be obtained at visits as specified in Table 2. BMI should 
be calculated at these visits. All findings should be recorded in the eCRF. 
11.5 Electrocardiograms 
A 12-lead, resting ECG should be obtained within 1 to 2 hours post morning dose at the visits 
indicated in the Schedule of Assessments (Table 2). ECG at all scheduled visits will be 
performed before blood withdrawal for any safety laboratory tests and/or PK analysis. 
 ECGs will be transmitted electronically to a central reader for determination of ventricular rate 
(bpm), PR (msec), QRS (msec), QT (msec), QTcF (msec) measurements, and any other results. 
An assessment of normal or abnormal will be recorded; if the ECG is considered abnormal, the 
abnormality will be documented on the eCRF. ECGs will be repeated if clinically significant 
abnormalities are observed or artifacts are present. 
11.6 Laboratory Assessments 
Laboratory assessment samples (Table 3) are to be obtained at designated visits as detailed in the 
Schedule of Assessments (Table 2). 
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Table 3. 
Laboratory Assessments 
Hematology 
Serum Chemistry 
Urine Analysis (Dipstick) 
Full and differential blood count 
Hct 
Hb 
MCH 
MCHC 
MCV 
Platelet count 
RBC count 
WBC count with differential 
 
Albumin 
ALT 
ALP 
AST 
Albumin 
Uric acid 
BUN or urea 
Carbon dioxide 
Creatinine 
Creatine kinase and subtypes 
Electrolytes (sodium, 
potassium, chloride, calcium, 
phosphorus) 
GGT 
Glucose 
LDH 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
HDL 
LDL 
Triglycerides 
Total protein 
Appearance 
pH 
Protein 
Glucose 
Ketone bodies 
Indicators of blood and WBCs 
Specific gravity 
Urobilinogen 
Occult blood 
WBCs 
HbA1c 
Prolactin 
COVID-19 
Coagulation 
PT 
Activated PTT 
Fibrinogen 
Pregnancy test: A urine pregnancy test for WOCBP should be performed at all scheduled visits. In case of 
positive urine pregnancy test result, a serum pregnancy test should be performed to confirm the result. 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; COVID-19 = coronavirus disease of 2019; GGT = gamma-
glutamyl transpeptidase; HCG = human chorionic gonadotropin; Hb = hemoglobin; Hct = hematocrit; HDL = 
high density lipoprotein; LDH = lactate dehydrogenase; LDL = low density lipoprotein; MCH = mean 
corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular 
volume; PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cell; WBC = white blood 
cell; WOCBP = women of childbearing potential. 
 
Venous blood of approximately 12 to 20 mL will be withdrawn for the tests listed above at 
scheduled time points as per Table 2.  
A minimum volume of 10 mL will be obtained to perform urinalysis and urine drug screen at 
scheduled time points as per Table 2.  
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Blood and urine samples will be analyzed at a central laboratory facility. Urine samples will be 
analyzed locally at investigator site by dipstick. If the dipstick indicates abnormality, the site will 
forward the sample to the central laboratory for further investigation. All laboratory reports must 
be reviewed, signed, and dated by the investigator. A legible copy of all reports must be filed 
with both the 
eCRF and medical record (source document) for that visit. Any 
laboratory test result considered by the investigator to be clinically significant should be 
considered an AE (clinically significant AEs include those that require an intervention). 
Clinically significant abnormal values occurring during the study will be followed up until repeat 
test results return to normal, stabilize, or are no longer clinically significant.
All the study subjects will be closely monitored for the drug-induced liver toxicity (detailed in
Section 11.7.5), during the study.
Other Laboratory Assessments:
A National Institute on Drug Abuse-5 (NIDA-5) urine drug screen (cannabinoids or 
marijuana, phencyclidine, amphetamines, opiates, and cocaine) will be performed 
throughout the study. 
Alcohol testing will be performed using a breathalyzer or blood alcohol test. 
11.7 Adverse Events
Adverse Events
An AE is any symptom, physical sign, syndrome, or disease that either emerges during the study 
or, if present at screening/baseline, worsens during the study, regardless of the suspected cause 
of the event. All medical and psychiatric conditions (except those related to the indication under 
study) present at screening/baseline will be documented in the medical history eCRF. Changes in 
these conditions and new symptoms, physical signs, syndromes, or diseases should be noted on 
the AE eCRF during the rest of the study. Clinically significant laboratory abnormalities should 
also be recorded as AEs. Surgical procedures that were planned before the subject enrolled in the 
study are not considered AEs if the conditions were known before study inclusion; the medical 
condition should be reported in the 
medical history.
In accordance with the protocol, the investigator and/or study staff will elicit AEs and 
intercurrent illness during and at the end of the study period and these will be recorded on the 
appropriate page of the eCRF. Adverse events will be elicited by asking the subject a nonleading 
the final lab 
tests are available.
Each AE is to be documented on the eCRF with reference to date of onset, duration, frequency, 
severity, relationship to KarXT, action taken with KarXT, treatment of event, and outcome. 
Furthermore, each AE is to be classified as being serious or nonserious. Changes in AEs and 
resolution dates are to be documented on the eCRF.
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For the purposes of this study, the period of observation for collection of AEs extends from the 
time immediately after the administration of KarXT on Day 1 until the EOS or ET. Follow-up of 
the AE, even after the date of therapy discontinuation, is required if the AE persists until the 
event resolves or stabilizes at a level acceptable to the investigator. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the event should be noted. If the intensity category changes over a number of days, 
then those changes should be recorded separately (with distinct onset dates). 
The severity of AEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events, version 5.0 (Grades 1 through 5). 
Specific guidelines for classifying AEs by intensity and relationship to KarXT are given in 
Table 4 and Table 5. 
Table 4. 
Classification of Adverse Events by Intensity 
MILD: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with 
everyday activities. 
MODERATE: An event that is sufficiently discomforting to interfere with normal everyday activities. 
SEVERE: An event that prevents normal everyday activities. 
 
Table 5. 
Classification of Adverse Events by Relationship to KarXT 
UNRELATED: This category applies to those AEs that are clearly and incontrovertibly due to extraneous 
causes (disease, environment, etc). 
UNLIKELY: This category applies to those AEs that are judged to be unrelated to the test drug but for which 
no extraneous cause may be found. An AE may be considered unlikely to be related to KarXT if or when it 
meets 2 of the following criteria: (1) it does not follow a reasonable temporal sequence from administration of 
the test drug; (2) it could readily have been produced by the 
 clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; (3) it does not follow a known pattern of 
response to the test drug; or (4) it does not reappear or worsen when the drug is readministered. 
POSSIBLY: This category applies to those AEs for which a connection with the test drug administration 
appears unlikely but cannot be ruled out with certainty. An AE may be considered possibly related if or when 
it meets 2 of the following criteria: (1) it follows a reasonable temporal sequence from administration of the 
drug; (2) it could not readily have been produced by the 
 clinical state, environmental or toxic factors, 
or other modes of therapy administered to the subject; or (3) it follows a known pattern of response to the test 
drug. 
PROBABLY: This category applies to those AEs that the investigator feels with a high degree of certainty are 
related to the test drug. An AE may be considered probably related if or when it meets 3 of the following 
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
reasonably explained by the known characteristics of the 
 clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; (3) it disappears or decreases on cessation or 
reduction in dose (note that there are exceptions when an AE does not disappear upon discontinuation of the 
drug, yet drug-relatedness clearly exists; for example, as in bone marrow depression, fixed drug eruptions, or 
tardive dyskinesia); or (4) it follows a known pattern of response to the test drug. 
DEFINITELY: This category applies to those AEs that the investigator feels are incontrovertibly related to test 
drug. An AE may be assigned an attribution of definitely related if or when it meets all of the following 
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
reasonably explained by the known characteristics of the 
 clinical state, environmental or toxic 
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factors, or other modes of therapy administered to the subject; (3) it disappears or decreases on cessation or 
reduction in dose and recurs with re-exposure to drug (if rechallenge occurs); and (4) it follows a known 
pattern of response to the test drug.
Abbreviation: AE = adverse event.
Adverse Events of Special Interest
Adverse event of special interest is orthostasis and it will be monitored.
Serious Adverse Events
An SAE is any untoward medical occurrence, in the view of either the investigator or Sponsor, 
that:
results in death,
is life-threatening,
results in inpatient hospitalization or prolongation of existing hospitalization (however, 
hospitalization for elective treatment of a pre-existing non-worsening condition is not 
considered an SAE; the details of such hospitalizations must be recorded on the medical 
history or physical examination page of the eCRF),
results in persistent or significant disability/incapacity, and/or
is a congenital anomaly/birth defect.
Other important medical events that may not be immediately life-threatening or result in death or 
hospitalization, based upon appropriate medical judgment, are considered SAEs if they are 
thought to jeopardize the subject and/or require medical or surgical intervention to prevent 1 of 
the outcomes defining an SAE. Serious AEs are critically important for the identification of 
serious, the event must be considered serious and evaluated by the Sponsor for expedited 
reporting.
Serious Adverse Event Reporting
An SAE occurring from the time the first dose of KarXT is administered, during the study, or 
within 1 week of stopping the treatment must be reported to the Catalyst Clinical Research 
Pharmacovigilance group and will be communicated to the Sponsor. Any such SAE due to any 
cause, whether or not related to the KarXT, must be reported within 24 hours of occurrence or 
when the investigator becomes aware of the event. Notification can be made using email.
Catalyst Clinical Research Pharmacovigilance email address: 
The event must be recorded on the standard AE eCRF. Preliminary reports of SAEs must be 
followed up by detailed descriptions later on, including clear and anonymized photocopies of 
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hospital case reports, consultant reports, autopsy reports, and other documents when requested 
and applicable. SAE reports must be made whether or not the investigator considers the event to 
be related to the investigational drug.
Appropriate remedial measures should be taken to treat the SAE, and the response should be 
recorded. Clinical, laboratory, and diagnostic measures should be employed as needed in order to 
determine the etiology of the problem. The investigator must report all additional follow-up 
evaluations to the Catalyst Clinical Research Pharmacovigilance group within 24 hours of 
becoming aware of the additional information or as soon as is practicable. All SAEs will be 
followed up until the investigator and Sponsor agree the event is satisfactorily resolved.
Any SAE that is not resolved by the end of the study or upon discontinuation of the 
participation in the study is to be followed up until it either resolves, stabilizes, returns to 
baseline values (if a baseline value is available), or is shown to not be attributable to the KarXT
or procedures.
The sponsor has incorporated the following for monitoring of drug-induced liver injuries:
An increase of serum alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) to >3 × ULN should be followed by repeat testing within 48 to 72 hours of all 4 of 
the usual serum measures (ALT, AST, ALP, and total bilirubin) to confirm the 
abnormalities and to determine if they are increasing or decreasing. An inquiry should be 
made about the symptoms (eg, fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, and rash).
Close observation should be initiated with ALT or AST >3 × ULN:
o
Repeat liver enzyme and serum bilirubin tests 2 or 3 times weekly. The frequency of 
retesting can decrease to once per week or less if abnormalities stabilize or the trial 
drug has been discontinued and the subject is asymptomatic.
o
Obtain a more detailed history of symptoms and prior or concurrent diseases.
o
Obtain a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug 
use, and special diets.
o
Rule out acute viral hepatitis types A, B, C, D, and E, autoimmune or alcoholic 
hepatitis, non-alcoholic steatohepatitis, hypoxic/ischemic hepatopathy, and biliary 
tract disease.
o
Obtain a history of exposure to environmental chemical agents.
o
Obtain additional tests to evaluate liver function, as appropriate (eg, international 
normalized ratio, and/or direct bilirubin).
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o
Consider gastroenterology or hepatology consultations.
Discontinuation of treatment should be considered if:
o
ALT or AST >8 × ULN
o
ALT or AST >5 × ULN for more than 2 weeks
o
ALT or AST >3 × ULN and (total bilirubin >2 × ULN or international normalized 
ratio >1.5)
o
ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or eosinophilia (>5%)
Hepatic adjudication of cases should include an evaluation for alternative causes such as 
viral, autoimmune, alcohol, hepatobiliary disorders, non-alcoholic steatohepatitis, 
concomitant medications, etc.
Follow-up to resolution of elevated liver enzymes.
Gamma-glutamyl transferase elevations alone should not prompt drug discontinuation.
Suspected Unexpected Serious Adverse Reactions
Adverse events that meet all of the following criteria will be classified as suspected unexpected 
serious adverse reactions (SUSARs) and reported to the appropriate regulatory authorities in 
accordance with applicable regulatory requirements for expedited reporting:
serious
unexpected (ie, the event is not consistent with the safety information in the IB or 
package insert of generic trospium)
there is at least a reasonable possibility that there is a causal relationship between the event 
and the study treatment
The investigator will assess whether an event is causally related to study treatment. The Sponsor 
meets the criteria for being reportable as a 7-day or 15-day safety report. SUSARs that are fatal 
or life-threatening must be reported to the regulatory authorities and the IEC/IRBs (where 
required) within 7 days after the Sponsor (or Syneos Health) has first knowledge of them, with a 
follow-up report submitted within a further 8 calendar days. Other SUSARs must be reported to 
the relevant regulatory authorities and the IEC/IRBs within 15 calendar days after the Sponsor 
(or Syneos Health) first has knowledge of them.
The Sponsor (or Syneos Health) is responsible for reporting SUSARs and any other events 
required to be reported in an expedited manner to the regulatory authorities and for informing 
investigators of reportable events, in compliance with applicable regulatory requirements within 
specific timeframes. Investigators will notify the relevant IEC/IRBs of reportable events within 
the applicable timeframes.
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Warnings and Precautions
Risk of Urinary Retention:
Trospium chloride tablets should be administered with caution to subjects with clinically 
significant bladder outflow obstruction because of the risk of urinary retention.
Angioedema:
Angioedema of the face, lips, tongue, and/or larynx has been reported with trospium chloride, the 
active ingredient in trospium chloride tablets. In one case, angioedema occurred after the first 
dose of trospium chloride. Angioedema associated with upper airway swelling may be 
life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, trospium chloride 
should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a 
patent airway should be promptly provided.
Decreased Gastrointestinal Motility:
Trospium should be administered with caution to subjects with GI obstructive disorders because 
of the risk of gastric retention. Trospium chloride, like other antimuscarinic agents, may decrease 
GI motility and should be used with caution in subjects with conditions such as ulcerative colitis, 
intestinal atony, and myasthenia gravis.
Controlled Narrow-angle Glaucoma:
In subjects being treated for narrow-angle glaucoma, trospium chloride should only be used if 
the potential benefits outweigh the risks and in that circumstance only, with careful monitoring.
Central Nervous System Effects:
Trospium chloride is associated with anticholinergic CNS effects. A variety of CNS 
anticholinergic effects have been reported, including dizziness, confusion, hallucinations, and 
somnolence. Subjects should be monitored for signs of anticholinergic CNS effects, particularly 
after beginning treatment or increasing the dose. Advise subjects not to drive or operate heavy 
machinery until they know how trospium chloride affects them. If a subject experiences 
anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.
Anticholinergic Adverse Reactions in Subjects with Moderate Renal Impairment:
Trospium is substantially excreted by the kidney. The effects of moderate renal impairment on 
systemic exposure are not known but systemic exposure is likely increased. Therefore, 
anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract 
infection, and urinary retention) are expected to be greater in subjects with moderate renal 
impairment.
Pregnancy
WOCBP must have a negative pregnancy test at baseline (Day 1). Following administration of 
KarXT, any known cases of pregnancy in female subjects will be reported until the subject
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completes or withdraws from the study. The pregnancy will be reported immediately by 
faxing/emailing a completed pregnancy report to the Sponsor (or designee) within 24 hours of 
knowledge of the event. The pregnancy will not be processed as an SAE; however, the 
investigator will follow-up with the subject until completion of the pregnancy and must assess 
the outcome in the shortest possible time, but not more than 30 days after completion of the 
pregnancy. The investigator should notify the Sponsor (or designee) of the pregnancy outcome 
by submitting a follow-up pregnancy report. If the outcome of the pregnancy involved
spontaneous or therapeutic abortion (any congenital anomaly detected in an aborted fetus is to be 
documented), stillbirth, neonatal death, or congenital anomaly, the investigator will report the 
event by faxing/emailing a completed pregnancy report form to the Sponsor (or designee) within 
24 hours of knowledge of the event. This event is considered as an SAE.
If the investigator becomes aware of a pregnancy occurring in the partner of a subject
participating in the study, the pregnancy should be reported to the Sponsor (or designee) within 
24 hours of knowledge of the event. Information regarding the pregnancy must only be 
submitted after obtaining written consent from the pregnant partner. The investigator will 
arrange counseling for the pregnant partner by a specialist to discuss the risks of continuing with 
the pregnancy and the possible effects on the fetus.
Upon discontinuation from the study, only those procedures that would not expose the subject to 
undue risk will be performed. The investigator should also be notified of pregnancy occurring 
during the study but confirmed after completion of the study. In the event that a subject is 
subsequently found to be pregnant after inclusion in the study, any pregnancy will be followed to 
term, and the status of mother and child will be reported to the Sponsor after delivery.
Overdose
The investigator must immediately notify the Sponsor of any occurrence of overdose with 
KarXT (total daily dose greater than 250/60 mg).
Signs and symptoms of overdose may vary considerably. They are usually manifested by 
increasing GI stimulation with epigastric distress, abdominal cramps, diarrhea and vomiting, 
excessive salivation, pallor, cold sweating, urinary urgency, blurring of vision, and eventually 
fasciculation and paralysis of voluntary muscles. Miosis, increases or decreases in blood pressure 
with or without bradycardia, and severe anxiety and panic may occur.
Supportive treatment should be used as indicated (artificial respiration, maintenance of airway, 
oxygen, etc). Atropine sulfate should be available for IV or intramuscular administration. Several 
doses ranging from 0.5 to 2.0 mg may be required. Epinephrine 0.1 to 1.0 mg subcutaneous may 
also be of value in overcoming severe cardiovascular or bronchoconstrictor responses.
Adverse events associated with overdoses should be reported on the eCRF.
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11.8 Simpson-Angus Rating Scale 
The SAS is an established instrument to measure drug-related extrapyramidal syndromes. It is a 
10-item testing instrument used to assess gait, arm dropping, shoulder shaking, elbow rigidity, 
wrist rigidity, leg pendulousness, head dropping, glabella tap, tremor, and salivation. The range 
of scores is from 0 to 40 with increased scores indicating increased severity. 
11.9 Barnes Rating Scale for Akathisia 
The Barnes Rating Scale for akathisia is a rating scale used to assess the severity of drug-induced 
akathisia, or restlessness, involuntary movements and inability to sit still. The range of scores is 
0 to 14, with higher scores indicating greater severity.[23] 
11.10 Abnormal Involuntary Movement Scale 
The AIMS is a rating scale that is used to measure involuntary movements know as tardive 
dyskinesia, which can sometimes develop as a side effect of long-term treatment with 
antipsychotic medications. It is a 12-item scale to assess orofacial, extremity, and truncal 
movements as well as the overa
the movements. Items are scored from 0 (none) to 4 (severe). A higher score indicates more 
severe dyskinesia. 
11.11 Columbia-Suicide Severity Rating Scale 
The C-SSRS is a tool designed to systematically assess and track suicidal AEs (suicidal behavior 
and suicidal ideation) throughout the study.[24] The strength of this suicide classification system 
is in its ability to comprehensively identify suicidal events while limiting the over-identification 
of suicidal behavior. The scale takes approximately 5 minutes to administer. The C-SSRS will be 
administered by a trained rater at the site. 
This study will utilize 2 versions of the C-SSRS. At the screening visit, the baseline/screening 
-SSRS 
will be administered. 
11.12 Functional Constipation Inquiry 
Constipation refers to bowel movements that are infrequent or hard to pass.[25] The stool is 
often hard and dry.[26] Other symptoms may include abdominal pain, bloating, and feeling as if 
one has not completely passed the bowel movement.[27] The normal frequency of bowel 
movements in adults is between 3 per day and 3 per week.[25] Constipation will be defined per 
the Rome III criteria, as less than 3 bowel movements per week, APPENDIX 2 
(Longswreth,1486,C3).[28] 
The Bristol Stool Form Scale has been correlated with a change in intestinal function, and has 
been shown to be a useful tool in clinical practice and research.[29] A sample Bristol Stool Form 
Scale is located in APPENDIX 2. 
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As a measure of anticholinergic effects, at each visit, subjects will be asked whether they have 
experienced constipation per the ROME III criteria since the last visit, and if yes, whether the 
constipation required intervention. If the subject answers yes, sites are instructed to ask subjects 
to provide event date and ensure event is documented as an AE and treatment is documented as 
concomitant medication. Subjects will not be required to collect and present their stool sample, 
nor will clinic staff be required to corroborate the subject assessment. 
Additional attention can be given to other complaints as well including: straining with bowel 
movements, excessive time needed to pass a bowel movement, hard stools, pain with bowel 
movements secondary to straining, abdominal pain, abdominal bloating, and the sensation of 
incomplete bowel evacuation.[27, 30] 
Treatment of constipation depends on the underlying cause and the duration that it has been 
present. For the purposes of constipation complaints during a clinical trial, the use of laxatives of 
a bulk forming agent, osmotic agent, stool softener, or lubricant type may be used. 
As definitions of constipation are typically based on a history of at least a week, site physician 
discretion will be allowed for initiation of such treatments. 
 
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12 EFFICACY ASSESSMENTS 
The Schedule of Assessments (Table 2) outlines the efficacy assessments to be performed 
throughout the study and their timing. 
12.1 Positive and Negative Syndrome Scale 
The PANSS is a clinician-administered scale used for measuring symptom severity of subjects 
with schizophrenia and is widely used in the study of antipsychotic therapy.[31] The PANSS 
rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general 
psychopathology symptom scales. Subjects are rated from 1 to 7 on each symptom scale. The 
positive symptoms in schizophrenia are the excess or distortion of normal function such as 
hallucinations, delusions, grandiosity, and hostility, and the negative symptoms in schizophrenia 
are the diminution or loss of normal functions. It takes approximately 45 to 50 minutes to 
administer. PANSS total score is the sum of all scales with a minimum score of 30 and a 
maximum score of 210.  
It is recommended, if at all possible, that the PANSS assessment should be performed before all 
the other scale assessments for all visits at which it is performed. 
12.2 Clinical Global Impression-Severity  
The CGI-S is a rating scale, completed independently by a clinician that is used to measure 
illness and symptom severity in subjects with mental disorders. It is used to rate the severity of a 
-S modified asks the clinician 1 question: 
 The 
-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 subjects.[32] 
This rating is based upon observed and reported symptoms, behavior, and function in the past 
7 days. As symptoms and behavior can fluctuate over a week, the score should reflect the 
average severity level across the 7 days. 
 
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13
PHARMACOKINETICS
13.1 Pharmacokinetic Sampling
Blood Samples
Blood samples for the analysis of xanomeline and trospium levels will be collected at the time
points indicated in the Schedule of Assessments (Table 2). Approximately 4 ml of blood will be 
collected at each scheduled time point. The actual date and time of each blood sample collection 
will be recorded.
On Days 8 and 14, a total of 3 PK samples will be collected at pre-dose in the morning, 1 hour 
(+5 min), and 2 hours (+10 min) after the morning dose. For Days 84, 168, and 364, a single 
sample before the morning dose will be collected. 
Note: In case of dose reduction, re-escalation, or re-titration, additional PK samples will be 
collected at 8 and 14 days post dose reduction, re-escalation, or re-titration in accordance with 
the Visits 3 and 4 schedules, respectively, and the original PK sampling schedule will be 
followed thereafter. Should the use of visit windows be necessary, PK sampling must accompany
the actual day of potential up-titration for Visit 3/Day 8. 
Note: A single PK sample may be drawn (preferably in the morning) if a relevant/significant AE 
is reported during a scheduled visit, or if there is a dose adjustment or relevant/significant AE 
reported during an unscheduled visit (no multiple draws). For ET that is related to an AE, the 
collection of a PK blood sample is not optional and should be drawn.
Details of PK blood sample collection, processing, storage, and shipping procedures will be 
provided in a separate laboratory manual.
13.2 Pharmacokinetic Analytical Methodology
The concentration of trospium and xanomeline will be determined from the plasma PK samples 
using a validated analytical method. Details of the method validation and sample analysis will be 
included with the final clinical study report.
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14 EXPLORATORY ASSESSMENTS 
The exploratory assessments cognition testing, prolactin levels, EMA, and cognition insight will 
be performed at scheduled visits, as per the Schedule of Assessments (Table 2). 
14.1 Cognition Testing - Cambridge Neuropsychological Test Automated Battery 
The computerized CANTAB provides an objective measure of cognitive function correlated to 
neural networks. A short cognitive battery measuring core cognitive domains of impairment in 
schizophrenia (ie, as per Brief Assessment of Cognition Schizophrenia key cognitive domains) 
will be employed for this study, and it will take approximately 30 minutes to complete. These 
CANTAB tests meet MATRICS workshop criteria.[33] Subjects will perform the test on a 
provisioned iPad with data immediately uploaded to the CANTAB Connect cloud-based 
platform (WiFi permitting). 
Cognition testing should not be done within 8 hours of receiving benzodiazepine or sleep 
medications. 
Table 6. 
Cognitive Tests and Cognitive Domains Assessed by the Cambridge 
Neuropsychological Test Automated Battery 
CANTAB Tests 
MATRICS Cognitive Domain 
Outcome Measures 
Rapid visual information 
processing 
Sustained attention/vigilance 
 Signal detection 
measure of how good the subject is 
at detecting the target sequence 
(string of three numbers); 
regardless of response tendency 
Verbal recognition memory 
Verbal memory and new learning 
Free Recall: The total number of 
words that are correctly recalled 
from the presentation phase by the 
subject during the immediate free 
recall stage 
Spatial Span 
Working memory 
Forward Span Length: The 
longest sequence of boxes 
successfully recalled by the subject 
One-touch stockings of Cambridge  
Executive Function 
Planning/Problem Solving 
Problems Solved on First Choice: 
The total number of assessed trials 
where the subject chose the correct 
answer on their first attempt 
Abbreviation: CANTAB = Cambridge Neuropsychological Test Automated Battery 
14.2 Change in Prolactin 
Blood samples to assess the change in prolactin levels will be obtained on scheduled visits as 
specified in Table 2. At each of these visits, blood sample must be collected before the morning 
dose of the KarXT, whenever possible. 
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14.3 Digital Biomarkers of Schizophrenia
Study subjects will be performing brief smartphone-based assessments using the AiCure 
application mentioned in Section 10.2.1. Video and audio of participant behavior captured during 
these assessments will be used to calculate visual and auditory markers of schizophrenia 
symptomatology. These digital biomarkers will be used as exploratory efficacy endpoints to 
measure change from baseline in disease severity. The following exploratory endpoints will be 
collected:
Overall emotional expressivity
Positive emotional expressivity 
Negative emotional expressivity
Audio intensity / speech volume Fundamental frequency of voice
Formant frequencies of voice
Vocal jitter
Vocal shimmer
Pause lengths during speech
Lexical diversity
Rate of speech
Euclidean head movement
Rotational head movement
14.4 EMA Wellness Assessments
Ecological Momentary Assessment
EMA is an ambulatory data collection technique that allows the real-time in vivo assessment of 
associated to negative symptoms and psychotic symptoms in schizophrenia through the use of 
smartphones. 
or with others, and activities and moods in the last hour. A pop-up visualization will signal 
participants, 3 times per day for 7 days, to respond to very brief (e.g., 3 minutes) questionnaires 
about their activities, mood, and symptom experiences during the last hour, per the Schedule of 
Assessments (Table 2). An abbreviated EMA survey, collecting only information on the 
for 3 days starting on Day 4 and Day 15. Daily assessment times will be adjusted to 
Insight into Cognitive Performance
Insight assessment will be conducted through testing on the Verbal Learning and Memory Test 
(VLMT). This assessment will be performed 3 times per EMA week beginning on the 4th day of 
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each EMA week. During each VLMT administration, subjects will be presented with a list of 
words over 3 trials, 30 seconds per trial. The list lengths vary between 6-, 12-, or 18-items with 
1 length per day and 3 different lengths during each EMA week. Immediately following each 
exposure to the list, subjects will be shown target and recognition foil words one-by-one and 
asked to indicate whether or not the word appeared on the list. 
In order to examine response bias and the ability to self-evaluate memory performance, 
immediately after each recognition trial, the subjects will be asked to indicate how many words 
they believe that they got correct, with the response options ranging from 0-36 words. They will 
also be asked how well they did compared to the previous trial and at the end of the 3 trials they 
will be asked if they improved over the 3 learning trials.
Data Collected on EMAW Platform
Data are encrypted and uploaded to secure servers whenever the phone is connected to Wi-Fi or 
if cellular data is available. If a Wi-Fi and cellular data are unavailable, EMA response data will 
be transferred during in-clinic visits.
efined with 
EMA prompts (home vs away and where if away); they will also be asked if they are alone or 
with others, and as being queried as to activities, symptoms, and moods in the last hour. 
Symptom scores will be reported as the severity score for each survey. The functioning 
behaviors reported during each survey will be recorded, and the symptom scores were 
time-linked to activities and locations at the time of assessment.
responses. Thus, the outcomes variables for location will be the number of surveys answered as 
home alone, home with someone, away alone, and away with someone. Individual activities will 
be quantified in terms of the total number of surveys where each activity was endorsed and the 
percentage of total number of activities per survey represented by each activity. Symptom 
severity will be sampled at each survey and will be examined in terms of the number of surveys 
where psychosis severity exceeded the PANSS-related threshold of definitely present (4 or 
more).  
Dependent variables for the insight assessment, the VLMT, are the number of correct 
identifications of target words per trial and a total score of correct identifications of targets and 
correct rejections of foils. The participants will also provide an immediate estimate of their 
memory task performance as soon as each recognition trial is over. Insight will be measured by 
the difference between objective performance on the task and self-reported number of words 
correct. The self-reported global impression of improvement over time will be related to actual 
improvement over the 3 learning trials and as well as self-reported accuracy at each assessment.
Performance will be linked to the EMA data over the course of the protocol, with objective and 
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the time of the assessment.  Changes in response bias will be defined as increasing congruence 
between objective and subjective memory performance over the course of the study. 
In order to perform a sophisticated examination of all survey data, EMA wellness (EMAW) will 
use a mixed model repeated measures analysis of variance (MMRM). EMAW will predict the 
time course 
-12), day (1-7) and survey (1-3) as the 
-level outcomes variable. EMAW will also predict 
the course of the mood and symptom variables similarly.  In order to examine the interaction 
as predictors of the course of the mood and psychosis symptoms. EMAW will also examine the 
frequency of activities over the course of the protocol with an identical analysis model, 
 
 
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15 STATISTICAL ANALYSIS 
A statistical analysis plan (SAP) will be prepared after the protocol is approved. This document 
will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. The SAP will serve as a complement to the protocol 
and supersedes it in case of differences. 
The statistical evaluation will be performed using SAS® software version 9.4 or higher 
(SAS Institute, Cary, NC). All data will be listed, and summary tables will be provided. 
Summary statistics will be presented by dose group. For continuous variables, data will be 
summarized with the number of subjects (N), mean, standard deviation, median, minimum, and 
maximum by treatment group. For categorical variables, data will be tabulated with the number 
and proportion of subjects for each category by treatment group. No statistical hypothesis testing 
will be performed. 
15.1 Determination of Sample Size 
As the primary objective of this study is to assess the long-term safety and tolerability of KarXT, 
the number of subjects anticipated is based on the number of subjects recruited into and 
completing the acute studies (KAR-007, KAR-009) and meeting the eligibility requirements for 
KAR-008. 
15.2 Analysis Populations 
Enrolled population: All subjects who have given informed consent for KAR-008. 
Safety population: All subjects who receive at least 1 dose of KarXT during the current study 
will be included in the safety population and will be used in the safety analysis. 
Modified ITT (mITT) population: All subjects who are enrolled, received at least 1 dose of 
KarXT, and have a valid PANSS assessment at baseline of the acute study and at baseline of 
KAR-008 will be included in the mITT population and will be used in the efficacy analysis. 
PK population: All subjects who have received at least 1 dose of KarXT and have at least 
1 measurable plasma concentration of KarXT will be included in the PK population. 
15.3 Safety Analysis 
Safety endpoints will be summarized for all subjects in the Safety population. The presentation 
of safety data will be based on the treatment received in KAR-008. 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 22.1 or higher. The incidence of TEAEs (defined as events with an onset 
date on or after the first dose of KarXT) will be summarized by System Organ Class and 
Preferred Term. All AEs will be listed by subject, along with information regarding onset, 
duration, relationship and severity to KarXT, action taken with KarXT, treatment of event, and 
outcome. 
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Orthostatic vital signs, clinical laboratory data, prolactin levels, ECG parameters, and physical 
examinations will be summarized using descriptive statistics, including observed and change 
from baseline values, as well as numbers of subjects with values outside limits of the normal 
range at each time point. Similar descriptive summaries will be provided for C-SSRS, SAS, 
BARS, AIMS, body weight, BMI, and waist circumference. 
15.4 Efficacy Analysis 
Efficacy analyses will be summarized based on the mITT population. The summaries described 
in this section will provide data on maintenance of effect of open-label KarXT over 52 weeks. 
As these variables are summarized over time and the initial values can be impacted by the 
treatment received in the acute study, the presentation will use a combination of acute/extension 
study treatment groups, which is intended to provide perspective on the change in these values 
from the acute study through the treatment period of KAR-008. Tabular presentations will 
display descriptive statistics for Baseline of the acute study and the observed and change from 
baseline study results by scheduled visit for KAR-008. 
Responder efficacy variables (PANSS responders) will be summarized descriptively. Response 
will be derived relative to the acute study Baseline assessment. 
Continuous efficacy variables based on the change from baseline (PANSS, CGI-S) will be 
summarized using descriptive statistics by scheduled visit. Tabular presentations will display 
descriptive statistics for the Baseline of the acute study and the observed and change from 
baseline results by scheduled visit for KAR-008. Figures for selected variables will also be 
generated in order to demonstrate the kinetics of response over time. 
15.5 Pharmacokinetic Analysis 
Plasma concentrations of xanomeline and trospium will be listed for all subjects. The profiles or 
time points obtained with protocol deviations affecting PK results will be flagged and may be 
excluded from summaries and analyses. 
The data will be presented graphically via individual plots and mean plots summarized by visit, 
and time point.  
15.6 Exploratory Analysis 
Change in cognition using CANTAB, digital biomarkers of schizophrenia, EMA, and cognition 
insight will be summarized using descriptive statistics. 
Further details will be provided in the SAP. 
15.7 Interim Analysis  
No interim analysis is planned for this study. 
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15.8 Handling of Missing Data 
For responder efficacy variables (PANSS responders), missing data may be handled by 
non-responder imputation, meaning that subjects who discontinue early or who have missing 
data at a given time point are imputed as though they did not achieve the given response. 
Supportive summaries will be based on observed case data. 
For continuous efficacy variables based on the change from baseline (PANSS, CGI-S), 
summaries will be based on observed case data.  
Additional methods of missing data imputation may be explored, and will be outlined in the 
SAP. 
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16
STUDY MANAGEMENT
16.1 Approval and Consent
Regulatory Guidelines
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki and/or all relevant regulations, as set forth in Parts 50, 56, 312, Subpart D, of Title 21 of 
the US Code of Federal Regulations (CFR), in compliance with International Council for 
Harmonisation (ICH) and good clinical practice (GCP) guidelines, and all applicable local, state 
and federal government regulations and laws.
Institutional Review Board/Independent Ethics Committee
Conduct of the study must be approved by an appropriately constituted IEC/IRB. Approval is 
required for the study protocol, protocol amendments (if applicable), IB, ICFs, recruitment 
material and subject information sheets and other subject-facing material.
Informed Consent
For each study subject, written informed consent will be obtained before any protocol-related 
activities. As part of this procedure, the PI or designee must explain orally and in writing the 
nature of the study, its purpose, procedures, expected duration, alternative therapy available, and 
the benefits and risks involved in study participation. The subject should be informed that he/she 
may withdraw from the study at any time, and the subject will receive all information that is 
required by local regulations and guidelines for ICH. The PI will provide the Sponsor or its 
representative with a copy of the IEC-/IRB-approved ICF before the start of the study.
The ICF should be revised whenever there are substantial changes to procedures or when new 
information becomes available that may affect the willingness of the subject to participate. 
Revisions to the consent form required during the study must be approved by the Sponsor and 
IEC/IRB, and a copy of the revised consent form is provided to the Sponsor. For any updated or 
revised consent forms, the subjects must be re-consented for continued participation in the study.
A pregnant partner consent form should be obtained before collecting any data from a female 
pregnant partner of a male subject, if she becomes pregnant during the course of the study or 
within 1 week of the last dose of KarXT.
A caregiver consent must be obtained (Ukraine only) before collecting any data from a caregiver 
pertaining to him or her and the subject.
Subject Registry (for the US only):
Clinical trial registries, such as clinical trial subject database (CTSdatabase) and Verified 
Clinical Trials (VCT), seek to reduce duplicate enrollment by identifying potential protocol 
violations and duplicate subjects before randomization. At the time of providing the informed 
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consent for the study, the investigator or designee will explain the IRB-approved Subject 
Database Authorization to the subject and witness the signature. 
On Day 1 before any other study procedures, site staff that have received training and login 
information access (www.ctsdatabase.com) to the database will enter the subject study ID 
number and authorized subject identifiers. Two reports, one from CTS and one from VCT, 
detailing any potential protocol violations or dual enrollment attempts will be generated and 
should be printed for source documentation. The report will detail each protocol violation 
detected and specific washout period dates where applicable. Participants who are identified as 
verification failures by CTS or VCT should not be enrolled without documented approval from 
Karuna or Syneos Health. 
At the last subject contact, CTSdatabase and VCT staff will automatically close out the subject 
(safety follow-up, ET, or completer) based on interactive response system (IXRS). 
Verified Clinical Trial Registry (for Ukraine only): 
research study status in order to mitigate safety concerns associated with duplicate enrollment 
and protocol deviations associated with multiple trial enrollment. Following proper regionally 
compliant informed consent and after obtaining a subject number from IXRS, each participant 
will be checked in the VCT database. Partial identifiers will be utilized. Participants who are 
identified as verification failures by VCT should not be enrolled without documented approval 
from Karuna or Syneos Health. 
16.2 Data Handling 
Any data to be recorded directly on the eCRFs (to be considered as source data) will be 
identified at the start of the study. Data reported on the eCRF that are derived from source 
documents should be consistent with the source documents, or the discrepancies must be 
explained. See also Section 16.3.  
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Clinical data will be entered by site personnel on eCRFs for transmission to the Sponsor. Data on 
eCRFs transmitted via the web-based data system must correspond to and be supported by source 
documentation maintained at the study site, unless the study site makes direct data entry to the 
databases for which no other original or source documentation is maintained. In such cases, the 
study site should document which eCRFs are subject to direct data entry and should have in 
place procedures to obtain and retain copies of the information submitted by direct data entry. 
All study forms and records transmitted to the Sponsor must only include coded identifiers such 
that directly identifying personal information is not transmitted. The primary method of data 
transmittal is via the secure, internet-based electronic data capture (EDC) system maintained by 
Syneos 
secure internet web site, where a user unique assigned username and password are required for 
access. 
Any changes made to data after collection will be made through the use of the EDC system. 
Electronic CRFs will be considered complete when all missing and/or incorrect data have been 
resolved. 
16.3 Source Documents 
Source documents are considered to be all information in original records and certified copies of 
original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. The investigator will provide direct 
access to source documents and/or source data in the facilitation of trial-related monitoring, 
audits, review by IECs/IRBs, and regulatory inspections. 
The investigator/institution should maintain adequate and accurate source documents and trial 
subjects. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, not obscure the original entry, and be explained if necessary. 
Data recorded on source documents will be transcribed onto eCRFs. Copies of completed eCRFs 
will be provided to the Sponsor and the sites at the end of the study. The completed eCRFs will 
be retained by the investigator. 
16.4 Record Retention 
Study records and source documents must be preserved for at least 15 years after the completion 
or discontinuation of/withdrawal from the study, at least 2 years after the drug being studied has 
received its last approval for sale, or at least 2 years after the drug development has stopped, and 
in accordance with the applicable local privacy laws, whichever is the longer time period. 
The investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subject health information, including, but not limited to, the 
Standards for Individually Identifiable Health Information, 45 CFR, Parts 160 and 164 (the 
HIPAA of 1996 Privacy Regulation). The investigator shall ensure that study subjects authorize 
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the use and disclosure of protected health information in accordance with HIPAA Privacy 
Regulation and in a form satisfactory to the Sponsor.
16.5 Monitoring
The study will be monitored according to the KAR-008 monitoring plan to ensure that it is 
conducted and documented properly according to the protocol, GCP, and all applicable 
regulatory requirements.
Monitoring visits, on-site and remote (telephone) or a combination and contacts will be made at 
appropriate times during the study. The PI will assure him/her and adequate site personnel are 
available throughout the study to collaborate with clinical monitors. Clinical monitors must have 
direct access to source documentation in order to check the completeness, clarity, and 
consistency of the data recorded in the eCRFs for each subject.
The investigator will make available to the clinical monitor all source documents and medical 
records necessary to review protocol adherence and eCRFs. In addition, the investigator will 
work closely with the clinical monitor and, as needed, provide them appropriate evidence that the 
study is being conducted in accordance with the protocol, applicable regulations, and GCP
guidelines.
16.6 Quality Control and Quality Assurance
The Sponsor or its designee will perform the quality assurance and quality control activities of 
this study; however, responsibility for the accuracy, completeness, security, and reliability of the 
study data presented to the Sponsor lies with the investigator generating the data.
The Sponsor will arrange audits as part of the implementation of quality assurance to ensure that 
the study is being conducted in compliance with the protocol, standard operating procedures, 
GCP, and all applicable regulatory requirements. Audits will be independent of and separate 
from the routine monitoring and quality control functions. Quality assurance procedures will be 
performed at study sites and during data management to assure that safety and efficacy data are 
adequate and well documented.
16.7 Protocol Amendment and Protocol Deviation
Protocol Amendment
Amendments to the protocol that entail corrections of typographical errors, clarifications of 
confusing wording, changes in study personnel, and minor modifications that have no effect on 
the safety of subjects or the conduct of the study will be classed as administrative amendments 
and will be submitted to the IEC/IRB for information only. Syneos Health will ensure that 
acknowledgement is received and filed. Amendments that are classed as substantial amendments 
must be submitted to the appropriate regulatory authorities and the IECs/IRBs for approval and 
will not be implemented at sites until such approvals are received, other than in the case of an 
urgent safety measure.
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Protocol Deviations
Should a protocol deviation occur, the Sponsor must be informed as soon as possible. Protocol 
deviations and/or violations and the reasons they occurred will be included in the clinical study 
report. Reporting of protocol deviations to the IEC/IRB and in accordance with applicable 
All protocol deviations will be tracked in the eCRF/EDC system. Deviations considered 
major will be identified as such before study unblinding during medical monitor periodic 
review.
Major protocol deviations will be tabulated including the frequency and percentage of subjects 
with each type of deviation by treatment group.
16.8 Ethical Considerations
This study will be conducted in accordance with this protocol, the accepted version of the 
Declaration of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, 
Subpart D, of Title 21 of the CFR; and in compliance with GCP guidelines.
IECs/IRBs will review and approve this protocol and the ICF. All subjects and/or caregivers are 
required to give written informed consent before participation in the study.
16.9 Financing and Insurance
Before the study commences, the Sponsor (or its designee) and the investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study. This agreement will 
be documented in a financial agreement that will be signed by the investigator (or the institution 
signatory) and the Sponsor (or its designee).
The investigator is required to have adequate current insurance to cover claims for negligence 
and/or malpractice (US only). The Sponsor will provide no-exclusion insurance coverage for the 
clinical study as required by national regulations.
16.10 Publication Policy/Disclosure of Data
Both the use of data and the publication policy are detailed within the clinical study agreement.
Intellectual property rights (and related matters) generated by the investigator and others 
performing the clinical study will be subject to the terms of a clinical study agreement that will 
be agreed between the institution and the Sponsor or their designee. With respect to such rights, 
the Sponsor or its designee will solely own all rights and interests in any materials, data, and 
intellectual property rights developed by investigators and others performing the clinical study 
described in this protocol, subject to the terms of any such agreement. In order to facilitate such 
ownership, investigators will be required to assign all such inventions either to their institution or 
directly to the Sponsor or its designee, as will be set forth in the clinical study agreement.
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17 REFERENCES 
1. Patel KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: overview and treatment options. P 
T. 2014;Sep 39(9):638-645. 
2. van Os J, Kapur S. Schizophrenia. Lancet. 2009 Aug 22;374(9690):635-645. 
3. Wu EQ, Shi L, Birnbaum H, Hudson T, Kessler R. Annual prevalence of diagnosed 
schizophrenia in the USA: a claims data analysis approach. Psychol Med. 2006 
Nov;36(11):1535-1540. 
4. Crismon L, Argo TR, Buckley PF. Schizophrenia. In: DiPiro JT, Talbert RL, Yee GC, et al., 
editors. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, New York: 
McGraw-Hill; 2014:1019-1046. 
5. Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome 
in schizophrenia: implications for MATRICS. Schizophr Res. 2004;72(1):41-51. 
6. Huhn M, Nikolakopoulou A, Schnider-Thoma J, et al. Comparative efficacy and tolerability 
of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a 
systematic review and network meta-analysis. Lancet. 2019;394(10202):939-951. 
7. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients 
with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223. 
8. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 
15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 
2013;382(9896):951-962. 
9. Emsley R, Chiliza B, Asmal L, Harvey BH. The nature of relapse in schizophrenia. BMC 
Psychiatry. 2013;13:50. 
10. Kahn RS, Sommer IE, Murray RM, et al. Schizophrenia. Nat Rev Dis Primers. 
2015;1:15067. 
11. Sellin AK, Shad M, Tamminga, C. Muscarinic agonists for the treatment of cognition in 
schizophrenia. CNS Spectr. 2008 Nov;13(11):985-996. 
12. Wess J, Eglen RM, Gautam D. Muscarinic acetylcholine receptors: mutant mice provide new 
insights for drug development. Nat Rev Drug Discov. 2007 Sep;6:(9):721-733. 
13. Mirza NR, Peters D, Sparks RG. Xanomeline and the antipsychotic potential of muscarinic 
receptor subtype selective agonists. CNS Drug Rev. 2003 Summer;9(2):159-186. 
14. Thorn CA, Moon J, Bourbonais CA, et al. Striatal, hippocampal, and cortical networks are 
differentially responsive to the M4- and M1-muscarinic acetylcholine receptor mediated 
effects of xanomeline. ACS Chem Neurosci. 2019;10(8):3910. 
15. Farde L, Suhara T, Halldin C, et al. PET study of the M1-agonists [11C]xanomeline and 
[11C]butylthio-TZTP in monkey and man. Dementia. 1996;7(4):187-195. 
16. Bodick NC, Offen WW, Levey AI, et al. Effect of xanomeline, a selective muscarinic 
receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch 
Neurol. 1997;54(4):465-473. 
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17. Bodick NC, Offen WW, Shannon HE, et al. The selective muscarinic agonist xaqnomeline 
Alzheimer Dis Assoc Disord. 1997; 11 Suppl 4:S16-22. 
18. Shekhar A, Potter WZ, Lightfoot J, et al. Selective muscarinic receptor agonist xanomeline 
as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008 Aug;165(8):1033-
1039. 
19. Staskin D, Sand P, Zinner N, Dmochowski R, Trospium Study Group. Once daily trospium 
chloride is effective and well tolerated for the treatment of overactive bladder; results from a 
multicenter phase III trial. J Urol. 2007;178(3 Pt 1):978-983; discussion 983-984. 
20. Scheife R, Takeda M. Central nervous system safety of anticholinergic drugs for the 
treatment of overactive bladder in the elderly. Clin Ther. 2005;27(2):144-153. 
21. Brannan SK, Paul SM and Breier A. Xanomeline plus trospium: A novel strategy to enhance 
pro-muscarinic efficacy and mitigate peripheral side effects. Proceedings of the ASCP annual 
meeting 2019. 
22. [HMA] Heads of Medicines Agencies. Clinical Trial Facilitation Group page. 
Recommendations related to contraception and pregnancy testing in clinical trials. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
September 15, 2014. Accessed 27 Mar 2020. 
23. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989 
May;154 (5):672-676. 
24. Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm 
of Suicide Assessment (C-
suicidal risk analysis of antidepressants. Am J Psychiatry. 2007 Jul;164(7):1035-1043. 
25. Chatoor D, Emmanuel A. Constipation and evacuation disorders. Best Pract Res Clin 
Gastroenterol. 2009;23(4):517-530. 
26. Constipation. National Institute of Diabetes and Digestive and Kidney Diseases. 
https://www.niddk.nih.gov/health-information/digestive-diseases/constipation/all-content. 
February 2015. Accessed 28 Mar 2020. 
27. American Gastroenterological Association, Bharucha AE, Dorn SD, Lembo A, Pressman A. 
American Gastroenterological Association medical position statement on constipation. 
Gastroenterology. 2013 Jan;144(1):211-217. 
28. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional 
bowel disorders. Gastroenterology. 2006 Apr;130(5):1480-1491. 
29. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol. 1997 Sep;32(9):920-924. 
30. Locke GR III, Pemberton JH, Phillips SF. American Gastroenterological Association 
Medical Position Statement: guidelines on constipation. Gastroenterology. 2000 
Dec;119(6):1761-1766. 
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31. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr Bull. 1987;13(2):261-276. 
32. Guy W. EDCEU Assessment Manual for Psychopharmacology  Revised. Rockville, MD, 
US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug 
Abuse, and Mental Health Administration, NIMH Psychopharmacology Research Branch, 
Division of Extramural Research Programs, 1976:534-7. DHEW Publication No ADM 
76-338. 
33. Buchanan RW, Davis M, Goff D, et al. A summary of the FDA-NIMH-MATRICS workshop 
on clinical trial design for neurocognitive drugs for schizophrenia. Schizophrenia Bulletin. 
2005 Jan;31(1):5-19. 
 
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18 APPENDICES 
 
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APPENDIX 1 CONTRACEPTION GUIDELINES 
Women of childbearing potential (WOCBP) and men whose sexual partners are WOCBP must 
use at least 1 highly effective method of contraception during the study and for 7 days after the 
last dose of study treatment.  
A woman is considered to be a WOCBP (fertile) following menarche and until becoming 
postmenopausal, unless she is permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause. A high 
follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.  
A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
Highly effective methods of contraception are those which have a failure rate of <1% (when 
implemented consistently and correctly) and include: 
 combined (containing estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation (administration may be oral, intravaginal, or transdermal) 
 progestogen-only hormonal contraception associated with inhibition of ovulation 
(administration may be oral, injectable, or implantable) 
 intrauterine device 
 intrauterine hormone-releasing system 
 bilateral tubal ligation or occlusion 
 vasectomy (provided that the male has a medical assessment of surgical success) 
 sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of risk in relation to the duration of the clinical trial, in line with the preferred and 
usual lifestyle of the subject) 
All subjects will be strongly advised that they (or the female partners of male subjects should not 
become pregnant while on study treatment or for 7 days after the last dose). A female subject 
will be advised that she must report immediately to the study site for pregnancy testing and 
appropriate management in the event that she may be pregnant. 
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Reference: [HMA] Heads of Medicines Agencies. Clinical Trial Facilitation Group page. 
Recommendations related to contraception and pregnancy testing in clinical trials. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
September 15, 2014. Accessed April 8, 2020. 
 
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APPENDIX 2 FUNCTIONAL CONSTIPATION INQUIRY 
 
 
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APPENDIX 3. 
ALTERNATIVE PROCEDURES DURING COVID-19 
PANDEMIC-RELATED PHYSICAL DISTANCING 
The table below (Alternative Schedule of Assessments) outlines the timing of procedures and 
assessments to be performed remotely at scheduled visits during COVID-19 pandemic-related 
physical distancing. During this situation, all the in-clinic visits will be performed remotely, 
either a Home Health Care nurse or the study site staff will visit the subject to complete the 
scheduled visit. In addition to augment the remote visit, the telemedicine can be used.  
 
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Alternative Schedule of Assessments 
DAY 
(± 3d, unless otherwise noted) 
56 
84 
102 
130 
168 
196 
224 
252 
280 
308 
336 
 
WEEK 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
VISIT 
7R 
9R 
11R 
13R 
15R 
17R 
19R 
21R 
23R 
25R 
27R 
UNS-Ra
TYPE OF VISIT Remote Remote Remote 
Remote 
Remote 
Remote 
Remote Remote Remote 
Remote Remote Remote
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (WOCBP only)b, # 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Urine drugs of abuse and alcohol testingc, # 
Height, body weight, BMI, waist 
circumferenced, # 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Spontaneous AEse, ## 
Review of concomitant medicationsf, ## 
Blood samples for clinical laboratory testsg, # 
 
 
X 
 
COVID-19 testingh, # 
 
 
X 
 
Blood sample for prolactini, # 
 
 
X 
 
Functional constipation inquiryj, ## 
Clinical observationsk, # 
KarXT dispensed and compliance 
evaluatedl, # 
PK blood drawm, # 
PANSSn,## 
C-SSRSo, ## 
CGI-S## 
BARS## 
AIMS## 
EMAp 
Cognitive insightq 
Digital biomarkers of schizophreniar 
Abbreviations: AE = adverse event; AIMS = Abnormal Involuntary Movement scale; BARS = Barnes Akathisia Rating Scale; BMI = body mass index; 
BP = blood pressure; CGI-S = Clinical Global Impress
-19 = Coronavirus Disease of 2019; C-SSRS = Columbia-Suicide Severity 
Rating Scale; d = day; EMA = ecological momentary assessment; HR = heart rate; PANSS = Positive and Negative Syndrome Scale; PK = pharmacokinetic; 
R = remote; UNS = unscheduled visit. 
# This procedure will be performed either by a Home Health Care nurse or the study site staff. 
## This procedure will be performed by telemedicine over a telephone or through video chat 
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* Procedure conducted by telemedicine over telephone or through video chat. 
** Procedure conducted by telemedicine through video chat only (telephone assessment will not be permitted). 
a. 
Other assessments as needed. 
b. 
A urine pregnancy test for WOCBP should be performed at scheduled visits. In case of positive urine pregnancy test result, the sample should be sent to 
central laboratory for further investigation. 
c. 
A National Institute on Drug Abuse-5 (NIDA-5) urine drug screen (cannabinoids or marijuana, phencyclidine, amphetamines, opiates, and cocaine) and 
test for alcohol (breathalyzer or blood alcohol level) will be performed at scheduled visits. 
d. 
Height is recorded from Study KAR-007/KAR-009. 
e. 
A part of interim clinical observations. AEs as reported by subjects or observed by clinical staff and occurs after dosing. Spontaneous AEs will be 
reviewed by telemedicine over telephone or through video chat. One PK blood sample may be drawn if a relevant/significant AE (based on medical 
judgment) is reported during a scheduled visit or if there is a dose titration or a relevant/significant AE reported during an unscheduled visit (no multiple 
draws). 
f. 
Concomitant medications will be reviewed by telemedicine over telephone or through video chat if the Home Health Care nurse performs the visit. 
g. 
Refer to Section 11.6 for individual laboratory tests. 
h. 
Optional COVID-
 
i. 
Blood sample for prolactin should be collected in the morning predose at scheduled visits. 
j. 
Functional constipation inquiry: At specified visits, subjects will be asked whether they have experienced constipation (per the ROME III criteria and 
Bristol Stool Form Scale; see APPENDIX 2) since the last visit and if yes, whether the constipation required intervention. If the subject answers yes, 
sites are instructed to ask subjects to provide event date and ensure the event is documented as an AE and treatment is documented as concomitant 
medication.  
k. 
Clinical observations include: collection of vital signs, review of spontaneous AEs, and concomitant medications. These assessments will be performed 
by a Home Health Care nurse and/or telemedicine over telephone or through video chat. Vital signs measurements should be measured at scheduled 
visits, while the subject is supine and standing after 2 minutes. BP includes systolic and diastolic BP and is to be taken in the same arm for the duration 
of the study. Beginning with Day 1, orthostatic vital signs should occur 2 (±1) hours after morning dosing whenever possible.  
l. 
See Pharmacy Manual for details on KarXT dispensing and compliance evaluation. 
m. 
A single PK blood sample will be collected in the morning before dosing on Days 84, 168.  
n. 
It is recommended, if at all possible, that the PANSS assessment should be performed before all the other scale assessments for all visits at which it is 
performed. The PANSS assessment includes the Marder Factor. 
o. 
The 
C-SSRS administration. At the Unscheduled visit, the C-SSRS should be performed to monitor subjects 
for suicidality. 
p. 
EMA will be completed by the subject at home on a cellular device 3 times per day for 7 days starting the day after the study visit. 
q. 
Cognitive insight will be completed by the subject at home on a cellular device 1 time per day for 7 days starting the day after the study visit. Refer to 
study Operational Manual for details. 
r. 
Digital biomarkers of schizophrenia will be calculated through completion of a smartphone-based assessment daily by the subject for 3 days after each 
remote study visit beginning the day after Visit 2. 
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1 
FINAL CLINICAL STUDY PROTOCOL  
Karuna Therapeutics 
Protocol Title: An Open-label Extension Study to Assess the Long-term Safety, 
Tolerability, and Efficacy of KarXT in Subjects with DSM-5 Schizophrenia
Protocol Number: KAR-008
IND Number:
127471
EudraCT Number: 
Not applicable
Name of Investigational Product:
KarXT 
Phase of Development:
Phase 3
Indication:
Schizophrenia
Sponsor:
Karuna Therapeutics
33 Arch Street 
Suite 3110 
Boston, MA 02110 
Tel: 
 
Email: 
 
Protocol Version:  
2.0 
Protocol Date:
23 Oct 2020 
-CONFIDENTIAL-
This document and its contents are the property of and confidential to Karuna Therapeutics. Any unauthorized 
copying or use of this document is prohibited. 
 
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PROTOCOL APPROVAL SIGNATURES
Protocol Title:
An Open-label Extension Study to Assess the Long-term Safety,
Tolerability, and Efficacy of KarXT in Subjects with DSM-5 
Schizophrenia
Protocol Number:
KAR-008
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Council for Harmonisation (ICH) guidelines for current 
Good Clinical Practice (GCP), and applicable regulatory requirements.
Sponsor Signatory
Karuna Therapeutics
Signature
Date (DD-Mmm-Y
Karuna Therapeutics
Signature
Date (DD-Mmm-YYYY)
Contract Research Organization Signatory 
Syneos Health
Signature
Date (DD-Mmm-YYYY
Biostatistician
Veristat
Signature
Date (DD-Mmm-YYYY
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INVESTIGATOR SIGNATURE PAGE
Protocol Title:
An Open-label Extension Study to Assess the Long-term Safety, Tolerability,
and Efficacy of KarXT in Subjects with DSM-5 Schizophrenia
Protocol Number: 
KAR-008
Confidentiality and Current Good Clinical Practice (GCP)/E6(R2) Compliance Statement  
I, the undersigned, have reviewed this protocol (and amendments), including appendices, 
and I will conduct the study as described in compliance with this protocol (and 
amendments), and relevant International Council for Harmonisation (ICH) guidelines 
including GCP and applicable regulatory requirements. 
 I am thoroughly familiar with the appropriate use of the KarXT, as described in this 
protocol and any other information provided by Karuna Therapeutics including, but not 
limited to, the current investigator’s brochure. 
 Prior to initiating the trial, I will provide the independent ethics committee 
(IEC)/institutional review board (IRB) all items subject to review and will obtain a 
written and dated approval/favorable opinion. Once the protocol has been approved by 
the IEC/IRB, I will not modify this protocol without obtaining prior approval of Karuna 
Therapeutics and of the IEC/IRB. I will submit the protocol amendments and/or any 
informed consent form modifications to Karuna Therapeutics and the IEC/IRB, and 
approval will be obtained before any amendments are implemented.
 I ensure that all persons or party assisting me with the study are adequately qualified and 
informed about the Karuna Therapeutics KarXT and of their delegated study-related 
duties and functions as described in the protocol. I will supervise these delegated persons 
or parties in the conduct of this trial. 
 I ensure that source documents and trial records that include all pertinent observations on 
each of the site’s trial subjects will be attributable, legible, contemporaneous, original, 
accurate, and complete.  
 I understand that all information obtained during the conduct of the study with regard to 
the subjects’ state of health will be regarded as confidential. No subjects’ names will be 
disclosed. All subjects will be identified by assigned numbers on all case report forms, 
laboratory samples, or source documents forwarded to the Sponsor. Clinical information 
may be reviewed by the Sponsor or its agents or regulatory agencies. Agreement must be 
obtained from the subject before disclosure of subject information to a third party.
 Information developed in this clinical study may be disclosed by Karuna Therapeutics to 
other clinical investigators, regulatory agencies, or other health authority or government 
agencies as required. 
<Name>
<Title>
Investigator Signature 
Date (DD-Mmm-YYYY) 
Institution
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2
SYNOPSIS
Title of Study:
An Open-label Extension Study to Assess the Long-term Safety, 
Tolerability, and Efficacy of KarXT in Subjects with DSM-5 Schizophrenia
Protocol Number:
KAR-008 
Investigators/Study Sites: 
Approximately 30 study sites in the United States and 10 study sites in 
Ukraine 
Phase of Development:
Phase 3
Objective(s):
Primary Objective:
The primary objective of the study is to assess the long-term safety and 
tolerability of KarXT in subjects with a Diagnostic and Statistical 
Manual-Fifth Edition (DSM-5) diagnosis of schizophrenia. 
Secondary Objective: 
The secondary objective of this study is to assess the long-term efficacy and 
monitor trough concentrations of xanomeline and trospium after 
administration of KarXT in adults with a DSM-5 diagnosis of 
schizophrenia: 
 
To evaluate the reduction in Positive and Negative Syndrome Scale 
(PANSS) total score 
 
To evaluate the reduction in PANSS positive score  
 
To evaluate the improvement in Clinical Global Impression-Severity 
(CGI-S) results  
 
To evaluate the reduction in PANSS negative score  
 
To evaluate the reduction in PANSS Marder Factor negative 
symptoms score 
 
To measure trough concentrations of xanomeline and trospium after 
administration of KarXT in adults who are acutely psychotic with a 
DSM-5 diagnosis of schizophrenia 
Exploratory Objective: 
The exploratory objectives of this study are 
 
To evaluate cognition with the Cambridge Neuropsychological Test 
Automated Battery (CANTAB) 
 
To evaluate prolactin levels after administration of KarXT 
 
To evaluate digital biomarkers of schizophrenia 
 
To evaluate ecological momentary assessment administered patient 
reported outcomes (EMA PRO) in schizophrenia 
 
To evaluate cognitive insight using an EMA administered verbal 
learning and memory test (EMA VLMT) in schizophrenia 
Study Endpoints: 
Primary safety endpoint: 
The primary safety endpoint is the incidence of treatment-emergent adverse 
events (TEAEs) 
Secondary safety endpoints: 
The secondary safety endpoints of the study are: 
 
Incidence of serious TEAEs 
 
Incidence of TEAEs leading to withdrawal 
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Secondary efficacy endpoints:
 
The secondary efficacy endpoints of the study are: 
 
Change from baseline in PANSS total score at Week 52 
 
Change from baseline in PANSS positive score at Week 52 
 
Change from baseline in PANSS negative score at Week 52 
 
Change from baseline in PANSS Negative Marder Factor score at 
Week 52 
 
Change from baseline in CGI-S score at Week 52 
 
Percentage of PANSS responders (a 30% change in PANSS total 
score) at Week 52  
Other Endpoints:  
Safety endpoints:
The other safety endpoints of the study are: 
 
Spontaneously reported adverse events of special interest (AESIs) 
 
Spontaneously reported procholinergic and anticholinergic symptoms 
 
Change from baseline in Simpson-Angus Rating Scale (SAS) 
 
Change from baseline in Barnes Rating Scale for Akathisia (BARS) 
 
Change from baseline in Abnormal Involuntary Movement Scale 
(AIMS) 
 
Change from baseline in body weight, body mass index (BMI), waist 
circumference  
 
Change from baseline in orthostatic vital signs (supine and standing 
after 2 minutes): blood pressure (systolic and diastolic) and heart rate 
 
Change from baseline in clinical laboratory assessments (hematology, 
clinical chemistry, coagulation, urinalysis, and drug screen) 
 
Change from baseline in 12-lead electrocardiogram (ECG)  
 
Change from baseline in physical examination  
 
Suicidal ideation scale with the use of Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
Pharmacokinetic Endpoint: 
The pharmacokinetic endpoint of the study is measurement of trough 
plasma concentrations of xanomeline and trospium.  
Exploratory Endpoints: 
The exploratory endpoints of the study are:  
 
Change from baseline in cognition measuring core domains of 
impairment in schizophrenia using CANTAB 
 
Change from baseline in prolactin levels 
 
Observed digital biomarkers of schizophrenia (US only) 
 
Observed EMA PRO in schizophrenia (US only) 
 
Observed cognitive insight using EMA VLMT in schizophrenia (US 
only) 
Study Design: 
This is a Phase 3 multicenter, 53-week, outpatient, open-label extension 
(OLE) study to evaluate the long-term safety, tolerability, and efficacy of 
KarXT in subjects with DSM-5 schizophrenia who previously completed 
the treatment period of one of the two Phase 3 double-blind studies, 
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KAR-007 or KAR-009. The study consists of a 52-week OLE treatment 
phase and a 7-day (±3 days) safety follow-up/end-of-study visit after the 
last KarXT dose for subjects who complete the treatment phase and those 
who prematurely discontinue from the study.  
After written informed consent, subjects who have completed the KAR-007 
or KAR-009 Phase 3 acute study and received the last dose of the study 
drug in that trial will be rolled over into the current OLE study. The 
assessments performed on Visit 10 (Day 35) of Studies KAR-007 or 
KAR-009 will be considered as baseline assessments along with any 
additional procedures that will be performed on Day 0 of the current study. 
Any scheduled Day 0 assessments that were not completed on Day 35 of 
the acute study (KAR-007 or KAR-009) must be completed on Day 0 of the 
current study.  
Day 0 of the current study should be completed on the same day as Day 35 
of the acute study after all Visit 10 (Day 35) procedures of the prior study 
KAR-007 or KAR-009 have been completed.  
Twice daily dosing with KarXT will commence in the morning of Day 1. 
Subjects who did not complete the full treatment period, or who early 
terminated Study KAR-007 or KAR-009, will not be eligible to enroll in 
this long-term extension study.  
A total of up to 350 subjects are planned to be enrolled in this study (aged 
18 to 65 years) across approximately 30 study sites in the United States and 
10 study sites in Ukraine. 
In this OLE study, all subjects will receive KarXT for up to 52 weeks. 
Regardless of treatment assignment in the preceding Phase 3 acute study 
(KAR-007 or KAR-009), all subjects will start on a lead-in dose of KarXT 
50/20 (50 mg xanomeline/20 mg trospium) 2 times per day (BID) for the 
first 2 days (Days 1 and 2), followed by KarXT 100/20 BID for the 
remainder of Week 1 (Days 3 to 7). At Visit 3 (Day 8), dosing will be 
titrated upwards to KarXT 125/30 BID unless the subject is continuing to 
experience adverse events (AEs) from the previous dose of KarXT 100/20 
BID. All subjects who are increased to KarXT 125/30 BID, depending on 
tolerability, will have the option to return to KarXT 100/20 BID. 
Re-escalation to 125/30 BID or re-titration in cases in which the subject has 
been off KarXT for a longer period of time (at least a week) is allowed and 
will require a discussion between the principal investigator and the medical 
monitor. Additional changes to KarXT dosing (e.g., temporary dose 
reductions) may be permitted as clinically indicated upon approval by the 
medical monitor.  
Beginning after Visit 5/Day 28, remote interim visits will be completed 
with flexibility between in-clinic visits, approximately once every 4 weeks. 
For interim visits, either a Home Health Care nurse or the study site staff 
will visit the subject to complete the scheduled visit. To augment at-home 
visits, telemedicine should be used at the investigator’s discretion to review 
any information collected during the in-home interim visit.  Also, when 
needed the sites will have the option to schedule a subject for an in-clinic 
visit in lieu of a remote interim visit. 
A safety follow-up/end-of-study/early termination visit (Visit 30/Day 371 
±3 days) will be performed for all subjects after the last dose of KarXT. 
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An Independent Safety Monitoring Committee will be responsible for 
periodically reviewing the safety data from this study and confirming that 
the study may continue. 
Study Population:
Inclusion Criteria:
Individuals must meet all of the following criteria to be included in the 
study: 
1. Subject is aged 18 to 65 years, at time of enrollment into the preceding 
acute study (KAR-007/009).   
2. Subject is capable of providing informed consent.  
a. 
A signed informed consent form must be provided before any 
study assessments are performed. 
b. Subject must be fluent in (oral and written) English (United 
States only) or local language (Ukraine only) to consent. 
3. Subject has completed the treatment period on study drug (through 
Day 35 -2 days) of Studies KAR-007 or KAR-009.  
4. Subject resides in a stable living situation, in the opinion of the 
investigator. 
5. Subject has an identified, reliable informant/caregiver willing to be 
able to address some questions related to certain study visits, if 
needed.   An informant/caregiver may not be necessary if the subject 
has 
 
6. Women of childbearing potential (WOCBP) or men whose sexual 
partners are WOCBP must be sexually abstinent (in line with their 
preferred and usual lifestyle) or willing and able to use at least 1 highly 
effective method of contraception during the study and for at least 
7 days after the last dose of KarXT. Sperm donation is not allowed for 
7 days after the final dose of KarXT. A female subject is considered to 
be a WOCBP after menarche and until she is in a postmenopausal state 
for 12 consecutive months or is otherwise permanently sterile (for 
which acceptable methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy). For the definition and list 
of highly effective methods of contraception, see Appendix 1. 
Exclusion Criteria: 
Subjects will be excluded from the study if 1 or more of the following 
criteria is/are applicable: 
1. 
Risk for suicidal behavior during the study as determined by the 
investigator’s clinical assessment and C-SSRS as confirmed by the 
following:  
a. 
Subject answers “Yes” to “suicidal ideation” Item 4 (active 
suicidal ideation with some intent to act, without specific 
plan) or Item 5 (active suicidal ideation with specific plan and 
intent) on the C-SSRS.  
b. Nonsuicidal self-injurious behavior is not exclusionary. 
2. 
Any clinically significant abnormality, including any finding(s) from 
the physical examination, vital signs, ECG, or laboratory test at the 
end-of-treatment visit of Studies KAR-007 or KAR-009 that the 
investigator, in consultation with the medical monitor, would consider 
to jeopardize the safety of the subject. 
3. 
Female subject is pregnant. 
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4.
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 his/her ability to adhere to the protocol 
visit schedule or fulfill visit requirements. 
5.
Subjects with extreme concerns relating to global pandemics such as 
coronavirus disease 2019 (COVID-19) that preclude study 
participation. 
6.
Risk of violent or destructive behavior.
7. 
Subjects participating in another investigational drug or device trial or 
planning on participating in another clinical trial during the course of 
the study. 
Planned Sample Size: 
A total of approximately 350 subjects are planned to be enrolled in this 
study.  
Investigational Therapy:
1.
Fixed dose KarXT 50/20 BID (50 mg xanomeline/20 mg trospium) 
oral (Days 1 to 2) 
2.
Fixed dose KarXT 100/20 BID (100 mg xanomeline/20 mg trospium) 
oral (Days 3 to 7) 
3. Fixed dose KarXT 125/30 BID (125 mg xanomeline/30 mg trospium) 
oral (Days 8 to 364, if tolerated)  
Reference Therapy: 
Not applicable. 
Treatment Duration:
Total study duration is up to 53 weeks, including a 52-week treatment 
phase and a 7-day follow-up/end-of-study phase. 
Safety assessments: 
Spontaneous AEs including AESIs; procholinergic and anticholinergic 
symptoms, serious AEs (SAEs) and AEs leading to discontinuation of 
KarXT; SAS; BARS; AIMS; body weight; BMI; waist circumference; 
orthostatic vital signs; clinical laboratory assessments (hematology, clinical 
chemistry, coagulation, urinalysis, and drug screen); 12-lead ECG; physical 
examination; and C-SSRS will be evaluated throughout the study as 
scheduled. 
Efficacy assessments:
PANSS total score, PANSS positive score, PANSS negative score, PANSS 
Negative Marder Factor score, and CGI-S score will be evaluated at 
scheduled visits. 
Pharmacokinetic assessment: 
Trough concentrations at scheduled visits.
Exploratory assessments
Cognition testing using CANTAB; prolactin levels; digital biomarkers of 
schizophrenia; EMA PRO and EMA VLMT will be evaluated during 
scheduled visits or on specified study days. 
Statistical Methods and 
Planned Analyses: 
Study Populations:
Enrolled population: All subjects who have given informed consent for 
KAR-008. 
Safety population: All subjects who receive at least 1 dose of KarXT during 
the current study will be included in the safety population and will be used 
in the safety analysis. 
Modified ITT (mITT) population: All subjects who are enrolled, received at 
least 1 dose of KarXT during the current study, have a valid PANSS 
assessment at KAR-008 baseline will be included in the mITT population 
and will be used in the efficacy analysis. 
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PK population: All subjects who have received at least 1 dose of KarXT
and have at least 1 measurable plasma concentration in the current study 
will be included in the PK population. 
The primary safety endpoint of the study is the incidence of TEAEs. 
Secondary safety endpoints are the incidence of serious TEAEs and the 
incidence of TEAEs leading to withdrawal of KarXT.  
The secondary efficacy endpoints are change from baseline to Week 52 in 
the PANSS total score, PANSS positive score, PANSS negative score, 
PANSS Negative Marder Factor score, CGI-S score, and the percentage of 
PANSS responders at Week 52.  
The exploratory endpoints of the study are change from baseline in 
cognition (CANTAB), prolactin levels, digital biomarkers, EMA PRO, and 
EMA VLMT. 
Descriptive statistics will be used to provide an overview of the safety and 
efficacy results. For continuous parameters, descriptive statistics will 
include n, mean, median, standard deviation, minimum and maximum; For 
categorical parameters, the number and percentage of subjects in each 
category will be presented. The denominator for percentages will be based 
on the number of subjects appropriate for the purposes of analysis. No 
statistical hypothesis testing will be performed. 
 
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3
TABLE OF CONTENTS
1
FINAL CLINICAL STUDY PROTOCOL ...................................................................1
2
SYNOPSIS........................................................................................................................4
3
TABLE OF CONTENTS..............................................................................................10
3.1
List of In-text Tables ..................................................................................................14
3.2
List of In-text Figures.................................................................................................14
4
LIST OF ABBREVIATIONS.......................................................................................15
5
INTRODUCTION.........................................................................................................18
5.1
Background on Schizophrenia....................................................................................18
5.2
Background on KarXT (Xanomeline Tartrate and Trospium Chloride)....................18
Nonclinical Studies ............................................................................................20
Completed Clinical Studies................................................................................23
5.3
Clinical Risks/Benefits of KarXT and Study Rationale.............................................32
6
STUDY OBJECTIVES AND ENDPOINTS ...............................................................35
6.1
Study Objectives.........................................................................................................35
Primary Objective ..............................................................................................35
Secondary Objective ..........................................................................................35
Exploratory Objectives ......................................................................................35
6.2
Study Endpoints..........................................................................................................35
Primary Safety Endpoint....................................................................................35
Secondary Endpoints..........................................................................................36
6.2.2.1
Safety Endpoints ..........................................................................................36
6.2.2.2
Efficacy Endpoints .......................................................................................36
Other Endpoints .................................................................................................36
6.2.3.1
Safety Endpoints ..........................................................................................36
6.2.3.2
Pharmacokinetic Endpoint ...........................................................................36
6.2.3.3
Exploratory Endpoints..................................................................................37
7
INVESTIGATIONAL PLAN.......................................................................................38
7.1
Description of Overall Study Design and Plan...........................................................38
7.2
Discussion of Study Design........................................................................................41
7.3
End of Study...............................................................................................................41
7.4
Independent Safety Monitoring Committee...............................................................42
8
SELECTION OF STUDY POPULATION.................................................................43
8.1
Inclusion Criteria........................................................................................................43
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8.2
Exclusion Criteria.......................................................................................................43
8.3
Safety Laboratory Evaluations for Eligibility ............................................................44
8.4
Study Withdrawal, Removal, and Replacement of Subjects......................................44
Pregnancy...........................................................................................................46
8.5
Completion of the Study or Lost to Follow-up ..........................................................47
8.6
Study Termination......................................................................................................47
9
TREATMENTS .............................................................................................................48
9.1
Details of Study Treatments.......................................................................................48
Identity of Study Treatments..............................................................................48
Packaging and Labeling.....................................................................................49
KarXT Storage ...................................................................................................49
KarXT Retention................................................................................................49
9.2
Dosage Schedule ........................................................................................................49
Day 0..................................................................................................................50
Visit 1/Day 1 Dosing..........................................................................................50
Visit 2/Day 3 Dosing..........................................................................................50
Visit 3/Day 8 ......................................................................................................50
Visit 4/Day 14 Dosing and PK Considerations..................................................51
Visits 5-29 Dosing and PK Considerations........................................................51
9.3
Measures to Minimize Bias: Study Treatment Assignment.......................................52
Method of Study Treatment Assignment...........................................................52
Blinding..............................................................................................................52
9.4
Dosage Modification ..................................................................................................52
Dose Modifications and PK Sampling Considerations......................................52
Extended Dosing Interruptions and Re-titration ................................................52
9.5
Treatment Accountability and Compliance................................................................53
9.6
Prior and Concomitant Therapy .................................................................................53
Prior and Concomitant Medications ..................................................................53
Concomitant Medications for Anxiety and/or Sleep Aid...................................54
10
STUDY PROCEDURES...............................................................................................55
10.1
Informed Consent .......................................................................................................62
10.2
Study Procedures........................................................................................................62
AiCure Adherence Technology .........................................................................62
11
SAFETY ASSESSMENTS............................................................................................65
11.1
Demographics, Medical History, and Psychiatric History.........................................65
11.2
Vital Signs ..................................................................................................................65
11.3
Complete/Targeted Physical Examination .................................................................65
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11.4
Weight, Height, Body Mass Index, and Waist Circumference ..................................66
11.5
Electrocardiograms.....................................................................................................66
11.6
Laboratory Assessments.............................................................................................66
11.7
Adverse Events...........................................................................................................68
Adverse Events ..................................................................................................68
Adverse Events of Special Interest ....................................................................70
Serious Adverse Events .....................................................................................70
Serious Adverse Event Reporting......................................................................71
Drug-Induced Liver Injury.................................................................................71
11.7.5.1
Trial Discontinuation Criteria Other than DILI and Pregnancy...................72
11.7.5.2
Individual Stopping Criteria.........................................................................72
11.7.5.3
Trial Stopping Rules.....................................................................................72
Suspected Unexpected Serious Adverse Reactions ...........................................73
Warnings and Precautions..................................................................................73
11.8
Pregnancy ...................................................................................................................74
11.9
Overdose.....................................................................................................................75
11.10 Simpson-Angus Rating Scale.....................................................................................76
11.11 Barnes Rating Scale for Akathisia..............................................................................76
11.12 Abnormal Involuntary Movement Scale ....................................................................76
11.13 Columbia-Suicide Severity Rating Scale ...................................................................76
11.14 Functional Constipation Inquiry.................................................................................76
12
EFFICACY ASSESSMENTS.......................................................................................78
12.1
Positive and Negative Syndrome Scale......................................................................78
12.2
Clinical Global Impression-Severity..........................................................................78
13
PHARMACOKINETICS..............................................................................................79
13.1
Pharmacokinetic Sampling.........................................................................................79
PK Blood Samples and Timing..........................................................................79
PK Blood Samples and KarXT Dosing Changes...............................................79
13.2
Pharmacokinetic Analytical Methodology.................................................................79
14
EXPLORATORY ASSESSMENTS ............................................................................80
14.1
Cognition Testing - Cambridge Neuropsychological Test Automated Battery .........80
14.2
Change in Prolactin ....................................................................................................80
14.3
Digital Biomarkers of Schizophrenia (US only) ........................................................81
14.4
EMA Wellness Assessments......................................................................................81
EMA Wellness – EMA PRO (US only).............................................................81
EMA Wellness - VLMT (US only)....................................................................82
Data Collected on EMAW Platform ..................................................................82
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15
STATISTICAL ANALYSIS.........................................................................................83
15.1
Determination of Sample Size....................................................................................83
15.2
Analysis Populations ..................................................................................................83
15.3
Safety Analysis...........................................................................................................83
15.4
Efficacy Analysis........................................................................................................84
15.5
Pharmacokinetic Analysis ..........................................................................................84
15.6
Exploratory Analysis..................................................................................................84
15.7
Interim Analysis .........................................................................................................84
15.8
Handling of Missing Data ..........................................................................................85
16
STUDY MANAGEMENT ............................................................................................86
16.1
Approval and Consent ................................................................................................86
Regulatory Guidelines........................................................................................86
Institutional Review Board/Independent Ethics Committee..............................86
Informed Consent...............................................................................................86
16.2
Data Handling.............................................................................................................87
16.3
Source Documents......................................................................................................88
16.4
Record Retention........................................................................................................88
16.5
Monitoring..................................................................................................................88
16.6
Quality Control and Quality Assurance .....................................................................89
16.7
Protocol Amendment and Protocol Deviation............................................................89
Protocol Amendment .........................................................................................89
Protocol Deviations............................................................................................89
16.8
Ethical Considerations................................................................................................90
16.9
Financing and Insurance.............................................................................................90
16.10 Publication Policy/Disclosure of Data........................................................................90
17
REFERENCES ..............................................................................................................91
18
APPENDICES................................................................................................................94
Appendix 1:
Contraception Guidelines.................................................................................94
Appendix 2:
Functional Constipation Inquiry ......................................................................96
Appendix 3:
Alternative Procedures During COVID-19 Pandemic-Related Physical 
Distancing ........................................................................................................98
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3.1
List of In-text Tables 
Table 1.
Study Drug Dosing Scheme ....................................................................................40
Table 2.
Schedule of Assessments ........................................................................................56
Table 3.
Laboratory Assessments..........................................................................................67
Table 4.
Classification of Adverse Events by Intensity ........................................................69
Table 5.
Classification of Adverse Events by Relationship to KarXT..................................69
Table 6.
Cognitive Tests and Cognitive Domains Assessed by the Cambridge 
Neuropsychological Test Automated Battery.........................................................80
3.2
List of In-text Figures
Figure 1. Change from Baseline in PANSS Total Scores (KAR-004) ...................................28
Figure 2. Change from Baseline in PANSS-Positive Scores (KAR-004) ..............................29
Figure 3. Change from Baseline in CGI-S (KAR-004) ..........................................................30
Figure 4. Change from Baseline in PANSS-Negative Scores (KAR-004).............................31
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4
LIST OF ABBREVIATIONS
Abbreviation 
Definition
AD 
Alzheimer’s disease
AE
adverse event
AESI
adverse event of special interest
AIMS
Abnormal Involuntary Movement Scale
ALT 
alanine aminotransferase 
APD
antipsychotic drug
AST 
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC0-12
area under the plasma concentration-time curve from 0 to 12 hours
AUC0-24
area under the plasma concentration-time curve from 0 to 24 hours 
BACS 
Brief Assessment of Cognition in Schizophrenia 
BARS 
Barnes Akathisia Rating Scale
BID
twice daily 
BMI 
body mass index
BP
blood pressure
CANTAB
Cambridge Neuropsychological Test Automated Battery
CFR
Code of Federal Regulations 
CGI-S 
Cmax 
maximum plasma concentration 
CNS 
central nervous system
COVID-19
coronavirus disease 2019
C-SSRS
Columbia-Suicide Severity Rating Scale 
DSM-5
EDC
electronic data capture
ECG
electrocardiogram 
EOS 
end of study 
EOT 
end of treatment 
ET
early termination
eCRF 
electronic case report form 
EMA 
Ecological Momentary Assessment 
EMAW
Ecological Momentary Assessment Wellness 
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Abbreviation 
Definition
EPS
extrapyramidal symptoms
ET
early termination
FDA
Food and Drug Administration
GCP 
Good Clinical Practice
GI
gastrointestinal 
HIPAA
Health Insurance Portability Accountability Act
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IRB
Institutional Review Board
ITT
intent-to-treat 
IWRS
interactive web response system 
IXRS 
interactive response system
MCC 
microcrystalline cellulose
MedDRA
Medical Dictionary for Regulatory Activities
MINI 
Mini International Neuropsychiatric Interview 
mITT
modified intent-to-treat
MMRM
mixed model repeated measures
OLE 
open-label extension
PANSS 
Positive and Negative Syndrome Scale
PI 
principal investigator
PK
pharmacokinetic(s)
PRO 
patient reported outcome 
SAS
Simpson-Angus Rating Scale 
SAE 
serious adverse event 
SAP
statistical analysis plan 
SAS
Simpson Angus Scale 
SUSAR
suspected unexpected serious adverse reaction
TEAE 
treatment-emergent adverse event
TID
thrice daily 
TK
toxicokinetic
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Abbreviation 
Definition
Tmax
time to maximum observed plasma concentration
ULN
upper limit of normal 
US
United States
VAS
visual analog scale
VLMT
Verbal Learning and Memory Test
WOCBP
women of childbearing potential
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5
INTRODUCTION 
5.1
Background on Schizophrenia
Schizophrenia is a long-term mental disorder involving a breakdown in the relation between 
thought, emotion, and behavior, and leads to faulty perception, inappropriate actions and 
feelings, withdrawal from reality and personal relationships into fantasy and delusion, and a 
sense of mental fragmentation. Symptoms include delusions, hallucination, disorganized speech 
or behavior, and impaired cognitive ability.[1] The prevalence of schizophrenia is between 0.6% 
and 1.9% in the United States population.[2] Moreover, a claims analysis has estimated that the 
annual prevalence of diagnosed schizophrenia in the United States (US) is 5.1 per 1000 lives.[3] 
It is found equally in males and females, with males usually having an earlier onset of 
symptoms.[4]  
Antipsychotic drugs (APDs) are the mainstay of treatment for schizophrenia.[5] All currently 
available antipsychotics act through blockage of all or subsets of dopamine receptors in the 
brain. First-generation APDs include chlorpromazine and haloperidol; treatment with these 
agents is marked by high rates of parkinsonian extrapyramidal symptoms (EPS) and tardive 
dyskinesia and they consequently have limited use today. The second-generation agents, that 
include risperidone, olanzapine, quetiapine, lurasidone, aripiprazole, and lumateperone, tend to 
have lower levels of EPS or tardive dyskinesia and are currently the most commonly prescribed 
APD class. However, the second-generation drugs also have problematic side effects that include 
significant weight gain, metabolic disturbances, sedation, and akathisia.[6, 7, 8] These side 
effects contribute to poor medication adherence resulting in frequent relapses and 
hospitalizations.[9, 10] Thus, there is a need for medications for schizophrenia which act through 
alternative mechanisms. 
Central muscarinic receptors have been hypothesized to be therapeutic treatments for 
schizophrenia based on several converging lines of evidence including both animal and human 
studies.[11, 12] There are 5 subtypes of muscarinic receptors (M1-M5). The therapeutic effect of 
central muscarinic receptor agonism is thought to be due to agonism of M1 and M4 receptors in 
the central nervous system (CNS).[13] However, compounds that agonize M1 and M4 receptors 
are often not specific enough not to also agonize M2 and M3 receptors outside of the CNS due to 
the highly conserved allosteric binding sites that the receptors share, leading to adverse events 
(AEs) related to activation of these peripheral receptors. Thus, any potential benefit of 
muscarinic agonists in schizophrenia (or other indications such as Alzheimer’s disease [AD]) has 
been outweighed by the occurrence of AEs associated with peripheral cholinergic side effects 
(nausea, vomiting, diarrhea, sweating, and excess salivation).
5.2
Background on KarXT (Xanomeline Tartrate and Trospium Chloride)
Xanomeline tartrate is a muscarinic-cholinergic receptor agonist. It has agonistic activity at all 
5 muscarinic receptors, but preferentially stimulates M1 and M4 receptors and binding to M1 and 
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M4 receptors in the CNS, which is thought to be responsible for the drug’s potential therapeutic 
effects (Roth, unpublished data). A recent study reports that xanomeline is a very potent M4
muscarinic agonist in vivo, measured by various second messenger assays.[14] Xanomeline also 
enters the brain rapidly achieving a brain to plasma ratio of greater than 10 making it an 
attractive CNS drug candidate.[15]  
Xanomeline does not have any direct binding activity on dopaminergic receptors, suggesting that 
its mechanism of action is unrelated to direct dopamine involvement. 
Previous double-blind, placebo-controlled clinical trials have provided strong evidence that 
xanomeline has clinically relevant antipsychotic efficacy. In a multicenter outpatient trial in AD 
(N = 343), 3 doses of xanomeline (up to 225 mg/day) and placebo were assessed for 
26 weeks.[16, 17] Significant dose-dependent improvements in psychotic symptoms relative to 
placebo were observed. Moreover, psychotic symptoms resolved quite rapidly in subjects who 
were symptomatic at baseline and a dose-dependent reduction in the emergence of psychotic 
symptoms versus placebo was also observed. In a completer analysis, cognitive improvement 
was also found suggesting longer treatment intervals may be necessary for cognitive 
enhancement.[16, 17] In a subsequent small (N = 20) double-blind, placebo-controlled inpatient 
trial in treatment-resistant subjects with schizophrenia, xanomeline (225 mg/day) demonstrated 
robust and relatively rapid improvement in psychosis compared to placebo. In addition, 
improvement in both negative symptoms and cognitive impairment was observed.[18] 
In both the AD and schizophrenia trials, as well as in previous healthy volunteer studies, 
dose-dependent “cholinergic” AEs were also reported, namely vomiting, nausea, diarrhea, 
sweating, and hypersalivation. These side effects were frequent and, at the higher doses of 
xanomeline, led to significant rates of discontinuation in the AD studies. This “cholinergic” AE 
profile curtailed further development of xanomeline as a single agent.  
It is believed that the procholinergic AEs associated with xanomeline are mediated by 
xanomeline’s stimulation of peripheral rather than central muscarinic receptors, which would 
make these AEs theoretically amenable to counteracting peripheral anticholinergic treatment. 
Trospium chloride is a peripherally acting muscarinic antagonist which binds to and antagonizes 
all 5 muscarinic receptor subtypes.[19] It is a commonly used generic drug approved for over 10 
years by the US Food and Drug Administration (FDA) and by European authorities to treat 
overactive bladder and is generally well tolerated.[19] Several human subject studies have 
demonstrated that trospium does not appreciably cross the blood-brain barrier, consistent with 
the drug’s quaternary ammonium structure.[20]  
KarXT is a novel combination of xanomeline tartrate and trospium chloride. Karuna 
hypothesized that the addition of trospium would mitigate peripheral procholinergic side effects 
(vomiting, nausea, diarrhea, sweating, and hyper-salivation) and thus provide a strategy to allow 
xanomeline to be administered and stimulate brain muscarinic receptors with a decreased side 
effect burden. Phase 1 studies in healthy volunteers of this combination demonstrated that 
KarXT reduced these side effects by 46% compared to xanomeline alone.[21] Moreover, the 
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remaining cholinergic AEs were generally mild to moderate in severity and transient in nature, 
often lasting a few hours without recurrence and were generally single-episode. In general, 
KarXT was well tolerated in healthy adult volunteers. These encouraging safety data prompted 
further work to assess KarXT for the treatment of schizophrenia and potentially other CNS 
disorders.
Karuna has recently completed an adequate and well-controlled, randomized, multi-center 
Phase 2, placebo-controlled, inpatient clinical trial of acute psychosis with schizophrenia in 
182 adult subjects (KAR-004). KarXT demonstrated a statistically significant and clinically 
meaningful 11.6 point mean reduction in total Positive and Negative Syndrome Scale (PANSS) 
at 5 weeks compared to placebo (p <0.0001), with statistical separation at each time point 
assessed (2, 4 and 5 weeks), and also demonstrated good overall safety and tolerability.
The purpose of the current study is to evaluate the long-term safety and tolerability of KarXT 
(xanomeline 125 mg/trospium 30 mg) administered twice daily (BID) in adult outpatients with 
Diagnostic and Statistical 
-5) diagnosis of schizophrenia. 
Xanomeline is currently not approved or marketed in any country. Trospium is marketed in the 
US and other regions of the world for the treatment of overactive bladder.
Nonclinical Studies
The following is a summary of the important nonclinical safety and toxicology studies. More 
detailed information can be found in the KarXT Investigator’s Brochure (IB).
The acute toxicity of xanomeline tartrate was evaluated in mice and rats. All animals were 
observed for 2 weeks for mortality and clinical signs of intolerance, and then necropsied for 
gross examinations. In-life findings attributed to the test article included excessive 
muscarinic-mediated pharmacology, such as excessive salivation, hypoactivity, ataxia, soft 
stools, exophthalmos, ocular discharge, tremors, and convulsions, with survivors typically 
appearing normal by Day 3 or Day 4. Gross findings at necropsy were generally unremarkable 
(eg, gas-distended or mucous-filled gastrointestinal [GI] tracts after oral dosing).
KarXT-301 was a 14-day, repeat dose study of KarXT in rats where relatively high doses of 
xanomeline and trospium were given, with either xanomeline alone or in combination with 
trospium. Seven groups of 10 rats/sex/group were administered either vehicle (reverse osmosis 
water), xanomeline alone at 37, 75, 150, or 300 mg/kg/day (split into BID doses, every 
12 hours), or xanomeline/trospium combination doses of 150/200 mg/kg/day or 
225/400 mg/kg/day, respectively (split into BID doses, every 12 hours). 
Satellite animals were included for the collection of plasma after the first and last doses for the 
determination of drug concentrations of each parent drug in support of toxicokinetic (TK) 
assessments.
There was no target-organ toxicity revealed by clinical pathology or by gross or microscopic 
assessments. All intolerance could be attributed to recognized pharmacology of either test article. 
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No dose-related ophthalmic observations were noted. Findings were not indicative of specific 
target organ toxicity. In short, no new hazard was identified. 
Clinical observations noted in most animals administered 300 mg/kg/day xanomeline included 
hypoactivity, clear oral discharge, dilated pupils, irregular or labored respiration, and rough 
haircoat, among other observations. These findings are generally consistent with the anticipated 
pharmacology of xanomeline.  
Three TK animals in the low-dose combination group died or were euthanized in extremis. It is 
unclear to what extent the combination treatment effects versus the different handling of these 
animals (including 3 plasma samplings per animal) contributed to these deaths. If gavage 
accidents were involved (as happened with some TK animals), then they were not detected at 
gross necropsy. There was no microscopic evidence of toxicity seen in any toxicity animals in 
this group or in the higher-dose combination group.
Three toxicology and 3 TK animal deaths (total of 6) occurred in the high-dose combination 
group. Two toxicology animals had evidence of gavage accidents. For the third, the cause of 
death was undetermined, and a test article-related effect cannot be ruled out, but esophageal 
muscular degeneration/regeneration is indicated in some dosing-related trauma. If gavage 
accidents were involved, then they were not detected at gross necropsy. There was no evidence 
of target organ microscopic findings in GI tract or any other tissue of any animal, including the 
early death toxicity animals.  
A pharmacodynamics (PD)-mediated reduction in GI motility is consistent with the 
anti-muscarinic effects of trospium on intestinal musculature. Fecal retention, malabsorption, 
cessation of eating, dehydration, and rapid deterioration followed with continued dosing. 
Cessation of dosing in the high-dose combination animals that survived led to rapid recovery, 
implying the deleterious effects had been PD-related. No effects on food consumption were seen 
in any xanomeline-alone group. The lack of microscopic findings in the GI tract of any early 
death or surviving animal implies that the adverse effects were pharmacologically mediated 
rather than direct target organ toxicity.
Twenty-eight Day Repeat-Dose Studies with Xanomeline in Rats and Monkeys: Rats were fed 
xanomeline tartrate at 0, 0.05, 0.1, or 0.2% daily and monkeys were fed xanomeline tartrate daily 
at 0, 5, 12.5, or 30 mg/kg. All animals survived until necropsy. Safety findings in rats included 
reduced body weight in the high-dose group, increases in gamma-glutamyl-transferase, 
cholesterol, and bilirubin, slight decreases in triglycerides, bile duct hyperplasia, higher serum 
potassium (males), and lower serum globulin (females). Findings in monkeys were dose-related 
and included signs of intolerance such as emesis, salivation, diarrhea, hypoactivity, weight loss, 
and treatment-related tachycardia in the high-dose animals. 
Forty-Day Repeat Dose Study of KarXT in Rats (KarXT-302): Six groups of 15 rats/sex/group 
were given vehicle, xanomeline alone at 75 or 150 mg/kg/day, trospium alone at 100 mg/kg/day, 
or xanomeline/trospium combination at doses of 75/50 mg/kg/day or 150/100 mg/kg/day, with 
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all doses split into BID doses. Satellite rats (TK animals) were included for collection of plasma 
after the first and last doses to determine concentrations of each drug. Dosing was initially 
planned to be 90 days, but was terminated after 40 days because of unexpected deaths in the TK 
animals. No target organ toxicity was seen. Safety findings included pharmacologically mediated 
constipation in the trospium alone and combination groups, and mild biliary hyperplasia in the 
high-dose xanomeline-alone and combination groups. There were 4 unscheduled deaths in TK 
animals; 2 in the high-dose xanomeline-alone group (150 g/kg/day) and 2 in the high-dose 
combination group (150 mg/kg/day xanomeline plus 100 mg/kg/day trospium). Both 
xanomeline-only animals had necropsy gross findings of a gavage accident and cause of death 
could not be determined. All toxicology animals survived to their scheduled sacrifice. The 
Sponsor considers that the volume depletion and trauma of multiple bleeds (3 per animal) 
followed by reduced absorption of fluids and nutrients secondary to reduced GI motility with 
continued BID dosing, explains the greater demise of TK animals relative to toxicity animals.  
Based on the results of the 90-day rat toxicology study, oral administration of trospium chloride 
and xanomeline tartrate alone or in combination to Crl:CD(SD) rats BID (12 hours ±60 minutes 
apart) at dosage levels of 25 and 50 mg/kg/dose trospium chloride, 37 and 75 mg/kg/dose 
xanomeline tartrate and a combination of 37/25, 75/25, and 75/50 mg/kg/dose xanomeline 
tartrate/trospium chloride for a minimum of 90 days resulted in minimal to moderate bile duct 
hyperplasia in the livers of the xanomeline tartrate and combination (xanomeline tartrate and 
trospium chloride) group males.  
Although there were no notable differences in the incidence of bile duct hyperplasia when 
comparing the single vs combination groups, there was an increased severity observed in the 
combination group males (specifically the 75/25 and 75/50 mg/kg/dose combination group 
males) when compared to the xanomeline tartrate group males at the terminal euthanasia. The 
bile duct hyperplasia was considered adverse in the high-dose xanomeline tartrate group males 
and in the 75/25 and 75/50 mg/kg/dose combination group males due to instances of moderate 
severity. Therefore, the no-observed-adverse-effect level was considered to be 50 mg/kg/dose for 
trospium chloride, 37 mg/kg/dose for xanomeline tartrate, and 37/25 mg/kg/dose for the 
combination of xanomeline tartrate/trospium chloride. At these doses for males, mean plasma 
AUC0-24 values were 27,700 pg•hr/mL for trospium, 146,000 pg•hr/mL for xanomeline, and 
4510 + 111,000 pg•hr/mL for trospium + xanomeline, respectively, on Day 91. 
At these doses for females, mean plasma AUC0-24 values were 9230 pg•hr/mL for trospium, 
267,000 pg•hr/mL for xanomeline, and 16,700 + 171,000 pg•hr/mL for trospium + xanomeline, 
respectively, on Day 91. The absence of bile duct hyperplasia in females cannot be explained 
from differences in drug exposure. At the recovery euthanasia, bile duct hyperplasia was still 
present, but was limited to minimal severity and there was a decreased incidence in both the 
xanomeline tartrate and combination group males. There was also no notable difference in 
severity between the single vs combination groups at the recovery euthanasia. Given the 
decreased incidence/severity, in combination with the improved histologic appearance of bile 
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ducts at the recovery euthanasia (ie, smaller/flattened epithelium, non-inflammatory, and an 
absence of portal bridging), changes at the recovery euthanasia were consistent with a partial 
resolution of bile duct hyperplasia. With an absence of correlating serum liver enzyme 
elevations, bile acid alterations or hepatocellular degeneration, necrosis or regeneration, and with 
the apparent reversibility following cessation of treatment, these findings appear to have been 
tolerable by the affected animals. Therefore, the maximum tolerated dose was considered to be 
50 mg/kg/dose for trospium chloride, 75 mg/kg/dose for xanomeline tartrate, and 
75/50 mg/kg/dose for the combination of xanomeline tartrate/trospium chloride. 
For males, corresponding mean plasma AUC0-24 values were 27,700 pg•hr/mL for trospium, 
822,000 pg•hr/mL for xanomeline, and 133,000 + 276,000 pg•hr/mL for trospium + xanomeline, 
respectively, on Day 91. For females, corresponding mean plasma AUC0-24 values were 
9230 pg•hr/mL for trospium, 2,090,000 pg•hr/mL for xanomeline, and 17,600 + 
950,000 pg•hr/mL for trospium + xanomeline, respectively, on Day 91.
In summary, no new “combination” findings were discovered; toxicology studies revealed the 
familiar exaggerations of systemic and CNS muscarinic effects that had previously been seen 
with xanomeline or trospium at high doses. Target organ findings with xanomeline alone were 
limited to biliary hyperplasia in the 28-day rat study but not the 28-day or 12-month monkey 
study, though similar findings were described in a 6-month monkey study. With KarXT, biliary 
hyperplasia was not observed in the 14-day rat study but was reported in the 40-day rat study. 
Notably, these hyperplastic findings are not thought to represent pre-neoplastic lesions, because 
they were of low severity; no fibrosis or associated hepatocellular changes, and no significant 
effects were seen on hepatobiliary-related serum chemistry.
Completed Clinical Studies
Refer to the IB for complete information regarding previous clinical studies conducted with 
xanomeline by Eli Lilly, and studies KAR-001, KAR-002, KAR-003 and KAR-004 conducted 
by Karuna Therapeutics using xanomeline with trospium.
To date, more than 840 subjects or volunteers have been exposed to xanomeline tartrate (oral 
formulation, either alone, in combination with trospium, or as the combination drug KarXT) in 
19 completed clinical studies conducted either by Eli Lilly or Karuna Therapeutics, some for as
long as 3 years. In those studies, significant improvements in cognition and reduced psychotic 
symptoms were observed.
A study of xanomeline monotherapy in subjects with schizophrenia was reported in 2008.[18] In 
this pilot study, the effects of xanomeline were examined in 20 schizophrenia subjects utilizing a 
double-blind, placebo-controlled, 4-week study design. Subjects treated with xanomeline did 
significantly better than subjects in the placebo group on Brief Psychiatric Rating Scale total 
scores and PANSS total scores (ie, 24-point change over placebo, p = 0.04). In the cognitive test 
battery, subjects in the xanomeline group showed improvements relative to placebo in some of 
the cognitive domains of verbal learning and short-term memory function. These studies 
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demonstrated the potential for xanomeline as a treatment for psychosis and cognition across 
multiple subject populations. 
Study H2Q-EW-E001, conducted by Eli Lilly, had 36 male healthy volunteers in 4 groups of 9, 
who were administered escalating single doses of xanomeline tartrate in increments of 1, 5, 10, 
25, 50, 75, 100 and 150 mg. Each group took 2 ascending doses of xanomeline tartrate and 1 
dose of placebo in a single subject blind manner. There were no serious AEs (SAEs). Adverse 
events included watery diarrhea, nausea, dizziness, sweating, shivering, mild disorientation, 
increased blood pressure (BP), increase(s) in sitting and standing heart rate, slight increase in 
supine systolic BP, and postural hypotension. 
The clinical experience with KarXT initiated by Karuna Therapeutics to date includes 
3 completed Phase 1, clinical pharmacology studies in healthy volunteers (KAR-001, KAR-002,
and KAR-003) and one completed Phase 2 study (KAR-004) in adult inpatients with DSM-5 
schizophrenia.
The first study conducted by Karuna, KAR-001 was a Phase 1, double-blind, randomized, 
multiple-dose, pilot study comparing xanomeline administered alone to xanomeline administered
in combination with trospium chloride in normal healthy volunteers. This study consisted of 
2 arms, in which xanomeline was administered three times daily (TID), alone, at a total daily 
dose of 225 mg in 1 arm, and the second arm received the same dose of xanomeline in 
combination with trospium chloride 20 mg administered BID, a total daily dose of 40 mg. 
Subjects were treated for 7 days. The goal was to determine whether this dosing regimen would 
reduce the cholinergic side effects of xanomeline by co-administration of the muscarinic 
antagonist, trospium. 
Overall, treatment with xanomeline 225 mg daily + trospium 40 mg daily administered over 
7 days was considered safe and well tolerated. The results of key and supportive endpoints 
showed a numerical reduction (although not statistically significant) in visual analog scale (VAS) 
scores for cholinergic events for the xanomeline + trospium treatment arm compared to the 
xanomeline-alone treatment arm. Specifically, consistent numerical reduction in VAS scores for 
the xanomeline + trospium treatment arm was observed for the supportive endpoints of 
maximum weekly individual VAS scores and mean daily maximum composite VAS scores.  
Results of the clinician-administered scales were supportive of a reduction in vomiting, feelings 
of nausea, excess salivation, and sweating that interfered with daily activities in the 
xanomeline + trospium treatment arm compared to the xanomeline-alone treatment arm. 
There were no meaningful differences between treatment groups in heart rate, resting BP, 
orthostatic BP or any electrocardiogram (ECG) parameters including QT. A small subset of 
subjects in both treatment arms had transient increases in heart rate and orthostatic BP changes 
which may have contributed to syncope and postural dizziness in those subjects. Two subjects 
(both in the xanomeline-alone arm) experienced syncope. The incidence of orthostatic AEs in the 
KarXT group was approximately one-half that of subjects in the xanomeline-alone group. 
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The most commonly reported treatment-emergent AEs (TEAEs) in KAR-
in either treatment arm) were hyperhidrosis, salivary hypersecretion, nausea, dizziness postural, 
and diarrhea. Subject incidences of these 5 TEAEs was higher in the xanomeline-alone treatment 
arm (61.8%) compared to the xanomeline + trospium treatment arm (34.3%). 
Overall, treatment with xanomeline 225 mg combined with trospium chloride 40 mg 
administered over 7 days was considered safe and well tolerated. The observed side effect profile 
was consistent with the known safety profile of xanomeline and trospium chloride. The incidence 
of TEAEs and cholinergic TEAEs was lower in the xanomeline + trospium treatment arm 
compared to the xanomeline-alone treatment arm.
Study KAR-002 was a Phase 1, double-blind, randomized, multiple-dose adaptive design pilot 
study to evaluate the safety and tolerability of KarXT in normal healthy volunteers. Subjects 
received either 100 mg xanomeline + 20 mg trospium BID or placebo. The first cohort of this 
study was stopped after 1.5 days when the FDA put the program on hold due to a preliminary rat 
finding in the 14-day study. This study used a new formulation of KarXT in which xanomeline 
and trospium were combined into a single dose form and given BID. Safety findings included an 
increase in orthostatic complaints. Caution should be used in drawing conclusions from this 
study, as subjects did not have time to reach steady state plasma levels from dosing, as only 
3 doses were given. 
Study KAR-003 was a Phase 1, double-blind, randomized, multiple-dose, adaptive design, 
inpatient pilot study to evaluate the safety and tolerability of KarXT in normal healthy 
volunteers. The primary objective of this study was to assess the safety and tolerability of 7 days 
of daily administration of KarXT at various dose combinations, administered BID. Subjects 
received either KarXT or placebo (3:1 ratio). All subjects on KarXT received 2 days of 50 mg 
xanomeline + 20 mg trospium BID, and then increased to different doses for Days 3 to 7. This 
study also used the new formulation of KarXT in which xanomeline and trospium were 
combined into a single dosage form and given BID.  
There was a relatively high degree of variability in xanomeline and trospium exposures between 
individuals in all cohorts, which is consistent with previous results with KarXT, 
xanomeline-alone, and trospium-alone. Peak plasma concentrations were observed at a median 
time of 2.0 hours for xanomeline and 1.0 hour for trospium across all treatment groups and study 
days.  
Although there was insufficient data to draw a definitive conclusion regarding the impact of 
trospium on the pharmacokinetics (PK) and bioavailability of xanomeline, or the impact of 
xanomeline on the pharmacokinetics and bioavailability of trospium, the PK results suggest that 
neither drug had a meaningful impact on the PK behavior of the other drug. 
During the 2-day lead-
cts) when all the subjects 
completed dosing were dry mouth, nausea, and constipation. For the treatment groups that 
completed dosing, although the incidence of TEAEs was lower in the KarXT 100/20 BID 
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(66.7%) group compared to KarXT 125/40 group (88.9%), the incidence of cholinergic TEAEs 
(nausea, vomiting, diarrhea, sweating, and excess salivation) was similar between the 2 groups. 
The most commonly reported TEAEs ( 20% of subjects in either treatment group) in these 
groups were dizziness, nausea, dry mouth, headache, vomiting, dyspepsia, somnolence, vision 
blurred, and dysuria. For the treatment groups that did not complete dosing (KarXT 150/20 BID 
group and KarXT 150/40 BID group), the cholinergic TEAEs were generally higher compared to 
the treatment groups that completed dosing.  
Overall, anticholinergic TEAEs appeared to occur primarily in the treatment groups that were 
dosed with 40 mg trospium BID (KarXT 150/40 BID and KarXT 125/40 BID groups), 
particularly when paired with 125 mg xanomeline BID, suggesting to consider slightly lowering 
the trospium dose from 40 mg BID in future studies. All TEAEs were mild or moderate in 
severity, and there were no SAEs or deaths. Treatment-emergent AEs were primarily cholinergic 
or orthostatic (and a few anticholinergic). Doses of 100 mg and 125 mg BID of xanomeline were 
well tolerated when paired with 20 mg and 40 mg BID of trospium, respectively. The safety and 
tolerability profile of KarXT 100/20 BID and KarXT 125/40 BID was acceptable and supports 
further evaluation at similar doses in future studies. Doses of KarXT 150/20 BID and 150/40 
BID were not well tolerated in this study. A pairing of 150 mg xanomeline with 40 mg trospium 
appeared to be better tolerated than 150/20, but some subjects still experienced tolerability 
issues. 
Study KAR-004 was a Phase 2 randomized, double-blinded study to assess the safety, 
tolerability, and efficacy of KarXT in adults with DSM-5 schizophrenia, hospitalized with acute 
psychosis. The primary objective of the study was to assess the efficacy of KarXT (125/30 BID) 
versus placebo in reducing PANSS total scores in adult inpatients with a DSM-5 diagnosis of 
schizophrenia. Subjects received either KarXT or placebo (1:1 ratio) for a treatment period of 
5 weeks. All subjects on KarXT received a lead-in dose of KarXT 50/20 BID for the first 2 days 
followed by KarXT 100/20 BID on Days 3 to 7. On Day 8, dosing was titrated upwards to 
KarXT 125/30 BID unless the subject was continuing to experience AEs from a previous dose 
increase of 100/20 BID. 
A total of 182 subjects were enrolled and randomized (92 placebo; 90 KarXT).  Of these 
subjects, 170 (87 [94.6%] placebo; 83 [92.2%] KarXT) received at least one dose of study drug 
and had at least one post-baseline PANSS assessment (Modified Intent to Treat population used 
for the efficacy analyses).  Discontinuation rates were similar between the 2 treatment groups; 37 
subjects discontinued the study early (19 [20.7%] placebo; 18 [20.0%] KarXT). The most 
common reason for early discontinuation was consent withdrawn (14 [15.2%] placebo; 14 
[15.6%] KarXT) followed by Adverse Event (2 [2.2%] placebo; 3 [3.3%] KarXT).
Treatment-emergent adverse events (TEAE) were reported in 43.3% of subjects in the placebo 
group and 53.9% of subjects in the KarXT group.  The most commonly reported TEAEs were 
or twice that of placebo) in the KarXT group than in the placebo group.   
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There were 27.8% and 42.7% of subjects in the placebo and KarXT groups, respectively, who 
experienced at least 1 TEAE related to study drug. The most commonly reported study drug 
related TEAEs for the placebo and KarXT total groups were nausea, constipation, dry mouth, 
dyspepsia, and vomiting and were more 
KarXT group than in the placebo group. The majority of the reported TEAEs were mild (27.8% 
placebo; 36.0% KarXT) or moderate (14.4% placebo; 16.9% KarXT) in severity. Two severe 
TEAEs were reported during the study.  One subject in the placebo group had a severe TEAE of 
worsening schizophrenia symptoms, and 1 subject in the KarXT high dose group had a severe 
event of increased psychosis which was reported as an SAE possibly related to KarXT by the 
investigator.  There were no other SAEs reported during the study and there were no deaths 
during the study.
The pattern and course of safety findings in KAR-004 were consistent with the known safety 
profile from earlier studies of both xanomeline monotherapy and xanomeline combined with 
trospium (KarXT). Even though the qualitative AE profile was consistent with earlier Phase 1 
PK/safety studies in healthy volunteers, the relative tolerability burden was lower in the current 
study of schizophrenia patients receiving KarXT than in the healthy volunteers.  In addition, the 
safety and tolerability of KarXT was favorable and notably free of many common side effects 
associated with current antipsychotic drugs. 
KarXT demonstrated statistically significant and clinically meaningful reduction in total PANSS 
score at all time points over 5 weeks compared to placebo (Figure 1). The primary efficacy 
endpoint result for the study (change from baseline (CFB) in PANSS total score between the 
placebo group and the KarXT group at Visit 9/Week 5) showed a statistically significant 
decrease in PANSS total score (p<0.0001). The statistically significant difference in CFB 
between the treatment groups was there at Visit 6/Week 2 (p<0.0001) and continued to Visit 
8/Week 4 and Visit 9/Week 5. Overall, the decrease from baseline in PANSS total score for the 
KarXT group was statistically significantly greater compared to the placebo group by treatment 
group for Visits 6, 8, and 9 (p<0.0001). 
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Figure 1.
Change from Baseline in PANSS Total Scores (KAR-004)
Abbreviations: LS = least squares; mITT = modified intent-to-treat; PANSS = Positive and Negative Syndrome 
Scale; SEM = standard error of the mean.
A significant reduction in the secondary endpoint of PANSS-positive scores was observed 
(p<0.0001) at Week 5 as well as the 2 earlier time points (ie, Weeks 2 and 4; see Figure 2).
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Figure 2.
Change from Baseline in PANSS-Positive Scores (KAR-004)
Abbreviations: LS = least squares; mITT = modified intent-to-treat; PANSS = Positive and Negative Syndrome 
Scale; SEM = standard error of the mean.
As regards the Clinical Global Impression – Severity of Illness (CGI-S), subjects in the KarXT 
group overall significantly improved in ratings compared to placebo, with a p-value of <0.001 at 
Week 5. At Week 5, 8% of placebo subjects improved (decreased) their CGI-S ratings at least 
2 levels versus 28.9% of KarXT subjects (see Figure 3).
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Figure 3.
Change from Baseline in CGI-S (KAR-004)
Abbreviation: CGI-
A statistically significant reduction in the secondary endpoint of PANSS-negative score was 
observed (p<0.001) at Week 5. Overall, the changes in the KarXT group were statistically 
significantly greater compared to the placebo group at Visits 6, 8, and 9 (p<0.001). The least 
square mean improvement for the placebo group was 1.32 points at Week 5 (Visit 9) and the 
mean improvement for the KarXT group was 3.85 points leading to a mean difference of 
2.53 points at Week 5 (Visit 9; see Figure 4).
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Figure 4.
Change from Baseline in PANSS-Negative Scores (KAR-004)
Abbreviations: LS = least squares; mITT = modified intent-to-treat; PANSS = Positive and Negative Syndrome 
Scale; SEM = standard error of the mean.
The overall safety/tolerability data were also fairly unambiguous; among the highlights: 
The overall discontinuation rate on KarXT was 20%, similar to placebo (21%). The number 
of discontinuations due to TEAEs was equal in the KarXT and placebo arms (N = 2 in each 
group)
The dose escalation rate on KarXT was high and similar to placebo:
o
91% of KarXT subjects escalated to 125/30 KarXT (vs 97% on placebo)
o
4% percent de-escalated back to 100/20 KarXT dose (vs 1% on placebo)
The overall TEAE rate on KarXT was 54% vs 43% on placebo:
o
The most common TEAEs were constipation, nausea, dry mouth, dyspepsia, and 
vomiting. None of these TEAEs were severe and none led to discontinuations
o
One SAE occurred in the study (the subject was on KarXT): the subject discontinued 
treatment and subsequently sought hospital care for worsening psychosis, meeting the 
regulatory definition of an SAE. 
o
No syncope or mean changes in BP were seen
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o A 5.5 bpm peak mean placebo adjusted resting heart rate increase with a downward 
trend after Week 2 was seen
o
One subject (on KarXT) was discontinued due to an elevated gamma-glutamyl 
transpeptidase (GGT)
o There were no new safety findings associated with KarXT that have not been observed 
with either xanomeline alone or trospium alone in previous trials 
 KarXT did not show evidence of many of the kinds of AEs that often occur in currently 
available antipsychotics for the treatment of schizophrenia  
 The rates of the following AEs were similar for KarXT and placebo: somnolence, weight 
gain, and EPS 
 Overall, the KAR-004 results confirm and extend the antipsychotic benefit of xanomeline 
observed in past studies of xanomeline alone and the well tolerated nature of KarXT.  
KAR-004 results support the continued development of KarXT into Phase 3 trials. 
Two randomized, double-blind, placebo-controlled Phase 3 trials (KAR-007 and KAR-009) are 
planned in which the subjects will be exposed to either KarXT or placebo (1:1) for a period of up 
to 5 weeks. Subjects who complete either of these 2 studies will be eligible to roll over into this 
long-term open-label study. 
5.3 
Clinical Risks/Benefits of KarXT and Study Rationale 
The risks and benefits of KarXT in humans are not fully known. KarXT is a fixed dose 
combination of xanomeline and trospium.  
The available clinical trial data indicate that KarXT has robust efficacy and a favorable safety 
profile that appears unique compared to all available APDs. Most of these clinical data were 
generated by subjects who were either “institutionalized” or studied in an “inpatient” hospital 
setting. Treatment with KarXT is not associated with weight gain, sedation, or meaningful EPS 
changes. In contrast, these serious side-effects pose a significant risk with other APD treatments 
for schizophrenia and can lead to discontinuation of treatment and significant morbidity. A Phase 
2 registration quality pivotal trial in 182 subjects met the primary endpoint with the PANSS total 
score showing a 11.6 point mean improvement compared to placebo with a highly significant 
(p < 0.0001) separation from placebo (-17.4 KarXT vs. -5.9 placebo) at Week 5. KarXT, as 
compared to placebo, demonstrated highly significant reduction in PANSS total scores 
(p < 0.0001) at all post randomization time points (Weeks 2, 4 and, 5) with a calculated effects 
size (Cohen’s d) of 0.75. KarXT, as compared to placebo, demonstrated significant improvement 
at all post randomization time points for PANSS positive symptom subscores, PANSS negative 
symptom subscores, PANSS Marder Factor negative symptom subscores, and CGI-S scores.
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Over 840 subjects or volunteers have been exposed to xanomeline tartrate (oral formulation; 
either alone, in combination with trospium, or as the combination drug KarXT) in clinical 
studies. These early clinical studies, as well as nonclinical pharmacology and toxicology studies, 
have not revealed any specific contraindications to the use of xanomeline. The most common 
side effects/symptoms are the cholinergic related effects: nausea, vomiting, excess salivation, 
excess sweating, and diarrhea. In addition, subjects treated with xanomeline alone have reported 
both syncope and orthostatic dizziness. The addition of trospium decreases the peripheral 
cholinergic effect of xanomeline creating a better tolerated therapy. In addition, a titration phase 
also increases the tolerability of KarXT.
Trospium chloride has been marketed in the US for 12 years. The most frequently reported AEs 
reported in pivotal trials were dry mouth, constipation, abdominal pain, headache, urinary 
retention, and abnormal vision and accommodation. For additional information, the package 
insert for trospium chloride tablets for oral use can be found in the IB. 
In a Phase 2 (KAR-004) clinical study, KarXT (100/20 and 125/30) significantly reduced the 
symptoms of schizophrenia in subjects with acute psychosis after treatment for 28 days. KarXT 
also showed an acceptable safety profile with the most common TEAEs being constipation, 
nausea, dry mouth, dyspepsia, and vomiting. All the reported TEAEs were mild or moderate in 
intensity. One SAE (psychotic disorder) was reported by a single subject and no deaths were 
reported in the study. KarXT was generally well-tolerated and found to be safe in this patient 
population. 
KarXT represents a novel approach to the treatment of patients with schizophrenia that will 
provide an important and meaningful alternative to current therapies. The current tolerability and 
AE profile and the efficacy of KarXT justify further development of KarXT in this patient 
population by advancing to Phase 3 trials. Two such Phase 3 trials (KAR-007 and KAR-009) are 
planned where the subjects will receive the study drug (KarXT or placebo) for 5 weeks. 
In the current study, regardless of treatment assignment in the preceding Phase 3 study 
(KAR-007 or KAR-009), all subjects will receive KarXT for a period of approximately 52 weeks 
with the primary objective of assessing the long-term safety and tolerability profile of KarXT in 
an out-patient setting. All subjects will start with a lead-in dose of KarXT 50/20 BID for Days 1 
to 2 and then the dose will be titrated to 100/20 BID for Days 3 to 7, allowing the subject to 
adjust to KarXT before receiving a higher dose of 125/30 BID starting on Visit 3 (Day 8), unless 
the subject is continuing to experience AEs from the previous dose increase of KarXT 100/20 
BID. All subjects who are increased to KarXT 125/30 BID, depending on tolerability, will have 
the option to return to KarXT 100/20 BID. Re-escalation to 125/30 BID or re-titration in cases 
where subject has been off KarXT for a longer period of time (at least a week) is allowed and 
will require a discussion between the principal investigator (PI) and the medical monitor.  
Dosing will occur every 12 ±4.5 hours each day, during waking hours. KarXT should be dosed 
on an empty stomach (ie, at least 1 hour before a meal or 2 to 3 hours after a meal).  
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The current study is designed to demonstrate that long-term treatment with KarXT in adult 
schizophrenia subjects is safe and tolerable. 
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6
STUDY OBJECTIVES AND ENDPOINTS
6.1
Study Objectives
Primary Objective
The primary objective of the study is to assess the long-term safety and tolerability of KarXT in 
subjects with a DSM-5 diagnosis of schizophrenia.
Secondary Objective
The secondary objective of this study is to assess the long-term efficacy and monitor trough 
concentrations of xanomeline and trospium after administration of KarXT in adults with a 
DSM-5 diagnosis of schizophrenia:
To evaluate the reduction in PANSS total score
To evaluate the reduction of PANSS positive score 
To evaluate the improvement in Clinical Global Impression Severity (CGI-S) results 
To evaluate the reduction of PANSS negative score 
To evaluate the reduction of PANSS Marder Factor negative symptoms score
To measure trough concentrations of xanomeline and trospium after administration of 
KarXT in adults who are acutely psychotic with a DSM-5 diagnosis of schizophrenia
Exploratory Objectives
The exploratory objectives of this study are:
To evaluate cognition with the Cambridge Neuropsychological Test Automated Battery 
(CANTAB)
To evaluate prolactin levels after administration of KarXT
To evaluate digital biomarkers of schizophrenia (US only)
To evaluate ecological momentary assessment administered patient reported outcomes 
(EMA PRO) in schizophrenia (US only)
To evaluate cognitive insight using an EMA administered verbal learning and memory 
test (EMA VLMT) in schizophrenia (US only)
6.2
Study Endpoints
Primary Safety Endpoint
The primary safety endpoint of this study is the incidence of treatment-emergent AEs (TEAE).
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Secondary Endpoints
6.2.2.1
Safety Endpoints
The secondary safety endpoints of this study are: 
Incidence of serious TEAEs
Incidence of TEAEs leading to withdrawal
6.2.2.2
Efficacy Endpoints
The secondary efficacy endpoints of this study are:
Change from baseline in PANSS total score at Week 52
Change from baseline in PANSS positive score at Week 52
Change from baseline in PANSS negative score at Week 52
Change from baseline in PANSS Negative Marder Factor score at Week 52
Change from baseline in CGI-S score at Week 52
Percentage of PANSS responders (a 30% change in PANSS total score) at Week 52
Other Endpoints
6.2.3.1
Safety Endpoints
Spontaneously reported adverse events of special interest (AESIs)
Spontaneously reported procholinergic and anticholinergic symptoms
Change from baseline in Simpson-Angus Rating Scale (SAS)
Change from baseline in Barnes Rating Scale for Akathisia (BARS)
Change from baseline in Abnormal Involuntary Movement Scale (AIMS)
Change from baseline in body weight, body mass index (BMI), waist circumference 
Change from baseline in orthostatic vital signs (supine and standing after 2 minutes): BP 
(systolic and diastolic) and heart rate
Change from baseline in clinical laboratory assessments (hematology, clinical chemistry, 
coagulation, urinalysis, and drug screen)
Change from baseline in 12-lead ECG 
Change from baseline in physical examination 
Suicidal ideation scale with the use of Columbia-Suicide Severity Rating Scale (C-SSRS)
6.2.3.2
Pharmacokinetic Endpoint
The PK endpoint of this study is measurement of trough plasma concentrations of xanomeline 
and trospium.
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6.2.3.3 
Exploratory Endpoints
The exploratory endpoints of this study are:  
 Change from baseline in cognition measuring core domains of impairment in 
schizophrenia using CANTAB 
 Change from baseline in prolactin levels 
 Observed digital biomarkers of schizophrenia (US only)
 Observed ecological momentary assessment administered patient reported outcomes 
(EMA PRO) in schizophrenia (US only) 
 Observed cognitive insight using an EMA administered verbal learning and memory test 
(EMA VLMT) in schizophrenia (US only) 
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7
INVESTIGATIONAL PLAN 
7.1
Description of Overall Study Design and Plan
This is a Phase 3 multicenter, 53-week, outpatient, open-label extension (OLE) study to evaluate
the long-term safety, tolerability, and efficacy of KarXT in subjects with DSM-5 schizophrenia 
who previously completed the treatment period of one of the two Phase 3 double-blind studies, 
KAR-007 or KAR-009. The study consists of a 52-week OLE treatment phase and a 7-day
(±3 days) follow-up/end-of-study (EOS) visit after the last KarXT dose for subjects who 
complete the treatment phase and those who prematurely discontinue from the study.  
After written informed consent, subjects who have completed either the KAR-007 or KAR-009 
Phase 3 acute study and received the last dose of the study drug in that trial will be rolled over 
into the current OLE study. The assessments performed on Visit 10 (Day 35) of Studies 
KAR-007 or KAR-009 will be considered as baseline assessments along with any additional 
procedures that will be performed on Day 0 of the current study. Any scheduled Day 0 
assessments that were not completed on Day 35 of the acute study (KAR-007 or KAR-009) must 
be completed on Day 0 of the current study.  
Day 0 of the current study should be completed on the same day as Day 35 of the acute study 
after all Visit 10 (Day 35) procedures of the prior study KAR-007 or KAR-009 have been 
completed.
Subjects who did not complete the full treatment period, or who early terminated studies 
KAR-007 or KAR-009, will not be eligible to enroll in this long-term extension study.   
A total of up to 350 subjects are planned to be enrolled in this study (aged 18 to 65 years at time 
of enrollment into the preceding acute study) across approximately 30 study sites in the United 
States and 10 study sites in Ukraine.  
In this OLE study, all subjects will receive KarXT for up to 52 weeks. Regardless of treatment 
assignment in the preceding Phase 3 acute study (KAR-007 or KAR-009), all subjects will start 
on a lead-in dose of KarXT 50/20 BID for the first 2 days (Days 1 and 2), followed by 
KarXT 100/20 BID for the remainder of Week 1 (Days 3 to 7). On Visit 3 (Day 8), dosing will 
be titrated upwards to KarXT 125/30 BID unless the subject is continuing to experience AEs 
from the previous dose of KarXT 100/20 BID. All subjects who are increased to KarXT 125/30 
BID, depending on tolerability, will have the option to return to KarXT 100/20 BID for the 
remainder of the treatment period. Re-escalation to 125/30 BID or re-titration in cases in which 
the subject has been off KarXT for a longer period of time (at least a week) is allowed and will 
require a discussion between the PI and the medical monitor. Additional changes to KarXT 
dosing (e.g., temporary dose reductions) may be permitted as clinically indicated upon approval 
by the medical monitor. 
Beginning after Visit 5/Day 28, remote interim visits will be completed with flexibility between 
the in-clinic visits, approximately once every 4 weeks. For interim visits, either a Home Health 
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Care nurse or the study site staff will visit the subject to complete the scheduled visit. To 
augment at-home visits, telemedicine should be used at the investigator’s discretion to review 
any information collected during the in-home interim visit. Also, when needed the sites will have 
the option to schedule a subject for an in-clinic visit in lieu of a remote interim visit. 
All subjects will have questionnaires administered throughout the study (see Schedule of 
Assessments Table 2). Analyses of change from baseline in diagnostic measures will be 
performed.
Safety will be assessed through spontaneous AEs including AESIs, procholinergic and 
anticholinergic symptoms; SAEs and AEs leading to discontinuation of KarXT; SAS; BARS; 
AIMS; body weight; BMI; waist circumference; orthostatic vital signs; clinical laboratory 
assessments (hematology, clinical chemistry, coagulation, urinalysis, and drug screen), 12-lead 
ECG; physical examination; and C-SSRS will be evaluated throughout the study as scheduled. 
Section 11 provides complete details on these safety assessments. 
Efficacy will be assessed through PANSS total score, PANSS-positive score, PANSS-negative 
score, PANSS Negative Marder Factor score, and CGI-S score at scheduled visits. Refer to 
Section 12 for more details. 
Details on PK assessments are provided in Section 13 and include monitoring of trough 
concentrations at scheduled visits. 
Exploratory assessments include cognition testing using CANTAB; prolactin levels; digital 
biomarkers of schizophrenia (US Only); Ecological Momentary Assessment (EMA) Patient 
Reported Outcomes (PRO; US Only) and EMA Verbal Learning and Memory Test (VLMT; US 
Only) which will be evaluated during scheduled visits or on specified study days. See Section 14 
for more details.  
A safety follow-up/end of study/ET visit (Visit 30/Day 371) will be performed for all subjects 
after the last dose of KarXT. 
An Independent Safety Monitoring Committee (ISMC) will be responsible for periodically 
reviewing the safety data from this study and confirming that the study may continue. 
Table 1 presents the Study Drug Dosing Scheme. 
 
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Table 1.
Study Drug Dosing Scheme
Period:
Open-Label Extension Treatmenta
End of 
Treatment 
EOS/ET/UNS
Day:
Day 1
Day 3 
+1 day 
Day 8b
±1 day 
Day 14 
±2 days 
Day 28c
±3 days 
Day 56
±3 days 
Days 84
to 350 
±3 days 
Day 364 ±3 
days 
Day 371 ±3 
days 
Visit: 
Visit 1 
Visit 2 
Visit 3 b 
Visit 4 
Visit 5c 
Visit 7 
Visits 9 
to 28 
Visit 29 
Visit 30 
Xanomeline/ 
trospium 
(KarXT)*: 
50/20 BID 
100/20 
BID 
125/30 
BID 
(Option: 
100/20 
BID)d 
125/30 
BID 
(Option: 
100/20 
BID)d,e 
125/30 
BID 
(Option: 
100/20 
BID)d,e 
125/30 
BID 
(Option: 
100/20 
BID)d,e 
125/30 
BID 
(Option: 
100/20 
BID)d,e 
125/30 BID 
(Option: 
100/20 
BID) d,e 
N/A 
Comment(s):
2-day 
lead-in 
dose 
Upward 
titration 
of dose 
Upward 
titration 
of dose 
 
7 (±3) days 
after the last 
dose or for ET 
from the study 
or UNS 
Abbreviations: 
BID = twice daily; EOS = end of study; ET = early termination; N/A = not applicable; PI = principal investigator; UNS = unscheduled. 
* All the KarXT doses are in mg xanomeline/mg trospium. 
a. At Visit 1 (Day 1) subjects will initiate dosing with KarXT BID independently, at home.  Visits 2, 3, 4, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, and 30 
are in-clinic/on-site visits. Visits 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, and 28 are interim visits. 
b. Subject to receive at least 8 doses of KarXT 100/20 prior to escalating to the KarXT 125/30 dose.  
c. Beginning after Visit 5/Day 28, interim visits will be completed with flexibility between in-clinic visits, approximately once every 4 weeks.  
d. All subjects who are increased to KarXT 125/30, depending on tolerability, will have the option to return to KarXT 100/20 BID. 
e. Re-escalation to 125/30 BID or re-titration in cases where subject has been off KarXT for a longer period of time (at least a week) is allowed and will require 
a discussion between the PI and the medical monitor. Additional changes to KarXT dosing (e.g., temporary dose reductions) may be permitted as clinically 
indicated upon approval by the medical monitor. 
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7.2
Discussion of Study Design
The KarXT clinical development program includes this open-label extension study to evaluate 
the long-term safety, tolerability, and efficacy data for KarXT in subjects with schizophrenia
who participated in either of the 2 Phase 3 double-blind clinical studies and completed the 
treatment period without any tolerability/safety issues.
This study will allow subjects that were randomized into a preceding Phase 3 study (KAR-007 or 
KAR-009) to reinstitute (or initiate treatment if a placebo subject) KarXT therapy. Subjects will 
receive KarXT (with the same lead-in dose of KarXT 50/20 BID), regardless of treatment 
assignment from the preceding Phase 3 study. Thus, subjects who received placebo during the 
preceding Phase 3 study who may not have demonstrated clinical benefit, nonetheless, may be 
considered appropriate for the current study, as all subjects will receive KarXT.  
The dosing plan for this study has been established and follows the earlier studies. All eligible 
subjects will receive the same lead-in doses of KarXT (KarXT 50/20 BID). Dosing will be 
titrated to 100/20 BID on Day 3 and further titrated to 125/30 BID on Visit 3 (Day 8), unless the 
subject continues to experience AE(s) from the previous dose increase of KarXT.  
During the study, all subjects who are increased to the highest dose of KarXT, depending on 
tolerability, will have the option to return to the next lower dose of KarXT (100/20 BID). 
Re-escalation to 125/30 BID or re-titration in cases where subject has been off KarXT for a 
longer period of time (at least a week) is allowed and will require a discussion between the PI 
and the medical monitor.  
Beginning after Visit 5/Day 28 (approximately 1 month of KarXT treatment), remote interim 
visits will be completed every 4 weeks between the in-clinic visits, to allow for subject safety 
monitoring and IP dispensing and accountability. For interim visits, either a Home Health Care 
nurse or the study site staff will visit the subject to complete the scheduled visit. To augment 
at-home visits, telemedicine should be used at the investigator’s discretion to review any 
information collected during the in-home interim visit. Also, when needed, the sites will have the 
option to schedule a subject for an in-clinic visit in lieu of a remote interim visit. 
A 52-week treatment phase is considered to be sufficient to demonstrate the long-term safety and 
tolerability of KarXT. A sample size of approximately 350 subjects is also determined to be an 
appropriate number of evaluable subjects to assess the long-term safety of KarXT administration. 
Section 5.2 details the nonclinical and clinical background information available on KarXT, 
including dose rationale.  
7.3 
End of Study 
A subject will have fulfilled the requirements for study completion if/when the subject has 
completed the study treatment, including the EOS visit or the last scheduled visit as indicated in 
the Schedule of Assessments (Table 2) in accordance with the protocol. 
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7.4
Independent Safety Monitoring Committee
For the purpose of this study, the ISMC is an independent group of individuals with pertinent 
expertise that reviews on a regular basis accumulating safety and tolerability data from the 
clinical study. The ISMC will include 3 clinicians and a reporting statistician. This committee 
will be responsible, on a periodic basis, for confirming the safety and tolerability of KarXT 
throughout the study, with particular focus on assessing for any new or long-term toxicities that 
might be involved with KarXT. 
The reviews will allow a comparison of event rates and detection of safety signals, and to 
identify important safety information. The ISMC charter will contain the details of the types of 
data to be reviewed, the defined triggers for review, the minimum frequency of meetings (timed, 
if no triggers), and the communication plan for disseminating review recommendations. 
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8
SELECTION OF STUDY POPULATION 
Section 7.1 provides information regarding the number of subjects planned to be enrolled.
8.1 
Inclusion Criteria 
Individuals must meet all of the following criteria to be included in the study: 
1. Subject is aged 18 to 65 years, at time of enrollment into the preceding acute study 
(KAR-007/009).  
2. Subject is capable of providing informed consent. 
a. A signed informed consent form must be provided before any study assessments 
are performed. 
b. Subject must be fluent in (oral and written) English (United States only) or local 
language (Ukraine only) to consent. 
3. Subject has completed the treatment period on study drug (through Day 35 -2 days) of 
Studies KAR-007 or KAR-009.
4. Subject resides in a stable living situation, in the opinion of the investigator.
5. Subject has an identified, reliable informant/caregiver willing to be able to address some 
questions related to certain study visits, if needed. An informant/caregiver may not be 
necessary if the subject has been the patient of the investigat
 
6. Women of childbearing potential (WOCBP) or men whose sexual partners are WOCBP 
must be sexually abstinent (in line with their preferred and usual lifestyle) or willing and 
able to use at least 1 highly effective method of contraception during the study and for at 
least 7 days after the last dose of KarXT. Sperm donation is not allowed for 7 days after 
the final dose of KarXT. A female subject is considered to be a WOCBP after menarche 
and until she is in a postmenopausal state for 12 consecutive months or is otherwise 
permanently sterile (for which acceptable methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy) [22]. For the definition and list of highly 
effective methods of contraception, see Appendix 1. 
8.2
Exclusion Criteria 
Subjects will be excluded from the study if 1 or more of the following criteria is/are applicable: 
1. Risk for suicidal behavior during the study as determined by the investigator’s clinical 
assessment and C-SSRS as confirmed by the following:  
a. 
Subject answers “Yes” to “suicidal ideation” Item 4 (active suicidal ideation with 
some intent to act, without specific plan) or Item 5 (active suicidal ideation with 
specific plan and intent) on the C-SSRS assessment. 
b. 
Nonsuicidal self-injurious behavior is not exclusionary. 
2. Any clinically significant abnormality including any finding(s) from the physical 
examination, vital signs, ECG, or laboratory test at the end-of-treatment visit of Studies
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KAR-007 or KAR-009 that the investigator, in consultation with the medical monitor, 
would consider to jeopardize the safety of the subject.
3. Female subject is pregnant.
4. 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 his/her ability to adhere to 
the protocol visit schedule or fulfill visit requirements.
5. Subjects with extreme concerns relating to global pandemics such as coronavirus disease 
2019 (COVID-19) that preclude study participation.
6. Risk of violent or destructive behavior. 
7. Subjects participating in another investigational drug or device trial or planning on 
participating in another clinical trial during the course of the study. 
 
8.3 
Safety Laboratory Evaluations for Eligibility 
Subjects may be enrolled into KAR-008 prior to receipt of the results from the safety laboratory 
evaluations collected on Visit 10 of the preceding acute study.  These subjects will be dosed on 
Day 1 of KAR-008; however, subjects may be withdrawn from KAR-008 depending upon the 
clinical significance of the results of the Visit 10 safety laboratory evaluations at the discretion of 
the PI in consultation with the medical monitor. Abnormal lab values deemed clinically 
significant must be recorded as AEs.  Subjects with elevated liver function tests (LFTs) per the 
DILI criteria must be withdrawn from further participation in KAR-008.  Retesting of labs is 
allowed x 1 with the exception of elevated LFTs. 
8.4 
Study Withdrawal, Removal, and Replacement of Subjects 
If a subject discontinues study treatment and is withdrawn from the study for any reason, the 
study site must immediately notify the medical monitor. The date and the reason for study 
discontinuation must be recorded on the electronic case report form (eCRF). Subjects who 
complete or discontinue early from the study will be asked to return to the study site within 
7 (±3) days of the last administration of KarXT to complete EOS assessments as indicated in the 
Schedule of Assessments (Table 2). 
In the event that a subject discontinues prematurely from the study because of a 
treatment-emergent AE (TEAE) or serious TEAE, the TEAE or serious TEAE will be followed 
up until it resolves (returns to normal or baseline values) or stabilizes, or until it is judged by the 
investigator to no longer be clinically significant. 
Once a subject is withdrawn from the study, the subject may not re-enter the study. 
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A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons 
including, but not limited to, the following:
 progressive disease 
 unacceptable toxicity or AE
 subject withdrawal of consent: at any time, a subject's participation in the study may be 
terminated at his/her request or on the basis of the investigator’s clinical judgment; the 
reason for subject withdrawal will be noted on the eCRF
intercurrent illness: a condition, injury, or disease unrelated to the primary diagnosis that 
became apparent during treatment and necessitated the subject’s termination from the 
study 
general or specific changes in the subject's condition that renders them ineligible for 
further treatment according to the inclusion/exclusion criteria (eg, subject has need for a 
medication prohibited by the protocol)
subject fails to adhere to the protocol requirements (eg, drug noncompliance [if a subject 
is off KarXT for >7 consecutive days])
violation of entry criteria, ie, enrolled subjects who are later discovered not to meet 
eligibility criteria 
 development of suicidal or assaultive behavior 
 alcohol abuse or illegal drug use 
 pregnancy, as indicated in Section 11.8   
 Sponsor’s decision to discontinue study 
Subjects who withdraw from the study will be encouraged to complete the same final evaluations 
as subjects completing the study according to this protocol, particularly safety evaluations. The 
aim is to record data in the same way as for subjects who completed the study. 
Reasonable efforts will be made to contact subjects who are lost to follow-up. A subject will be 
considered lost to follow-up if he or she repeatedly fails to return for scheduled visits and is 
unable to be contacted by the study center. These efforts must be documented in the subject’s 
file. Subjects with AEs ongoing at end of study will be followed until the AE is resolved or the 
subject is considered to be in stable condition. 
The Sponsor has the right to terminate the study at any time in case of SAEs or if special 
circumstances concerning the KarXT become known, making further treatment of subjects 
impossible. In this event, the investigator(s) will be informed of the reason for study termination. 
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Pregnancy
No evidence of mutagenicity, or treatment effects on reproduction, fertility, or fetal parameters 
have been demonstrated in animals following administration of xanomeline, but there are no 
adequate and well-controlled studies in pregnant women (FDA Pregnancy Category B). Animal 
reproduction studies of trospium chloride have shown an adverse effect on the fetus, but 
potential benefits may warrant the use of the drug in pregnant women despite the risk (FDA 
Pregnancy Category C).
Therefore, WOCBP in this study must be willing to use a highly effective method of birth 
control (see Appendix 1 for a list of acceptable highly effective methods of contraception) during 
the study and for 7 days after the last dose of KarXT. WOCBP will have a urine pregnancy test 
on Day 0 (before receiving KarXT) and thereafter, as designated at other scheduled visits
(Table 2). In case of positive urine pregnancy test result, a serum sample should be sent to the 
central laboratory to confirm the result. Pregnant women are excluded from this study because 
the effects of KarXT on the developing human fetus are unknown with the potential for 
teratogenic or abortifacient effects.
Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment 
of the mother with KarXT, women who become pregnant must discontinue KarXT immediately.
The effects of KarXT on sperm are unknown. Male subjects whose sexual partners are WOCBP 
must agree to use a highly effective method of birth control (see Appendix 1 for a list of 
acceptable highly effective methods of contraception) and must not impregnate a sexual partner 
during or for 7 days after the last dose of KarXT. They must also agree to refrain from sperm 
donation for 7 days after the last dose of KarXT.
WOCBP will be instructed that known or suspected pregnancy occurring during the study should 
be confirmed and reported to the investigator. If a female subject becomes pregnant, the 
investigator must withdraw her from the study without delay. The subject must not receive any 
further doses of the KarXT. The investigator must notify the Sponsor or their designee of any 
female subject or female partner of a male subject that becomes pregnant while participating in 
the study. If the female subject or the female partner of the male subject is willing and able to 
consent to pregnancy follow-up, she will be followed until her pregnancy reaches term. Only 
those procedures that would not expose the pregnant female patient to undue risk will be 
performed. See Section 11.8 for further reporting and monitoring details.
Full details of the pregnancy will be recorded on the withdrawal page (exit form) of the eCRF, or 
a Pregnancy Reporting Form will be completed if the subject has completed the study. 
Notification of the pregnancy should be submitted via the Pregnancy Reporting Form within 
24 hours of knowledge of the pregnancy. Pregnancy is not to be considered an AE; however, it 
must be reported using the same procedure as described for reporting SAEs, Section 11.7.4.
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8.5
Completion of the Study or Lost to Follow-up 
The study will be completed when all subjects have completed their study-related procedures in 
accordance with the protocol. 
Every reasonable effort will be made to contact subjects who are lost to follow-up to obtain EOS
information. Details regarding follow-up efforts are to be documented in the subject’s medical 
records/source documentation. 
8.6 
Study Termination 
The availability of any new adverse safety information related to KarXT may result in stopping 
the study. An investigator, Sponsor, or Institutional Ethics Committee (IEC)/Institutional Review 
Board (IRB) may take such actions. If the study is terminated for safety reasons, subjects will be 
notified immediately and assured that appropriate treatment and follow-up will be available. If an 
investigator terminates the study, the Sponsor, subjects, and IEC/IRB will be informed about the 
reason for such action. Similarly, if the Sponsor terminates the study, it will inform the 
investigators, the IEC/IRB, and the subjects of the reason for such an action. Similar 
notifications will be sent by the IEC/IRB if it takes such an action.
 
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9
TREATMENTS
9.1
Details of Study Treatments
KarXT is formulated as hard hydroxypropyl methylcellulose oral capsules containing 2 distinct 
populations of drug beads, 1 of which is loaded with xanomeline tartrate and the other of which 
is loaded with trospium chloride. Each capsule contains the free base equivalent of xanomeline 
and trospium according to the desired dosage strength. In addition to the active ingredients, the 
drug beads contain microcrystalline cellulose (MCC). The beads are not coated and are 
formulated for immediate release of the active ingredients.
Identity of Study Treatments
Active study agents for treatment group will be size 0, Swedish orange, opaque, and 
hydroxypropyl methylcellulose hard capsules. For the 2-day lead-in period (Days 1 and 2), 
subjects will receive capsule strength KarXT 50/20 BID, followed by 2 capsules of KarXT 
50/10 mg BID or a dosage of 100/20 mg BID for a total daily dose of 200/40 mg for the 
remainder of Week 1 (Days 3 to 7). At the beginning of Visit 3 (Day 8), dosing may be increased 
to 2 capsules of KarXT 62.5/15 mg or a dosage of 125/30 mg BID for a total daily dose of 
250/60 mg, depending on tolerability. Investigators have the option to return a subject to KarXT 
100/20 mg BID. Re-escalation to 125/30 BID or re-titration in cases where subject has been off 
KarXT for a longer period of time (at least a week) is allowed and will require a discussion 
between the PI and the medical monitor.
Additional changes to KarXT dosing (e.g., temporary dose reductions) may be permitted as 
clinically indicated upon approval by the medical monitor (see also Section 9.4).
Note: In case of dose reduction, re-escalation, or re-titration, additional PK samples will be 
collected at 8 and 14 days (+/- 2) post dose change in accordance with the Visits 3 and 4 
schedules, unless these additional samples overlap with regularly scheduled PK samples.  
Otherwise unscheduled visits should be performed to collect these additional samples.
KarXT 50/10 mg is composed of 44.4% xanomeline tartrate, 5.8% trospium chloride, excipients 
37.59% MCC, 11.5% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a size 0, 
Swedish orange, hydroxypropyl methylcellulose hard capsule.
KarXT 50/20 mg is composed of 33.4% xanomeline tartrate, 8.7% trospium chloride, excipients 
39.8% MCC, 17.3% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a size 0, Swedish 
orange, hydroxypropyl methylcellulose hard capsule.
KarXT 62.5/15 mg is composed of 41.7% xanomeline tartrate, 6.5% trospium chloride, 
excipients 38.1% MCC, 12.9% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a 
size 0, Swedish orange, hydroxypropyl methylcellulose hard capsule.
All investigational agents are to be stored according to requirements.
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Packaging and Labeling
The study packaging and labeling will be performed by Corealis Pharma, located in Laval, 
Quebec, Canada and Catalent Pharma Solutions, located in Winchester, Kentucky (labelling for 
the US sites), and Catalent Pharma Solutions, located in Philadelphia, Pennsylvania (labelling for 
Ukrainian sites). All packaging and labeling operations will be performed according to Good 
Manufacturing Practice for Medicinal Products and the relevant regulatory requirements.
Bulk supply bottles are labeled with the name of the drug, recommended storage conditions, the 
name and address of the manufacturer and the Investigational Use Statement (for the US sites: 
“Caution: New Drug – Limited by Federal [USA] Law to Investigational Use” and for the 
Ukrainian sites: “For clinical trial use only” or similar wording).
Further details on labeling of investigational product will be provided in the Pharmacy Manual.
Subjects will be provided an automated medication dispenser which will be prefilled with 
medication at scheduled intervals. Full details on study medication dispensing can be found in 
the Pharmacy Manual. 
KarXT Storage
Prior to dispensing KarXT to the subjects, it must be stored at controlled room temperature
15°C-25°C.
KarXT Retention
KarXT must be retained until completion or termination of the study, and written authorization 
from the Sponsor has been received. All unused and used KarXT must be destroyed at the site or 
returned, as specified by Sponsor. It is the investigator’s responsibility to ensure that the Sponsor 
has provided written authorization prior to return or destruction, and that appropriate records of 
the disposal are documented and maintained. No used or unused KarXT may be disposed until 
fully accounted for by the study monitor.
9.2
Dosage Schedule
Subjects who roll over into KAR-008 will start dosing with KarXT on Day 1 of the current 
study.  Day 0 (baseline) procedures must be completed prior to Day 1 and should be completed 
the same day as Visit 10 (Day 35) of the preceding acute study KAR-007 or KAR-009. The 
assessments performed on Visit 10 (Day 35) of Studies KAR-007 or KAR-009 will be 
considered as baseline assessments along with any additional procedures that will be performed 
on Day 0 of the current study. Any scheduled Day 0 assessments that were not completed on Day 
35 of the acute study (KAR-007 or KAR-009) must be completed on Day 0 of the current study. 
The first dose of the KarXT will be self-administered in the morning of Day 1 and the last dose 
will be self-administered in the morning of EOT Visit (Day 364). KarXT should be administered 
daily BID on an empty stomach (ie, at least 1 hour before a meal or 2 to 3 hours after a meal). 
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Some considerations for dosing and PK blood withdrawals are provided in the subsections 
below. As described in Section 10.2, KarXT dosing adherence will be monitored using AiCure 
Technology. Additionally, KarXT will be dispensed to individual subjects via MedReady, an 
automated medication dispenser. 
Day 0
The site pharmacist will prefill the pill trays of two automated medication dispensers with 
sufficient quantities of KarXT for the first 8 days of dosing (Visits 1-3), one for the 
morning doses and the other for the evening doses.  
After AiCure training and registration and MedReady activation and training, sites will 
send the subject home with instruction to begin self-administration of KarXT BID in the 
morning of Day 1.  
For all KarXT doses, the first dose is to be self-administered in the morning and the 
evening dose will be self-administered at 12 (±4.5) hours after the morning dose.  
Visit 1/Day 1 Dosing
Initiate BID dosing with KarXT 50/20 x 4 doses.
All subjects must have taken 4 doses of the KarXT 50/20 before dose escalation to 
KarXT 100/20 BID. As the medication dispenser will be prefilled with the prescribed 
next dose of KarXT, subjects should be instructed to contact the investigator in the event 
they did not take all 4 doses of KarXT 50/20 prior to Visit 2/Day 3.
Visit 2/Day 3 Dosing
Initiate BID dosing with KarXT 100/20 x 10 doses.
All the subjects must have taken at least 8 doses of the KarXT 100/20 before dose 
escalation to KarXT 125/30 BID. As the medication dispenser will be prefilled with the 
prescribed next dose of KarXT, subjects should be instructed to contact the investigator in 
the event they did not take at least 8 doses of KarXT 100/20 prior to Visit 3/Day 8.
Remind subject to hold the morning dose on day of next clinic visit (Visit 3/Day 8) as that 
dose will be taken while at the clinic, after the pre-dose PK sample is drawn.
Remind the subject to bring allocated MedReady dispensers to the next clinic visit. 
Visit 3/Day 8
If dose escalation to the KarXT 125/30 level is confirmed by investigator order on 
Visit 3/Day 8, initiate BID dosing of KarXT 125/30
The first morning dose of KarXT 125/30 at Visit 3 is to be administered in the clinic
(after the pre-dose PK blood draw) (Table 2).  
If the use of visit windows becomes necessary, PK sampling must accompany the actual 
day of uptitration for Visit 3/Day 8. 
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3 PK samples will be collected at pre-dose in the morning, 1 hour (+10 min), and 2 hours 
(+10 min) post-dose. 
The site pharmacist will prefill two MedReady pill dispensing trays with sufficient 
quantities of KarXT to continue BID dosing until next clinic visit/assessment for 
tolerability.(until Visit 4), one for the morning doses and the other for the evening doses.  
The pharmacist or site staff may swap out the used pill trays in the allocated Medready 
dispensers with the new refilled supply. 
Remind subject to hold the morning dose on day of next clinic visit (Visit 4/Day 14) as 
that dose will be taken while at the clinic, after the pre-dose PK sample is drawn.  
Remind the subject to bring allocated MedReady dispensers to the next clinic visit. 
In the event that the subject is not escalated to KarXT 125/30 at Visit 3, in accordance with 
investigator order, dispense sufficient quantities of KarXT 100/20 to continue BID dosing until 
next clinic visit/assessment for tolerability. 
Visit 4/Day 14 Dosing and PK Considerations
If dose of KarXT 125/30 BID was confirmed by investigator order on Visit 3/Day 8, the 
site pharmacist will prefill 2 MedReady pills trays with sufficient quantities of KarXT 
125/30 to continue BID dosing until next clinic visit/assessment for tolerability.(until 
Visit 5), one tray for the morning doses and the other for evening doses.
The pharmacist or site staff may swap out the used pill trays in the allocated Medready 
dispensers with the new refilled supply. 
The first morning dose of KarXT at Visit 4 is to be administered in the clinic (after the 
pre-dose PK blood draw) (Table 2).
If the use of visit windows becomes necessary, PK sampling must accompany the actual 
day of uptitration for Visit 4/Day 14.
3 PK samples will be collected at pre-dose in the morning, 1 hour (+10 min), and 2 hours 
(+10 min) post-dose.
Remind the subject to bring allocated MedReady dispensers to the next clinic visit.
In the event that the subject was not escalated to KarXT 125/30 at Visit 3, in accordance with 
investigator order, dispense sufficient quantities of KarXT 100/20 to continue BID dosing until
next clinic visit/assessment for tolerability.
Visits 5-29 Dosing and PK Considerations
For each study visit, the site pharmacist will prefill two MedReady pill dispensing trays 
with sufficient quantities of KarXT for the next 14 days of dosing (Visits 5-29), one for 
the morning doses and the other for the evening doses, in accordance with the investigator 
order, confirming prescribed KarXT dose.  
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The pharmacist, site staff, or home health care staff may swap out the used pill trays in 
the allocated Medready dispensers with the new refilled supply, depending upon the visit 
location (in-clinic versus remote). 
Remind the subject to bring allocated MedReady dispensers to each in-clinic visit for 
refill. 
For Days 84, 168, and 364, collection of a single PK sample before the morning dose is 
preferred.  However, timing of the sample is not mandatory and will not be captured as a 
protocol deviation if collected after the morning dose (but must be collected on required 
visit day).  
See Section 9.4.1 for management of KarXT dose changes and PK sampling.
9.3
Measures to Minimize Bias: Study Treatment Assignment
Method of Study Treatment Assignment
The 9-digit Subject Number previously assigned to the subject in the Study KAR-007/KAR-009 
will continue to be used in the current Study KAR-008. This number will be associated with the 
subject throughout the current study.
Blinding
This is an open-label study; therefore, blinding is not applicable.
9.4
Dosage Modification
Subjects will self-administer the KarXT as described in Section 7.1 and in accordance with the 
Schedule of Assessments (Table 2). The KarXT doses were selected based on the previous 
preclinical and clinical studies (see Section 5.2). Per the protocol, subjects will be evaluated for 
dose adjustments starting at Visit 3 through the remainder of the treatment period (see 
Section 9.2).
Additional changes to KarXT dosing (e.g., temporary dose reductions) may be permitted as 
clinically indicated upon approval by the medical monitor.
Dose Modifications and PK Sampling Considerations
In case of dose reduction, re-escalation, or re-titration, additional PK samples should be collected 
at 8 and 14 days (+/- 2) post dose change in accordance with the Visits 3 and 4 schedules, unless 
these additional samples overlap with regularly scheduled PK samples. Otherwise unscheduled 
visits should be performed to collect these additional samples.
Extended Dosing Interruptions and Re-titration
Re-escalation to 125/30 BID or re-titration in cases where subject has been off the KarXT for a 
longer period of time (at least a week) is allowed and will require a discussion between the 
principal investigator (PI) and the medical monitor.
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All subjects approved by the PI and medical monitor will resume KarXT by repeating the lead-in 
dosing scheme used at the start of study. Subjects will start with a lead-in dose of KarXT 
50/20 BID for the first 2 days after restarting study drug. Then the dose will be titrated to 100/20 
BID for at least the next 4 days, allowing the subject to adjust to KarXT before receiving a 
higher dose of 125/30 BID after restarting study drug, unless the subject is continuing to 
experience AEs from the previous dose, in which case the subject will remain on 
KarXT 100/20 BID.
9.5
Treatment Accountability and Compliance
The pharmacist or other designated individual will maintain records of study treatment delivered 
to the study site, the inventory at the study site, the distribution to each subject, and the return of 
materials to the Sponsor or designee for storage or disposal. These records should include dates, 
quantities, batch/serial numbers, expiration dates, temperature log, and unique code numbers 
assigned to the product and study subjects.
Administration of KarXT will be supervised by study site personnel (during in-clinic visits) and
by a digital compliance tool to ensure adherence (AiCure technology). Also, KarXT will be 
dispensed using MedReady time-controlled dispensing device, which dispenses KarXT at 
scheduled intervals. Subjects will be advised to return the MedReady device to the site staff at 
each in-clinic visit for drug accountability and refilling.
At all dispensing visits, the empty or unused MedReady pill trays will be collected by the Home 
Health Care nurse and/or site staff, depending upon visit location (ie, in-clinic or remotely in 
home). In case a Home Health Care nurse performs the interim visit, they will perform a 
preliminary drug accountability before shipping the empty or partially empty pill trays to the 
study site for final accountability check. Full details can be found in the Pharmacy Manual.
Investigators will maintain records that adequately document that the subjects were provided 
with the correct study treatment supply and reconcile the usage of the study drug. Investigational 
product will not be returned to the Sponsor or designee or destroyed until accountability has been 
fully monitored through the end of the study. KarXT accountability will be assessed periodically 
by the assigned study monitor.
9.6
Prior and Concomitant Therapy
Prior and Concomitant Medications
Concomitant medications ongoing as of Visit 10/Day 35 of the preceding acute study (KAR-007 
or KAR-009) will be captured in the eCRF as baseline therapy. Thereafter, all medications and 
other treatments taken by the subject during the study, including those treatments initiated before 
the start of the study drug administration, must be recorded on the KAR-008 eCRF.
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Restricted prior therapies are provided below.
During the study (ie, from the time of enrollment at baseline visit [Day 0] until study completion
[EOT/ET]), subjects should refrain from the use of any new concomitant medications without the 
prior approval of the investigator. The administration of any other concomitant medications 
during the study period is prohibited without the prior approval of the investigator unless its use 
is deemed necessary in a medical emergency. Any medication or therapy that is taken by or 
administered to the subject during the course of the study must be recorded in the eCRF. The 
entry must include the dose, regimen, route, indication, and dates of use.
All the subjects enrolled into the study must not take the below mentioned prohibited 
medications for the duration of the treatment period.
Oral antipsychotic medications, monoamine oxidase inhibitors, mood stabilizers (ie, 
lithium), anticonvulsants (eg, lamotrigine, Depakote), tricyclic antidepressants (eg, 
imipramine, desipramine), selective serotonin reuptake inhibitors, or any other 
psychoactive medications except for anxiolytics that were taken on an as needed basis 
(eg, lorazepam, chloral hydrate). 
Long acting injectable antipsychotics (including INVEGA TRINZA®). 
Note: Please direct questions relating to prohibited medications to the medical monitor.
Concomitant Medications for Anxiety and/or Sleep Aid
Subjects are allowed to take benzodiazepines (up to 4 mg lorazepam/day or equivalent) for 
anxiety, agitation, and insomnia on a PRN basis. Subjects may also use non-benzodiazepine 
medications (eg, zolpidem, zaleplon) as a sleep aid, also on a PRN basis. Study sites must record 
the use of such medications in the eCRF and subject’s source document. 
Note: Cognition testing should not be done within 8 hours of receiving a benzodiazepine or sleep 
medication.
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10
STUDY PROCEDURES 
Table 2 outlines the timing of procedures and assessments to be performed throughout the study. 
Section 11.6 specifies laboratory assessment samples to be obtained. See Sections 11, 12, 13, and 
14 for additional details regarding efficacy, safety, PK, and exploratory assessments, 
respectively.
See Appendix 3 for alternative visit procedures that may be used to replace scheduled on-site 
study visits during COVID-19 pandemic-related quarantine or mandated physical distancing.
COVID-19 testing will be completed in accordance with clinical site standard operating 
procedures. If a subject tests positive for COVID-19 during the study, they may be quarantined 
as needed and any scheduled visits should be rescheduled or alternative procedures (see 
Appendix 3) may be followed at the discretion of the investigator. If the subject requires 
hospitalization, an SAE should be reported and the subject should be followed up as outlined in 
Section 11.7.3.
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Table 2.
Schedule of Assessments
DAY
0
 
1
3
(+1d)
8
(± 1d)
14
(± 2d)
28
(± 3d)
42
(± 3d)
56
(± 3d)
70
(± 3d)
84
(± 3d)
98
(± 3d)
112
(± 3d)
126
(± 3d)
140
(± 3d)
154
(± 3d)
168
(± 3d)
WEEK
1
2
4a
6
8
10
12
14
16
18
20
22
24
VISITBaseline1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
TYPE OF VISIT Clinic
Clinic
Clinic
Clinic Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim
Clinic
PROCEDURE
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written informed consent
Subject eligibility verification 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (WOCBP 
only)b
X 
X 
X
X
X 
X
X
Urine drugs of abuse and alcohol 
testingc 
Review of inclusion/exclusion 
criteria
X
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, body weight, BMI, waist 
circumferenced 
X
X
X
X
X
X
X
Complete physical examinatione
X
Targeted physical examinationf 
Spontaneous AEsg
X
Review of concomitant 
medicationsh
Vital signs: BP and HRi
Resting ECG (12-lead)j
X
X
X
Blood samples for clinical 
laboratory testsk
X
X
X
X
X
Blood sample for prolactin
X
X
X
Functional constipation inquiryl
X
Interim clinical observationsm
Safety follow up of any AE 
and/or conmed changes reported 
by the HHC staff, as neededn
Determination of dose titration
PK blood drawo
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DAY 
 
0
1 
3 
(+1d)
8 
(± 1d)
14 
(± 2d)
28 
(± 3d)
42 
(± 3d)
56 
(± 3d)
70 
(± 3d)
84 
(± 3d)
98 
(± 3d)
112 
(± 3d)
126 
(± 3d)
140 
(± 3d)
154 
(± 3d)
168 
(± 3d)
WEEK
1
2
4a
6
8
10
12
14
16
18
20
22
24
VISIT Baseline1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14
15 
TYPE OF VISIT
Clinic 
  
Clinic Clinic Clinic Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic 
PROCEDURE
PANSSp
C-SSRSq 
 
CGI-S scale
Cognition testingr
SAS 
BARS
AIMS 
AiCure registration and trainings
MedReady registration and 
trainings    
KarXT dispensed using 
MedReadys
Subject self-administration of 
KarXT using AiCure app  
EMA registration and trainingt
EMA PROu
EMA VLMTv
Digital biomarkers using AiCure 
appw
 
 
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Table 2
Schedule of Assessments (Continued from Visits 16 to 30)
DAY 182 
(± 3d)
196 
(± 3d)
210
(± 3d)
224 
(± 3d)
238 
(± 3d)
252 
(± 3d)
266 
(± 3d)
280 
(± 3d)
294 
(± 3d)
308
(± 3d)
322 
(± 3d)
336 
(± 3d)
350
(± 3d)
364 
(± 3d)
371
(± 3d)
WEEK
26
28
30
32
34
36 
38 
40 
42 
44 
46 
48 
50 
52 
53 
VISIT
16
17
18
19
20
21
22
23
24
25
26
27
28
29
(EOT)
30
(EOS/ET/UNS)3
TYPE OF VISIT Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic
Clinic
PROCEDURE 
Urine pregnancy test 
(WOCBP only)b 
X
X
X
X
X
X
X
X
Urine drugs of abuse and 
alcohol testingc 
Height, body weight, BMI, 
waist circumferenced
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Complete physical 
examinatione
X
Targeted physical 
examinationf 
X
X
X
X
X
X
X
Spontaneous AEsg
Review of concomitant 
medicationsh 
Vital signs: BP and HRi
Resting ECG (12-lead)j
X
Blood samples for clinical 
laboratory testsk
X
X
X
Blood sample for prolactin
X
Functional constipation 
inquiryl
Interim clinical 
observationsm
Safety follow up of any 
AE and/or conmed 
changes reported by the 
HHC staff, as neededn
PK blood drawo
PANSSp
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DAY 182 
(± 3d)
196 
(± 3d)
210
(± 3d)
224 
(± 3d)
238 
(± 3d)
252 
(± 3d)
266 
(± 3d)
280 
(± 3d)
294 
(± 3d)
308
(± 3d)
322 
(± 3d)
336 
(± 3d)
350
(± 3d)
364 
(± 3d)
371
(± 3d)
WEEK
26
28
30
32
34
36 
38 
40 
42 
44 
46 
48 
50 
52 
53 
VISIT 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29
(EOT)
30
(EOS/ET/UNS)3
TYPE OF VISIT Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic
Clinic
PROCEDURE
C-SSRSq
CGI-S scale 
Cognition testingr
SAS
BARS 
AIMS
KarXT dispensed using 
MedReady dispensers
Subject self-administration 
of KarXT using AiCure 
apps
EMA PROu
EMA VLMTv
Digital biomarkers using 
AiCure appw
Abbreviations: AE = adverse event; AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; BL = baseline; BMI = body 
mass index; BP = blood pressure; CGI-
-SSRS = Columbia-Suicide Severity Rating Scale; d = day; 
ECG = electrocardiogram; EMAW = EMA Wellness; EOS = end of study; EOT = end of treatment; ET = early termination; HR = heart rate; PANSS = Positive 
and Negative Syndrome Scale; PK = pharmacokinetic; QTcF = QT interval corrected by Fridericia; SAS = Simpson-Angus Rating Scale; UNS = unscheduled 
visit. 
See Appendix 3 for alterative visit procedures that may be used to replace scheduled on-site study visits during COVID-19 pandemic-related quarantine or 
mandated physical distancing. 
1. Baseline Day 0 assessments should be rolled over from Day 35/Visit 10 of the preceding study (KAR-007/009) whenever possible (exception: cognition 
which should be rolled over from Day 32).  Includes pregnancy testing, complete physical exam, vital signs, ECG, safety laboratory evaluations, functional 
constipation inquiry, PANSS, C-SSRS, CGI-S, SAS, AIMS and BARS. 
2. (X) = optional. See accompanying footnote for details 
3. Other assessments as needed. 
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a.
Beginning after Visit 5/Day 28, interim visits will be completed every 2 weeks with flexibility between the in-clinic visits, which will occur every 
month. For interim visits, either a Home Health Care nurse or the study site staff will visit the subject to complete the scheduled visit. Telemedicine 
should be utilized at the investigator’s discretion to complete a portion of a visit or follow-up on information collected.   Also, when needed, the sites 
will have the option to schedule a subject for an in-clinic visit in lieu of an interim visit. 
b. A urine pregnancy test for WOCBP should be performed at scheduled visits. If a urine pregnancy test is positive, a serum sample should be sent to 
central laboratory for confirmation of the result. A new urine pregnancy test should be performed on Day 0 visit only if subject left the inpatient unit 
after completion of Visit 10 of the preceding acute study but prior to completion of the Day 0 procedures of the current study. 
c. 
A National Institute on Drug Abuse-5 (NIDA-5) urine drug screen (cannabinoids or marijuana, phencyclidine, amphetamines, opiates, and cocaine) 
and test for alcohol (breathalyzer or blood alcohol level) will be performed at the indicated scheduled visits.  Should be performed on Day 0 visit 
only if subject left the inpatient unit after completion of Visit 10 of the preceding acute study but prior to completion of the Day 0 procedures of the 
current study. 
d. Baseline height is recorded from Study KAR-007/KAR-009 Screen visit.  Baseline body weight, BMI and waist circumference recorded from 
KAR-007/009 Visit 10. At the indicated study visits, body weight and waist circumference will be measured and BMI calculated.  
e. 
A complete physical examination includes body temperature (°C), general appearance, head/eyes/ears/nose/throat (HEENT), examination of thorax 
and, assessment of cardiac, musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited neurological examination. 
f. 
A targeted physical examination includes at a minimum body temperature, a check of general appearance, as well as examination of organ systems 
that are relevant to the investigator based on review of the subject’s reported AEs, review of systems, or concomitant medication use. These also 
include symptom-driven physical examinations which will be performed as clinically indicated at any study visit. A targeted physical examination at 
Day 0 is optional, and only required if the subject has reported a new AE in the time since completing Visit 10 of the preceding acute study. 
g. Adverse events as reported by subjects or observed by clinical staff. Adverse events ongoing as of Visit 10 of the preceding acute study will be 
recorded in the KAR-008 Medical History eCRF. Adverse events occurring after dosing with KarXT in the current study will be recorded in the 
KAR-008 AE eCRF. One PK blood sample may be drawn if a relevant/significant AE (based on medical judgment) is reported during a scheduled 
visit or if there is a dose titration or a relevant/significant AE reported during an unscheduled visit (no multiple draws). 
h. Concomitant medications ongoing as of Visit 10/Day 35 of the preceding acute study will be captured in the eCRF as baseline therapy.  Thereafter, 
all medications and other treatments taken by the subject during the study, including those treatments initiated before the start of the study, must be 
recorded on the KAR-008 eCRF. 
i. 
Vital signs measurements should be taken at all in-clinic visits, while the subject is supine and standing after 2 minutes. BP includes systolic and 
diastolic BP and is to be taken in the same arm for the duration of the study. During in-clinic visits orthostatic vital signs should occur 2 (±1) hours 
after morning dose of KarXT whenever possible.   
j. 
ECG should be obtained within 1 to 2 hours post morning dose whenever possible. ECG at all indicated visits should be performed before blood 
withdrawal for any safety laboratory tests and/or PK analysis. ECGs will be transmitted electronically to a central reader for determination of 
ventricular rate (bpm), PR (msec), QRS (msec), QT (msec), and QTcF (msec) measurements. 
k. Refer to Section 11.6 for individual laboratory tests. For urinalysis, a urine dipstick will be performed at the site. In the event of abnormalities, the 
sample will be sent to the central laboratory for full microscopic urinalysis. At the indicated interim visits the safety laboratory evaluations samples 
will be collected by the home care health nurse or site staff. 
l. 
Functional constipation inquiry: At specified visits, subjects will be asked whether they have experienced constipation (per the ROME III criteria and 
Bristol Stool Form Scale; see Appendix 2) since the last visit and if yes, whether the constipation required intervention. If the subject answers yes, 
sites are instructed to ask subjects to provide event date and ensure the event is documented as an AE and treatment is documented as concomitant 
medication.  
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m. Interim clinical observations include collection of vital signs, review of spontaneous AEs, and concomitant medications. These assessments will be 
performed by a Home Health Care (HHC) nurse and/or site staff visiting the patient at home. Vital signs measurements should be taken at all interim 
visits, while the subject is supine and standing after 2 minutes. BP includes systolic and diastolic BP and should be taken in the same arm for the 
duration of the study whenever possible.   
n. For any new AEs or concomitant medication reported by the HHC nurse, site staff must follow up with subjects directly via telemedicine over 
telephone or through video chat and complete a safety follow-up evaluation. 
o.
PK blood samples will be collected in the morning before dosing on Days 8, 14, 84, 168 and 364. On Days 8 and 14, three PK samples will be 
collected at pre-dose in the morning, 1 hour (+10 min), and 2 hours (+10 min) post-dose. For Days 84, 168, and 364, collection of a single sample 
before the morning dose is preferred. However, timing of the sample is not mandatory and will not be captured as a protocol deviation if collected 
after the morning dose (but must be collected on required visit day). Note: In cases of dose reduction, re-escalation, or re-titration, additional PK 
samples should be collected at 8 and 14 days (+/- 2) post dose change in accordance with the Visits 3 and 4 schedules, unless these additional 
samples overlap with regularly scheduled PK samples. Otherwise unscheduled visits should be performed to collect these additional samples. 
p.
It is recommended, if at all possible, that the PANSS assessment should be performed before all the other scale assessments for all visits at which it 
is performed.  
q. The “since last visit” version should be used for C-SSRS administration. At the Unscheduled visit, the C-SSRS should be performed to monitor 
subjects for suicidality. 
r. 
Cognition testing is performed using CANTAB. Cognition testing should not be done within 8 hours of receiving a benzodiazepine or sleep 
medication. Cognition testing at Visit 30 will only be performed if the visit is a result of Early Termination of a subject. 
s. 
Refer to the Study Operations Manual for details.  
t. 
Refer to the Study Operations Manual for details. 
u. EMA PRO will be completed by the subject at home on a cellular device 3 times per day for 7 days every 28 days, beginning on Day 29. An 
abbreviated version of the assessment will be utilized on Days 4-6 and 15-17 to familiarize subjects with the process. Refer to Study Operational 
Manual for details. 
v. Cognitive insight will be assessed using the EMA VLMT.  The assessment will be completed by the subject at home on a cellular device 1 time per 
day for 3 days every 28 days beginning on Day 32. Refer to Study Operational Manual for details. 
w. Digital biomarkers of schizophrenia will be calculated through completion of a smartphone-based assessment daily by the subject for 3 days 
collected initially on Days 4-6, 9-11, and 15-17. Subsequently subjects will complete assessments daily for 3 days every 28 days, beginning on Day 
29. Refer to Study Operational Manual for details. 
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10.1 Informed Consent
Informed consent forms must be approved for use by the reviewing Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB). Before performing any study-related 
procedures, the investigator (or designee) will obtain written informed consent from the subject
and/or caregiver (Ukraine only).
10.2 Study Procedures
Assessments and their timing are to be performed as outlined in the Schedule of Assessments 
(Table 2). Section 11.6 specifies laboratory assessment samples to be obtained. 
Safety assessments are described in Section 11 and include spontaneous AEs including AESIs;
procholinergic and anticholinergic symptoms, SAEs and AEs leading to discontinuation of the 
KarXT; SAS; BARS; AIMS; body weight; BMI; waist circumference; orthostatic vital signs; 
ECG; clinical laboratory assessments (hematology, clinical chemistry, coagulation, urinalysis, 
and drug screen); physical examination; and C-SSRS.
Efficacy assessments are described in Section 12 and include PANSS and CGI-S scores.
PK assessments are described in Section 13 and include monitoring of trough concentrations of 
xanomeline and trospium.
Exploratory assessments are described in Section 14 and include cognition testing using 
CANTAB; prolactin levels; digital biomarkers of schizophrenia; EMA PRO; and EMA VLMT.
The investigator may, at his/her discretion, arrange for a subject to have an unscheduled 
assessment, especially in the case of AEs that require follow-up or are considered by the 
investigator to be possibly related to the use of KarXT. The unscheduled visit page in the eCRF 
must be completed. The assessments and procedures that may be performed during an 
unscheduled visit are outlined in the Schedule of Assessments (Table 2). Additional assessments 
can be performed as needed, at the discretion of the investigator, and following discussion with 
the medical monitor.
Study discontinuation procedures are described in Section 8.4 and Section 8.6.
AiCure Adherence Technology
The AiCure technology will be used to monitor study medication adherence in all subjects, both 
in the US and the Ukraine. Additionally, the AiCure technology will be used to capture Digital 
Biomarker Assessment of schizophrenia symptoms of subjects in the US only.
Medication Adherence (US and Ukraine):
This study will employ a medication adherence monitoring platform (herein after referred to as 
Platform) for all subjects in the study. The Platform uses artificial intelligence on smartphones to 
confirm medication ingestion. In addition, built-in reminders and a communication system allow 
real-time intervention in case of drug interruptions. 
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Use of this Platform will in no way supersede or replace the physician and/or prescribed 
medication protocol of the subjects. Because the Platform does not change the medication 
protocol of the subjects, but rather encourages adherence to the predefined protocol, use of this 
Platform presents minimal risk to the subjects. Use of the Platform will be required for all 
subjects in the study.
The monitoring Platform requires that all subjects take each dose of the medication while using a 
smartphone. Participants will download the AiCure application on their personal smartphone 
device; for participants who do not have a smartphone or do not wish to use their personal 
smartphone, site personnel will provide the participant with one of the preloaded backup 
provisioned devices.
When at home, study subjects will receive a medication reminder at a time within a predefined 
window. This notification reminds subjects to take their medication dose while using the 
Platform. Subjects will follow a series of prescribed steps in front of the front-facing webcam to 
visually confirm their ingestion of the medication. The application on the smartphone will make 
an automated determination of whether the subject has properly taken their medication at the 
prescribed time. There is no need for a healthcare provider to review the administration, nor 
would a healthcare provider need to be available at the time the subject takes their medication. 
The amount of guidance that the device provides to the subject is automatically reduced as the 
subject becomes more proficient at using the application. 
Digital Biomarker Assessment (US only):
For subjects enrolled at US sites only, subjects will be performing brief smartphone-based 
assessments using the AiCure application. Video and audio of participant behavior captured 
during these assessments will be used to calculate visual and auditory markers of schizophrenia 
symptomatology. These digital biomarkers will be used as exploratory efficacy endpoints to 
measure change from baseline in disease severity. See Section 14.4 for endpoint discussion. The 
material will be presented to subjects in one of two ways. In the first, material will be presented 
to subjects, and will include questionnaires provided at regular intervals during the study. Images 
may also be shown to subjects, and they will be asked to describe each image in a few sentences 
to the camera of the smartphone.   
Data Collected on the AiCure Platform: 
After the device confirms proper medication ingestion, video recordings will be encrypted and 
transmitted to a secure centralized location for further analysis, including testing for duplicate 
enrollment. Video and audio recordings from the Digital Biomarker assessments will be 
encrypted and transmitted in a similar manner. The captured data and video is reviewable 
through a roles and rules restricted system ensuring privacy of the information. The system is 
compliant with applicable US and European data privacy laws, including General Data 
Protection Regulation (GDPR) (EU) 2016/679 the Health Insurance Portability and 
Accountability Act (HIPAA), which protects the privacy and security of healthcare information.
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Phone numbers of the patients may also be collected and stored in an encrypted manner. Storing 
the phone numbers will allow for direct communication with patients, including automated 
messaging from the Platform device and contact by healthcare providers or other monitoring 
personnel. At no time is the phone number visible to healthcare providers or monitoring 
personnel. Individuals outside the clinical sites will not be provided with patient names, nor will 
they be given access to patient medical records. 
The Platform may provide significant benefits to study subjects as well as to the other 
stakeholders in the trial. Subjects will benefit from rapid and tailored intervention in case of 
non-adherence (drug interruptions) without having to visit the clinic for unscheduled visits. 
Healthcare providers will have access to real-time and continuous adherence data without having 
to rely on self-reported data or frequent study visits by patients. Subjects who regularly fail to 
take their medication will be contacted by healthcare providers or other study monitoring 
personnel for retraining. 
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11
SAFETY ASSESSMENTS 
Safety assessments (spontaneous AEs including AESIs; procholinergic and anticholinergic 
symptoms; SAEs and AEs leading to discontinuation of the KarXT; SAS; BARS; AIMS; body 
weight; BMI; waist circumference; orthostatic vital signs; ECG; clinical laboratory assessments 
[hematology, clinical chemistry, coagulation, urinalysis, and drug screen]; physical examination; 
and C-SSRS) will be performed at protocol-specified visits, as specified in the Schedule of 
Assessments (Table 2).  
11.1 Demographics, Medical History, and Psychiatric History
Demographic data, and medical and psychiatric history will be recorded from the Phase 3, 
double-blind, acute study (KAR-007/KAR-009).  
Illnesses first occurring or detected during the study and/or worsening of a concomitant illness 
during the study are to be documented as AEs on the eCRF in accordance with Section 11.7. All 
changes that are not present at baseline or described in the past medical history and identified as 
clinically noteworthy must be recorded as AEs. 
11.2 Vital Signs 
Orthostatic vital signs (systolic and diastolic BP and heart rate measurements) will be evaluated 
at all scheduled visits indicated in the Schedule of Assessments (Table 2). All vital signs will be 
measured supine and standing after 2 minutes. Blood pressure measurements are to be taken in 
the same arm for the duration of the study. During in-clinic visits, beginning with Visit 2 
(Day 3), orthostatic vital signs should occur 2 (±1) hours after morning dosing, whenever 
possible.   
Vital sign measurements will be repeated if clinically significant or machine/equipment errors 
occur. Out-of-range BP, or heart rate measurements will be repeated at the investigator’s 
discretion. Any confirmed, clinically significant vital sign measurements must be recorded as 
AEs.
11.3 Complete/Targeted Physical Examination
A complete physical examination (body temperature, general appearance, 
head/eyes/ears/nose/throat [HEENT], examination of thorax and abdomen, assessment of 
cardiac, musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited 
neurological examination) will be performed at visits as specified in Table 2. Physical 
examinations will be performed by a physician.
A targeted physical examination includes at a minimum body temperature, a check of general 
appearance, as well as examination of organ systems that are relevant to the investigator, based 
on review of the subject’s reported AEs, review of systems, or concomitant medication use. 
These also include symptom-driven physical examinations which will be performed as clinically 
indicated at any study visit.
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11.4 Weight, Height, Body Mass Index, and Waist Circumference 
The baseline height measurement will be recorded from the lead-in Study KAR-007/009 Screen 
visit.  The baseline body weight, BMI and waist circumference measurements will be recorded 
from the KAR-007/009 Visit 10.  At the indicated visits of the current study (Table 2), body 
weight and waist circumference will be measured and BMI calculated. All findings should be 
recorded in the eCRF. 
11.5 Electrocardiograms 
A 12-lead, resting ECG should be obtained within 1 to 2 hours post morning dose at the visits 
indicated in the Schedule of Assessments (Table 2). ECG at all scheduled visits should be 
performed before blood withdrawal for any safety laboratory tests and/or PK analysis. 
ECGs will be transmitted electronically to a central reader for determination of ventricular 
rate (bpm), PR (msec), QRS (msec), QT (msec), and QTcF (msec) measurements. An assessment 
of normal or abnormal will be recorded; if the ECG is considered abnormal, the abnormality will 
be documented on the eCRF. ECGs will be repeated if clinically significant abnormalities are 
observed or artifacts are present. 
11.6 Laboratory Assessments 
Laboratory assessment samples (Table 3) are to be obtained at designated visits as detailed in the 
Schedule of Assessments (Table 2). 
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Table 3.
Laboratory Assessments 
Hematology
Serum Chemistry
Urine Analysis (Dipstick)
Full and differential blood count 
Hct 
Hb 
MCH 
MCHC 
MCV 
Platelet count 
RBC count 
WBC count with differential 
Albumin 
ALT 
ALP 
AST 
Albumin 
Uric acid 
BUN or urea 
Carbon dioxide 
Creatinine 
Creatine kinase and subtypes 
Electrolytes (sodium, 
potassium, chloride, calcium, 
phosphorus) 
GGT 
Glucose 
LDH 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
HDL 
LDL 
Triglycerides 
Total protein
Appearance 
pH 
Protein 
Glucose 
Ketone bodies 
Indicators of blood and WBCs 
Specific gravity 
Urobilinogen 
Occult blood 
WBCs 
HbA1c 
Prolactin 
  
Coagulation 
PT 
Activated PTT 
Fibrinogen 
Pregnancy test: A urine pregnancy test for WOCBP should be performed per the schedule of assessments 
(Table 2).  In case of positive urine pregnancy test result, a serum sample should be sent to the central 
laboratory to confirm the result. 
Full and microscopic urinalysis:  
Chemical exam: SG, pH, bilirubin, urobilinogen, protein, glucose, ketone, hemoglobin, myoglobin, leukocyte 
esterase, nitrite, ascorbic acid 
Microscopic exam: RBCs, WBCs, epithelial cells, bacteria, yeasts, parasites, casts, crystals 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; GGT = gamma-glutamyl transpeptidase; HCG = human 
chorionic gonadotropin; Hb = hemoglobin; Hct = hematocrit; HDL = high density lipoprotein; LDH = lactate 
dehydrogenase; LDL = low density lipoprotein; MCH = mean corpuscular hemoglobin; MCHC = mean 
corpuscular hemoglobin concentration; MCV = mean corpuscular volume; PT = prothrombin time; 
PTT = partial thromboplastin time; RBC = red blood cell; WBC = white blood cell; WOCBP = women of 
childbearing potential. 
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Venous blood of approximately 12 to 20 mL will be withdrawn for the tests listed above at 
scheduled time points as per Table 2. 
A minimum volume of 10 mL will be obtained to perform urinalysis (if abnormalities observed 
on dipstick) and urine drug screen at scheduled time points as per Table 2. 
Blood and urine samples (microscopic analysis) will be analyzed at a central laboratory facility. 
Urine samples will first be analyzed by dipstick at the site. If the results of the dipstick indicate 
abnormalities to be further investigated, the sample will be sent to the central laboratory and a 
microscopic analysis will be performed. All laboratory reports must be reviewed, signed, and 
dated by the investigator. A legible copy of all reports must be filed with both the subject’s eCRF 
and medical record (source document) for that visit. Any laboratory test result considered by the 
investigator to be clinically significant should be considered an AE (clinically significant AEs 
include those that require an intervention). Clinically significant abnormal values occurring 
during the study will be followed up until repeat test results return to normal, stabilize, or are no 
longer clinically significant.
All the study subjects will be closely monitored for the drug-induced liver toxicity (detailed in
Section 11.7.5), during the study.
Other Laboratory Assessments:
A National Institute on Drug Abuse-5 (NIDA-5) urine drug screen (cannabinoids or 
marijuana, phencyclidine, amphetamines, opiates, and cocaine) will be performed using a 
dipstick throughout the study. 
Alcohol testing will be performed using a breathalyzer or blood alcohol test. 
11.7 Adverse Events
Adverse Events
An AE is any symptom, physical sign, syndrome, or disease that either emerges during the study 
or, if present at screening/baseline, worsens during the study, regardless of the suspected cause 
of the event. All medical and psychiatric conditions (except those related to the indication under 
study) present at screening/baseline will be documented in the medical history eCRF. Changes in 
these conditions and new symptoms, physical signs, syndromes, or diseases should be noted on 
the AE eCRF during the rest of the study. Clinically significant laboratory abnormalities should 
also be recorded as AEs. Surgical procedures that were planned before the subject enrolled in the 
study are not considered AEs if the conditions were known before study inclusion; the medical 
condition should be reported in the subject’s medical history.
In accordance with the protocol, the investigator and/or study staff will elicit AEs and 
intercurrent illness during and at the end of the study period and these will be recorded on the 
appropriate page of the eCRF. Adverse events will be elicited by asking the subject a nonleading 
question, for example, “Have you experienced any new or changed symptoms since we last 
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asked?” The eCRF will be completed at the end of the study as soon as the results of the final lab 
tests are available.
Each AE is to be documented on the eCRF with reference to date of onset, duration, frequency, 
severity, relationship to KarXT, action taken with KarXT, treatment of event, and outcome. 
Furthermore, each AE is to be classified as being serious or nonserious. Changes in AEs and 
resolution dates are to be documented on the eCRF. 
For the purposes of this study, the period of observation for collection of AEs extends from the 
time immediately after the administration of KarXT on Day 1 until the EOS or ET. Follow-up of 
the AE, even after the date of therapy discontinuation, is required if the AE persists until the 
event resolves or stabilizes at a level acceptable to the investigator.
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the event should be noted. If the intensity category changes over a number of days, 
then those changes should be recorded separately (with distinct onset dates). 
The severity of AEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0 (Grades 1 through 5).
Specific guidelines for classifying AEs by intensity and relationship to KarXT are given in 
Table 4 and Table 5. 
Table 4. 
Classification of Adverse Events by Intensity
MILD: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with 
everyday activities. 
MODERATE: An event that is sufficiently discomforting to interfere with normal everyday activities.
SEVERE: An event that prevents normal everyday activities. 
Table 5.
Classification of Adverse Events by Relationship to KarXT 
UNRELATED: This category applies to those AEs that are clearly and incontrovertibly due to extraneous 
causes (disease, environment, etc). 
UNLIKELY: This category applies to those AEs that are judged to be unrelated to the test drug but for which 
no extraneous cause may be found. An AE may be considered unlikely to be related to KarXT if or when it 
meets 2 of the following criteria: (1) it does not follow a reasonable temporal sequence from administration of 
the test drug; (2) it could readily have been produced by the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; (3) it does not follow a known pattern of 
response to the test drug; or (4) it does not reappear or worsen when the drug is readministered. 
POSSIBLY: This category applies to those AEs for which a connection with the test drug administration 
appears unlikely but cannot be ruled out with certainty. An AE may be considered possibly related if or when 
it meets 2 of the following criteria: (1) it follows a reasonable temporal sequence from administration of the 
drug; (2) it could not readily have been produced by the subject’s clinical state, environmental or toxic factors, 
or other modes of therapy administered to the subject; or (3) it follows a known pattern of response to the test 
drug. 
PROBABLY: This category applies to those AEs that the investigator feels with a high degree of certainty are 
related to the test drug. An AE may be considered probably related if or when it meets 3 of the following 
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
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reasonably explained by the known characteristics of the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; (3) it disappears or decreases on cessation or 
reduction in dose (note that there are exceptions when an AE does not disappear upon discontinuation of the 
drug, yet drug-relatedness clearly exists; for example, as in bone marrow depression, fixed drug eruptions, or 
tardive dyskinesia); or (4) it follows a known pattern of response to the test drug.
DEFINITELY: This category applies to those AEs that the investigator feels are incontrovertibly related to test 
drug. An AE may be assigned an attribution of definitely related if or when it meets all of the following 
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
reasonably explained by the known characteristics of the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; (3) it disappears or decreases on cessation or 
reduction in dose and recurs with re-exposure to drug (if rechallenge occurs); and (4) it follows a known 
pattern of response to the test drug.
Abbreviation: AE = adverse event.
Adverse Events of Special Interest
The AEs of special interest will be monitored and include orthostasis and liver function test 
elevations inclusive of drug-induced liver injury (DILI).
Serious Adverse Events
An SAE is any untoward medical occurrence, in the view of either the investigator or Sponsor, 
that:
results in death,
is life-threatening,
results in inpatient hospitalization or prolongation of existing hospitalization (however, 
hospitalization for elective treatment of a pre-existing non-worsening condition is not 
considered an SAE; the details of such hospitalizations must be recorded on the medical 
history or physical examination page of the eCRF),
results in persistent or significant disability/incapacity, and/or
is a congenital anomaly/birth defect.
Other important medical events that may not be immediately life-threatening or result in death or 
hospitalization, based upon appropriate medical judgment, are considered SAEs if they are 
thought to jeopardize the subject and/or require medical or surgical intervention to prevent 1 of 
the outcomes defining an SAE. Serious AEs are critically important for the identification of 
significant safety problems; therefore, it is important to take into account both the investigator’s 
and the Sponsor’s assessment. If either the Sponsor or the investigator believes that an event is 
serious, the event must be considered serious and evaluated by the Sponsor for expedited 
reporting.
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Serious Adverse Event Reporting
An SAE occurring from the time the first dose of KarXT is administered, during the study, or 
within 1 week of stopping the treatment must be reported to the Catalyst Clinical Research 
Pharmacovigilance group and will be communicated to the Sponsor. Any such SAE due to any 
cause, whether or not related to the KarXT, must be reported within 24 hours of occurrence or 
when the investigator becomes aware of the event. Notification can be made using email.
Catalyst Clinical Research Pharmacovigilance email address: 
The event must be recorded on the standard AE eCRF. Preliminary reports of SAEs must be 
followed up by detailed descriptions later on, including clear and anonymized photocopies of 
hospital case reports, consultant reports, autopsy reports, and other documents when requested 
and applicable. SAE reports must be made whether or not the investigator considers the event to 
be related to the investigational drug.
Appropriate remedial measures should be taken to treat the SAE, and the response should be 
recorded. Clinical, laboratory, and diagnostic measures should be employed as needed in order to 
determine the etiology of the problem. The investigator must report all additional follow-up 
evaluations to the Catalyst Clinical Research Pharmacovigilance group within 24 hours of 
becoming aware of the additional information or as soon as is practicable. All SAEs will be 
followed up until the investigator and Sponsor agree the event is satisfactorily resolved.
Any SAE that is not resolved by the end of the study or upon discontinuation of the subject’s
participation in the study is to be followed up until it either resolves, stabilizes, returns to 
baseline values (if a baseline value is available), or is shown to not be attributable to the KarXT
or procedures.
Drug-Induced Liver Injury
The sponsor has incorporated the following for monitoring of drug-induced liver injuries:
An increase of serum alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) to >3 × ULN should be followed by repeat testing within 48 to 72 hours of all 4 of 
the usual serum measures (ALT, AST, ALP, and total bilirubin) to confirm the 
abnormalities and to determine if they are increasing or decreasing. An inquiry should be 
made about the symptoms (eg, fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, and rash).
Close observation should be initiated with ALT or AST >3 × ULN:
o
Repeat liver enzyme and serum bilirubin tests 2 or 3 times weekly. The frequency of 
retesting can decrease to once per week or less if abnormalities stabilize or the trial 
drug has been discontinued and the subject is asymptomatic.
o
Obtain a more detailed history of symptoms and prior or concurrent diseases.
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o Obtain a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug 
use, and special diets.
o
Rule out acute viral hepatitis types A, B, C, D, and E, autoimmune or alcoholic 
hepatitis, non-alcoholic steatohepatitis, hypoxic/ischemic hepatopathy, and biliary 
tract disease. 
o Obtain a history of exposure to environmental chemical agents. 
o Obtain additional tests to evaluate liver function, as appropriate (eg, international 
normalized ratio, and/or direct bilirubin). 
o Consider gastroenterology or hepatology consultations. 
 Discontinuation of treatment should be considered if: 
o ALT or AST >8 × ULN 
o ALT or AST >5 × ULN for more than 2 weeks 
o ALT or AST >3 × ULN and (total bilirubin >2 × ULN or international normalized 
ratio >1.5) 
o ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or eosinophilia (>5%) 
 Hepatic adjudication of cases should include an evaluation for alternative causes such as 
viral, autoimmune, alcohol, hepatobiliary disorders, non-alcoholic steatohepatitis, 
concomitant medications, etc. 
 Follow-up to resolution of elevated liver enzymes. 
 Gamma-glutamyl transferase elevations alone should not prompt drug discontinuation. 
Subjects must be monitored closely. If close monitoring is not possible, the study drug should be 
discontinued. 
11.7.5.1 
Trial Discontinuation Criteria Other than DILI and Pregnancy 
11.7.5.2 
Individual Stopping Criteria
Based on NCI 
 Grade 4 
AE. Discontinuation or reduction in the dosage of the study drug for Grade 3 AEs other than 
DILI AEs (see Section 11.7.5) will be at the discretion of the investigator. 
11.7.5.3 
Trial Stopping Rules 
The safety and tolerability aspects of KarXT will be overseen by an ISMC. The ISMC will meet 
periodically and review the unblinded data and will be responsible for advising the sponsor on 
ways to safeguard the interests of the clinical study subjects. The committee is expected to 
recommend sponsor whether to: 
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a.
Continue the clinical study without modification; or
b. Continue the clinical study with modification (listing the specific modifications 
recommended); or
c.
Terminate the study.
Suspected Unexpected Serious Adverse Reactions
Adverse events that meet all of the following criteria will be classified as suspected unexpected 
serious adverse reactions (SUSARs) and reported to the appropriate regulatory authorities in 
accordance with applicable regulatory requirements for expedited reporting:
serious
unexpected (ie, the event is not consistent with the safety information in the IB or 
package insert of generic trospium)
there is at least a reasonable possibility that there is a causal relationship between the event 
and the study treatment
The investigator will assess whether an event is causally related to study treatment. The Sponsor 
(or Syneos Health) will consider the investigator’s assessment and determine whether the event 
meets the criteria for being reportable as a 7-day or 15-day safety report. SUSARs that are fatal 
or life-threatening must be reported to the regulatory authorities and the IEC/IRBs (where 
required) within 7 days after the Sponsor (or Syneos Health) has first knowledge of them, with a 
follow-up report submitted within a further 8 calendar days. Other SUSARs must be reported to 
the relevant regulatory authorities and the IEC/IRBs within 15 calendar days after the Sponsor 
(or Syneos Health) first has knowledge of them.
The Sponsor (or Syneos Health) is responsible for reporting SUSARs and any other events 
required to be reported in an expedited manner to the regulatory authorities and for informing 
investigators of reportable events, in compliance with applicable regulatory requirements within 
specific timeframes. Investigators will notify the relevant IEC/IRBs of reportable events within 
the applicable timeframes.
Warnings and Precautions
Risk of Urinary Retention:
Trospium chloride tablets should be administered with caution to subjects with clinically 
significant bladder outflow obstruction because of the risk of urinary retention.
Angioedema:
Angioedema of the face, lips, tongue, and/or larynx has been reported with trospium chloride, the 
active ingredient in trospium chloride tablets. In one case, angioedema occurred after the first 
dose of trospium chloride. Angioedema associated with upper airway swelling may be 
life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, trospium chloride 
should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a 
patent airway should be promptly provided.
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Decreased Gastrointestinal Motility: 
Trospium should be administered with caution to subjects with GI obstructive disorders because 
of the risk of gastric retention. Trospium chloride, like other antimuscarinic agents, may decrease 
GI motility and should be used with caution in subjects with conditions such as ulcerative colitis, 
intestinal atony, and myasthenia gravis. 
Controlled Narrow-angle Glaucoma:
In subjects being treated for narrow-angle glaucoma, trospium chloride should only be used if 
the potential benefits outweigh the risks and in that circumstance only, with careful monitoring.
Central Nervous System Effects:
Trospium chloride is associated with anticholinergic CNS effects. A variety of CNS 
anticholinergic effects have been reported, including dizziness, confusion, hallucinations, and 
somnolence. Subjects should be monitored for signs of anticholinergic CNS effects, particularly 
after beginning treatment or increasing the dose. Advise subjects not to drive or operate heavy 
machinery until they know how trospium chloride affects them. If a subject experiences 
anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.
Anticholinergic Adverse Reactions in Subjects with Moderate Renal Impairment:
Trospium is substantially excreted by the kidney. The effects of moderate renal impairment on 
systemic exposure are not known but systemic exposure is likely increased. Therefore, 
anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract 
infection, and urinary retention) are expected to be greater in subjects with moderate renal 
impairment.
Elevation of liver enzymes:
Elevated liver enzymes have been reported in previous studies of xanomeline alone in 
Alzheimer’s disease patients. It is notable however, the hepatic enzyme elevations were not 
observed in the Phase 1 studies in healthy volunteers and that the liver function test elevations 
observed in the Phase 2 schizophrenia study (KAR-004) with KarXT (a combination of 
xanomeline and trospium) were quite limited in contrast to the effects observed with xanomeline 
in the elderly Alzheimer’s population. Moreover, even in the Alzheimer disease patients who 
experienced more hepatic enzyme elevations, the data demonstrate reversibility even with 
continued xanomeline treatment in those patients where there was sufficient follow-up data. 
Importantly, there were no Hy’s law cases or elevations in total bilirubin to a value of >2X upper 
limit of reference range in either the xanomeline or KarXT datasets. 
11.8 Pregnancy 
WOCBP must have a negative pregnancy test at baseline (Day 0).  
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The investigator must notify the Sponsor (or designee) of any female subject or female partner of 
a male subject that becomes pregnant while participating in the study. Any known cases of 
pregnancy will be reported until the subject completes or withdraws from the study. 
The pregnancy will be reported immediately by faxing/emailing a completed pregnancy report to 
the Sponsor (or designee) within 24 hours of knowledge of the event. The pregnancy will not be 
processed as an SAE; however, the investigator will follow-up with the subject until completion 
of the pregnancy and must assess the outcome in the shortest possible time, but not more than 
30 days after completion of the pregnancy.  
If a female subject becomes pregnant, the investigator must withdraw her from the study without 
delay. The subject must not receive any further doses of the KarXT. Upon discontinuation from 
the study, only those procedures that would not expose the subject to undue risk will be 
performed. 
If the female subject or the female partner of the male subject is willing and able to consent to 
pregnancy follow-up, she will be followed until her pregnancy reaches term. Information 
regarding the pregnancy must only be submitted after obtaining written consent from the 
pregnant partner. The investigator will arrange counseling for the pregnant partner by a specialist 
to discuss the risks of continuing with the pregnancy and the possible effects on the fetus. 
The investigator should notify the Sponsor (or designee) of the pregnancy outcome by 
submitting a follow-up pregnancy report. If the outcome of the pregnancy involved spontaneous 
or therapeutic abortion (any congenital anomaly detected in an aborted fetus is to be 
documented), stillbirth, neonatal death, or congenital anomaly, the investigator will report the 
event by faxing/emailing a completed pregnancy report form to the Sponsor (or designee) within 
24 hours of knowledge of the event. This event is considered as an SAE. 
The investigator should also be notified of pregnancy occurring during the study but confirmed 
after completion of the study. In the event that a subject is subsequently found to be pregnant 
after inclusion in the study, any pregnancy will be followed to term, and the status of mother and 
child will be reported to the Sponsor after delivery. 
11.9 Overdose 
The investigator must immediately notify the Sponsor of any occurrence of overdose with 
KarXT (total daily dose greater than 250/60 mg). 
Signs and symptoms of overdose may vary considerably. They are usually manifested by 
increasing GI stimulation with epigastric distress, abdominal cramps, diarrhea and vomiting, 
excessive salivation, pallor, cold sweating, urinary urgency, blurring of vision, and eventually 
fasciculation and paralysis of voluntary muscles. Miosis, increases or decreases in blood pressure 
with or without bradycardia, and severe anxiety and panic may occur. 
Supportive treatment should be used as indicated (artificial respiration, maintenance of airway, 
oxygen, etc). Atropine sulfate should be available for IV or intramuscular administration. Several 
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doses ranging from 0.5 to 2.0 mg may be required. Epinephrine 0.1 to 1.0 mg subcutaneous may 
also be of value in overcoming severe cardiovascular or bronchoconstrictor responses.
Adverse events associated with overdoses should be reported on the eCRF.
11.10 Simpson-Angus Rating Scale
The SAS is an established instrument to measure drug-related extrapyramidal syndromes. It is a 
10-item testing instrument used to assess gait, arm dropping, shoulder shaking, elbow rigidity, 
wrist rigidity, leg pendulousness, head dropping, glabella tap, tremor, and salivation. The range 
of scores is from 0 to 40 with increased scores indicating increased severity. 
11.11 Barnes Rating Scale for Akathisia 
The Barnes Rating Scale for akathisia is a rating scale used to assess the severity of drug-induced 
akathisia, or restlessness, involuntary movements and inability to sit still. The range of scores is 
0 to 14, with higher scores indicating greater severity.[23] 
11.12 Abnormal Involuntary Movement Scale 
The AIMS is a rating scale that is used to measure involuntary movements know as tardive 
dyskinesia, which can sometimes develop as a side effect of long-term treatment with 
antipsychotic medications. It is a 12-item scale to assess orofacial, extremity, and truncal 
movements as well as the overall severity, incapacitation, and the subject’s level of awareness of 
the movements. Items are scored from 0 (none) to 4 (severe). A higher score indicates more 
severe dyskinesia. 
11.13 Columbia-Suicide Severity Rating Scale 
The C-SSRS is a tool designed to systematically assess and track suicidal AEs (suicidal behavior 
and suicidal ideation) throughout the study.[24] The strength of this suicide classification system 
is in its ability to comprehensively identify suicidal events while limiting the over-identification 
of suicidal behavior. The scale takes approximately 5 minutes to administer. The C-SSRS will be 
administered by a trained rater at the site. 
11.14 Functional Constipation Inquiry 
Constipation refers to bowel movements that are infrequent or hard to pass.[25] The stool is 
often hard and dry.[26] Other symptoms may include abdominal pain, bloating, and feeling as if 
one has not completely passed the bowel movement.[27] The normal frequency of bowel 
movements in adults is between 3 per day and 3 per week.[25] Constipation will be defined per 
the Rome III criteria, as less than 3 bowel movements per week, Appendix 2 
(Longswreth,1486,C3).[28] 
The Bristol Stool Form Scale has been correlated with a change in intestinal function, and has 
been shown to be a useful tool in clinical practice and research.[29] A sample Bristol Stool Form 
Scale is located in Appendix 2. 
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As a measure of anticholinergic effects, at specified visits (Table 2), subjects will be asked 
whether they have experienced constipation per the ROME III criteria since the last visit, and if 
yes, whether the constipation required intervention. If the subject answers yes, sites are 
instructed to ask subjects to provide event date and ensure event is documented as an AE and 
treatment is documented as concomitant medication. Subjects will not be required to collect and 
present their stool sample, nor will clinic staff be required to corroborate the subject assessment. 
Additional attention can be given to other complaints as well including: straining with bowel 
movements, excessive time needed to pass a bowel movement, hard stools, pain with bowel 
movements secondary to straining, abdominal pain, abdominal bloating, and the sensation of 
incomplete bowel evacuation.[27, 30]
Treatment of constipation depends on the underlying cause and the duration that it has been 
present. For the purposes of constipation complaints during a clinical trial, the use of laxatives of 
a bulk forming agent, osmotic agent, stool softener, or lubricant type may be used.
As definitions of constipation are typically based on a history of at least a week, site physician 
discretion will be allowed for initiation of such treatments. 
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12
EFFICACY ASSESSMENTS 
The Schedule of Assessments (Table 2) outlines the efficacy assessments to be performed 
throughout the study and their timing. 
12.1 Positive and Negative Syndrome Scale
The PANSS is a clinician-administered scale used for measuring symptom severity of subjects 
with schizophrenia and is widely used in the study of antipsychotic therapy.[31] The PANSS 
rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general 
psychopathology symptom scales. Subjects are rated from 1 to 7 on each symptom scale. The 
positive symptoms in schizophrenia are the excess or distortion of normal function such as 
hallucinations, delusions, grandiosity, and hostility, and the negative symptoms in schizophrenia 
are the diminution or loss of normal functions. It takes approximately 45 to 50 minutes to 
administer. PANSS total score is the sum of all scales with a minimum score of 30 and a 
maximum score of 210.  
It is recommended, if at all possible, that the PANSS assessment should be performed before all 
the other scale assessments for all visits at which it is performed. 
12.2 Clinical Global Impression-Severity 
The CGI-S is a rating scale, completed independently by a clinician that is used to measure 
illness and symptom severity in subjects with mental disorders. It is used to rate the severity of a 
subject’s illness at the time of assessment. The CGI-S modified asks the clinician 1 question: 
“Considering your total clinical experience, how mentally ill is the subject at this time?” The 
clinician’s answer is 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 subjects.[32] 
This rating is based upon observed and reported symptoms, behavior, and function in the past 
7 days. As symptoms and behavior can fluctuate over a week, the score should reflect the 
average severity level across the 7 days.
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13
PHARMACOKINETICS
13.1 Pharmacokinetic Sampling
PK Blood Samples and Timing
Blood samples for the analysis of xanomeline and trospium levels will be collected at the time
points indicated in the Schedule of Assessments (Table 2). Approximately 4 ml of blood will be 
collected at each scheduled time point. The actual date and time of each blood sample collection 
will be recorded.
On Days 8 and 14, a total of 3 PK samples will be collected at pre-dose in the morning, 1 hour 
(+10 min), and 2 hours (+10 min) after the morning dose. For Days 84, 168, and 364, a single 
sample before the morning dose will be collected. The time windows must be adhered to for the 
Day 8 and 14 samples.  For other visits where PK samples are drawn preferred timing is prior to 
morning dose of KarXT for the day but is not mandatory. With the exception of Days 8 & 14, 
PK samples not drawn prior to the day’s morning dose of KarXT will not be captured as protocol 
deviations. 
PK Blood Samples and KarXT Dosing Changes
In cases of dose reduction, re-escalation, or re-titration, additional PK samples should be 
collected at 8 and 14 days (+/- 2) post dose change in accordance with the Visits 3 and 4 
schedules, unless these additional samples overlap with regularly scheduled PK samples. 
Otherwise unscheduled visits should be performed to collect these additional samples.
A single PK sample may be drawn (preferably in the morning) if a relevant/significant AE is 
reported during a scheduled visit, or if there is a dose adjustment or relevant/significant AE 
reported during an unscheduled visit (no multiple draws). For ET that is related to an AE, the 
collection of a PK blood sample is not optional and should be drawn.
Details of PK blood sample collection, processing, storage, and shipping procedures will be 
provided in a separate laboratory manual.
13.2 Pharmacokinetic Analytical Methodology
The concentration of trospium and xanomeline will be determined from the plasma PK samples 
using a validated analytical method. Details of the method validation and sample analysis will be 
included with the final clinical study report.
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14
EXPLORATORY ASSESSMENTS
The exploratory assessments cognition testing, prolactin levels, digital biomarkers, EMA PRO, 
and EMA VLMT will be performed at scheduled visits or study days, as per the Schedule of 
Assessments (Table 2).
14.1 Cognition Testing - Cambridge Neuropsychological Test Automated Battery
The computerized CANTAB provides an objective measure of cognitive function correlated to 
neural networks. A short cognitive battery measuring core cognitive domains of impairment in 
schizophrenia (ie, as per Brief Assessment of Cognition Schizophrenia key cognitive domains) 
will be employed for this study, and it will take approximately 30 minutes to complete. These 
CANTAB tests meet MATRICS workshop criteria.[33] Subjects will perform the test on a 
provisioned iPad with data immediately uploaded to the CANTAB Connect cloud-based 
platform (Wi-Fi permitting). 
Cognition testing should not be done within 8 hours of receiving benzodiazepine or sleep 
medications. 
Table 6. 
Cognitive Tests and Cognitive Domains Assessed by the Cambridge 
Neuropsychological Test Automated Battery 
CANTAB Tests
MATRICS Cognitive Domain 
Outcome Measures
Rapid visual information 
processing 
Sustained attention/vigilance
A’ Prime: Signal detection 
measure of how good the subject is 
at detecting the target sequence 
(string of three numbers); 
regardless of response tendency 
Verbal recognition memory 
Verbal memory and new learning 
Free Recall: The total number of 
words that are correctly recalled 
from the presentation phase by the 
subject during the immediate free 
recall stage 
Spatial Span
Working memory 
Forward Span Length: The 
longest sequence of boxes 
successfully recalled by the subject
One-touch stockings of Cambridge 
Executive Function 
Planning/Problem Solving 
Problems Solved on First Choice: 
The total number of assessed trials 
where the subject chose the correct 
answer on their first attempt 
Abbreviation: CANTAB = Cambridge Neuropsychological Test Automated Battery 
14.2 Change in Prolactin
Blood samples to assess the change in prolactin levels will be obtained on scheduled visits as 
specified in Table 2.   
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14.3 Digital Biomarkers of Schizophrenia (US only)
Study subjects will be performing brief smartphone-based assessments using the AiCure 
application mentioned in Section 10.2.1. Video and audio of participant behavior captured during 
these assessments will be used to calculate visual and auditory markers of schizophrenia 
symptomatology. These digital biomarkers will be used as exploratory efficacy endpoints to 
measure change from baseline in disease severity. The following exploratory endpoints will be 
collected:
Overall emotional expressivity
Positive emotional expressivity 
Negative emotional expressivity
Audio intensity / speech volume Fundamental frequency of voice
Formant frequencies of voice
Vocal jitter
Vocal shimmer
Pause lengths during speech
Lexical diversity
Rate of speech
Euclidean head movement
Rotational head movement
14.4 EMA Wellness Assessments
EMA Wellness – EMA PRO (US only)
EMA is an ambulatory data collection technique that allows the real-time in vivo assessment of 
functioning behaviors. In the present study, EMA Patient Reported Outcomes (PRO) will be 
used to assess the subject’s functioning associated to negative symptoms and psychotic 
symptoms in schizophrenia through the use of smartphones for subjects enrolled at US sites only. 
EMA PRO surveys are multiple choice questions about the subject’s current location, if they are 
alone or with others, and activities and moods in the last hour. A pop-up visualization will signal 
participants, 3 times per day for 7 days, to respond to very brief (e.g., 3 minutes) questionnaires 
about their activities, mood, and symptom experiences during the last hour, per the Schedule of 
Assessments (Table 2). An abbreviated EMA PRO survey, collecting only information on the 
subject’s location, alone or with others, and activities and moods will be given 3 times per day 
for 3 days starting on Day 4 and Day 15. Daily assessment times will be adjusted to 
accommodate each subject’s typical sleep and wake schedules. 
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EMA Wellness - VLMT (US only)
Cognitive insight assessment will be conducted through testing on the Verbal Learning and 
Memory Test (VLMT), which will be completed by subjects enrolled at US sites only. This 
assessment will be performed at home on a cellular device 1 time per day for 3 days every 
28 days beginning on Day 32. During each VLMT administration, subjects will be presented 
with a list of 6-, 12-, or 18- words over in 3 separate trials each lasting 30 seconds. Immediately 
following each exposure to the list, subjects will be shown target and recognition foil words 
one-by-one and asked to indicate whether or not the word appeared on the list. 
In order to examine response bias and the ability to self-evaluate memory performance, 
immediately after each recognition trial, the subjects will be asked to indicate how many words 
they believe that they got correct. They will also be asked how well they did as compared to the 
previous trial and at the end of the 3 trials they will be asked if they improved over the 3 learning 
trials.
Data Collected on EMAW Platform
Data are encrypted and uploaded to secure servers whenever the phone is connected to Wi-Fi or 
if cellular data is available. If a Wi-Fi and cellular data are unavailable, EMA response data will 
be transferred during in-clinic visits.
During each EMA PRO, subjects will be asked about their location (home vs away and where if 
away); they will also be asked if they are alone or with others, and about their activities, 
symptoms of schizophrenia, and moods in the last hour. 
Data collected during the VLMT include the identification of target words and rejections of foils. 
The participants will also provide an immediate estimate of their memory task performance as 
soon as each recognition trial is over.
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15
STATISTICAL ANALYSIS 
A statistical analysis plan (SAP) will be prepared after the protocol is approved. This document 
will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. The SAP will serve as a complement to the protocol 
and supersedes it in case of differences.
The statistical evaluation will be performed using SAS® software version 9.4 or higher 
(SAS Institute, Cary, NC). All data will be listed, and summary tables will be provided.
Summary statistics will be presented by dose group. For continuous variables, data will be 
summarized with the number of subjects (N), mean, standard deviation, median, minimum, and 
maximum by treatment group. For categorical variables, data will be tabulated with the number 
and proportion of subjects for each category by treatment group. No statistical hypothesis testing 
will be performed. 
15.1 Determination of Sample Size 
As the primary objective of this study is to assess the long-term safety and tolerability of KarXT, 
the number of subjects anticipated is based on the number of subjects recruited into and 
completing the acute studies (KAR-007, KAR-009) and meeting the eligibility requirements for 
KAR-008. 
15.2 Analysis Populations 
Enrolled population: All subjects who have given informed consent for KAR-008. 
Safety population: All subjects who receive at least 1 dose of KarXT during the current study 
will be included in the safety population and will be used in the safety analysis. 
Modified ITT (mITT) population: All subjects who are enrolled, received at least 1 dose of 
KarXT, and have a valid PANSS assessment at KAR-008 baseline will be included in the mITT 
population and will be used in the efficacy analysis. 
PK population: All subjects who have received at least 1 dose of KarXT and have at least 
1 measurable plasma concentration of KarXT will be included in the PK population. 
15.3 Safety Analysis
Safety endpoints will be summarized for all subjects in the Safety population. The presentation 
of safety data will be based on the treatment received in KAR-008. 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 22.1 or higher. The incidence of TEAEs (defined as events with an onset 
date on or after the first dose of KarXT) will be summarized by System Organ Class and 
Preferred Term. All AEs will be listed by subject, along with information regarding onset, 
duration, relationship and severity to KarXT, action taken with KarXT, treatment of event, and 
outcome. 
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Orthostatic vital signs, clinical laboratory data, prolactin levels, ECG parameters, and physical 
examinations will be summarized using descriptive statistics, including observed and change 
from baseline values, as well as numbers of subjects with values outside limits of the normal 
range at each time point. Similar descriptive summaries will be provided for C-SSRS, SAS, 
BARS, AIMS, body weight, BMI, and waist circumference. 
15.4 Efficacy Analysis 
Efficacy analyses will be summarized based on the mITT population. The summaries described 
in this section will provide data on maintenance of effect of open-label KarXT over 52 weeks. 
As these variables are summarized over time and the initial values can be impacted by the 
treatment received in the acute study, the presentation will use a combination of acute/extension 
study treatment groups, which is intended to provide perspective on the change in these values 
from the acute study through the treatment period of KAR-008. Tabular presentations will 
display descriptive statistics for Baseline of the acute study and the observed and change from 
baseline study results by scheduled visit for KAR-008. 
Responder efficacy variables (PANSS responders) will be summarized descriptively. Response 
will be derived relative to the acute study Baseline assessment. 
Continuous efficacy variables based on the change from baseline (PANSS, CGI-S) will be 
summarized using descriptive statistics by scheduled visit. Tabular presentations will display 
descriptive statistics for the Baseline of the acute study and the observed and change from 
baseline results by scheduled visit for KAR-008. Figures for selected variables will also be 
generated in order to demonstrate the kinetics of response over time. 
15.5 Pharmacokinetic Analysis 
Plasma concentrations of xanomeline and trospium will be listed for all subjects. The profiles or 
time points obtained with protocol deviations affecting PK results will be flagged and may be 
excluded from summaries and analyses. 
The data will be presented graphically via individual plots and mean plots summarized by visit, 
and time point.  
15.6 Exploratory Analysis 
The following will be summarized using descriptive statistics: change in cognition using 
CANTAB; digital biomarkers of schizophrenia; EMA PRO and EMA VLMT.  
Further details will be provided in the SAP. 
15.7 Interim Analysis 
No interim analysis is planned for this study. 
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15.8 Handling of Missing Data 
For responder efficacy variables (PANSS responders), missing data may be handled by 
non-responder imputation, meaning that subjects who discontinue early or who have missing 
data at a given time point are imputed as though they did not achieve the given response. 
Supportive summaries will be based on observed case data.
For continuous efficacy variables based on the change from baseline (PANSS, CGI-S), 
summaries will be based on observed case data.  
Additional methods of missing data imputation may be explored and will be outlined in the SAP. 
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16
STUDY MANAGEMENT
16.1 Approval and Consent
Regulatory Guidelines
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki and/or all relevant regulations, as set forth in Parts 50, 56, 312, Subpart D, of Title 21 of 
the US Code of Federal Regulations (CFR), in compliance with International Council for 
Harmonisation (ICH) and good clinical practice (GCP) guidelines, and all applicable local, state 
and federal government regulations and laws.
Institutional Review Board/Independent Ethics Committee
Conduct of the study must be approved by an appropriately constituted IEC/IRB. Approval is 
required for the study protocol, protocol amendments (if applicable), IB, ICFs, recruitment 
material and subject information sheets and other subject-facing material.
Informed Consent
For each study subject, written informed consent will be obtained before any protocol-related 
activities. As part of this procedure, the PI or designee must explain orally and in writing the 
nature of the study, its purpose, procedures, expected duration, alternative therapy available, and 
the benefits and risks involved in study participation. The subject should be informed that they
may withdraw from the study at any time, and the subject will receive all information that is 
required by local regulations and guidelines for ICH. The PI will provide the Sponsor or its 
representative with a copy of the IEC-/IRB-approved ICF before the start of the study.
The ICF should be revised whenever there are substantial changes to procedures or when new 
information becomes available that may affect the willingness of the subject to participate. 
Revisions to the consent form required during the study must be approved by the Sponsor and 
IEC/IRB, and a copy of the revised consent form is provided to the Sponsor. For any updated or 
revised consent forms, the subjects must be re-consented for continued participation in the study.
A pregnant partner consent form should be obtained before collecting any data from a female 
pregnant partner of a male subject, if she becomes pregnant during the course of the study or 
within 1 week of the last dose of KarXT.
A caregiver consent must be obtained (Ukraine only) before collecting any data from a caregiver 
pertaining to him or her and the subject.
Subject Registry 
Clinical trial registries, such as clinical trial subject database (CTSdatabase, US only) and 
Verified Clinical Trials (VCT, US and Ukraine), seek to reduce duplicate enrollment by 
identifying potential protocol violations and duplicate subjects before randomization. At the time 
of providing the informed consent for the initial KAR-007 or -009 study, the investigator or 
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designee will have explained the IRB/IEC-approved Subject Database Authorization to the 
subject and witnessed the signature. That executed authorization form remains in effect for 
KAR-007 and KAR-008 or KAR-009 and KAR-008 study participation.
At the beginning of screening for KAR-007 or KAR-009, following consents execution and 
subject number assignment and before other study procedures, site staff that had received 
training and login information access (www.subjectregistry.com) to the database entered the 
subject study ID number and authorized subject identifiers. Two reports, one from CTS and one 
from VCT, detailing any potential protocol violations or dual enrollment attempts were 
generated and were printed for source documentation. The reports detailed each protocol 
violation detected and specific washout period dates where applicable.  
At participating sites in the Ukraine, only VCT was used to verify participants’ current and past 
research study status. Following proper regionally compliant informed consent and after 
obtaining a subject number from IXRS, each Ukraine based KAR-009 participant was checked in 
the VCT database. Partial identifiers were utilized. 
Throughout the initial KAR-007 or KAR-009 study, and during this open label extension study, 
tracking of actively enrolled subjects will continue based on updates by coordinators in the 
interactive response system.  At the last subject contact, CTSdatabase and VCT staff will 
automatically close out the subject (safety follow-up, ET, or completer) based on interactive 
response system (IXRS). 
16.2 Data Handling 
Any data to be recorded directly on the eCRFs (to be considered as source data) will be 
identified at the start of the study. Data reported on the eCRF that are derived from source 
documents should be consistent with the source documents, or the discrepancies must be 
explained. See also Section 16.3.  
Clinical data will be entered by site personnel on eCRFs for transmission to the Sponsor. Data on 
eCRFs transmitted via the web-based data system must correspond to and be supported by source 
documentation maintained at the study site unless the study site makes direct data entry to the 
databases for which no other original or source documentation is maintained. In such cases, the 
study site should document which eCRFs are subject to direct data entry and should have in 
place procedures to obtain and retain copies of the information submitted by direct data entry. 
All study forms and records transmitted to the Sponsor must only include coded identifiers such 
that directly identifying personal information is not transmitted. The primary method of data 
transmittal is via the secure, internet-based electronic data capture (EDC) system maintained by 
Syneos Health. Access to the EDC system is available to only authorized users via the study’s 
secure internet web site, where a user unique assigned username and password are required for 
access. 
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Any changes made to data after collection will be made through the use of the EDC system. 
Electronic CRFs will be considered complete when all missing and/or incorrect data have been 
resolved.
16.3 Source Documents
Source documents are considered to be all information in original records and certified copies of 
original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. The investigator will provide direct 
access to source documents and/or source data in the facilitation of trial-related monitoring, 
audits, review by IECs/IRBs, and regulatory inspections. 
The investigator/institution should maintain adequate and accurate source documents and trial 
records that include all pertinent observations on each of the site’s trial subjects. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, not obscure the original entry, and be explained if necessary. 
Data recorded on source documents will be transcribed onto eCRFs. Copies of completed eCRFs 
will be provided to the Sponsor and the sites at the end of the study. The completed eCRFs will 
be retained by the investigator. 
16.4 Record Retention 
Study records and source documents must be preserved for at least 15 years after the completion 
or discontinuation of/withdrawal from the study, at least 2 years after the drug being studied has 
received its last approval for sale, or at least 2 years after the drug development has stopped, and 
in accordance with the applicable local privacy laws, whichever is the longer time period. 
The investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subject health information, including, but not limited to, the 
Standards for Individually Identifiable Health Information, 45 CFR, Parts 160 and 164 (the 
HIPAA of 1996 Privacy Regulation). The investigator shall ensure that study subjects authorize 
the use and disclosure of protected health information in accordance with HIPAA Privacy 
Regulation and in a form satisfactory to the Sponsor. 
16.5 Monitoring 
The study will be monitored according to the KAR-008 monitoring plan to ensure that it is 
conducted and documented properly according to the protocol, GCP, and all applicable 
regulatory requirements. 
Monitoring visits may include on-site or remote visits and may also utilize periodic telephone 
contacts. The PI will assure they and adequate site personnel are available throughout the study 
to collaborate with clinical monitors. Clinical monitors must have direct access to source 
documentation in order to check the completeness, clarity, and consistency of the data recorded 
in the eCRFs for each subject. 
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The investigator will make available to the clinical monitor all source documents and medical 
records necessary to review protocol adherence and eCRFs. In addition, the investigator will 
work closely with the clinical monitor and as needed, provide them appropriate evidence that the 
study is being conducted in accordance with the protocol, applicable regulations, and GCP
guidelines.
16.6 Quality Control and Quality Assurance
The Sponsor or its designee will perform the quality assurance and quality control activities of 
this study; however, responsibility for the accuracy, completeness, security, and reliability of the 
study data presented to the Sponsor lies with the investigator generating the data.
The Sponsor or its designee will arrange audits as part of the implementation of quality 
assurance to ensure that the study is being conducted in compliance with the protocol, standard 
operating procedures, GCP, and all applicable regulatory requirements. Audits will be 
independent of and separate from the routine monitoring and quality control functions. Quality 
assurance procedures will be performed at study sites and during data management to assure that 
safety and efficacy data are adequate and well documented.
16.7 Protocol Amendment and Protocol Deviation
Protocol Amendment
Amendments to the protocol that entail corrections of typographical errors, clarifications of 
confusing wording, changes in study personnel, and minor modifications that have no effect on 
the safety of subjects or the conduct of the study will be classed as administrative amendments 
and will be submitted to the IEC/IRB for information only. Syneos Health will ensure that 
acknowledgement is received and filed. Amendments that are classed as substantial amendments 
must be submitted to the appropriate regulatory authorities and the IECs/IRBs for approval and 
will not be implemented at sites until such approvals are received, other than in the case of an 
urgent safety measure.
Protocol Deviations
Should a protocol deviation occur, the Sponsor must be informed as soon as possible. Protocol 
deviations and/or violations and the reasons they occurred will be included in the clinical study 
report. Reporting of protocol deviations to the IEC/IRB and in accordance with applicable 
regulatory authority mandates is an investigator’s responsibility.
All protocol deviations will be tracked in the Clinical Trial Management System.
Deviations considered major will be identified as such before study unblinding during 
medical monitor periodic review.
Major protocol deviations will be tabulated including the frequency and percentage of subjects 
with each type of deviation by treatment group.
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16.8 Ethical Considerations
This study will be conducted in accordance with this protocol, the accepted version of the 
Declaration of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, 
Subpart D, of Title 21 of the CFR; and in compliance with GCP guidelines.
IECs/IRBs will review and approve this protocol and the ICF. All subjects and/or caregivers
(Ukraine only) are required to give written informed consent before participation in the study.
16.9 Financing and Insurance 
Before the study commences, the Sponsor (or its designee) and the investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study. This agreement will 
be documented in a financial agreement that will be signed by the investigator (or the institution 
signatory) and the Sponsor (or its designee). 
The investigator is required to have adequate current insurance to cover claims for negligence 
and/or malpractice (US only). The Sponsor will provide no-exclusion insurance coverage for the 
clinical study as required by national regulations.
16.10 Publication Policy/Disclosure of Data 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Intellectual property rights (and related matters) generated by the investigator and others 
performing the clinical study will be subject to the terms of a clinical study agreement that will 
be agreed between the institution and the Sponsor or their designee. With respect to such rights, 
the Sponsor or its designee will solely own all rights and interests in any materials, data, and 
intellectual property rights developed by investigators and others performing the clinical study 
described in this protocol, subject to the terms of any such agreement. In order to facilitate such 
ownership, investigators will be required to assign all such inventions either to their institution or 
directly to the Sponsor or its designee, as will be set forth in the clinical study agreement.
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17
REFERENCES 
1. Patel KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: overview and treatment options. P 
T. 2014;Sep 39(9):638-645. 
2. van Os J, Kapur S. Schizophrenia. Lancet. 2009 Aug 22;374(9690):635-645.
3. Wu EQ, Shi L, Birnbaum H, Hudson T, Kessler R. Annual prevalence of diagnosed 
schizophrenia in the USA: a claims data analysis approach. Psychol Med. 2006 
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4. Crismon L, Argo TR, Buckley PF. Schizophrenia. In: DiPiro JT, Talbert RL, Yee GC, et al., 
editors. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, New York: 
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5. Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome 
in schizophrenia: implications for MATRICS. Schizophr Res. 2004;72(1):41-51.
6. Huhn M, Nikolakopoulou A, Schnider-Thoma J, et al. Comparative efficacy and tolerability 
of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a 
systematic review and network meta-analysis. Lancet. 2019;394(10202):939-951. 
7. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients 
with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223. 
8. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 
15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 
2013;382(9896):951-962.
9. Emsley R, Chiliza B, Asmal L, Harvey BH. The nature of relapse in schizophrenia. BMC 
Psychiatry. 2013;13:50.
10. Kahn RS, Sommer IE, Murray RM, et al. Schizophrenia. Nat Rev Dis Primers. 
2015;1:15067.
11. Sellin AK, Shad M, Tamminga, C. Muscarinic agonists for the treatment of cognition in 
schizophrenia. CNS Spectr. 2008 Nov;13(11):985-996. 
12. Wess J, Eglen RM, Gautam D. Muscarinic acetylcholine receptors: mutant mice provide new 
insights for drug development. Nat Rev Drug Discov. 2007 Sep;6:(9):721-733. 
13. Mirza NR, Peters D, Sparks RG. Xanomeline and the antipsychotic potential of muscarinic 
receptor subtype selective agonists. CNS Drug Rev. 2003 Summer;9(2):159-186. 
14. Thorn CA, Moon J, Bourbonais CA, et al. Striatal, hippocampal, and cortical networks are 
differentially responsive to the M4- and M1-muscarinic acetylcholine receptor mediated 
effects of xanomeline. ACS Chem Neurosci. 2019;10(8):3910. 
15. Farde L, Suhara T, Halldin C, et al. PET study of the M1-agonists [11C]xanomeline and 
[11C]butylthio-TZTP in monkey and man. Dementia. 1996;7(4):187-195. 
16. Bodick NC, Offen WW, Levey AI, et al. Effect of xanomeline, a selective muscarinic 
receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch 
Neurol. 1997;54(4):465-473. 
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17. Bodick NC, Offen WW, Shannon HE, et al. The selective muscarinic agonist xaqnomeline 
improves both the cognitive deficits and behavioral symptoms of Alzheimer’s disease. 
Alzheimer Dis Assoc Disord. 1997; 11 Suppl 4:S16-22.
18. Shekhar A, Potter WZ, Lightfoot J, et al. Selective muscarinic receptor agonist xanomeline 
as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008 Aug;165(8):1033-
1039. 
19. Staskin D, Sand P, Zinner N, Dmochowski R, Trospium Study Group. Once daily trospium 
chloride is effective and well tolerated for the treatment of overactive bladder; results from a 
multicenter phase III trial. J Urol. 2007;178(3 Pt 1):978-983; discussion 983-984. 
20. Scheife R, Takeda M. Central nervous system safety of anticholinergic drugs for the 
treatment of overactive bladder in the elderly. Clin Ther. 2005;27(2):144-153. 
21. Brannan SK, Paul SM and Breier A. Xanomeline plus trospium: A novel strategy to enhance 
pro-muscarinic efficacy and mitigate peripheral side effects. Proceedings of the ASCP annual 
meeting 2019.
22. [HMA] Heads of Medicines Agencies. Clinical Trial Facilitation Group page. 
Recommendations related to contraception and pregnancy testing in clinical trials. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
September 15, 2014. Accessed 27 Mar 2020. 
23. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989 
May;154 (5):672-676.
24. Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm 
of Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric 
suicidal risk analysis of antidepressants. Am J Psychiatry. 2007 Jul;164(7):1035-1043. 
25. Chatoor D, Emmanuel A. Constipation and evacuation disorders. Best Pract Res Clin 
Gastroenterol. 2009;23(4):517-530.
26. Constipation. National Institute of Diabetes and Digestive and Kidney Diseases. 
https://www.niddk.nih.gov/health-information/digestive-diseases/constipation/all-content. 
February 2015. Accessed 28 Mar 2020. 
27. American Gastroenterological Association, Bharucha AE, Dorn SD, Lembo A, Pressman A. 
American Gastroenterological Association medical position statement on constipation. 
Gastroenterology. 2013 Jan;144(1):211-217. 
28. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional 
bowel disorders. Gastroenterology. 2006 Apr;130(5):1480-1491. 
29. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol. 1997 Sep;32(9):920-924. 
30. Locke GR III, Pemberton JH, Phillips SF. American Gastroenterological Association 
Medical Position Statement: guidelines on constipation. Gastroenterology. 2000 
Dec;119(6):1761-1766. 
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31. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr Bull. 1987;13(2):261-276.
32. Guy W. EDCEU Assessment Manual for Psychopharmacology – Revised. Rockville, MD, 
US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug 
Abuse, and Mental Health Administration, NIMH Psychopharmacology Research Branch, 
Division of Extramural Research Programs, 1976:534-7. DHEW Publication No ADM 
76-338.
33. Buchanan RW, Davis M, Goff D, et al. A summary of the FDA-NIMH-MATRICS workshop 
on clinical trial design for neurocognitive drugs for schizophrenia. Schizophrenia Bulletin. 
2005 Jan;31(1):5-19. 
 
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18
APPENDICES 
Appendix 1: Contraception Guidelines
Women of childbearing potential (WOCBP) and men whose sexual partners are WOCBP must 
use at least 1 highly effective method of contraception during the study and for 7 days after the 
last dose of study treatment. 
A woman is considered to be a WOCBP (fertile) following menarche and until becoming 
postmenopausal, unless she is permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause. A high 
follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.  
A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy.
Highly effective methods of contraception are those which have a failure rate of <1% (when 
implemented consistently and correctly) and include: 
 combined (containing estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation (administration may be oral, intravaginal, or transdermal) 
 progestogen-only hormonal contraception associated with inhibition of ovulation 
(administration may be oral, injectable, or implantable) 
 intrauterine device 
 intrauterine hormone-releasing system 
 bilateral tubal ligation or occlusion 
 vasectomy (provided that the male has a medical assessment of surgical success)
 sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of risk in relation to the duration of the clinical trial, in line with the preferred and 
usual lifestyle of the subject) 
All subjects will be strongly advised that they (or the female partners of male subjects should not 
become pregnant while on study treatment or for 7 days after the last dose). A female subject 
will be advised that she must report immediately to the study site for pregnancy testing and 
appropriate management in the event that she may be pregnant.
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Reference: [HMA] Heads of Medicines Agencies. Clinical Trial Facilitation Group page. 
Recommendations related to contraception and pregnancy testing in clinical trials. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
September 15, 2014. Accessed April 8, 2020. 
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Appendix 2: Functional Constipation Inquiry 
 
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Appendix 3: Alternative Procedures During COVID-19 Pandemic-Related Physical 
Distancing
The table below (Alternative Schedule of Assessments) outlines the timing of alternative visits 
procedures and assessments that may be used to replace scheduled on-site study visits during 
COVID-19 pandemic-related quarantine or mandated physical distancing.
A Home Health Care nurse or the study site staff will visit the subject to complete the scheduled
alternate visit. To augment the remote visit, the telemedicine will be used.  
 
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Alternative Schedule of Assessments
DAY
(± 3d, unless otherwise noted)
56
84
112
140
168
196
224
252
280
308
336
WEEK
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
 
VISIT
7R
9R
11R
13R
15R
17R
19R
21R
23R
25R
27R
UNS-Ra
TYPE OF VISIT Remote
Remote Remote Remote Remote Remote Remote
Remote Remote Remote
Remote Remote
PROCEDURE
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (WOCBP only) (1),b  
X 
X
X 
X 
X 
X 
X
X 
X
X 
X 
X 
Urine drugs of abuse and alcohol testing (1),c 
Body weight, BMI, waist circumference (1),d
X
X
X
X
X
X
X
X
X
X
X
X
Blood samples for clinical laboratory tests 
(1),e 
X
Blood sample for prolactin (1)
X
Functional constipation inquiry (2),f 
Clinical observations (1),g
Safety follow up of any AE and/or conmed 
changes reported by the HHC staff, as needed 
(2),h
PK blood draw (1),i 
PANSS (3),j
C-SSRS (3),k
CGI-S (3)
BARS (3)
AIMS (3)
KarXT dispensed using MedReady dispenser
(1),l
Subject self-administration of KarXT using 
AiCure app (1),l
EMA PROm
EMA VLMTn
Digital biomarkers of schizophrenia o
Abbreviations: AE = adverse event; AIMS = Abnormal Involuntary Movement scale; BARS = Barnes Akathisia Rating Scale; BMI = body mass index;
BP = blood pressure; CGI-S = Clinical Global Impress
; C-SSRS = Columbia-Suicide Severity Rating Scale; d = day; EMA = ecological 
momentary assessment; HR = heart rate; PANSS = Positive and Negative Syndrome Scale; PK = pharmacokinetic; R = remote; UNS = unscheduled visit. 
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(1)
This procedure will be performed either by a Home Health Care nurse or the study site staff.
(2) 
This procedure will be performed by telemedicine over a telephone or through video chat.  
(3) 
Procedure conducted by telemedicine through video chat only (telephone assessment will not be permitted). 
 
a. 
Other assessments as needed.   
b. 
A urine pregnancy test for WOCBP should be performed at indicated visits. If a urine pregnancy test is positive, a serum sample should be sent to central 
laboratory for confirmation of the result. 
c. 
A National Institute on Drug Abuse-5 (NIDA-5) urine drug screen (cannabinoids or marijuana, phencyclidine, amphetamines, opiates, and cocaine) and 
test for alcohol (breathalyzer or blood alcohol level) will be performed at indicated visits.    
d. 
At the indicated study visits, body weight and waist circumference will be measured and BMI calculated. 
e. 
Refer to Section 0 for individual laboratory tests. For urinalysis, a urine dipstick will be performed locally. In the event of abnormalities, the sample will 
be sent to the central laboratory for full microscopic urinalysis. 
f. 
Functional constipation inquiry: At specified visits, subjects will be asked whether they have experienced constipation (per the ROME III criteria and 
Bristol Stool Form Scale; see APPENDIX 2) since the last visit and if yes, whether the constipation required intervention. If the subject answers yes, sites 
are instructed to ask subjects to provide event date and ensure the event is documented as an AE and treatment is documented as concomitant medication.  
g. 
Clinical observations include collection of vital signs, review of spontaneous AEs, and concomitant medications. These assessments will be performed by 
a Home Health Care (HHC) nurse and/or site staff visiting the patient at home. Vital signs measurements should be taken at all alternate visits, while the 
subject is supine and standing after 2 minutes. BP includes systolic and diastolic BP and should be taken in the same arm for the duration of the study 
whenever possible.   
 
Adverse events as reported by subjects or observed by clinical staff. Adverse events occurring after dosing with KarXT in the current study (and 
resolution) will be recorded in the KAR-008 AE eCRF. One PK blood sample may be drawn if a relevant/significant AE (based on medical 
judgment) is reported during a scheduled visit or if there is a dose titration or a relevant/significant AE reported during an unscheduled visit (no 
multiple draws).    
 
All medications and other treatments taken by the subject during the study, including those treatments initiated before the start of the study, must 
be recorded on the KAR-008 eCRF. For any new AEs or concomitant medication reported by the HHC nurse, site staff must follow up with 
subjects directly via telemedicine over telephone or through video chat and complete a safety follow-up evaluation. 
h. 
For any new AEs or concomitant medication reported by the HHC nurse, site staff must follow up with subjects directly via telemedicine over telephone 
or through video chat and complete a safety follow-up evaluation.   
i. 
PK blood samples will be collected in the morning before dosing on Days 84, 168, and 364. On these days collection of a single sample before the 
morning dose is preferred. However, timing of the sample is not mandatory and will not be captured as a protocol deviation if collected after the morning 
dose (but must be collected on required visit day).  Note: In cases of dose reduction, re-escalation, or re-titration, additional PK samples should be 
collected at 8 and 14 days (+/- 2) post dose change in accordance with the Visits 3 and 4 schedules, unless these additional samples overlap with regularly 
scheduled PK samples. Otherwise unscheduled visits should be performed to collect these additional samples. 
j. 
It is recommended, if at all possible, that the PANSS assessment should be performed before all the other scale assessments for all visits at which it is 
performed. The PANSS assessment includes the Marder Factor. 
k. 
The “since last visit” version should be used for C-SSRS administration. At the Unscheduled visit, the C-SSRS should be performed to monitor subjects 
for suicidality. 
l. 
See Study Operations Manual for details.  
m. 
EMA PRO will be completed by the subject at home on a cellular device 3 times per day for 7 days every 28 days, beginning on Day 29.   
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n.
Cognitive insight will be assessed using the EMA VLMT. The assessment will be completed by the subject at home on a cellular device 1 time per day 
for 3 days every 28 days beginning on Day 32. Refer to Study Operational Manual for details. 
o. 
Digital biomarkers of schizophrenia will be calculated through completion of a smartphone-based assessment daily by the subject for 3 days collected 
daily for 3 days every 28 days, beginning on Day 29. 
 
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1 
FINAL CLINICAL STUDY PROTOCOL  
 
Karuna Therapeutics 
Protocol Title: An Open-label Extension Study to Assess the Long-term Safety, 
Tolerability, and Efficacy of KarXT in Subjects with DSM-5 Schizophrenia 
 
Protocol Number: KAR-008 
 
IND Number: 
127471 
EudraCT Number: 
Not applicable 
Name of Investigational Product: 
KarXT 
Phase of Development: 
Phase 3 
Indication: 
Schizophrenia 
Sponsor: 
Karuna Therapeutics 
33 Arch Street 
Suite 3110 
Boston, MA 02110 
Tel: 
 
Email: 
 
Protocol Version:  
Version 3.0 
Protocol Date: 
30 Jun 2021 
 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to Karuna Therapeutics. Any unauthorized 
copying or use of this document is prohibited. 
 
 
 
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PROTOCOL APPROVAL SIGNATURES
Protocol Title:
An Open-label Extension Study to Assess the Long-term Safety,
Tolerability, and Efficacy of KarXT in Subjects with DSM-5 
Schizophrenia
Protocol Number:
KAR-008
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Council for Harmonisation (ICH) guidelines for current 
Good Clinical Practice (GCP), and applicable regulatory requirements.
Sponsor Signatory
Karuna Therapeutics
Signature
Date (DD-Mmm-YYYY)
Karuna Therapeutics
Signature
Date
Contract Research Organization Signatory 
Syneos Health
Signature
Date (DD-Mmm-YYYY)
Biostatistician
Veristat
Signature
Date (DD-Mmm-YYYY)
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INVESTIGATOR SIGNATURE PAGE
Protocol Title: 
An Open-label Extension Study to Assess the Long-term Safety, Tolerability, 
and Efficacy of KarXT in Subjects with DSM-5 Schizophrenia 
Protocol Number: 
KAR-008 
Confidentiality and Current Good Clinical Practice (GCP)/E6(R2) Compliance Statement  
 I, the undersigned, have reviewed this protocol (and amendments), including appendices, 
and I will conduct the study as described in compliance with this protocol (and 
amendments), and relevant International Council for Harmonisation (ICH) guidelines 
including GCP and applicable regulatory requirements. 
 I am thoroughly familiar with the appropriate use of the KarXT, as described in this 
protocol and any other information provided by Karuna Therapeutics including, but not 
limited to, t
. 
 Prior to initiating the trial, I will provide the independent ethics committee 
(IEC)/institutional review board (IRB) all items subject to review and will obtain a 
written and dated approval/favorable opinion. Once the protocol has been approved by 
the IEC/IRB, I will not modify this protocol without obtaining prior approval of Karuna 
Therapeutics and of the IEC/IRB. I will submit the protocol amendments and/or any 
informed consent form modifications to Karuna Therapeutics and the IEC/IRB, and 
approval will be obtained before any amendments are implemented. 
 I ensure that all persons or party assisting me with the study are adequately qualified and 
informed about the Karuna Therapeutics KarXT and of their delegated study-related 
duties and functions as described in the protocol. I will supervise these delegated persons 
or parties in the conduct of this trial. 
 I ensure that source documents and trial records that include all pertinent observations on 
accurate, and complete.  
 I understand that all information obtained during the conduct of the study with regard to 
the 
 state of health will be regarded as confidential. No 
 names will be 
disclosed. All subjects will be identified by assigned numbers on all case report forms, 
laboratory samples, or source documents forwarded to the Sponsor. Clinical information 
may be reviewed by the Sponsor or its agents or regulatory agencies. Agreement must be 
obtained from the subject before disclosure of subject information to a third party. 
 Information developed in this clinical study may be disclosed by Karuna Therapeutics to 
other clinical investigators, regulatory agencies, or other health authority or government 
agencies as required. 
<Name> 
 
<Title> 
Investigator Signature 
 
 
 
Date (DD-Mmm-YYYY) 
 
 
Institution 
 
 
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2 
SYNOPSIS 
Title of Study: 
An Open-label Extension Study to Assess the Long-term Safety, 
Tolerability, and Efficacy of KarXT in Subjects with DSM-5 Schizophrenia 
Protocol Number: 
KAR-008 
Investigators/Study Sites: 
Approximately 30 study sites in the United States and 10 study sites in 
Ukraine 
Phase of Development: 
Phase 3 
Objective(s): 
Primary Objective: 
The primary objective of the study is to assess the long-term safety and 
tolerability of KarXT in subjects with a Diagnostic and Statistical 
Manual-Fifth Edition (DSM-5) diagnosis of schizophrenia. 
Secondary Objectives: 
The secondary objective of this study is to assess the long-term efficacy and 
evaluate plasma concentrations of xanomeline and trospium after 
administration of KarXT in adults with a DSM-5 diagnosis of 
schizophrenia: 
 
To evaluate the reduction in Positive and Negative Syndrome Scale 
(PANSS) total score 
 
To evaluate the reduction in PANSS positive score  
 
To evaluate the improvement in Clinical Global Impression Severity 
(CGI-S) results  
 
To evaluate the reduction in PANSS negative score  
 
To evaluate the reduction in PANSS Marder Factor negative 
symptoms score 
 
Exploratory Objectives: 
The exploratory objectives of this study are: 
 
To evaluate cognition with the Cambridge Neuropsychological Test 
Automated Battery (CANTAB) 
 
To evaluate prolactin levels after administration of KarXT 
 
To evaluate digital biomarkers of schizophrenia 
 
To evaluate ecological momentary assessment administered patient 
reported outcomes (EMA PRO) in schizophrenia 
 
To evaluate cognitive insight using an EMA administered verbal 
learning and memory test (EMA VLMT) in schizophrenia 
Study Endpoints: 
Primary safety endpoint:  
The primary safety endpoint is the incidence of treatment-emergent adverse 
events (TEAEs) 
Secondary safety endpoints: 
The secondary safety endpoints of the study are: 
 
Incidence of serious TEAEs 
 
Incidence of TEAEs leading to withdrawal 
 
Secondary efficacy endpoints: 
 
The secondary efficacy endpoints of the study are: 
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Change from baseline in PANSS total score at Week 52
 
Change from baseline in PANSS positive score at Week 52 
 
Change from baseline in PANSS negative score at Week 52 
 
Change from baseline in PANSS Negative Marder Factor score at 
Week 52 
 
Change from baseline in CGI-S score at Week 52 
 
Percentage of PANSS responders (a 30% change in PANSS total 
score) at Week 52  
Other Endpoints:  
Safety endpoints: 
The other safety endpoints of the study are: 
 
Spontaneously reported adverse events of special interest (AESIs) 
 
Spontaneously reported procholinergic and anticholinergic symptoms 
 
Change from baseline in Simpson-Angus Rating Scale (SAS) 
 
Change from baseline in Barnes Rating Scale for Akathisia (BARS) 
 
Change from baseline in Abnormal Involuntary Movement Scale 
(AIMS) 
 
Change from baseline in body weight, body mass index (BMI), waist 
circumference  
 
Change from baseline in orthostatic vital signs (supine and standing 
after 2 minutes): blood pressure (systolic and diastolic) and heart rate 
 
Change from baseline in clinical laboratory assessments (hematology, 
clinical chemistry, coagulation, urinalysis, and drug screen) 
 
Change from baseline in 12-lead electrocardiogram (ECG)  
 
Change from baseline in physical examination  
 
Suicidal ideation scale with the use of Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
Pharmacokinetic Endpoint: 
 
Comparison of the plasma concentrations of xanomeline and trospium 
measured in this study to the plasma concentrations predicted by a 
population pharmacokinetic (PK) model of studies KAR-007 and 
KAR-009 
Exploratory Endpoints: 
The exploratory endpoints of the study are:  
 
Change from baseline in cognition measuring core domains of 
impairment in schizophrenia using CANTAB 
 
Change from baseline in prolactin levels 
 
Observed digital biomarkers of schizophrenia (US only) 
 
Observed EMA PRO in schizophrenia (US only) 
 
Observed cognitive insight using EMA VLMT in schizophrenia (US 
only) 
Study Design: 
This is a Phase 3 multicenter, 53-week, outpatient, open-label extension 
(OLE) study to evaluate the long-term safety, tolerability, and efficacy of 
KarXT in subjects with DSM-5 schizophrenia who previously completed 
the treatment period of one of the two Phase 3 double-blind studies, 
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KAR-007 or KAR-009. The study consists of a 52-week OLE treatment 
phase and a 7-day (±3 days) safety follow-up/end-of-study visit after the 
last KarXT dose for subjects who complete the treatment phase and those 
who prematurely discontinue from the study.  
After written informed consent, subjects who have completed the KAR-007 
or KAR-009 Phase 3 acute study and received the last dose of the study 
drug in that trial will be rolled over into the current OLE study. The 
assessments performed on Visit 10 (Day 35) of studies KAR-007 or 
KAR-009 will be considered as baseline assessments along with any 
additional procedures that will be performed on Day 0 of the current study. 
Any scheduled Day 0 assessments that were not completed on Day 35 of 
the acute study (KAR-007 or KAR-009) must be completed on Day 0 of the 
current study.  
It is preferable that Baseline/Day 0 procedures of the current study  be 
completed on the same day as Day 35 of the acute study after all Visit 10 
(Day 35) procedures of the prior study KAR-007 or KAR-009 have been 
completed. However, with medical monitor approval, an extension of up to 
3 days can be granted to complete Baseline/Day 0 procedures. This 
extension cannot be completed inpatient.  
With medical monitor approval, participants may be permitted to complete 
the first 3 days (Visit 1/Day 1 to Visit 2/Day 3) of KAR-008 on the 
inpatient unit.  
Twice-daily dosing with KarXT will commence in the morning of Day 1. 
Subjects who did not complete the full treatment period, or who early 
terminated study KAR-007 or KAR-009, will not be eligible to enroll in 
this long-term extension study.  
Approximately 350 subjects are planned to be enrolled in this study (aged 
18 to 65 years) across approximately 30 study sites in the United States and 
10 study sites in Ukraine. 
In this OLE study, all subjects will receive KarXT for up to 52 weeks. 
Regardless of treatment assignment in the preceding Phase 3 acute study 
(KAR-007 or KAR-009), all subjects will start on a lead-in dose of KarXT 
50/20 (50 mg xanomeline/20 mg trospium) 2 times per day (BID) for the 
first 2 days (Days 1 and 2), followed by KarXT 100/20 BID for the 
remainder of Week 1 (Days 3 to 7). At Visit 3 (Day 8), dosing will be 
titrated upwards to KarXT 125/30 BID unless the subject is continuing to 
experience adverse events (AEs) from the previous dose of KarXT 100/20 
BID. All subjects who are increased to KarXT 125/30 BID, depending on 
tolerability, will have the option to return to KarXT 100/20 BID. 
Re-escalation to 125/30 BID or re-titration in cases in which the subject has 
been off KarXT for a longer period of time (at least a week) is allowed and 
will require a discussion between the principal investigator and the medical 
monitor. Additional changes to KarXT dosing (e.g., temporary dose 
reductions) may be permitted as clinically indicated upon approval by the 
medical monitor.  
Beginning after Visit 9/Day 84, interim visits will be completed with 
flexibility between in-clinic visits, approximately once every 4 weeks. 
Interim visits will be conducted by telemedicine; however, sites will have 
the option to schedule on-site interim visits as needed to facilitate subject 
retention and ensure adherence to study objectives. Additional unscheduled 
study visits may be conducted as needed. 
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A safety follow-up/end-of-study visit (Visit 30/Day 371 ±3 days) will be 
performed for all subjects after the last dose of KarXT. 
An Independent Safety Monitoring Committee will be responsible for 
periodically reviewing the safety data from this study and confirming that 
the study may continue. 
Study Population: 
Inclusion Criteria:  
Individuals must meet all of the following criteria to be included in the 
study: 
1. Subject is aged 18 to 65 years, at time of enrollment into the preceding 
acute study (KAR-007 or KAR-009).   
2. Subject is capable of providing informed consent.  
a. 
A signed informed consent form must be provided before any 
study assessments are performed. 
b. Subject must be fluent in (oral and written) English (United 
States only) or local language (Ukraine only) to consent. 
3. Subject has completed the treatment period on study drug (through 
Day 35 -2 days) of studies KAR-007 or KAR-009.  
4. Subject resides in a stable living situation, in the opinion of the 
investigator. 
5. Subject has an identified, reliable informant/caregiver willing to be 
able to address some questions related to certain study visits, if 
needed.   An informant/caregiver may not be necessary if the subject 
ar.  
6. Women of childbearing potential (WOCBP) or men whose sexual 
partners are WOCBP must be willing and able to adhere to the 
contraception guidelines as defined in Section 8.4.1 and Appendix 1. 
Exclusion Criteria: 
Subjects will be excluded from the study if 1 or more of the following 
criteria is/are applicable: 
1. 
Risk for suicidal behavior during the study as determined by the 
-SSRS as confirmed by the 
following:  
a. 
Subject answers 
suicidal ideation with some intent to act, without specific 
plan) or Item 5 (active suicidal ideation with specific plan and 
intent) on the C-SSRS.  
b. Nonsuicidal self-injurious behavior is not exclusionary. 
2. 
Any clinically significant abnormality, including any finding(s) from 
the physical examination, vital signs, ECG, or laboratory test at the 
end-of-treatment visit of Studies KAR-007 or KAR-009 that the 
investigator, in consultation with the medical monitor, would consider 
to jeopardize the safety of the subject. 
3. 
Female subject is pregnant, breast feeding or planning to become 
pregnant during the course of the study. 
4. 
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 his/her ability to adhere to the protocol 
visit schedule or fulfill visit requirements. 
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5. 
Subjects with extreme concerns relating to global pandemics such as 
coronavirus disease 2019 (COVID-19) that preclude study 
participation. 
6. 
Risk of violent or destructive behavior. 
7. 
Subjects participating in another investigational drug or device trial or 
planning on participating in another clinical trial during the course of 
the study. 
Planned Sample Size: 
Approximately 350 subjects are planned to be enrolled in this study.  
Investigational Therapy: 
1. Fixed dose KarXT 50/20 BID (50 mg xanomeline/20 mg trospium) 
oral (Days 1 to 2) 
2. Fixed dose KarXT 100/20 BID (100 mg xanomeline/20 mg trospium) 
oral (Days 3 to 7) 
3. Fixed dose KarXT 125/30 BID (125 mg xanomeline/30 mg trospium) 
oral (Days 8 to 364, if tolerated)  
Reference Therapy: 
Not applicable. 
Treatment Duration: 
Total study duration is up to 53 weeks, including a 52-week treatment 
phase and a 7-day follow-up/end-of-study phase. 
Safety assessments: 
Spontaneous AEs including AESIs; procholinergic and anticholinergic 
symptoms, serious AEs (SAEs) and AEs leading to discontinuation of 
KarXT; SAS; BARS; AIMS; body weight; BMI; waist circumference; 
orthostatic vital signs; clinical laboratory assessments (hematology, clinical 
chemistry, coagulation, urinalysis, and drug screen); 12-lead ECG; physical 
examination; and C-SSRS will be evaluated throughout the study as 
scheduled. 
Efficacy assessments: 
PANSS total score, PANSS positive score, PANSS negative score, PANSS 
Negative Marder Factor score, and CGI-S score will be evaluated at 
scheduled visits. 
Pharmacokinetic assessment: 
Blood samples will be collected at scheduled visits for bioanalysis of 
plasma concentrations of xanomeline and trospium, and will be compared 
to the plasma concentrations predicted by a population pharmacokinetic 
(PK) model of studies KAR-007 and KAR-009. 
Exploratory assessments 
Cognition testing using CANTAB; prolactin levels; digital biomarkers of 
schizophrenia; EMA PRO and EMA VLMT will be evaluated during 
scheduled visits or on specified study days. 
Statistical Methods and 
Planned Analyses: 
Study Populations: 
Enrolled population: All subjects who have given informed consent for 
KAR-008. 
Safety population: All subjects who receive at least 1 dose of KarXT during 
the current study will be included in the safety population and will be used 
in the safety analysis. 
Modified ITT (mITT) population: All subjects who are enrolled, received at 
least 1 dose of KarXT during the current study, have a valid PANSS 
assessment at KAR-008 baseline will be included in the mITT population 
and will be used in the efficacy analysis. 
PK population: All subjects who have received at least 1 dose of KarXT 
and have at least 1 measurable plasma concentration in the current study 
will be included in the PK population. 
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The primary safety endpoint of the study is the incidence of TEAEs. 
Secondary safety endpoints are the incidence of serious TEAEs and the 
incidence of TEAEs leading to withdrawal of KarXT.  
The secondary efficacy endpoints are change from baseline to Week 52 in 
the PANSS total score, PANSS positive score, PANSS negative score, 
PANSS Negative Marder Factor score, CGI-S score, and the percentage of 
PANSS responders at Week 52.  
The exploratory endpoints of the study are change from baseline in 
cognition (CANTAB), prolactin levels, digital biomarkers, EMA PRO, and 
EMA VLMT. 
Descriptive statistics will be used to provide an overview of the safety and 
efficacy results. For continuous parameters, descriptive statistics will 
include n, mean, median, standard deviation, minimum and maximum; For 
categorical parameters, the number and percentage of subjects in each 
category will be presented. The denominator for percentages will be based 
on the number of subjects appropriate for the purposes of analysis. No 
statistical hypothesis testing will be performed. 
 
 
 
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3
TABLE OF CONTENTS
1
FINAL CLINICAL STUDY PROTOCOL ...................................................................1
2
SYNOPSIS........................................................................................................................4
3
TABLE OF CONTENTS..............................................................................................10
3.1
List of In-text Tables ..................................................................................................14
3.2
List of In-text Figures.................................................................................................14
4
LIST OF ABBREVIATIONS.......................................................................................15
5
INTRODUCTION .........................................................................................................18
5.1
Background on Schizophrenia....................................................................................18
5.2
Background on KarXT (Xanomeline Tartrate and Trospium Chloride)....................18
Nonclinical Studies ............................................................................................20
Completed Clinical Studies................................................................................23
5.3
Clinical Risks/Benefits of KarXT and Study Rationale.............................................32
6
STUDY OBJECTIVES AND ENDPOINTS ...............................................................35
6.1
Study Objectives.........................................................................................................35
Primary Objective ..............................................................................................35
Secondary Objective ..........................................................................................35
Exploratory Objectives ......................................................................................35
6.2
Study Endpoints..........................................................................................................35
Primary Safety Endpoint....................................................................................35
Secondary Endpoints..........................................................................................35
6.2.2.1
Safety Endpoints ..........................................................................................35
6.2.2.2
Efficacy Endpoints .......................................................................................36
Other Endpoints .................................................................................................36
6.2.3.1
Safety Endpoints ..........................................................................................36
6.2.3.2
Pharmacokinetic Endpoint ...........................................................................36
6.2.3.3
Exploratory Endpoints..................................................................................36
7
INVESTIGATIONAL PLAN .......................................................................................38
7.1
Description of Overall Study Design and Plan...........................................................38
7.2
Discussion of Study Design........................................................................................41
7.3
End of Study...............................................................................................................41
7.4
Independent Safety Monitoring Committee ...............................................................41
8
SELECTION OF STUDY POPULATION.................................................................43
8.1
Inclusion Criteria........................................................................................................43
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8.2
Exclusion Criteria.......................................................................................................43
8.3
Safety Laboratory Evaluations for Eligibility ............................................................44
8.4
Study Withdrawal, Removal, and Replacement of Subjects......................................44
Pregnancy...........................................................................................................45
8.5
Completion of the Study or Lost to Follow-up ..........................................................46
8.6
Study Termination......................................................................................................47
9
TREATMENTS .............................................................................................................48
9.1
Details of Study Treatments .......................................................................................48
Identity of Study Treatments..............................................................................48
Packaging and Labeling.....................................................................................48
KarXT Storage ...................................................................................................49
KarXT Retention................................................................................................49
9.2
Dosage Schedule ........................................................................................................49
Day 0..................................................................................................................49
Visit 1/Day 1 Dosing..........................................................................................50
Visit 2/Day 3 Dosing..........................................................................................50
Visit 3/Day 8 ......................................................................................................50
Visit 4/Day 14 Dosing and PK Considerations..................................................51
Visits 5-29 Dosing and PK Considerations........................................................51
9.3
Measures to Minimize Bias: Study Treatment Assignment .......................................52
Method of Study Treatment Assignment...........................................................52
Blinding..............................................................................................................52
9.4
Dosage Modification ..................................................................................................52
Dose Modifications and PK Sampling Considerations.... Error! Bookmark not 
defined.
Extended Dosing Interruptions and Re-titration ................................................52
9.5
Treatment Accountability and Compliance................................................................52
9.6
Prior and Concomitant Therapy .................................................................................53
Prior and Concomitant Medications ..................................................................53
Concomitant Medications for Anxiety and/or Sleep Aid...................................53
10
STUDY PROCEDURES...............................................................................................55
10.1
Informed Consent .......................................................................................................62
10.2
Study Procedures........................................................................................................62
AiCure Adherence Technology .........................................................................62
11
SAFETY ASSESSMENTS............................................................................................65
11.1
Demographics, Medical History, and Psychiatric History .........................................65
11.2
Vital Signs ..................................................................................................................65
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11.3
Complete/Targeted Physical Examination .................................................................65
11.4
Weight, Height, Body Mass Index, and Waist Circumference ..................................66
11.5
Electrocardiograms.....................................................................................................66
11.6
Laboratory Assessments.............................................................................................66
11.7
Adverse Events...........................................................................................................68
Adverse Events ..................................................................................................68
Adverse Events of Special Interest ....................................................................70
Serious Adverse Events .....................................................................................70
Serious Adverse Event Reporting......................................................................70
Drug-Induced Liver Injury.................................................................................71
11.7.5.1
Trial Discontinuation Criteria Other than DILI and Pregnancy...................72
11.7.5.2
Individual Stopping Criteria.........................................................................72
11.7.5.3
Trial Stopping Rules.....................................................................................72
Suspected Unexpected Serious Adverse Reactions ...........................................73
Warnings and Precautions..................................................................................73
11.8
Pregnancy ...................................................................................................................74
11.9
Overdose.....................................................................................................................75
11.10 Simpson-Angus Rating Scale.....................................................................................76
11.11 Barnes Rating Scale for Akathisia..............................................................................76
11.12 Abnormal Involuntary Movement Scale ....................................................................76
11.13 Columbia-Suicide Severity Rating Scale ...................................................................76
11.14 Functional Constipation Inquiry.................................................................................76
12
EFFICACY ASSESSMENTS.......................................................................................78
12.1
Positive and Negative Syndrome Scale......................................................................78
12.2
Clinical Global Impression-Severity..........................................................................78
13
PHARMACOKINETICS..............................................................................................79
13.1
Pharmacokinetic Sampling.........................................................................................79
PK Blood Samples and Timing..........................................................................79
PK Blood Samples and KarXT Dosing ChangesError! Bookmark not defined.
13.2
Pharmacokinetic Analytical Methodology.................................................................79
14
EXPLORATORY ASSESSMENTS ............................................................................80
14.1
Cognition Testing - Cambridge Neuropsychological Test Automated Battery .........80
14.2
Change in Prolactin ....................................................................................................80
14.3
Digital Biomarkers of Schizophrenia (US only) ........................................................81
14.4
EMA Wellness Assessments......................................................................................81
EMA Wellness EMA PRO (US only).............................................................81
EMA Wellness - VLMT (US only)....................................................................82
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Data Collected on EMAW Platform ..................................................................82
15
STATISTICAL ANALYSIS.........................................................................................83
15.1
Determination of Sample Size....................................................................................83
15.2
Analysis Populations ..................................................................................................83
15.3
Safety Analysis...........................................................................................................83
15.4
Efficacy Analysis........................................................................................................84
15.5
Pharmacokinetic Analysis ..........................................................................................84
15.6
Exploratory Analysis..................................................................................................84
15.7
Interim Analysis .........................................................................................................84
15.8
Handling of Missing Data ..........................................................................................85
16
STUDY MANAGEMENT ............................................................................................86
16.1
Approval and Consent ................................................................................................86
Regulatory Guidelines........................................................................................86
Institutional Review Board/Independent Ethics Committee..............................86
Informed Consent...............................................................................................86
16.2
Data Handling.............................................................................................................87
16.3
Source Documents......................................................................................................88
16.4
Record Retention........................................................................................................88
16.5
Monitoring..................................................................................................................88
16.6
Quality Control and Quality Assurance .....................................................................89
16.7
Protocol Amendment and Protocol Deviation............................................................89
Protocol Amendment .........................................................................................89
Protocol Deviations............................................................................................89
16.8
Ethical Considerations................................................................................................90
16.9
Financing and Insurance.............................................................................................90
16.10 Publication Policy/Disclosure of Data........................................................................90
17
REFERENCES ..............................................................................................................91
18
APPENDICES................................................................................................................94
Appendix 1:
Contraception Guidelines.................................................................................94
Appendix 2:
Functional Constipation Inquiry ......................................................................95
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3.1 
List of In-text Tables 
Table 1. Study Drug Dosing Scheme ....................................................................................40 
Table 2. Schedule of Assessments ........................................................................................56 
Table 3. Laboratory Assessments..........................................................................................67 
Table 4. Classification of Adverse Events by Intensity ........................................................69 
Table 5. Classification of Adverse Events by Relationship to KarXT..................................69 
Table 6. Cognitive Tests and Cognitive Domains Assessed by the Cambridge 
Neuropsychological Test Automated Battery .........................................................80 
 
3.2 
List of In-text Figures 
Figure 1. Change from Baseline in PANSS Total Scores (KAR-004) ...................................28 
Figure 2. Change from Baseline in PANSS-Positive Scores (KAR-004) ..............................29 
Figure 3. Change from Baseline in CGI-S (KAR-004) ..........................................................30 
Figure 4. Change from Baseline in PANSS-Negative Scores (KAR-004).............................31 
 
 
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4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AD 
 
AE 
adverse event 
AESI 
adverse event of special interest 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
alanine aminotransferase 
APD 
antipsychotic drug 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-24 
area under the plasma concentration-time curve from 0 to 24 hours 
BACS 
Brief Assessment of Cognition in Schizophrenia 
BARS 
Barnes Akathisia Rating Scale 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global 
 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSM-5 
 
EDC 
electronic data capture 
ECG 
electrocardiogram 
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination 
eCRF 
electronic case report form 
EMA 
Ecological Momentary Assessment 
EMAW 
Ecological Momentary Assessment Wellness 
EPS 
extrapyramidal symptoms 
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Abbreviation 
Definition 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability Accountability Act 
IB 
 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
IXRS 
interactive response system 
MCC 
microcrystalline cellulose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini International Neuropsychiatric Interview 
mITT 
modified intent-to-treat 
MMRM 
mixed model repeated measures 
OLE 
open-label extension 
PANSS 
Positive and Negative Syndrome Scale 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PRO 
patient reported outcome  
SAS 
Simpson-Angus Rating Scale 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson Angus Scale 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TID 
thrice daily 
TK 
toxicokinetic 
Tmax 
time to maximum plasma concentration 
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Abbreviation 
Definition 
ULN 
upper limit of normal  
US 
United States 
VAS 
visual analog scale 
VLMT 
Verbal Learning and Memory Test 
WOCBP 
women of childbearing potential 
 
 
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5 
INTRODUCTION 
5.1 
Background on Schizophrenia 
Schizophrenia is a long-term mental disorder involving a breakdown in the relation between 
thought, emotion, and behavior, and leads to faulty perception, inappropriate actions and 
feelings, withdrawal from reality and personal relationships into fantasy and delusion, and a 
sense of mental fragmentation. Symptoms include delusions, hallucination, disorganized speech 
or behavior, and impaired cognitive ability.[1] The prevalence of schizophrenia is between 0.6% 
and 1.9% in the United States population.[2] Moreover, a claims analysis has estimated that the 
annual prevalence of diagnosed schizophrenia in the United States (US) is 5.1 per 1000 lives.[3] 
It is found equally in males and females, with males usually having an earlier onset of 
symptoms.[4]  
Antipsychotic drugs (APDs) are the mainstay of treatment for schizophrenia.[5] All currently 
available antipsychotics act through blockage of all or subsets of dopamine receptors in the 
brain. First-generation APDs include chlorpromazine and haloperidol; treatment with these 
agents is marked by high rates of parkinsonian extrapyramidal symptoms (EPS) and tardive 
dyskinesia and they consequently have limited use today. The second-generation agents, that 
include risperidone, olanzapine, quetiapine, lurasidone, aripiprazole, and lumateperone, tend to 
have lower levels of EPS or tardive dyskinesia and are currently the most commonly prescribed 
APD class. However, the second-generation drugs also have problematic side effects that include 
significant weight gain, metabolic disturbances, sedation, and akathisia.[6, 7, 8] These side 
effects contribute to poor medication adherence resulting in frequent relapses and 
hospitalizations.[9, 10] Thus, there is a need for medications for schizophrenia which act through 
alternative mechanisms. 
Central muscarinic receptors have been hypothesized to be therapeutic treatments for 
schizophrenia based on several converging lines of evidence including both animal and human 
studies.[11, 12] There are 5 subtypes of muscarinic receptors (M1-M5). The therapeutic effect of 
central muscarinic receptor agonism is thought to be due to agonism of M1 and M4 receptors in 
the central nervous system (CNS).[13] However, compounds that agonize M1 and M4 receptors 
are often not specific enough not to also agonize M2 and M3 receptors outside of the CNS due to 
the highly conserved allosteric binding sites that the receptors share, leading to adverse events 
(AEs) related to activation of these peripheral receptors. Thus, any potential benefit of 
 [AD]) has 
been outweighed by the occurrence of AEs associated with peripheral cholinergic side effects 
(nausea, vomiting, diarrhea, sweating, and excess salivation). 
5.2 
Background on KarXT (Xanomeline Tartrate and Trospium Chloride) 
Xanomeline tartrate is a muscarinic-cholinergic receptor agonist. It has agonistic activity at all 
5 muscarinic receptors, but preferentially stimulates M1 and M4 receptors and binding to M1 and 
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M4 receptors in the CNS, which 
effects (Roth, unpublished data). A recent study reports that xanomeline is a very potent M4 
muscarinic agonist in vivo, measured by various second messenger assays.[14] Xanomeline also 
enters the brain rapidly achieving a brain to plasma ratio of greater than 10 making it an 
attractive CNS drug candidate.[15]  
Xanomeline does not have any direct binding activity on dopaminergic receptors, suggesting that 
its mechanism of action is unrelated to direct dopamine involvement. 
Previous double-blind, placebo-controlled clinical trials have provided strong evidence that 
xanomeline has clinically relevant antipsychotic efficacy. In a multicenter outpatient trial in AD 
(N = 343), 3 doses of xanomeline (up to 225 mg/day) and placebo were assessed for 
26 weeks.[16, 17] Significant dose-dependent improvements in psychotic symptoms relative to 
placebo were observed. Moreover, psychotic symptoms resolved quite rapidly in subjects who 
were symptomatic at baseline and a dose-dependent reduction in the emergence of psychotic 
symptoms versus placebo was also observed. In a completer analysis, cognitive improvement 
was also found suggesting longer treatment intervals may be necessary for cognitive 
enhancement.[16, 17] In a subsequent small (N = 20) double-blind, placebo-controlled inpatient 
trial in treatment-resistant subjects with schizophrenia, xanomeline (225 mg/day) demonstrated 
robust and relatively rapid improvement in psychosis compared to placebo. In addition, 
improvement in both negative symptoms and cognitive impairment was observed.[18] 
In both the AD and schizophrenia trials, as well as in previous healthy volunteer studies, 
dose-
sweating, and hypersalivation. These side effects were frequent and, at the higher doses of 
xanomeline, led 
profile curtailed further development of xanomeline as a single agent.  
It is believed that the procholinergic AEs associated with xanomeline are mediated by 
mulation of peripheral rather than central muscarinic receptors, which would 
make these AEs theoretically amenable to counteracting peripheral anticholinergic treatment. 
Trospium chloride is a peripherally acting muscarinic antagonist which binds to and antagonizes 
all 5 muscarinic receptor subtypes.[19] It is a commonly used generic drug approved for over 10 
years by the US Food and Drug Administration (FDA) and by European authorities to treat 
overactive bladder and is generally well tolerated.[19] Several human subject studies have 
demonstrated that trospium does not appreciably cross the blood-brain barrier, consistent with 
20]  
KarXT is a novel combination of xanomeline tartrate and trospium chloride. Karuna 
hypothesized that the addition of trospium would mitigate peripheral procholinergic side effects 
(vomiting, nausea, diarrhea, sweating, and hyper-salivation) and thus provide a strategy to allow 
xanomeline to be administered and stimulate brain muscarinic receptors with a decreased side 
effect burden. Phase 1 studies in healthy volunteers of this combination demonstrated that 
KarXT reduced these side effects by 46% compared to xanomeline alone.[21] Moreover, the 
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remaining cholinergic AEs were generally mild to moderate in severity and transient in nature, 
often lasting a few hours without recurrence and were generally single-episode. In general, 
KarXT was well tolerated in healthy adult volunteers. These encouraging safety data prompted 
further work to assess KarXT for the treatment of schizophrenia and potentially other CNS 
disorders.
Karuna has recently completed an adequate and well-controlled, randomized, multi-center 
Phase 2, placebo-controlled, inpatient clinical trial of acute psychosis with schizophrenia in 
182 adult subjects (KAR-004). KarXT demonstrated a statistically significant and clinically 
meaningful 11.6 point mean reduction in total Positive and Negative Syndrome Scale (PANSS) 
at 5 weeks compared to placebo (p <0.0001), with statistical separation at each time point 
assessed (2, 4 and 5 weeks), and also demonstrated good overall safety and tolerability.
The purpose of the current study is to evaluate the long-term safety and tolerability of KarXT 
(xanomeline 125 mg/trospium 30 mg) administered twice daily (BID) in adult outpatients with 
Diagnostic and Statistical 
-5) diagnosis of schizophrenia. 
Xanomeline is currently not approved or marketed in any country. Trospium is marketed in the 
US and other regions of the world for the treatment of overactive bladder.
Nonclinical Studies
The following is a summary of the important nonclinical safety and toxicology studies. More 
detailed information can be found in the KarXT 
The acute toxicity of xanomeline tartrate was evaluated in mice and rats. All animals were 
observed for 2 weeks for mortality and clinical signs of intolerance, and then necropsied for 
gross examinations. In-life findings attributed to the test article included excessive 
muscarinic-mediated pharmacology, such as excessive salivation, hypoactivity, ataxia, soft 
stools, exophthalmos, ocular discharge, tremors, and convulsions, with survivors typically 
appearing normal by Day 3 or Day 4. Gross findings at necropsy were generally unremarkable
(eg, gas-distended or mucous-filled gastrointestinal [GI] tracts after oral dosing).
KarXT-301 was a 14-day, repeat dose study of KarXT in rats where relatively high doses of 
xanomeline and trospium were given, with either xanomeline alone or in combination with 
trospium. Seven groups of 10 rats/sex/group were administered either vehicle (reverse osmosis 
water), xanomeline alone at 37, 75, 150, or 300 mg/kg/day (split into BID doses, every 
12 hours), or xanomeline/trospium combination doses of 150/200 mg/kg/day or 
225/400 mg/kg/day, respectively (split into BID doses, every 12 hours). 
Satellite animals were included for the collection of plasma after the first and last doses for the 
determination of drug concentrations of each parent drug in support of toxicokinetic (TK) 
assessments.
There was no target-organ toxicity revealed by clinical pathology or by gross or microscopic 
assessments. All intolerance could be attributed to recognized pharmacology of either test article. 
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No dose-related ophthalmic observations were noted. Findings were not indicative of specific 
target organ toxicity. In short, no new hazard was identified.  
Clinical observations noted in most animals administered 300 mg/kg/day xanomeline included 
hypoactivity, clear oral discharge, dilated pupils, irregular or labored respiration, and rough 
haircoat, among other observations. These findings are generally consistent with the anticipated 
pharmacology of xanomeline.  
Three TK animals in the low-dose combination group died or were euthanized in extremis. It is 
unclear to what extent the combination treatment effects versus the different handling of these 
animals (including 3 plasma samplings per animal) contributed to these deaths. If gavage 
accidents were involved (as happened with some TK animals), then they were not detected at 
gross necropsy. There was no microscopic evidence of toxicity seen in any toxicity animals in 
this group or in the higher-dose combination group. 
Three toxicology and 3 TK animal deaths (total of 6) occurred in the high-dose combination 
group. Two toxicology animals had evidence of gavage accidents. For the third, the cause of 
death was undetermined, and a test article-related effect cannot be ruled out, but esophageal 
muscular degeneration/regeneration is indicated in some dosing-related trauma. If gavage 
accidents were involved, then they were not detected at gross necropsy. There was no evidence 
of target organ microscopic findings in GI tract or any other tissue of any animal, including the 
early death toxicity animals.  
A pharmacodynamics (PD)-mediated reduction in GI motility is consistent with the 
anti-muscarinic effects of trospium on intestinal musculature. Fecal retention, malabsorption, 
cessation of eating, dehydration, and rapid deterioration followed with continued dosing. 
Cessation of dosing in the high-dose combination animals that survived led to rapid recovery, 
implying the deleterious effects had been PD-related. No effects on food consumption were seen 
in any xanomeline-alone group. The lack of microscopic findings in the GI tract of any early 
death or surviving animal implies that the adverse effects were pharmacologically mediated 
rather than direct target organ toxicity. 
Twenty-eight Day Repeat-Dose Studies with Xanomeline in Rats and Monkeys: Rats were fed 
xanomeline tartrate at 0, 0.05, 0.1, or 0.2% daily and monkeys were fed xanomeline tartrate daily 
at 0, 5, 12.5, or 30 mg/kg. All animals survived until necropsy. Safety findings in rats included 
reduced body weight in the high-dose group, increases in gamma-glutamyl-transferase, 
cholesterol, and bilirubin, slight decreases in triglycerides, bile duct hyperplasia, higher serum 
potassium (males), and lower serum globulin (females). Findings in monkeys were dose-related 
and included signs of intolerance such as emesis, salivation, diarrhea, hypoactivity, weight loss, 
and treatment-related tachycardia in the high-dose animals. 
Forty-Day Repeat Dose Study of KarXT in Rats (KarXT-302): Six groups of 15 rats/sex/group 
were given vehicle, xanomeline alone at 75 or 150 mg/kg/day, trospium alone at 100 mg/kg/day, 
or xanomeline/trospium combination at doses of 75/50 mg/kg/day or 150/100 mg/kg/day, with 
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all doses split into BID doses. Satellite rats (TK animals) were included for collection of plasma 
after the first and last doses to determine concentrations of each drug. Dosing was initially 
planned to be 90 days, but was terminated after 40 days because of unexpected deaths in the TK 
animals. No target organ toxicity was seen. Safety findings included pharmacologically mediated 
constipation in the trospium alone and combination groups, and mild biliary hyperplasia in the 
high-dose xanomeline-alone and combination groups. There were 4 unscheduled deaths in TK 
animals; 2 in the high-dose xanomeline-alone group (150 g/kg/day) and 2 in the high-dose 
combination group (150 mg/kg/day xanomeline plus 100 mg/kg/day trospium). Both 
xanomeline-only animals had necropsy gross findings of a gavage accident and cause of death 
could not be determined. All toxicology animals survived to their scheduled sacrifice. The 
Sponsor considers that the volume depletion and trauma of multiple bleeds (3 per animal) 
followed by reduced absorption of fluids and nutrients secondary to reduced GI motility with 
continued BID dosing, explains the greater demise of TK animals relative to toxicity animals.  
Based on the results of the 90-day rat toxicology study, oral administration of trospium chloride 
and xanomeline tartrate alone or in combination to Crl:CD(SD) rats BID (12 hours ±60 minutes 
apart) at dosage levels of 25 and 50 mg/kg/dose trospium chloride, 37 and 75 mg/kg/dose 
xanomeline tartrate and a combination of 37/25, 75/25, and 75/50 mg/kg/dose xanomeline 
tartrate/trospium chloride for a minimum of 90 days resulted in minimal to moderate bile duct 
hyperplasia in the livers of the xanomeline tartrate and combination (xanomeline tartrate and 
trospium chloride) group males.  
Although there were no notable differences in the incidence of bile duct hyperplasia when 
comparing the single vs combination groups, there was an increased severity observed in the 
combination group males (specifically the 75/25 and 75/50 mg/kg/dose combination group 
males) when compared to the xanomeline tartrate group males at the terminal euthanasia. The 
bile duct hyperplasia was considered adverse in the high-dose xanomeline tartrate group males 
and in the 75/25 and 75/50 mg/kg/dose combination group males due to instances of moderate 
severity. Therefore, the no-observed-adverse-effect level was considered to be 50 mg/kg/dose for 
trospium chloride, 37 mg/kg/dose for xanomeline tartrate, and 37/25 mg/kg/dose for the 
combination of xanomeline tartrate/trospium chloride. At these doses for males, mean plasma 
AUC0-24 
 91.  
At these doses for females, mean plasma AUC0-24 
267,000 pg hr/mL for xanomeline, and 16,700 + 171,000 
 + xanomeline, 
respectively, on Day 91. The absence of bile duct hyperplasia in females cannot be explained 
from differences in drug exposure. At the recovery euthanasia, bile duct hyperplasia was still 
present, but was limited to minimal severity and there was a decreased incidence in both the 
xanomeline tartrate and combination group males. There was also no notable difference in 
severity between the single vs combination groups at the recovery euthanasia. Given the 
decreased incidence/severity, in combination with the improved histologic appearance of bile 
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ducts at the recovery euthanasia (ie, smaller/flattened epithelium, non-inflammatory, and an 
absence of portal bridging), changes at the recovery euthanasia were consistent with a partial 
resolution of bile duct hyperplasia. With an absence of correlating serum liver enzyme 
elevations, bile acid alterations or hepatocellular degeneration, necrosis or regeneration, and with 
the apparent reversibility following cessation of treatment, these findings appear to have been 
tolerable by the affected animals. Therefore, the maximum tolerated dose was considered to be 
50 mg/kg/dose for trospium chloride, 75 mg/kg/dose for xanomeline tartrate, and 
75/50 mg/kg/dose for the combination of xanomeline tartrate/trospium chloride. 
For males, corresponding mean plasma AUC0-24
822,000
respectively, on Day 91. For females, corresponding mean plasma AUC0-24 values were 
9230
950,000
tudies revealed the 
familiar exaggerations of systemic and CNS muscarinic effects that had previously been seen 
with xanomeline or trospium at high doses. Target organ findings with xanomeline alone were 
limited to biliary hyperplasia in the 28-day rat study but not the 28-day or 12-month monkey 
study, though similar findings were described in a 6-month monkey study. With KarXT, biliary 
hyperplasia was not observed in the 14-day rat study but was reported in the 40-day rat study. 
Notably, these hyperplastic findings are not thought to represent pre-neoplastic lesions, because 
they were of low severity; no fibrosis or associated hepatocellular changes, and no significant 
effects were seen on hepatobiliary-related serum chemistry.
Completed Clinical Studies
Refer to the IB for complete information regarding previous clinical studies conducted with 
xanomeline by Eli Lilly, and studies KAR-001, KAR-002, KAR-003 and KAR-004 conducted 
by Karuna Therapeutics using xanomeline with trospium.
To date, more than 840 subjects or volunteers have been exposed to xanomeline tartrate (oral 
formulation, either alone, in combination with trospium, or as the combination drug KarXT) in 
19 completed clinical studies conducted either by Eli Lilly or Karuna Therapeutics, some for as
long as 3 years. In those studies, significant improvements in cognition and reduced psychotic 
symptoms were observed.
A study of xanomeline monotherapy in subjects with schizophrenia was reported in 2008.[18] In 
this pilot study, the effects of xanomeline were examined in 20 schizophrenia subjects utilizing a 
double-blind, placebo-controlled, 4-week study design. Subjects treated with xanomeline did 
significantly better than subjects in the placebo group on Brief Psychiatric Rating Scale total 
scores and PANSS total scores (ie, 24-point change over placebo, p = 0.04). In the cognitive test 
battery, subjects in the xanomeline group showed improvements relative to placebo in some of 
the cognitive domains of verbal learning and short-term memory function. These studies 
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demonstrated the potential for xanomeline as a treatment for psychosis and cognition across 
multiple subject populations.  
Study H2Q-EW-E001, conducted by Eli Lilly, had 36 male healthy volunteers in 4 groups of 9, 
who were administered escalating single doses of xanomeline tartrate in increments of 1, 5, 10, 
25, 50, 75, 100 and 150 mg. Each group took 2 ascending doses of xanomeline tartrate and 1 
dose of placebo in a single subject blind manner. There were no serious AEs (SAEs). Adverse 
events included watery diarrhea, nausea, dizziness, sweating, shivering, mild disorientation, 
increased blood pressure (BP), increase(s) in sitting and standing heart rate, slight increase in 
supine systolic BP, and postural hypotension. 
The clinical experience with KarXT initiated by Karuna Therapeutics to date includes 
3 completed Phase 1, clinical pharmacology studies in healthy volunteers (KAR-001, KAR-002, 
and KAR-003) and one completed Phase 2 study (KAR-004) in adult inpatients with DSM-5 
schizophrenia. 
The first study conducted by Karuna, KAR-001 was a Phase 1, double-blind, randomized, 
multiple-dose, pilot study comparing xanomeline administered alone to xanomeline administered 
in combination with trospium chloride in normal healthy volunteers. This study consisted of 
2 arms, in which xanomeline was administered three times daily (TID), alone, at a total daily 
dose of 225 mg in 1 arm, and the second arm received the same dose of xanomeline in 
combination with trospium chloride 20 mg administered BID, a total daily dose of 40 mg. 
Subjects were treated for 7 days. The goal was to determine whether this dosing regimen would 
reduce the cholinergic side effects of xanomeline by co-administration of the muscarinic 
antagonist, trospium. 
Overall, treatment with xanomeline 225 mg daily + trospium 40 mg daily administered over 
7 days was considered safe and well tolerated. The results of key and supportive endpoints 
showed a numerical reduction (although not statistically significant) in visual analog scale (VAS) 
scores for cholinergic events for the xanomeline + trospium treatment arm compared to the 
xanomeline-alone treatment arm. Specifically, consistent numerical reduction in VAS scores for 
the xanomeline + trospium treatment arm was observed for the supportive endpoints of 
maximum weekly individual VAS scores and mean daily maximum composite VAS scores.  
Results of the clinician-administered scales were supportive of a reduction in vomiting, feelings 
of nausea, excess salivation, and sweating that interfered with daily activities in the 
xanomeline + trospium treatment arm compared to the xanomeline-alone treatment arm. 
There were no meaningful differences between treatment groups in heart rate, resting BP, 
orthostatic BP or any electrocardiogram (ECG) parameters including QT. A small subset of 
subjects in both treatment arms had transient increases in heart rate and orthostatic BP changes 
which may have contributed to syncope and postural dizziness in those subjects. Two subjects 
(both in the xanomeline-alone arm) experienced syncope. The incidence of orthostatic AEs in the 
KarXT group was approximately one-half that of subjects in the xanomeline-alone group. 
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The most commonly reported treatment-emergent AEs (TEAEs) in KAR-
in either treatment arm) were hyperhidrosis, salivary hypersecretion, nausea, dizziness postural, 
and diarrhea. Subject incidences of these 5 TEAEs was higher in the xanomeline-alone treatment 
arm (61.8%) compared to the xanomeline + trospium treatment arm (34.3%).  
Overall, treatment with xanomeline 225 mg combined with trospium chloride 40 mg 
administered over 7 days was considered safe and well tolerated. The observed side effect profile 
was consistent with the known safety profile of xanomeline and trospium chloride. The incidence 
of TEAEs and cholinergic TEAEs was lower in the xanomeline + trospium treatment arm 
compared to the xanomeline-alone treatment arm. 
Study KAR-002 was a Phase 1, double-blind, randomized, multiple-dose adaptive design pilot 
study to evaluate the safety and tolerability of KarXT in normal healthy volunteers. Subjects 
received either 100 mg xanomeline + 20 mg trospium BID or placebo. The first cohort of this 
study was stopped after 1.5 days when the FDA put the program on hold due to a preliminary rat 
finding in the 14-day study. This study used a new formulation of KarXT in which xanomeline 
and trospium were combined into a single dose form and given BID. Safety findings included an 
increase in orthostatic complaints. Caution should be used in drawing conclusions from this 
study, as subjects did not have time to reach steady state plasma levels from dosing, as only 
3 doses were given. 
Study KAR-003 was a Phase 1, double-blind, randomized, multiple-dose, adaptive design, 
inpatient pilot study to evaluate the safety and tolerability of KarXT in normal healthy 
volunteers. The primary objective of this study was to assess the safety and tolerability of 7 days 
of daily administration of KarXT at various dose combinations, administered BID. Subjects 
received either KarXT or placebo (3:1 ratio). All subjects on KarXT received 2 days of 50 mg 
xanomeline + 20 mg trospium BID, and then increased to different doses for Days 3 to 7. This 
study also used the new formulation of KarXT in which xanomeline and trospium were 
combined into a single dosage form and given BID.  
There was a relatively high degree of variability in xanomeline and trospium exposures between 
individuals in all cohorts, which is consistent with previous results with KarXT, 
xanomeline-alone, and trospium-alone. Peak plasma concentrations were observed at a median 
time of 2.0 hours for xanomeline and 1.0 hour for trospium across all treatment groups and study 
days.  
Although there was insufficient data to draw a definitive conclusion regarding the impact of 
trospium on the pharmacokinetics (PK) and bioavailability of xanomeline, or the impact of 
xanomeline on the pharmacokinetics and bioavailability of trospium, the PK results suggest that 
neither drug had a meaningful impact on the PK behavior of the other drug. 
During the 2-day lead-
completed dosing were dry mouth, nausea, and constipation. For the treatment groups that 
completed dosing, although the incidence of TEAEs was lower in the KarXT 100/20 BID 
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(66.7%) group compared to KarXT 125/40 group (88.9%), the incidence of cholinergic TEAEs 
(nausea, vomiting, diarrhea, sweating, and excess salivation) was similar between the 2 groups. 
The most commonly reported TEAEs ( 20% of subjects in either treatment group) in these 
groups were dizziness, nausea, dry mouth, headache, vomiting, dyspepsia, somnolence, vision 
blurred, and dysuria. For the treatment groups that did not complete dosing (KarXT 150/20 BID 
group and KarXT 150/40 BID group), the cholinergic TEAEs were generally higher compared to 
the treatment groups that completed dosing.  
Overall, anticholinergic TEAEs appeared to occur primarily in the treatment groups that were 
dosed with 40 mg trospium BID (KarXT 150/40 BID and KarXT 125/40 BID groups), 
particularly when paired with 125 mg xanomeline BID, suggesting to consider slightly lowering 
the trospium dose from 40 mg BID in future studies. All TEAEs were mild or moderate in 
severity, and there were no SAEs or deaths. Treatment-emergent AEs were primarily cholinergic 
or orthostatic (and a few anticholinergic). Doses of 100 mg and 125 mg BID of xanomeline were 
well tolerated when paired with 20 mg and 40 mg BID of trospium, respectively. The safety and 
tolerability profile of KarXT 100/20 BID and KarXT 125/40 BID was acceptable and supports 
further evaluation at similar doses in future studies. Doses of KarXT 150/20 BID and 150/40 
BID were not well tolerated in this study. A pairing of 150 mg xanomeline with 40 mg trospium 
appeared to be better tolerated than 150/20, but some subjects still experienced tolerability 
issues. 
Study KAR-004 was a Phase 2 randomized, double-blinded study to assess the safety, 
tolerability, and efficacy of KarXT in adults with DSM-5 schizophrenia, hospitalized with acute 
psychosis. The primary objective of the study was to assess the efficacy of KarXT (125/30 BID) 
versus placebo in reducing PANSS total scores in adult inpatients with a DSM-5 diagnosis of 
schizophrenia. Subjects received either KarXT or placebo (1:1 ratio) for a treatment period of 
5 weeks. All subjects on KarXT received a lead-in dose of KarXT 50/20 BID for the first 2 days 
followed by KarXT 100/20 BID on Days 3 to 7. On Day 8, dosing was titrated upwards to 
KarXT 125/30 BID unless the subject was continuing to experience AEs from a previous dose 
increase of 100/20 BID.   
A total of 182 subjects were enrolled and randomized (92 placebo; 90 KarXT).  Of these 
subjects, 170 (87 [94.6%] placebo; 83 [92.2%] KarXT) received at least one dose of study drug 
and had at least one post-baseline PANSS assessment (Modified Intent to Treat population used 
for the efficacy analyses).  Discontinuation rates were similar between the 2 treatment groups; 37 
subjects discontinued the study early (19 [20.7%] placebo; 18 [20.0%] KarXT). The most 
common reason for early discontinuation was consent withdrawn (14 [15.2%] placebo; 14 
[15.6%] KarXT) followed by Adverse Event (2 [2.2%] placebo; 3 [3.3%] KarXT). 
Treatment-emergent adverse events (TEAE) were reported in 43.3% of subjects in the placebo 
group and 53.9% of subjects in the KarXT group.  The most commonly reported TEAEs were 
constipa
or twice that of placebo) in the KarXT group than in the placebo group.   
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There were 27.8% and 42.7% of subjects in the placebo and KarXT groups, respectively, who 
experienced at least 1 TEAE related to study drug. The most commonly reported study drug 
related TEAEs for the placebo and KarXT total groups were nausea, constipation, dry mouth, 
in the 
KarXT group than in the placebo group. The majority of the reported TEAEs were mild (27.8% 
placebo; 36.0% KarXT) or moderate (14.4% placebo; 16.9% KarXT) in severity. Two severe 
TEAEs were reported during the study.  One subject in the placebo group had a severe TEAE of 
worsening schizophrenia symptoms, and 1 subject in the KarXT high dose group had a severe 
event of increased psychosis which was reported as an SAE possibly related to KarXT by the 
investigator.  There were no other SAEs reported during the study and there were no deaths 
during the study. 
The pattern and course of safety findings in KAR-004 were consistent with the known safety 
profile from earlier studies of both xanomeline monotherapy and xanomeline combined with 
trospium (KarXT). Even though the qualitative AE profile was consistent with earlier Phase 1 
PK/safety studies in healthy volunteers, the relative tolerability burden was lower in the current 
study of schizophrenia patients receiving KarXT than in the healthy volunteers.  In addition, the 
safety and tolerability of KarXT was favorable and notably free of many common side effects 
associated with current antipsychotic drugs. 
KarXT demonstrated statistically significant and clinically meaningful reduction in total PANSS 
score at all time points over 5 weeks compared to placebo (Figure 1). The primary efficacy 
endpoint result for the study (change from baseline (CFB) in PANSS total score between the 
placebo group and the KarXT group at Visit 9/Week 5) showed a statistically significant 
decrease in PANSS total score (p<0.0001). The statistically significant difference in CFB 
between the treatment groups was there at Visit 6/Week 2 (p<0.0001) and continued to Visit 
8/Week 4 and Visit 9/Week 5. Overall, the decrease from baseline in PANSS total score for the 
KarXT group was statistically significantly greater compared to the placebo group by treatment 
group for Visits 6, 8, and 9 (p<0.0001). 
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Figure 1. 
Change from Baseline in PANSS Total Scores (KAR-004) 
 
Abbreviations: LS = least squares; mITT = modified intent-to-treat; PANSS = Positive and Negative Syndrome 
Scale; SEM = standard error of the mean. 
A significant reduction in the secondary endpoint of PANSS-positive scores was observed 
(p<0.0001) at Week 5 as well as the 2 earlier time points (ie, Weeks 2 and 4; see Figure 2). 
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Figure 2. 
Change from Baseline in PANSS-Positive Scores (KAR-004) 
 
Abbreviations: LS = least squares; mITT = modified intent-to-treat; PANSS = Positive and Negative Syndrome 
Scale; SEM = standard error of the mean. 
 
As regards the Clinical Global Impression  Severity of Illness (CGI-S), subjects in the KarXT 
group overall significantly improved in ratings compared to placebo, with a p-value of <0.001 at 
Week 5. At Week 5, 8% of placebo subjects improved (decreased) their CGI-S ratings at least 
2 levels versus 28.9% of KarXT subjects (see Figure 3). 
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Figure 3. 
Change from Baseline in CGI-S (KAR-004) 
 
Abbreviation: CGI-
 
 
A statistically significant reduction in the secondary endpoint of PANSS-negative score was 
observed (p<0.001) at Week 5. Overall, the changes in the KarXT group were statistically 
significantly greater compared to the placebo group at Visits 6, 8, and 9 (p<0.001). The least 
square mean improvement for the placebo group was 1.32 points at Week 5 (Visit 9) and the 
mean improvement for the KarXT group was 3.85 points leading to a mean difference of 
2.53 points at Week 5 (Visit 9; see Figure 4). 
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Figure 4. 
Change from Baseline in PANSS-Negative Scores (KAR-004) 
 
Abbreviations: LS = least squares; mITT = modified intent-to-treat; PANSS = Positive and Negative Syndrome 
Scale; SEM = standard error of the mean. 
 
The overall safety/tolerability data were also fairly unambiguous; among the highlights:  
 The overall discontinuation rate on KarXT was 20%, similar to placebo (21%). The number 
of discontinuations due to TEAEs was equal in the KarXT and placebo arms (N = 2 in each 
group) 
 The dose escalation rate on KarXT was high and similar to placebo: 
o 91% of KarXT subjects escalated to 125/30 KarXT (vs 97% on placebo) 
o 4% percent de-escalated back to 100/20 KarXT dose (vs 1% on placebo) 
 The overall TEAE rate on KarXT was 54% vs 43% on placebo: 
o The most common TEAEs were constipation, nausea, dry mouth, dyspepsia, and 
vomiting. None of these TEAEs were severe and none led to discontinuations 
o One SAE occurred in the study (the subject was on KarXT): the subject discontinued 
treatment and subsequently sought hospital care for worsening psychosis, meeting the 
regulatory definition of an SAE.   
o No syncope or mean changes in BP were seen 
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o A 5.5 bpm peak mean placebo adjusted resting heart rate increase with a downward 
trend after Week 2 was seen 
o One subject (on KarXT) was discontinued due to an elevated gamma-glutamyl 
transpeptidase (GGT) 
o There were no new safety findings associated with KarXT that have not been observed 
with either xanomeline alone or trospium alone in previous trials 
 KarXT did not show evidence of many of the kinds of AEs that often occur in currently 
available antipsychotics for the treatment of schizophrenia  
 The rates of the following AEs were similar for KarXT and placebo: somnolence, weight 
gain, and EPS 
 Overall, the KAR-004 results confirm and extend the antipsychotic benefit of xanomeline 
observed in past studies of xanomeline alone and the well tolerated nature of KarXT.  
KAR-004 results support the continued development of KarXT into Phase 3 trials. 
Two randomized, double-blind, placebo-controlled Phase 3 trials (KAR-007 and KAR-009) are 
planned in which the subjects will be exposed to either KarXT or placebo (1:1) for a period of up 
to 5 weeks. Subjects who complete either of these 2 studies will be eligible to roll over into this 
long-term open-label study. 
5.3 
Clinical Risks/Benefits of KarXT and Study Rationale 
The risks and benefits of KarXT in humans are not fully known. KarXT is a fixed dose 
combination of xanomeline and trospium.  
The available clinical trial data indicate that KarXT has robust efficacy and a favorable safety 
profile that appears unique compared to all available APDs. Most of these clinical data were 
setting. Treatment with KarXT is not associated with weight gain, sedation, or meaningful EPS 
changes. In contrast, these serious side-effects pose a significant risk with other APD treatments 
for schizophrenia and can lead to discontinuation of treatment and significant morbidity. A Phase 
2 registration quality pivotal trial in 182 subjects met the primary endpoint with the PANSS total 
score showing a 11.6 point mean improvement compared to placebo with a highly significant 
(p < 0.0001) separation from placebo (-17.4 KarXT vs. -5.9 placebo) at Week 5. KarXT, as 
compared to placebo, demonstrated highly significant reduction in PANSS total scores 
(p < 0.0001) at all post randomization time points (Weeks 2, 4 and, 5) with a calculated effects 
at all post randomization time points for PANSS positive symptom subscores, PANSS negative 
symptom subscores, PANSS Marder Factor negative symptom subscores, and CGI-S scores. 
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Over 840 subjects or volunteers have been exposed to xanomeline tartrate (oral formulation; 
either alone, in combination with trospium, or as the combination drug KarXT) in clinical 
studies. These early clinical studies, as well as nonclinical pharmacology and toxicology studies, 
have not revealed any specific contraindications to the use of xanomeline. The most common 
side effects/symptoms are the cholinergic related effects: nausea, vomiting, excess salivation, 
excess sweating, and diarrhea. In addition, subjects treated with xanomeline alone have reported 
both syncope and orthostatic dizziness. The addition of trospium decreases the peripheral 
cholinergic effect of xanomeline creating a better tolerated therapy. In addition, a titration phase 
also increases the tolerability of KarXT. 
Trospium chloride has been marketed in the US for 12 years. The most frequently reported AEs 
reported in pivotal trials were dry mouth, constipation, abdominal pain, headache, urinary 
retention, and abnormal vision and accommodation. For additional information, the package 
insert for trospium chloride tablets for oral use can be found in the IB. 
In a Phase 2 (KAR-004) clinical study, KarXT (100/20 and 125/30) significantly reduced the 
symptoms of schizophrenia in subjects with acute psychosis after treatment for 28 days. KarXT 
also showed an acceptable safety profile with the most common TEAEs being constipation, 
nausea, dry mouth, dyspepsia, and vomiting. All the reported TEAEs were mild or moderate in 
intensity. One SAE (psychotic disorder) was reported by a single subject and no deaths were 
reported in the study. KarXT was generally well-tolerated and found to be safe in this patient 
population. 
KarXT represents a novel approach to the treatment of patients with schizophrenia that will 
provide an important and meaningful alternative to current therapies. The current tolerability and 
AE profile and the efficacy of KarXT justify further development of KarXT in this patient 
population by advancing to Phase 3 trials. Two such Phase 3 trials (KAR-007 and KAR-009) are 
planned where the subjects will receive the study drug (KarXT or placebo) for 5 weeks.  
In the current study, regardless of treatment assignment in the preceding Phase 3 study 
(KAR-007 or KAR-009), all subjects will receive KarXT for a period of approximately 52 weeks 
with the primary objective of assessing the long-term safety and tolerability profile of KarXT in 
an out-patient setting. All subjects will start with a lead-in dose of KarXT 50/20 BID for Days 1 
to 2 and then the dose will be titrated to 100/20 BID for Days 3 to 7, allowing the subject to 
adjust to KarXT before receiving a higher dose of 125/30 BID starting on Visit 3 (Day 8), unless 
the subject is continuing to experience AEs from the previous dose increase of KarXT 100/20 
BID. All subjects who are increased to KarXT 125/30 BID, depending on tolerability, will have 
the option to return to KarXT 100/20 BID. Re-escalation to 125/30 BID or re-titration in cases 
where subject has been off KarXT for a longer period of time (at least a week) is allowed and 
will require a discussion between the principal investigator (PI) and the medical monitor.  
Dosing will occur every 12 ±4.5 hours each day, during waking hours. KarXT should be dosed 
on an empty stomach (ie, at least 1 hour before a meal or 2 to 3 hours after a meal).  
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The current study is designed to demonstrate that long-term treatment with KarXT in adult 
schizophrenia subjects is safe and tolerable.  
 
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6
STUDY OBJECTIVES AND ENDPOINTS
6.1
Study Objectives
Primary Objective
The primary objective of the study is to assess the long-term safety and tolerability of KarXT in 
subjects with a DSM-5 diagnosis of schizophrenia.
Secondary Objectives
The secondary objective of this study is to assess the long-term efficacy and evaluate plasma 
concentrations of xanomeline and trospium after administration of KarXT in adults with a 
DSM-5 diagnosis of schizophrenia:
To evaluate the reduction in PANSS total score
To evaluate the reduction of PANSS positive score 
To evaluate the improvement in Clinical Global Impression Severity (CGI-S) results 
To evaluate the reduction of PANSS negative score 
To evaluate the reduction of PANSS Marder Factor negative symptoms score
Exploratory Objectives
The exploratory objectives of this study are:
To evaluate cognition with the Cambridge Neuropsychological Test Automated Battery 
(CANTAB)
To evaluate prolactin levels after administration of KarXT
To evaluate digital biomarkers of schizophrenia (US only)
To evaluate ecological momentary assessment administered patient reported outcomes 
(EMA PRO) in schizophrenia (US only)
To evaluate cognitive insight using an EMA administered verbal learning and memory 
test (EMA VLMT) in schizophrenia (US only)
6.2
Study Endpoints
Primary Safety Endpoint
The primary safety endpoint of this study is the incidence of treatment-emergent AEs (TEAE).
Secondary Endpoints
6.2.2.1
Safety Endpoints
The secondary safety endpoints of this study are: 
Incidence of serious TEAEs
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Incidence of TEAEs leading to withdrawal
6.2.2.2
Efficacy Endpoints
The secondary efficacy endpoints of this study are:
Change from baseline in PANSS total score at Week 52
Change from baseline in PANSS positive score at Week 52
Change from baseline in PANSS negative score at Week 52
Change from baseline in PANSS Negative Marder Factor score at Week 52
Change from baseline in CGI-S score at Week 52
Percentage of PANSS responders (a 30% change in PANSS total score) at Week 52
Other Endpoints
6.2.3.1
Safety Endpoints
Spontaneously reported adverse events of special interest (AESIs)
Spontaneously reported procholinergic and anticholinergic symptoms
Change from baseline in Simpson-Angus Rating Scale (SAS)
Change from baseline in Barnes Rating Scale for Akathisia (BARS)
Change from baseline in Abnormal Involuntary Movement Scale (AIMS)
Change from baseline in body weight, body mass index (BMI), waist circumference 
Change from baseline in orthostatic vital signs (supine and standing after 2 minutes): BP 
(systolic and diastolic) and heart rate
Change from baseline in clinical laboratory assessments (hematology, clinical chemistry, 
coagulation, urinalysis, and drug screen)
Change from baseline in 12-lead ECG 
Change from baseline in physical examination 
Suicidal ideation scale with the use of Columbia-Suicide Severity Rating Scale (C-SSRS)
6.2.3.2
Pharmacokinetic Endpoint
Comparison of the plasma concentrations of xanomeline and trospium measured in this 
study to the plasma concentrations predicted by a population pharmacokinetic (PK)
model of studies KAR-007 and KAR-009
6.2.3.3
Exploratory Endpoints
The exploratory endpoints of this study are: 
Change from baseline in cognition measuring core domains of impairment in 
schizophrenia using CANTAB
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 Change from baseline in prolactin levels 
 Observed digital biomarkers of schizophrenia (US only) 
 Observed ecological momentary assessment administered patient reported outcomes 
(EMA PRO) in schizophrenia (US only) 
 Observed cognitive insight using an EMA administered verbal learning and memory test 
(EMA VLMT) in schizophrenia (US only) 
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7 
INVESTIGATIONAL PLAN 
7.1 
Description of Overall Study Design and Plan 
This is a Phase 3 multicenter, 53-week, outpatient, open-label extension (OLE) study to evaluate 
the long-term safety, tolerability, and efficacy of KarXT in subjects with DSM-5 schizophrenia 
who previously completed the treatment period of one of the two Phase 3 double-blind studies, 
KAR-007 or KAR-009. The study consists of a 52-week OLE treatment phase and a 7-day 
(±3 days) follow-up/end-of-study (EOS) visit after the last KarXT dose for subjects who 
complete the treatment phase and those who prematurely discontinue from the study.  
After written informed consent, subjects who have completed either the KAR-007 or KAR-009 
Phase 3 acute study and received the last dose of the study drug in that trial will be rolled over 
into the current OLE study. The assessments performed on Visit 10 (Day 35) of studies 
KAR-007 or KAR-009 will be considered as baseline assessments along with any additional 
procedures that will be performed on Day 0 of the current study. Any scheduled Day 0 
assessments that were not completed on Day 35 of the acute study (KAR-007 or KAR-009) must 
be completed on Day 0 of the current study.  
It is preferable that Baseline/Day 0 procedures of the current study be completed on the same day 
as Day 35 of the acute study after all Visit 10 (Day 35) procedures of the prior study KAR-007 
or KAR-009 have been completed. However, with medical monitor approval, an extension of up 
to 3 days can be granted to complete Baseline/Day 0 procedures. This extension cannot be 
completed inpatient.  
With medical monitor approval, participants may be permitted to complete the first 3 days (Visit 
1/Day 1 to Visit 2/Day 3) of KAR-008 on the inpatient unit. 
Subjects who did not complete the full treatment period, or who early terminated studies 
KAR--007 or KAR--009, will not be eligible to enroll in this long-term extension study.   
Approximately 350 subjects are planned to be enrolled in this study (aged 18 to 65 years at time 
of enrollment into the preceding acute study) across approximately 30 study sites in the United 
States and 10 study sites in Ukraine.  
In this OLE study, all subjects will receive KarXT for up to 52 weeks. Regardless of treatment 
assignment in the preceding Phase 3 acute study (KAR-007 or KAR-009), all subjects will start 
on a lead-in dose of KarXT 50/20 BID for the first 2 days (Days 1 and 2), followed by 
KarXT 100/20 BID for the remainder of Week 1 (Days 3 to 7). On Visit 3 (Day 8), dosing will 
be titrated upwards to KarXT 125/30 BID unless the subject is continuing to experience AEs 
from the previous dose of KarXT 100/20 BID. All subjects who are increased to KarXT 125/30 
BID, depending on tolerability, will have the option to return to KarXT 100/20 BID for the 
remainder of the treatment period. Re-escalation to 125/30 BID or re-titration in cases in which 
the subject has been off KarXT for a longer period of time (at least a week) is allowed and will 
require a discussion between the PI and the medical monitor. Additional changes to KarXT 
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dosing (e.g., temporary dose reductions) may be permitted as clinically indicated upon approval 
by the medical monitor. 
Beginning after Visit 9/Day 84, interim visits will be completed with flexibility between in-clinic 
visits, approximately once every 4 weeks. Interim visits will be conducted by telemedicine; 
however, sites will have the option to schedule on-site interim visits as needed to facilitate 
subject retention and ensure adherence to study objectives. Additional unscheduled study visits 
may be conducted as needed. 
All subjects will have questionnaires administered throughout the study (see Schedule of 
Assessments Table 2). Analyses of change from baseline in diagnostic measures will be 
performed. 
Safety will be assessed through spontaneous AEs including AESIs, procholinergic and 
anticholinergic symptoms; SAEs and AEs leading to discontinuation of KarXT; SAS; BARS; 
AIMS; body weight; BMI; waist circumference; orthostatic vital signs; clinical laboratory 
assessments (hematology, clinical chemistry, coagulation, urinalysis, and drug screen), 12-lead 
ECG; physical examination; and C-SSRS will be evaluated throughout the study as scheduled. 
Section 11 provides complete details on these safety assessments. 
Efficacy will be assessed through PANSS total score, PANSS-positive score, PANSS-negative 
score, PANSS Negative Marder Factor score, and CGI-S score at scheduled visits. Refer to 
Section 12 for more details. 
Plasma concentrations of xanomeline and trospium will be evaluated. Details are provided in 
Section 13. 
Exploratory assessments include cognition testing using CANTAB; prolactin levels; digital 
biomarkers of schizophrenia (US Only); Ecological Momentary Assessment (EMA) Patient 
Reported Outcomes (PRO; US Only) and EMA Verbal Learning and Memory Test (VLMT; US 
Only) which will be evaluated during scheduled visits or on specified study days. See Section 14 
for more details.  
A safety follow-up/end of study (EOS) visit  (Visit 30/Day 371) will be performed for all 
subjects after the last dose of KarXT. 
An Independent Safety Monitoring Committee (ISMC) will be responsible for periodically 
reviewing the safety data from this study and confirming that the study may continue. 
Table 1 presents the Study Drug Dosing Scheme. 
 
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Table 1. 
Study Drug Dosing Scheme   
 
Period: 
Open-Label Extension Treatmenta 
EOT/ET 
EOS/UNS 
Day: 
Day 1 
Day 3 
+1 day 
Day 8b 
±1 day 
Day 14 
±2 days 
Days 28 
to 70 ±3 
days 
Days 84 to 
350 ±3 
days 
Day 364 ±3 
days 
Day 371 ±3 
days 
Visit: 
Visit 1 
Visit 2 
Visit 3 b 
Visit 4 
Visit 5 
Visits 9 c to 
28 
Visit 29 
Visit 30 
Xanomeline/ 
trospium chloride 
(KarXT)*: 
50/20 BID 
100/20 
BID 
125/30 
BID 
(Option: 
100/20 
BID)d 
125/30 
BID 
(Option: 
100/20 
BID)d,e 
125/30 
BID 
(Option: 
100/20 
BID)d,e 
125/30 BID 
(Option: 
100/20 
BID)d,e 
125/30 BID 
(Option: 
100/20 BID) 
d,e 
N/A 
Comment(s): 
2-day 
lead-in 
dose 
Upward 
titration 
of dose 
Upward 
titration 
of dose 
 
7 (±3) days 
after the last 
dose or for ET 
from the study 
or UNS 
Abbreviations: 
BID = twice daily; EOS = end of study; EOT = end of treatment; ET = early termination; N/A = not applicable; 
PI = principal investigator; UNS = unscheduled. 
* All the KarXT doses are in mg xanomeline/mg trospium. 
a. At Visit 1 (Day 1) subjects will initiate dosing with KarXT BID.  Visits 2, 3, 4, 5, 6, 7, 8, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, and 30 are in-clinic/on-site 
visits. Visits 10, 12, 14, 16, 18, 20, 22, 24, 26, and 28 are interim visits and should be conducted via telemedicine. 
b. Subject to receive at least 8 doses of KarXT 100/20 prior to escalating to the KarXT 125/30 dose.  
c. Beginning after Visit 9/Day 84, interim visits will be completed with flexibility between in-clinic visits, approximately once every 4 weeks.  
d. All subjects who are increased to KarXT 125/30, depending on tolerability, will have the option to return to KarXT 100/20 BID. 
e. Re-escalation to 125/30 BID or re-titration in cases where subject has been off KarXT for a longer period of time (at least a week) is allowed and will require 
a discussion between the PI and the medical monitor. Additional changes to KarXT dosing (e.g., temporary dose reductions) may be permitted as clinically 
indicated upon approval by the medical monitor. 
 
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7.2 
Discussion of Study Design 
The KarXT clinical development program includes this open-label extension study to evaluate 
the long-term safety, tolerability, and efficacy data for KarXT in subjects with schizophrenia 
who participated in either of the 2 Phase 3 double-blind clinical studies and completed the 
treatment period without any tolerability/safety issues. 
This study will allow subjects that were randomized into a preceding Phase 3 study (KAR-007 or 
KAR-009) to reinstitute (or initiate treatment if a placebo subject) KarXT therapy. Subjects will 
receive KarXT (with the same lead-in dose of KarXT 50/20 BID), regardless of treatment 
assignment from the preceding Phase 3 study. Thus, subjects who received placebo during the 
preceding Phase 3 study who may not have demonstrated clinical benefit, nonetheless, may be 
considered appropriate for the current study, as all subjects will receive KarXT.  
The dosing plan for this study has been established and follows the earlier studies. All eligible 
subjects will receive the same lead-in doses of KarXT (KarXT 50/20 BID). Dosing will be 
titrated to 100/20 BID on Day 3 and further titrated to 125/30 BID on Visit 3 (Day 8), unless the 
subject continues to experience AE(s) from the previous dose increase of KarXT.  
During the study, all subjects who are increased to the highest dose of KarXT, depending on 
tolerability, will have the option to return to the next lower dose of KarXT (100/20 BID). 
Re-escalation to 125/30 BID or re-titration in cases where subject has been off KarXT for a 
longer period of time (at least a week) is allowed and will require a discussion between the PI 
and the medical monitor.  
Beginning after Visit 9/Day 84, interim visits will be completed with flexibility between in-clinic 
visits, approximately once every 4 weeks. Interim visits will be conducted by telemedicine; 
however, sites will have the option to schedule on-site interim visits as needed to facilitate 
subject retention and ensure adherence to study objectives. Additional unscheduled study visits 
may be conducted as needed. A 52-week treatment phase is considered to be sufficient to 
demonstrate the long-term safety and tolerability of KarXT. A sample size of approximately 350 
subjects is also determined to be an appropriate number of evaluable subjects to assess the long-
term safety of KarXT administration. Section 5.2 details the nonclinical and clinical background 
information available on KarXT, including dose rationale.  
7.3 
End of Study 
A subject will have fulfilled the requirements for study completion if/when the subject has 
completed the study treatment, including the EOS visit or the last scheduled visit as indicated in 
the Schedule of Assessments (Table 2) in accordance with the protocol. 
7.4 
Independent Safety Monitoring Committee 
For the purpose of this study, the ISMC is an independent group of individuals with pertinent 
expertise that reviews on a regular basis accumulating safety and tolerability data from the 
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clinical study. The ISMC will include 3 clinicians and a reporting statistician. This committee 
will be responsible, on a periodic basis, for confirming the safety and tolerability of KarXT 
throughout the study, with particular focus on assessing for any new or long-term toxicities that 
might be involved with KarXT. 
The reviews will allow a comparison of event rates and detection of safety signals, and to 
identify important safety information. The ISMC charter will contain the details of the types of 
data to be reviewed, the defined triggers for review, the minimum frequency of meetings (timed, 
if no triggers), and the communication plan for disseminating review recommendations. 
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8 
SELECTION OF STUDY POPULATION 
Section 7.1 provides information regarding the number of subjects planned to be enrolled. 
8.1 
Inclusion Criteria 
Individuals must meet all of the following criteria to be included in the study: 
1. Subject is aged 18 to 65 years, at time of enrollment into the preceding acute study 
(KAR-007 or KAR-009).  
2. Subject is capable of providing informed consent. 
a. A signed informed consent form must be provided before any study assessments 
are performed. 
b. Subject must be fluent in (oral and written) English (United States only) or local 
language (Ukraine only) to consent. 
3. Subject has completed the treatment period on study drug (through Day 35 -2 days) of 
Studies KAR-007 or KAR-009.  
4. Subject resides in a stable living situation, in the opinion of the investigator. 
5. Subject has an identified, reliable informant/caregiver willing to be able to address some 
questions related to certain study visits, if needed. An informant/caregiver may not be 
necessary if the s
 
6. Women of childbearing potential (WOCBP) or men whose sexual partners are WOCBP 
must be willing and able to adhere to the contraception guidelines as defined in Section 
8.4.1 and Appendix 1. 
 
8.2 
Exclusion Criteria 
Subjects will be excluded from the study if 1 or more of the following criteria is/are applicable: 
1. 
assessment and C-SSRS as confirmed by the following:  
a. 
Subject answers Y
some intent to act, without specific plan) or Item 5 (active suicidal ideation with 
specific plan and intent) on the C-SSRS assessment. 
b. 
Nonsuicidal self-injurious behavior is not exclusionary. 
2. Any clinically significant abnormality including any finding(s) from the physical 
examination, vital signs, ECG, or laboratory test at the end-of-treatment visit of studies 
KAR-007 or KAR-009 that the investigator, in consultation with the medical monitor, 
would consider to jeopardize the safety of the subject. 
3. Female subject is pregnant, breast feeding or planning to become pregnant during the 
course of the study.  
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4. 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 his/her ability to adhere to 
the protocol visit schedule or fulfill visit requirements. 
5. Subjects with extreme concerns relating to global pandemics such as coronavirus disease 
2019 (COVID-19) that preclude study participation. 
6. Risk of violent or destructive behavior. 
7. Subjects participating in another investigational drug or device trial or planning on 
participating in another clinical trial during the course of the study. 
 
8.3 
Safety Laboratory Evaluations for Eligibility 
Subjects may be enrolled into KAR-008 prior to receipt of the results from the safety laboratory 
evaluations collected on Visit 10 of the preceding acute study.  These subjects will be dosed on 
Day 1 of KAR-008; however, subjects may be withdrawn from KAR-008 depending upon the 
clinical significance of the results of the Visit 10 safety laboratory evaluations at the discretion of 
the PI in consultation with the medical monitor. Abnormal lab values deemed clinically 
significant must be recorded as AEs.  Subjects with elevated liver function tests (LFTs) per the 
DILI criteria must be withdrawn from further participation in KAR-008.  Retesting of labs is 
allowed once, with the exception of elevated LFTs. 
8.4 
Study Withdrawal, Removal, and Replacement of Subjects 
If a subject discontinues study treatment and is withdrawn from the study for any reason, the 
study site must immediately notify the medical monitor. The date and the reason for study 
discontinuation must be recorded on the electronic case report form (eCRF). Subjects who 
complete or discontinue early from the study will be asked to return to the study site within 
7 (±3) days of the last administration of KarXT to complete EOS assessments as indicated in the 
Schedule of Assessments (Table 2). 
In the event that a subject discontinues prematurely from the study because of a treatment 
emergent AE (TEAE) or serious TEAE, the TEAE or serious TEAE will be followed up until it 
resolves (returns to normal or baseline values) or stabilizes, or until it is judged by the 
investigator to no longer be clinically significant. 
Once a subject is withdrawn from the study, the subject may not re-enter the study. 
A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons 
including, but not limited to, the following: 
 progressive disease 
 unacceptable toxicity or AE 
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subject withdrawal of consent: at any time, a subject's participation in the study may be 
terminated at his/her request or on the basis of the 
clinical judgment; the 
reason for subject withdrawal will be noted on the eCRF
intercurrent illness: a condition, injury, or disease unrelated to the primary diagnosis that 
became apparent during treatment and necessitated the subject s termination from the 
study
general or specific changes in the subject's condition that renders them ineligible for 
further treatment according to the inclusion/exclusion criteria (eg, subject has need for a 
medication prohibited by the protocol)
subject fails to adhere to the protocol requirements (eg, drug noncompliance [if a subject 
is off KarXT for >7 consecutive days])
violation of entry criteria, ie, enrolled subjects who are later discovered not to meet 
eligibility criteria
development of suicidal or assaultive behavior
alcohol abuse or illegal drug use
pregnancy, as indicated in Section 11.8
Subjects who withdraw from the study will be encouraged to complete the same final evaluations 
as subjects completing the study according to this protocol, particularly safety evaluations. The 
aim is to record data in the same way as for subjects who completed the study.
Reasonable efforts will be made to contact subjects who are lost to follow-up. A subject will be 
considered lost to follow-up if he or she repeatedly fails to return for scheduled visits and is 
unable to be contacted by the study center. These efforts m
file. Subjects with AEs ongoing at end of study will be followed until the AE is resolved or the 
subject is considered to be in stable condition.
The Sponsor has the right to terminate the study at any time in case of SAEs or if special 
circumstances concerning the KarXT become known, making further treatment of subjects 
impossible. In this event, the investigator(s) will be informed of the reason for study termination.
Pregnancy
No evidence of mutagenicity, or treatment effects on reproduction, fertility, or fetal parameters 
have been demonstrated in animals following administration of xanomeline, but there are no 
adequate and well-controlled studies in pregnant women (FDA Pregnancy Category B). Animal 
reproduction studies of trospium chloride have shown an adverse effect on the fetus, but 
potential benefits may warrant the use of the drug in pregnant women despite the risk (FDA 
Pregnancy Category C).
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Therefore, WOCBP in this study must be willing to use a highly effective method of birth 
control (see Appendix 1 for a list of acceptable highly effective methods of contraception) during 
the study and for 30 days after the last dose of KarXT. WOCBP will have a urine pregnancy test 
on Day 0 (before receiving KarXT) and thereafter, as designated at other scheduled visits 
(Table 2). In case of positive urine pregnancy test result, a serum sample should be sent to the 
central laboratory to confirm the result. Pregnant women are excluded from this study because 
the effects of KarXT on the developing human fetus are unknown with the potential for 
teratogenic or abortifacient effects. 
Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment 
of the mother with KarXT, women who become pregnant must discontinue KarXT immediately. 
The effects of KarXT on sperm are unknown. Male subjects whose sexual partners are WOCBP 
must agree to use a highly effective method of birth control (see Appendix 1 for a list of 
acceptable highly effective methods of contraception) and must not impregnate a sexual partner 
during or for 30 days after the last dose of KarXT. They must also agree to refrain from sperm 
donation for 30 days after the last dose of KarXT. 
WOCBP will be instructed that known or suspected pregnancy occurring during the study should 
be confirmed and reported to the investigator. If a female subject becomes pregnant, the 
investigator must withdraw her from the study without delay. The subject must not receive any 
further doses of the KarXT. The investigator must notify the Sponsor or their designee of any 
female subject or female partner of a male subject that becomes pregnant while participating in 
the study. If the female subject or the female partner of the male subject is willing and able to 
consent to pregnancy follow-up, she will be followed until her pregnancy reaches term. Only 
those procedures that would not expose the pregnant female patient to undue risk will be 
performed. See Section 11.8 for further reporting and monitoring details. 
Full details of the pregnancy will be recorded on the withdrawal page (exit form) of the eCRF, or 
a Pregnancy Reporting Form will be completed if the subject has completed the study. 
Notification of the pregnancy should be submitted via the Pregnancy Reporting Form within 
24 hours of knowledge of the pregnancy. Pregnancy is not to be considered an AE; however, it 
must be reported using the same procedure as described for reporting SAEs, Section 11.7.4. 
8.5 
Completion of the Study or Lost to Follow-up 
The study will be completed when all subjects have completed their study-related procedures in 
accordance with the protocol. 
Every reasonable effort will be made to contact subjects who are lost to follow-up to obtain EOS 
information. Details regarding follow-up efforts are to 
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8.6 
Study Termination 
The availability of any new adverse safety information related to KarXT may result in stopping 
the study. An investigator, Sponsor, or Institutional Ethics Committee (IEC)/Institutional Review 
Board (IRB) may take such actions. If the study is terminated for safety reasons, subjects will be 
notified immediately and assured that appropriate treatment and follow-up will be available. If an 
investigator terminates the study, the Sponsor, subjects, and IEC/IRB will be informed about the 
reason for such action. Similarly, if the Sponsor terminates the study, it will inform the 
investigators, the IEC/IRB, and the subjects of the reason for such an action. Similar 
notifications will be sent by the IEC/IRB if it takes such an action. 
 
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9
TREATMENTS
9.1
Details of Study Treatments
KarXT is formulated as hard hydroxypropyl methylcellulose oral capsules containing 2 distinct 
populations of drug beads, 1 of which is loaded with xanomeline tartrate and the other of which 
is loaded with trospium chloride. Each capsule contains the free base equivalent of xanomeline 
and trospium according to the desired dosage strength. In addition to the active ingredients, the 
drug beads contain microcrystalline cellulose (MCC). The beads are not coated and are 
formulated for immediate release of the active ingredients.
Identity of Study Treatments
Active study agents for treatment group will be size 0, Swedish orange, opaque, and 
hydroxypropyl methylcellulose hard capsules. For the 2-day lead-in period (Days 1 and 2), 
subjects will receive capsule strength KarXT 50/20 BID, followed by 2 capsules of KarXT 
50/10 mg BID or a dosage of 100/20 mg BID for a total daily dose of 200/40 mg for the 
remainder of Week 1 (Days 3 to 7). At the beginning of Visit 3 (Day 8), dosing may be increased 
to 2 capsules of KarXT 62.5/15 mg or a dosage of 125/30 mg BID for a total daily dose of 
250/60 mg, depending on tolerability. Investigators have the option to return a subject to KarXT 
100/20 mg BID. Re-escalation to 125/30 BID or re-titration in cases where subject has been off 
KarXT for a longer period of time (at least a week) is allowed and will require a discussion 
between the PI and the medical monitor.
Additional changes to KarXT dosing (e.g., temporary dose reductions) may be permitted as 
clinically indicated upon approval by the medical monitor (see also Section 9.4).
KarXT 50/10 mg is composed of 44.4% xanomeline tartrate, 5.8% trospium chloride, excipients 
37.59% MCC, 11.5% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a size 0, 
Swedish orange, hydroxypropyl methylcellulose hard capsule.
KarXT 50/20 mg is composed of 33.4% xanomeline tartrate, 8.7% trospium chloride, excipients 
39.8% MCC, 17.3% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a size 0, Swedish 
orange, hydroxypropyl methylcellulose hard capsule.
KarXT 62.5/15 mg is composed of 41.7% xanomeline tartrate, 6.5% trospium chloride, 
excipients 38.1% MCC, 12.9% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a 
size 0, Swedish orange, hydroxypropyl methylcellulose hard capsule.
All investigational agents are to be stored according to requirements as specified on the 
Investigational Product label.
Packaging and Labeling
The study packaging and labeling will be performed by Corealis Pharma, located in Laval, 
Quebec, Canada and Catalent Pharma Solutions, located in Winchester, Kentucky (labelling for 
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the US sites), and Catalent Pharma Solutions, located in Philadelphia, Pennsylvania (labelling for 
Ukrainian sites). All packaging and labeling operations will be performed according to Good 
Manufacturing Practice for Medicinal Products and the relevant regulatory requirements.
Bulk supply bottles are labeled with the name of the drug, recommended storage conditions, the 
name and address of the manufacturer and the Investigational Use Statement (for the US sites: 
and for the 
).
Further details on labeling of investigational product will be provided in the Pharmacy Manual.
KarXT Storage
Prior to dispensing KarXT to the subjects, it must be stored at controlled room temperature
15°C-25°C.
KarXT Retention
KarXT must be retained until completion or termination of the study, and written authorization 
from the Sponsor has been received. All unused and used KarXT must be destroyed at the site or 
has provided written authorization prior to return or destruction, and that appropriate records of 
the disposal are documented and maintained. No used or unused KarXT may be disposed until 
fully accounted for by the study monitor.
9.2
Dosage Schedule
Subjects who roll over into KAR-008 will start dosing with KarXT on Day 1 of the current 
study. Baseline/Day 0 procedures must be completed prior to Day 1 and preferably on the same 
day as Visit 10 (Day 35) of the preceding acute study KAR-007 or KAR-009. The assessments 
performed on Visit 10 (Day 35) of studies KAR-007 or KAR-009 will be considered as baseline 
assessments along with any additional procedures that must be performed up to Day 1 of the 
current study. 
The first dose of the KarXT will be self-administered in the morning of Day 1 and the last dose 
will be self-administered in the morning of EOT Visit (Day 364). KarXT should be administered 
daily BID on an empty stomach (ie, at least 1 hour before a meal or 2 to 3 hours after a meal). 
Some considerations for dosing and PK blood withdrawals are provided in the subsections 
below. As described in Section 10.2, KarXT dosing adherence will be monitored using AiCure 
Technology. 
Day 0
The site pharmacist will prefill 1 child resistant pill bottle with sufficient quantities of
50mg/20mg of KarXT for the first 2 days of dosing.
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Sites will send the subject home with instruction to begin self-administration of KarXT 
BID in the morning of Day 1. 
For all KarXT doses, the first dose is to be self-administered in the morning and the 
evening dose will be self-administered at 12 (±4.5) hours after the morning dose. 
Remind the subject to bring their pill bottle to the next clinic visit.
Visit 1/Day 1 Dosing
Initiate BID dosing with KarXT 50/20 x 4 doses.
Subjects who remain on-site for Day 1 should self-administer KarXT using the AiCure 
device after completing AiCure training and registration.
All subjects must have taken 4 doses of the KarXT 50/20 before dose escalation to 
KarXT 100/20 BID. Subjects should be instructed to contact the investigator in the event 
they did not take all 4 doses of KarXT 50/20 prior to Visit 2/Day 3.
Visit 2/Day 3 Dosing
The site pharmacist will prefill 1 child-resistant bottle with a sufficient quantity of 
50mg/10mg pills to accommodate BID dosing of KarXT at 100/20 level until the next 
clinic visit.
Initiate BID dosing with KarXT 100/20 using the AiCure device. Subjects who have not 
taken their morning dose of 50/20 KarXT at the time of the study visit should receive 
their first dose of KarXT 100/20 at the time of the study visit. Subjects who have not yet 
completed AiCure training and registration must do so prior to dosing.
All the subjects must have taken at least 8 doses of the KarXT 100/20 before dose 
escalation to KarXT 125/30 BID. Subjects should be instructed to contact the investigator
in the event they did not take at least 8 doses of KarXT 100/20 prior to Visit 3/Day 8.
Remind the subject to bring their pill bottle to the next clinic visit.
Visit 3/Day 8
If dose escalation to the KarXT 125/30 level is confirmed by investigator order, the site 
pharmacist will prefill 1 child resistant bottle with a sufficient quantity of 62.5 mg/15 mg
pills to accommodate BID dosing of KarXT at 125/30 level until the next clinic visit.
If the subject has not yet taken their morning dose of 100/20 KarXT at the time of the 
study visit, the subject should receive their first dose of KarXT 125/30 at the time of the 
study visit. 
A single PK sample should be drawn at Visit 3/Day 8, and the dose of KarXT and time of 
most recent dosing should be recorded. Whenever possible, the PK sample should be 
obtained within 1 to 2 hours of dosing.
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Remind the subject to bring their pill bottle to the next clinic visit.
In the event that the subject is not escalated to KarXT 125/30, in accordance with investigator 
order, dispense sufficient quantities of 50 mg/10 mg pills to continue BID dosing of KarXT at 
the 100/20 level until next clinic visit.
Visit 4/Day 14 Dosing and PK Considerations
If dose of KarXT 125/30 BID was confirmed by investigator order, the site pharmacist 
will prefill 1 child resistant bottle with a sufficient quantity of 62.5 mg/15mg pills to 
accommodate BID dosing of KarXT at 125/30 level until the next clinic visit.
A single PK sample should be drawn at Visit 4/Day 14, and the dose of KarXT and time 
of most recent dosing should be recorded.
Remind the subject to bring their pill bottle to the next clinic visit.
If dose of KarXT 100/20 BID was confirmed by investigator order, dispense sufficient quantities 
of 50 mg/10 mg pills to continue BID dosing of KarXT at the 100/20 level until next clinic visit.
Visits 5 to 8 (Days 28 to 70) Dosing 
If dose of KarXT 125/30 BID was confirmed by investigator order, the site pharmacist 
will prefill 1 child resistant bottle with a sufficient quantity of 62.5 mg/15 mg pills to 
accommodate BID dosing of KarXT at the 125/30 level until the next clinic visit.
Remind the subject to bring their pill bottle to the next clinic visit.
If dose of KarXT 100/20 BID was confirmed by investigator order, dispense sufficient quantities 
of 50 mg/10 mg pills to continue BID dosing of KarXT at the 100/20 level until next clinic visit.
Visits 9 to 29 (Days 84 to 364) Dosing 
If dose of KarXT 125/30 BID was confirmed by investigator order, the site pharmacist 
will prefill two child resistant bottles with a sufficient quantity of 62.5 mg/15 mg pills to 
accommodate BID dosing of KarXT at the 125/30 level until the next clinic visit.
For Days 84, 168, and 280, a single PK sample will be collected and the dose of KarXT 
and time of most recent dosing should be recorded.
See Section 9.4.1 for management of KarXT dose changes and PK sampling.
Remind the subject to bring their pill bottles to the next clinic visit.
If dose of KarXT 100/20 BID was confirmed by investigator order, dispense sufficient quantities 
of 50 mg/10 mg pills to continue BID dosing of KarXT at the 100/20 level until next clinic visit.
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9.3
Measures to Minimize Bias: Study Treatment Assignment
Method of Study Treatment Assignment
The 9-digit Subject Number previously assigned to the subject in the study KAR-007/KAR-009 
will continue to be used in the current study KAR-008. This number will be associated with the 
subject throughout the current study.
Blinding
This is an open-label study; therefore, blinding is not applicable.
9.4
Dosage Modification
Subjects will self-administer the KarXT as described in Section 7.1 and in accordance with the 
Schedule of Assessments (Table 2). The KarXT doses were selected based on the previous 
preclinical and clinical studies (see Section 5.2). Per the protocol, subjects will be evaluated for 
dose adjustments starting at Visit 3 through the remainder of the treatment period (see 
Section 9.2).
Additional changes to KarXT dosing (e.g., temporary dose reductions) may be permitted as 
clinically indicated upon approval by the medical monitor.
Extended Dosing Interruptions and Re-titration
Re-escalation to 125/30 BID or re-titration in cases where subject has been off the KarXT for a 
longer period of time (at least a week) is allowed and will require a discussion between the 
principal investigator (PI) and the medical monitor.
All subjects approved by the PI and medical monitor will resume KarXT by repeating the lead-in 
dosing scheme used at the start of study. Subjects will start with a lead-in dose of KarXT 
50/20 BID for the first 2 days after restarting study drug. Then the dose will be titrated to 100/20 
BID for at least the next 4 days, allowing the subject to adjust to KarXT before receiving a 
higher dose of 125/30 BID after restarting study drug, unless the subject is continuing to 
experience AEs from the previous dose, in which case the subject will remain on 
KarXT 100/20 BID.
9.5
Treatment Accountability and Compliance
The pharmacist or other designated individual will maintain records of study treatment delivered 
to the study site, the inventory at the study site, the distribution to each subject, and the return of 
materials to the Sponsor or designee for storage or disposal. These records should include dates, 
quantities, batch/serial numbers, expiration dates, temperature log, and unique code numbers 
assigned to the product and study subjects.
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Administration of KarXT will be supervised by study site personnel (during in-clinic visits) and
by a digital compliance tool to ensure adherence (AiCure technology). The pharmacist (or 
designee) will be responsible for dispensing KarXT into labeled child-resistant pill bottles for 
subjects use when at home. The quantity of KarXT capsules dispensed should be sufficient to 
cover the period (including visit window) until next planned study visit.  Please refer to the 
Schedule of Assessments in Section 10 and the study Pharmacy Manual for details. 
Investigators will maintain records that adequately document that the subjects were provided 
with the correct study treatment supply and reconcile the usage of the study drug. Investigational 
product will not be returned to the Sponsor or designee or destroyed until accountability has been 
fully monitored through the end of the study. KarXT accountability will be assessed periodically 
by the assigned study monitor.
9.6
Prior and Concomitant Therapy
Prior and Concomitant Medications
Concomitant medications ongoing as of Visit 10/Day 35 of the preceding acute study (KAR-007 
or KAR-009) will be captured in the eCRF as baseline therapy. Thereafter, all medications and 
other treatments taken by the subject during the study, including those treatments initiated before 
the start of the study drug administration, must be recorded on the KAR-008 eCRF.
Restricted prior therapies are provided below.
During the study (ie, from the time of enrollment at baseline visit [Day 0] until study completion
(EOS), subjects should refrain from the use of any new concomitant medications without the 
prior approval of the investigator. The administration of any other concomitant medications 
during the study period is prohibited without the prior approval of the investigator unless its use 
is deemed necessary in a medical emergency. Any medication or therapy that is taken by or 
administered to the subject during the course of the study must be recorded in the eCRF. The 
entry must include the dose, regimen, route, indication, and dates of use.
All the subjects enrolled into the study must not take the below mentioned prohibited 
medications for the duration of the treatment period.
Oral or long acting injectable antipsychotic medications, monoamine oxidase inhibitors, 
mood stabilizers (ie, lithium), anticonvulsants (eg, lamotrigine, Depakote), tricyclic 
antidepressants (eg, imipramine, desipramine), selective serotonin reuptake inhibitors, or 
any other psychoactive medications except for anxiolytics that were taken on an as 
needed basis (eg, lorazepam, chloral hydrate). 
Note: Please direct questions relating to prohibited medications to the medical monitor.
Concomitant Medications for Anxiety and/or Sleep Aid
Subjects are allowed to take benzodiazepines (up to 4 mg lorazepam/day or equivalent) for 
anxiety, agitation, and insomnia on a PRN basis. Subjects may also use non-benzodiazepine 
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medications (eg, zolpidem, zaleplon) as a sleep aid, also on a PRN basis. Study sites must record 
the use of such medications in the eCRF and 
source document.  
Note: Cognition testing should not be done within 8 hours of receiving a benzodiazepine or sleep 
medication. 
 
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10 STUDY PROCEDURES 
Table 2 outlines the timing of procedures and assessments to be performed throughout the study. 
Section 11.6 specifies laboratory assessment samples to be obtained. See Sections 11, 12, 13, and 
14 for additional details regarding efficacy, safety, PK, and exploratory assessments, 
respectively. 
COVID-19 testing will be completed in accordance with clinical site standard operating 
procedures. If a subject tests positive for COVID-19 during the study, they may be quarantined 
as needed and any scheduled visits should be rescheduled or conducted via telemedicine per the 
discretion of the investigator. If the subject requires hospitalization, an SAE should be reported 
and the subject should be followed up as outlined in Section 11.7.3. 
 
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Table 2. 
Schedule of Assessments  
DAY 
 
 
0 
 
1 
 
3 
(+1d) 
8 
(± 1d) 
14 
(± 2d) 
28 
(± 3d) 
42 
(± 3d) 
56 
(± 3d) 
70 
(± 3d) 
84 
(± 3d) 
98 
(± 3d) 
112 
(± 3d) 
126 
(± 3d) 
140 
(± 3d) 
154 
(± 3d) 
168 
(± 3d) 
WEEK 
 
1 
 
 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
VISIT Baseline1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10a 
11 
12 
13 
14 
15 
TYPE OF VISIT Clinic 
  
Clinic Clinic Clinic Clinic Clinic Clinic Clinic Clinic Interim Clinic Interim Clinic Interim Clinic 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject eligibility verification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (WOCBP 
only)b 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Urine drugs of abuse and alcohol 
testingc 
 
 
 
 
 
X 
 
 
Review of inclusion/exclusion 
criteria 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, body weight, BMI, waist 
circumferenced  
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Complete physical examinatione 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical examinationf 
Spontaneous AEsg 
X 
  
 
 
 
 
 
 
Review of concomitant 
medicationsh 
 
 
 
 
 
 
 
Vital signs: BP and HRi 
 
 
 
 
 
 
 
Resting ECG (12-lead)j 
X 
   
 
 
X 
 
 
 
 
 
 
X 
Blood samples for clinical 
laboratory testsk 
X 
 
 
 
X 
X 
 
 
X 
 
 
X 
Blood sample for prolactinl  
X 
 
 
 
X 
 
 
 
 
 
 
X 
Functional constipation inquirym 
X 
 
 
 
 
 
X 
 
Determination of dose titration 
 
 
PK blood drawn 
PANSSo 
C-SSRSp 
 
CGI-S scale 
Cognition testingq 
 
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DAY 
 
 
0 
 
1 
 
3 
(+1d) 
8 
(± 1d) 
14 
(± 2d) 
28 
(± 3d) 
42 
(± 3d) 
56 
(± 3d) 
70 
(± 3d) 
84 
(± 3d) 
98 
(± 3d) 
112 
(± 3d) 
126 
(± 3d) 
140 
(± 3d) 
154 
(± 3d) 
168 
(± 3d) 
WEEK 
 
1 
 
 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
VISIT Baseline1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10a 
11 
12 
13 
14 
15 
TYPE OF VISIT Clinic 
  
Clinic Clinic Clinic Clinic Clinic Clinic Clinic Clinic Interim Clinic Interim Clinic Interim Clinic 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAS 
BARS 
AIMS 
AiCure registration and trainingr 
KarXT dispensed 
Subject self-administration of 
KarXT using AiCure apps  
EMA registration and trainingt 
EMA PROu 
EMA VLMTv 
Digital biomarkers using AiCure 
appw 
 
 
 
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Table 2 
Schedule of Assessments (Continued from Visits 16 to 30) 
DAY 
 
182 
(± 3d) 
196 
(± 3d) 
210 
(± 3d) 
224 
(± 3d) 
238 
(± 3d) 
252 
(± 3d) 
266 
(± 3d) 
280 
(± 3d) 
294 
(± 3d) 
308 
(± 3d) 
322 
(± 3d) 
336 
(± 3d) 
350 
(± 3d) 
364 
(± 3d) 
371 
(± 3d) 
WEEK 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52 
53 
VISIT 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
(EOT/
ET) 
30 
(EOS/ UNS)3 
TYPE OF VISIT Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic 
Clinic 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(WOCBP only)b 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Urine drugs of abuse and 
alcohol testingc 
Height, body weight, BMI, 
waist circumferenced 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Complete physical 
examinatione 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Targeted physical 
examinationf 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Spontaneous AEsg 
Review of concomitant 
medicationsh 
Vital signs: BP and HRi 
Resting ECG (12-lead)j 
 
 
 
 
 
X 
 
 
 
Blood samples for clinical 
laboratory testsk 
 
X 
 
 
 
X 
 
 
 
Blood sample for 
prolactinl 
 
 
 
 
 
X 
 
 
 
Functional constipation 
inquirym 
PK blood drawn 
PANSSo 
C-SSRSp 
CGI-S scale 
Cognition testingq 
SAS 
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DAY 
 
182 
(± 3d) 
196 
(± 3d) 
210 
(± 3d) 
224 
(± 3d) 
238 
(± 3d) 
252 
(± 3d) 
266 
(± 3d) 
280 
(± 3d) 
294 
(± 3d) 
308 
(± 3d) 
322 
(± 3d) 
336 
(± 3d) 
350 
(± 3d) 
364 
(± 3d) 
371 
(± 3d) 
WEEK 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52 
53 
VISIT 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
(EOT/
ET) 
30 
(EOS/ UNS)3 
TYPE OF VISIT Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic 
Clinic 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BARS 
AIMS 
KarXT dispensed 
Subject self-administration 
of KarXT using AiCure 
apps 
EMA PROu 
EMA VLMTv 
Digital biomarkers using 
AiCure appw 
Abbreviations: AE = adverse event; AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; BL = baseline; BMI = body 
mass index; BP = blood pressure; CGI-
-SSRS = Columbia-Suicide Severity Rating Scale; d = day; 
ECG = electrocardiogram; EMAW = EMA Wellness; EOS = end of study; EOT = end of treatment; ET = early termination; HR = heart rate; PANSS = Positive 
and Negative Syndrome Scale; PK = pharmacokinetic; QTcF = QT interval corrected by Fridericia; SAS = Simpson-Angus Rating Scale; UNS = unscheduled 
visit. 
1. Baseline Day 0 assessments should be rolled over from Day 35/Visit 10 of the preceding study (KAR-007 or KAR-009) whenever possible (exception: 
cognition which should be rolled over from Day 32).  Includes pregnancy testing, complete physical exam, vital signs, ECG, safety laboratory evaluations, 
functional constipation inquiry, PANSS, C-SSRS, CGI-S, SAS, AIMS and BARS. 
2. (X) = Optional and to be completed only if Day 0 visit does not take place on the same day of Day 35/Visit 10 of the preceding study. See footnotes for 
additional details. 
3. Other assessments as needed. 
4. This procedure is optional and should only be performed for participants who have terminated early. 
 
 
a. 
Beginning after Visit 9/Day 84, interim visits will be completed every 4 weeks with flexibility between the in-clinic visits, which will occur every month. 
Interim visits will be conducted by site staff using telemedicine (audio only, or audio + video). When needed, the sites will have the option to schedule a 
subject for an in-clinic visit. 
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b. A urine pregnancy test for WOCBP should be performed at scheduled visits. If a urine pregnancy test is positive, a serum sample should be sent to central 
laboratory for confirmation of the result. A new urine pregnancy test should be performed on Day 0 visit only if subject left the inpatient unit after 
completion of Visit 10 of the preceding acute study but prior to completion of the Day 0 procedures of the current study. 
c. 
A National Institute on Drug Abuse-5 (NIDA-5) urine drug screen (cannabinoids or marijuana, phencyclidine, amphetamines, opiates, and cocaine) and test 
for alcohol (breathalyzer or urine alcohol level) will be performed at the indicated scheduled visits.  Should be performed on Day 0 visit only if subject left 
the inpatient unit after completion of Visit 10 of the preceding acute study but prior to completion of the Day 0 procedures of the current study. 
d. Baseline height is recorded from Study KAR-007/KAR-009 Screen visit.  Baseline body weight, BMI and waist circumference recorded from KAR--007/-
009 Visit 10. At the indicated study visits, body weight and waist circumference will be measured and BMI calculated.  
e. 
A complete physical examination includes body temperature (°C), general appearance, head/eyes/ears/nose/throat (HEENT), examination of thorax and, 
assessment of cardiac, musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited neurological examination. 
f. 
A targeted physical examination includes at a minimum body temperature, a check of general appearance, as well as examination of organ systems that are 
view of systems, or concomitant medication use. These also include symptom-
driven physical examinations which will be performed as clinically indicated at any study visit. A targeted physical examination at Day 0 is optional, and 
only required if the subject has reported a new AE in the time since completing Visit 10 of the preceding acute study. 
g. Adverse events as reported by subjects or observed by clinical staff. Adverse events ongoing as of Visit 10 of the preceding acute study will be recorded in 
the KAR-008 Medical History eCRF. Adverse events occurring after dosing with KarXT in the current study will be recorded in the KAR-008 AE eCRF. 
One PK blood sample may be drawn if a relevant/significant AE (based on medical judgment) is reported during a scheduled visit or if there is a dose 
titration or a relevant/significant AE reported during an unscheduled visit (no multiple draws). For interim visits, spontaneous AEs will be collected by 
telemedicine. 
h. Concomitant medications ongoing as of Visit 10/Day 35 of the preceding acute study will be captured in the eCRF as baseline therapy.  Thereafter, all 
medications and other treatments taken by the subject during the study, including those treatments initiated before the start of the study, must be recorded 
on the KAR-008 eCRF. For interim visits, concomitant medications will be collected by telemedicine. 
i. 
Vital signs measurements should be taken at all in-clinic visits, while the subject is supine and standing after 2 minutes. BP includes systolic and diastolic 
BP and is to be taken in the same arm for the duration of the study. During in-clinic visits orthostatic vital signs should occur 2 (±1) hours after morning 
dose of KarXT whenever possible.   
j. 
ECG should be obtained within 1 to 2 hours post morning dose whenever possible. ECG at all indicated visits should be performed before blood withdrawal 
for any safety laboratory tests and/or PK analysis. ECGs will be transmitted electronically to a central reader for determination of ventricular rate (bpm), PR 
(msec), QRS (msec), QT (msec), and QTcF (msec) measurements. 
k. Refer to Section 11.6 for individual laboratory tests. For urinalysis, a urine dipstick will be performed at the site. In the event of abnormalities, the sample 
will be sent to the central laboratory for full microscopic urinalysis.  
l. 
Prolactin sample is optional when using local labs. 
m. Functional constipation inquiry: At specified visits, subjects will be asked whether they have experienced constipation (per the ROME III criteria and 
Bristol Stool Form Scale; see Appendix 2) since the last visit and if yes, whether the constipation required intervention. If the subject answers yes, sites are 
instructed to ask subjects to provide event date and ensure the event is documented as an AE and treatment is documented as concomitant medication.  
n. PK blood samples will be collected on Days 8, 14, 84, 168, and 280. At Day 8 the PK sample should be obtained within 1 to 2 hours post dose whenever 
possible. In cases of dose reduction, re-escalation, or re-titration, an additional PK sample may be collected per investigator discretion in consultation with 
the medical monitor. 
o. It is recommended, if at all possible, that the PANSS assessment should be performed before all the other scale assessments for all visits at which it is 
performed.  
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p. 
 should be used for C-SSRS administration. At the Unscheduled visit, the C-SSRS should be performed to monitor subjects for 
suicidality. 
q. Cognition testing is performed using CANTAB. Cognition testing should not be done within 8 hours of receiving a benzodiazepine or sleep medication.  
r. 
Refer to the Study Operations Manual for details. AiCure should be used to self-administer KarXT beginning on Day 1 whenever possible. All subjects 
must begin using AiCure adherence monitoring to self-administer KarXT no later than Visit 2, Day 3. 
s. 
Subjects must complete AiCure training and registration no later than Visit 2/Day 3 and prior to escalating to the 100/20 KarXT dose. See Study Operations 
Manual for more details. 
t. 
US Only. See Study Operations Manual for additional details. 
u. EMA PRO (US Only) will be completed by the subject at home on a cellular device 3 times per day for 7 days every 28 days, beginning on Day 29. An 
abbreviated version of the assessment will be utilized on Days 4-6 and 15-17 to familiarize subjects with the process. Refer to Study Operational Manual 
for details. 
v. Cognitive insight (US Only) will be assessed using the EMA VLMT.  The assessment will be completed by the subject at home on a cellular device 1 time 
per day for 2 days every 28 days beginning on Day 32. Refer to Study Operational Manual for details. 
w. Digital biomarkers of schizophrenia (US Only) will be calculated through completion of a smartphone-based assessment daily by the subject for 3 days 
collected initially on Days 4-6, 9-11, and 15-17. Subsequently subjects will complete assessments daily for 3 days every 28 days, beginning on Day 29. 
Refer to Study Operational Manual for details. 
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10.1 Informed Consent
Informed consent forms must be approved for use by the reviewing Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB). Before performing any study-related 
procedures, the investigator (or designee) will obtain written informed consent from the subject
and/or caregiver (Ukraine only).
10.2 Study Procedures
Assessments and their timing are to be performed as outlined in the Schedule of Assessments 
(Table 2). Section 11.6 specifies laboratory assessment samples to be obtained. 
Safety assessments are described in Section 11 and include spontaneous AEs including AESIs;
procholinergic and anticholinergic symptoms, SAEs and AEs leading to discontinuation of the 
KarXT; SAS; BARS; AIMS; body weight; BMI; waist circumference; orthostatic vital signs; 
ECG; clinical laboratory assessments (hematology, clinical chemistry, coagulation, urinalysis, 
and drug screen); physical examination; and C-SSRS.
Efficacy assessments are described in Section 12 and include PANSS and CGI-S scores.
PK assessments are described in Section 13.
Exploratory assessments are described in Section 14 and include cognition testing using 
CANTAB; prolactin levels; digital biomarkers of schizophrenia; EMA PRO; and EMA VLMT.
The investigator may, at his/her discretion, arrange for a subject to have an unscheduled 
assessment, especially in the case of AEs that require follow-up or are considered by the 
investigator to be possibly related to the use of KarXT. The unscheduled visit page in the eCRF 
must be completed. The assessments and procedures that may be performed during an 
unscheduled visit are outlined in the Schedule of Assessments (Table 2). Additional assessments 
can be performed as needed, at the discretion of the investigator, and following discussion with 
the medical monitor.
Study discontinuation procedures are described in Section 8.4 and Section 8.6.
AiCure Adherence Technology
AiCure technology will be used to monitor study medication adherence in all subjects, both in 
the US and the Ukraine. Subjects must complete registration and training and begin utilizing 
AiCure technology no later than Visit 2/Day 3, prior to escalating from 50/20 to 100/20 KarXT. 
See Operations Manual for additional details. Additionally, the AiCure technology will be used 
to capture Digital Biomarker Assessment of schizophrenia symptoms of subjects in the US only.
Medication Adherence (US and Ukraine):
This study will employ a medication adherence monitoring platform (herein after referred to as 
Platform) for all subjects in the study. The Platform uses artificial intelligence on smartphones to 
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confirm medication ingestion. In addition, built-in reminders and a communication system allow 
real-time intervention in case of drug interruptions.  
Use of this Platform will in no way supersede or replace the physician and/or prescribed 
medication protocol of the subjects. Because the Platform does not change the medication 
protocol of the subjects, but rather encourages adherence to the predefined protocol, use of this 
Platform presents minimal risk to the subjects. Use of the Platform will be required for all 
subjects in the study. 
The monitoring Platform requires that all subjects take each dose of the medication while using a 
smartphone. Participants will download the AiCure application on their personal smartphone 
device; for participants who do not have a smartphone or do not wish to use their personal 
smartphone, site personnel will provide the participant with one of the preloaded backup 
provisioned devices. 
When at home, study subjects will receive a medication reminder at a time within a predefined 
window. This notification reminds subjects to take their medication dose while using the 
Platform. Subjects will follow a series of prescribed steps in front of the front-facing webcam to 
visually confirm their ingestion of the medication. The application on the smartphone will make 
an automated determination of whether the subject has properly taken their medication at the 
prescribed time. There is no need for a healthcare provider to review the administration, nor 
would a healthcare provider need to be available at the time the subject takes their medication. 
The amount of guidance that the device provides to the subject is automatically reduced as the 
subject becomes more proficient at using the application. 
Digital Biomarker Assessment (US only): 
For subjects enrolled at US sites only, subjects will be performing brief smartphone-based 
assessments using the AiCure application. Video and audio of participant behavior captured 
during these assessments will be used to calculate visual and auditory markers of schizophrenia 
symptomatology. These digital biomarkers will be used as exploratory efficacy endpoints to 
measure change from baseline in disease severity. See Section 14.4 for endpoint discussion. The 
material will be presented to subjects in one of two ways. In the first, material will be presented 
to subjects, and will include questionnaires provided at regular intervals during the study. Images 
may also be shown to subjects, and they will be asked to describe each image in a few sentences 
to the camera of the smartphone.   
Data Collected on the AiCure Platform: 
After the device confirms proper medication ingestion, video recordings will be encrypted and 
transmitted to a secure centralized location for further analysis, including testing for duplicate 
enrollment. Video and audio recordings from the Digital Biomarker assessments will be 
encrypted and transmitted in a similar manner. The captured data and video is reviewable 
through a roles and rules restricted system ensuring privacy of the information. The system is 
compliant with applicable US and European data privacy laws, including General Data 
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Protection Regulation (GDPR) (EU) 2016/679 the Health Insurance Portability and 
Accountability Act (HIPAA), which protects the privacy and security of healthcare information. 
Phone numbers of the patients may also be collected and stored in an encrypted manner. Storing 
the phone numbers will allow for direct communication with patients, including automated 
messaging from the Platform device and contact by healthcare providers or other monitoring 
personnel. At no time is the phone number visible to healthcare providers or monitoring 
personnel. Individuals outside the clinical sites will not be provided with patient names, nor will 
they be given access to patient medical records. 
The Platform may provide significant benefits to study subjects as well as to the other 
stakeholders in the trial. Subjects will benefit from rapid and tailored intervention in case of 
non-adherence (drug interruptions) without having to visit the clinic for unscheduled visits. 
Healthcare providers will have access to real-time and continuous adherence data without having 
to rely on self-reported data or frequent study visits by patients. Subjects who regularly fail to 
take their medication will be contacted by healthcare providers or other study monitoring 
personnel for retraining. 
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11 SAFETY ASSESSMENTS 
Safety assessments (spontaneous AEs including AESIs; procholinergic and anticholinergic 
symptoms; SAEs and AEs leading to discontinuation of the KarXT; SAS; BARS; AIMS; body 
weight; BMI; waist circumference; orthostatic vital signs; ECG; clinical laboratory assessments 
[hematology, clinical chemistry, coagulation, urinalysis, and drug screen]; physical examination; 
and C-SSRS) will be performed at protocol-specified visits, as specified in the Schedule of 
Assessments (Table 2).  
11.1 Demographics, Medical History, and Psychiatric History 
Demographic data, and medical and psychiatric history will be recorded from the Phase 3, 
double-blind, acute study (KAR-007/KAR-009).  
Illnesses first occurring or detected during the study and/or worsening of a concomitant illness 
during the study are to be documented as AEs on the eCRF in accordance with Section 11.7. All 
changes that are not present at baseline or described in the past medical history and identified as 
clinically noteworthy must be recorded as AEs. 
11.2 Vital Signs 
Orthostatic vital signs (systolic and diastolic BP and heart rate measurements) will be evaluated 
at all scheduled visits indicated in the Schedule of Assessments (Table 2). All vital signs will be 
measured supine and standing after 2 minutes. Blood pressure measurements are to be taken in 
the same arm for the duration of the study. During in-clinic visits, beginning with Visit 2 
(Day 3), orthostatic vital signs should occur 2 (±1) hours after morning dosing, whenever 
possible.   
Vital sign measurements will be repeated if clinically significant or machine/equipment errors 
occur. Out-of-
discretion. Any confirmed, clinically significant vital sign measurements must be recorded as 
AEs. 
11.3 Complete/Targeted Physical Examination 
A complete physical examination (body temperature, general appearance, 
head/eyes/ears/nose/throat [HEENT], examination of thorax and abdomen, assessment of 
cardiac, musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited 
neurological examination) will be performed at visits as specified in Table 2. Physical 
examinations will be performed by a physician or qualified designee. 
A targeted physical examination includes at a minimum body temperature, a check of general 
appearance, as well as examination of organ systems that are relevant to the investigator, based 
comitant medication use. 
These also include symptom-driven physical examinations which will be performed as clinically 
indicated at any study visit. 
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11.4 Weight, Height, Body Mass Index, and Waist Circumference 
The baseline height measurement will be recorded from the lead-in Study KAR-007 or KAR-009 
Screen visit.  The baseline body weight, BMI and waist circumference measurements will be 
recorded from the KAR-007 or KAR-009 Visit 10.  At the indicated visits of the current study 
(Table 2), body weight and waist circumference will be measured and BMI calculated. All 
findings should be recorded in the eCRF. 
11.5 Electrocardiograms 
A 12-lead, resting ECG should be obtained within 1 to 2 hours post morning dose at the visits 
indicated in the Schedule of Assessments (Table 2), whenever possible. ECG at all scheduled 
visits should be performed before blood withdrawal for any safety laboratory tests and/or PK 
analysis. 
ECGs will be transmitted electronically to a central reader for determination of ventricular 
rate (bpm), PR (msec), QRS (msec), QT (msec), and QTcF (msec) measurements. An assessment 
of normal or abnormal will be recorded; if the ECG is considered abnormal, the abnormality will 
be documented on the eCRF. ECGs will be repeated if clinically significant abnormalities are 
observed or artifacts are present. 
11.6 Laboratory Assessments 
Laboratory assessment samples (Table 3) are to be obtained at designated visits as detailed in the 
Schedule of Assessments (Table 2). 
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Table 3. 
Laboratory Assessments 
Hematology 
Serum Chemistry 
Urine Analysis (Dipstick) 
Full and differential blood count 
Hct 
Hb 
MCH 
MCHC 
MCV 
Platelet count 
RBC count 
WBC count with differential 
 
ALT 
ALP 
AST 
Albumin 
Uric acid 
BUN or urea 
Carbon dioxide 
Creatinine 
Creatine kinase and subtypes 
Electrolytes (sodium, 
potassium, chloride, calcium, 
phosphorus) 
GGT 
Glucose 
LDH 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
HDL 
LDL 
Triglycerides 
Total protein 
Appearance 
pH 
Protein 
Glucose 
Ketone bodies 
Indicators of blood and WBCs 
Specific gravity 
Urobilinogen 
Occult blood 
WBCs 
HbA1c (glycated Hb test) 
Prolactin 
  
Coagulation 
PT 
Activated PTT 
Fibrinogen 
Pregnancy test: A urine pregnancy test for WOCBP should be performed per the schedule of assessments 
(Table 2).  In case of positive urine pregnancy test result, a serum sample should be sent to the central 
laboratory to confirm the result. 
Full and microscopic urinalysis:  
Chemical exam: SG, pH, bilirubin, urobilinogen, protein, glucose, ketone, hemoglobin, leukocyte esterase, 
nitrite, ascorbic acid 
Microscopic exam: RBCs, WBCs, epithelial cells, bacteria, yeasts, parasites, casts, crystals 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; GGT = gamma-glutamyl transpeptidase; HCG = human 
chorionic gonadotropin; Hb = hemoglobin; Hct = hematocrit; HDL = high density lipoprotein; LDH = lactate 
dehydrogenase; LDL = low density lipoprotein; MCH = mean corpuscular hemoglobin; MCHC = mean 
corpuscular hemoglobin concentration; MCV = mean corpuscular volume; PT = prothrombin time; 
PTT = partial thromboplastin time; RBC = red blood cell; WBC = white blood cell; WOCBP = women of 
childbearing potential. 
 
Venous blood of approximately 12 to 20 mL will be withdrawn for the tests listed above at 
scheduled time points as per Table 2.  
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A minimum volume of 10 mL will be obtained to perform urinalysis (if abnormalities observed 
on dipstick) and urine drug screen at scheduled time points as per Table 2. 
Blood and urine samples (microscopic analysis) will be analyzed at a central laboratory facility. 
Urine samples will first be analyzed by dipstick at the site. If the results of the dipstick indicate 
abnormalities to be further investigated, the sample will be sent to the central laboratory and a 
microscopic analysis will be performed. All laboratory reports must be reviewed, signed, and 
dated by the investigator. A legible copy of all reports must be filed with both the 
eCRF 
and medical record (source document) for that visit. Any laboratory test result considered by the 
investigator to be clinically significant should be considered an AE (clinically significant AEs 
include those that require an intervention). Clinically significant abnormal values occurring 
during the study will be followed up until repeat test results return to normal, stabilize, or are no 
longer clinically significant.
All the study subjects will be closely monitored for the drug-induced liver toxicity (detailed in
Section 11.7.5), during the study.
Other Laboratory Assessments:
A National Institute on Drug Abuse-5 (NIDA-5) urine drug screen (cannabinoids or 
marijuana, phencyclidine, amphetamines, opiates, and cocaine) will be performed using a 
dipstick throughout the study. 
Alcohol testing will be performed using a breathalyzer or urine alcohol test. 
11.7 Adverse Events
Adverse Events
An AE is any symptom, physical sign, syndrome, or disease that either emerges during the study 
or, if present at screening/baseline, worsens during the study, regardless of the suspected cause 
of the event. All medical and psychiatric conditions (except those related to the indication under 
study) present at screening/baseline will be documented in the medical history eCRF. Changes in 
these conditions and new symptoms, physical signs, syndromes, or diseases should be noted on 
the AE eCRF during the rest of the study. Clinically significant laboratory abnormalities should 
also be recorded as AEs. Surgical procedures that were planned before the subject enrolled in the 
study are not considered AEs if the conditions were known before study inclusion; the medical 
condition should be reported in the 
medical history.
In accordance with the protocol, the investigator and/or study staff will elicit AEs and 
intercurrent illness during and at the end of the study period and these will be recorded on the 
appropriate page of the eCRF. Adverse events will be elicited by asking the subject a nonleading 
soon as the results of the final lab 
tests are available.
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Each AE is to be documented on the eCRF with reference to date of onset, duration, frequency, 
severity, relationship to KarXT, action taken with KarXT, treatment of event, and outcome. 
Furthermore, each AE is to be classified as being serious or nonserious. Changes in AEs and 
resolution dates are to be documented on the eCRF. 
For the purposes of this study, the period of observation for collection of AEs extends from the 
time immediately after the administration of KarXT on Day 1 until the EOS or ET. Follow-up of 
the AE, even after the date of therapy discontinuation, is required if the AE persists until the 
event resolves or stabilizes at a level acceptable to the investigator. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the event should be noted. If the intensity category changes over a number of days, 
then those changes should be recorded separately (with distinct onset dates). 
The severity of AEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0 (Grades 1 through 5). 
Specific guidelines for classifying AEs by intensity and relationship to KarXT are given in 
Table 4 and Table 5. 
Table 4. 
Classification of Adverse Events by Intensity 
MILD: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with 
everyday activities. 
MODERATE: An event that is sufficiently discomforting to interfere with normal everyday activities. 
SEVERE: An event that prevents normal everyday activities. 
 
Table 5. 
Classification of Adverse Events by Relationship to KarXT 
UNRELATED: This category applies to those AEs that are clearly and incontrovertibly due to extraneous 
causes (disease, environment, etc). 
UNLIKELY: This category applies to those AEs that are judged to be unrelated to the test drug but for which 
no extraneous cause may be found. An AE may be considered unlikely to be related to KarXT if or when it 
meets 2 of the following criteria: (1) it does not follow a reasonable temporal sequence from administration of 
the test drug; (2) it could readily have been produced by the 
 clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; (3) it does not follow a known pattern of 
response to the test drug; or (4) it does not reappear or worsen when the drug is readministered. 
POSSIBLY: This category applies to those AEs for which a connection with the test drug administration 
appears unlikely but cannot be ruled out with certainty. An AE may be considered possibly related if or when 
it meets 2 of the following criteria: (1) it follows a reasonable temporal sequence from administration of the 
drug; (2) it could not readily have been produced by the 
 clinical state, environmental or toxic factors, 
or other modes of therapy administered to the subject; or (3) it follows a known pattern of response to the test 
drug. 
PROBABLY: This category applies to those AEs that the investigator feels with a high degree of certainty are 
related to the test drug. An AE may be considered probably related if or when it meets 3 of the following 
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
reasonably explained by the known characteristics of the 
 clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; (3) it disappears or decreases on cessation or 
reduction in dose (note that there are exceptions when an AE does not disappear upon discontinuation of the 
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drug, yet drug-relatedness clearly exists; for example, as in bone marrow depression, fixed drug eruptions, or 
tardive dyskinesia); or (4) it follows a known pattern of response to the test drug.
DEFINITELY: This category applies to those AEs that the investigator feels are incontrovertibly related to test 
drug. An AE may be assigned an attribution of definitely related if or when it meets all of the following 
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
reasonably explained by the known characteristics of the 
clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; (3) it disappears or decreases on cessation or 
reduction in dose and recurs with re-exposure to drug (if rechallenge occurs); and (4) it follows a known 
pattern of response to the test drug.
Abbreviation: AE = adverse event.
Adverse Events of Special Interest
The AEs of special interest will be monitored and include orthostasis and liver function test 
elevations inclusive of drug-induced liver injury (DILI).
Serious Adverse Events
An SAE is any untoward medical occurrence, in the view of either the investigator or Sponsor, 
that:
results in death,
is life-threatening,
results in inpatient hospitalization or prolongation of existing hospitalization (however, 
hospitalization for elective treatment of a pre-existing non-worsening condition is not 
considered an SAE; the details of such hospitalizations must be recorded on the medical 
history or physical examination page of the eCRF),
results in persistent or significant disability/incapacity, and/or
is a congenital anomaly/birth defect.
Other important medical events that may not be immediately life-threatening or result in death or 
hospitalization, based upon appropriate medical judgment, are considered SAEs if they are 
thought to jeopardize the subject and/or require medical or surgical intervention to prevent 1 of 
the outcomes defining an SAE. Serious AEs are critically important for the identification of 
either the Sponsor or the investigator believes that an event is 
serious, the event must be considered serious and evaluated by the Sponsor for expedited 
reporting.
Serious Adverse Event Reporting
An SAE occurring from the time the first dose of KarXT is administered, during the study, or 
within 1 week of stopping the treatment must be reported to the Catalyst Clinical Research 
Pharmacovigilance group and will be communicated to the Sponsor. Any such SAE due to any 
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cause, whether or not related to the KarXT, must be reported within 24 hours of occurrence or 
when the investigator becomes aware of the event. Notification can be made using email.
Catalyst Clinical Research Pharmacovigilance email address: 
The event must be recorded on the standard AE eCRF. Preliminary reports of SAEs must be 
followed up by detailed descriptions later on, including clear and anonymized photocopies of 
hospital case reports, consultant reports, autopsy reports, and other documents when requested 
and applicable. SAE reports must be made whether or not the investigator considers the event to 
be related to the investigational drug.
Appropriate remedial measures should be taken to treat the SAE, and the response should be 
recorded. Clinical, laboratory, and diagnostic measures should be employed as needed in order to 
determine the etiology of the problem. The investigator must report all additional follow-up 
evaluations to the Catalyst Clinical Research Pharmacovigilance group within 24 hours of 
becoming aware of the additional information or as soon as is practicable. All SAEs will be 
followed up until the investigator and Sponsor agree the event is satisfactorily resolved.
Any SAE that is not resolved by the end of the study or upon discontinuation of the subject
participation in the study is to be followed up until it either resolves, stabilizes, returns to 
baseline values (if a baseline value is available), or is shown to not be attributable to the KarXT
or procedures.
Drug-Induced Liver Injury
The sponsor has incorporated the following for monitoring of drug-induced liver injuries:
An increase of serum alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) to >3 × ULN should be followed by repeat testing within 48 to 72 hours of all 4 of 
the usual serum measures (ALT, AST, ALP, and total bilirubin) to confirm the 
abnormalities and to determine if they are increasing or decreasing. An inquiry should be 
made about the symptoms (eg, fatigue, nausea, vomiting, right upper quadrant pain or
tenderness, fever, and rash).
Close observation should be initiated with ALT or AST >3 × ULN:
o
Repeat liver enzyme and serum bilirubin tests 2 or 3 times weekly. The frequency of 
retesting can decrease to once per week or less if abnormalities stabilize or the trial 
drug has been discontinued and the subject is asymptomatic.
o
Obtain a more detailed history of symptoms and prior or concurrent diseases.
o
Obtain a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug 
use, and special diets.
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o Rule out acute viral hepatitis types A, B, C, D, and E, autoimmune or alcoholic 
hepatitis, non-alcoholic steatohepatitis, hypoxic/ischemic hepatopathy, and biliary 
tract disease. 
o Obtain a history of exposure to environmental chemical agents. 
o Obtain additional tests to evaluate liver function, as appropriate (eg, international 
normalized ratio, and/or direct bilirubin). 
o Consider gastroenterology or hepatology consultations. 
 Discontinuation of treatment should be considered if: 
o ALT or AST >8 × ULN 
o ALT or AST >5 × ULN for more than 2 weeks 
o ALT or AST >3 × ULN and (total bilirubin >2 × ULN or international normalized 
ratio >1.5) 
o ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or eosinophilia (>5%) 
 Hepatic adjudication of cases should include an evaluation for alternative causes such as 
viral, autoimmune, alcohol, hepatobiliary disorders, non-alcoholic steatohepatitis, 
concomitant medications, etc. 
 Follow-up to resolution of elevated liver enzymes. 
 Gamma-glutamyl transferase elevations alone should not prompt drug discontinuation.  
Subjects must be monitored closely. If close monitoring is not possible, the study drug should be 
discontinued. 
11.7.5.1 
Trial Discontinuation Criteria Other than DILI and Pregnancy 
11.7.5.2 
Individual Stopping Criteria 
Based on NCI 
 Grade 4 
AE. Discontinuation or reduction in the dosage of the study drug for Grade 3 AEs other than 
DILI AEs (see Section 11.7.5) will be at the discretion of the investigator. 
11.7.5.3 
Trial Stopping Rules 
The safety and tolerability aspects of KarXT will be overseen by an ISMC. The ISMC will meet 
periodically and review the unblinded data and will be responsible for advising the sponsor on 
ways to safeguard the interests of the clinical study subjects. The committee is expected to 
recommend sponsor whether to: 
a. Continue the clinical study without modification; or 
b. Continue the clinical study with modification (listing the specific modifications 
recommended); or 
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c.
Terminate the study.
Suspected Unexpected Serious Adverse Reactions
Adverse events that meet all of the following criteria will be classified as suspected unexpected 
serious adverse reactions (SUSARs) and reported to the appropriate regulatory authorities in 
accordance with applicable regulatory requirements for expedited reporting:
serious
unexpected (ie, the event is not consistent with the safety information in the IB or 
package insert of generic trospium)
there is at least a reasonable possibility that there is a causal relationship between the event 
and the study treatment
The investigator will assess whether an event is causally related to study treatment. The Sponsor 
meets the criteria for being reportable as a 7-day or 15-day safety report. SUSARs that are fatal 
or life-threatening must be reported to the regulatory authorities and the IEC/IRBs (where 
required) within 7 days after the Sponsor (or Syneos Health) has first knowledge of them, with a 
follow-up report submitted within a further 8 calendar days. Other SUSARs must be reported to 
the relevant regulatory authorities and the IEC/IRBs within 15 calendar days after the Sponsor 
(or Syneos Health) first has knowledge of them.
The Sponsor (or Syneos Health) is responsible for reporting SUSARs and any other events 
required to be reported in an expedited manner to the regulatory authorities and for informing 
investigators of reportable events, in compliance with applicable regulatory requirements within 
specific timeframes. Investigators will notify the relevant IEC/IRBs of reportable events within 
the applicable timeframes.
Warnings and Precautions
Risk of Urinary Retention:
Trospium chloride tablets should be administered with caution to subjects with clinically 
significant bladder outflow obstruction because of the risk of urinary retention.
Angioedema:
Angioedema of the face, lips, tongue, and/or larynx has been reported with trospium chloride, the 
active ingredient in trospium chloride tablets. In one case, angioedema occurred after the first 
dose of trospium chloride. Angioedema associated with upper airway swelling may be 
life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, trospium chloride 
should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a 
patent airway should be promptly provided.
Decreased Gastrointestinal Motility:
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Trospium should be administered with caution to subjects with GI obstructive disorders because 
of the risk of gastric retention. Trospium chloride, like other antimuscarinic agents, may decrease 
GI motility and should be used with caution in subjects with conditions such as ulcerative colitis, 
intestinal atony, and myasthenia gravis. 
Controlled Narrow-angle Glaucoma: 
In subjects being treated for narrow-angle glaucoma, trospium chloride should only be used if 
the potential benefits outweigh the risks and in that circumstance only, with careful monitoring. 
Central Nervous System Effects: 
Trospium chloride is associated with anticholinergic CNS effects. A variety of CNS 
anticholinergic effects have been reported, including dizziness, confusion, hallucinations, and 
somnolence. Subjects should be monitored for signs of anticholinergic CNS effects, particularly 
after beginning treatment or increasing the dose. Advise subjects not to drive or operate heavy 
machinery until they know how trospium chloride affects them. If a subject experiences 
anticholinergic CNS effects, dose reduction or drug discontinuation should be considered. 
Anticholinergic Adverse Reactions in Subjects with Moderate Renal Impairment: 
Trospium is substantially excreted by the kidney. The effects of moderate renal impairment on 
systemic exposure are not known but systemic exposure is likely increased. Therefore, 
anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract 
infection, and urinary retention) are expected to be greater in subjects with moderate renal 
impairment. 
Elevation of liver enzymes: 
Elevated liver enzymes have been reported in previous studies of xanomeline alone in 
observed in the Phase 1 studies in healthy volunteers and that the liver function test elevations 
observed in the Phase 2 schizophrenia study (KAR-004) with KarXT (a combination of 
xanomeline and trospium) were quite limited in contrast to the effects observed with xanomeline 
in the el
experienced more hepatic enzyme elevations, the data demonstrate reversibility even with 
continued xanomeline treatment in those patients where there was sufficient follow-up data. 
limit of reference range in either the xanomeline or KarXT datasets. 
11.8 Pregnancy 
WOCBP must have a negative pregnancy test at baseline (Day 0).  
The investigator must notify the Sponsor (or designee) of any female subject or female partner of 
a male subject that becomes pregnant while participating in the study. Any known cases of 
pregnancy will be reported until the subject completes or withdraws from the study.  
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The pregnancy will be reported immediately by faxing/emailing a completed pregnancy report to 
the Sponsor (or designee) within 24 hours of knowledge of the event. The pregnancy will not be 
processed as an SAE; however, the investigator will follow-up with the subject until completion 
of the pregnancy and must assess the outcome in the shortest possible time, but not more than 
30 days after completion of the pregnancy.  
If a female subject becomes pregnant, the investigator must withdraw her from the study without 
delay. The subject must not receive any further doses of the KarXT. Upon discontinuation from 
the study, only those procedures that would not expose the subject to undue risk will be 
performed. 
If the female subject or the female partner of the male subject is willing and able to consent to 
pregnancy follow-up, she will be followed until her pregnancy reaches term. Information 
regarding the pregnancy must only be submitted after obtaining written consent from the 
pregnant partner. The investigator will arrange counseling for the pregnant partner by a specialist 
to discuss the risks of continuing with the pregnancy and the possible effects on the fetus. 
The investigator should notify the Sponsor (or designee) of the pregnancy outcome by 
submitting a follow-up pregnancy report. If the outcome of the pregnancy involved spontaneous 
or therapeutic abortion (any congenital anomaly detected in an aborted fetus is to be 
documented), stillbirth, neonatal death, or congenital anomaly, the investigator will report the 
event by faxing/emailing a completed pregnancy report form to the Sponsor (or designee) within 
24 hours of knowledge of the event. This event is considered as an SAE. 
The investigator should also be notified of pregnancy occurring during the study but confirmed 
after completion of the study. In the event that a subject is subsequently found to be pregnant 
after inclusion in the study, any pregnancy will be followed to term, and the status of mother and 
child will be reported to the Sponsor after delivery. 
11.9 Overdose 
The investigator must immediately notify the Sponsor of any occurrence of overdose with 
KarXT (total daily dose greater than 250/60 mg). 
Signs and symptoms of overdose may vary considerably. They are usually manifested by 
increasing GI stimulation with epigastric distress, abdominal cramps, diarrhea and vomiting, 
excessive salivation, pallor, cold sweating, urinary urgency, blurring of vision, and eventually 
fasciculation and paralysis of voluntary muscles. Miosis, increases or decreases in blood pressure 
with or without bradycardia, and severe anxiety and panic may occur. 
Supportive treatment should be used as indicated (artificial respiration, maintenance of airway, 
oxygen, etc). Atropine sulfate should be available for IV or intramuscular administration. Several 
doses ranging from 0.5 to 2.0 mg may be required. Epinephrine 0.1 to 1.0 mg subcutaneous may 
also be of value in overcoming severe cardiovascular or bronchoconstrictor responses. 
Adverse events associated with overdoses should be reported on the eCRF. 
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11.10 Simpson-Angus Rating Scale 
The SAS is an established instrument to measure drug-related extrapyramidal syndromes. It is a 
10-item testing instrument used to assess gait, arm dropping, shoulder shaking, elbow rigidity, 
wrist rigidity, leg pendulousness, head dropping, glabella tap, tremor, and salivation. The range 
of scores is from 0 to 40 with increased scores indicating increased severity. 
11.11 Barnes Rating Scale for Akathisia 
The Barnes Rating Scale for akathisia is a rating scale used to assess the severity of drug-induced 
akathisia, or restlessness, involuntary movements and inability to sit still. The range of scores is 
0 to 14, with higher scores indicating greater severity.[23] 
11.12 Abnormal Involuntary Movement Scale 
The AIMS is a rating scale that is used to measure involuntary movements know as tardive 
dyskinesia, which can sometimes develop as a side effect of long-term treatment with 
antipsychotic medications. It is a 12-item scale to assess orofacial, extremity, and truncal 
evel of awareness of 
the movements. Items are scored from 0 (none) to 4 (severe). A higher score indicates more 
severe dyskinesia. 
11.13 Columbia-Suicide Severity Rating Scale 
The C-SSRS is a tool designed to systematically assess and track suicidal AEs (suicidal behavior 
and suicidal ideation) throughout the study.[24] The strength of this suicide classification system 
is in its ability to comprehensively identify suicidal events while limiting the over-identification 
of suicidal behavior. The scale takes approximately 5 minutes to administer. The C-SSRS will be 
administered by a trained rater at the site. 
11.14 Functional Constipation Inquiry 
Constipation refers to bowel movements that are infrequent or hard to pass.[25] The stool is 
often hard and dry.[26] Other symptoms may include abdominal pain, bloating, and feeling as if 
one has not completely passed the bowel movement.[27] The normal frequency of bowel 
movements in adults is between 3 per day and 3 per week.[25] Constipation will be defined per 
the Rome III criteria, as less than 3 bowel movements per week, Appendix 2 
(Longswreth,1486,C3).[28] 
The Bristol Stool Form Scale has been correlated with a change in intestinal function, and has 
been shown to be a useful tool in clinical practice and research.[29] A sample Bristol Stool Form 
Scale is located in Appendix 2. 
As a measure of anticholinergic effects, at specified visits (Table 2), subjects will be asked 
whether they have experienced constipation per the ROME III criteria since the last visit, and if 
yes, whether the constipation required intervention. If the subject answers yes, sites are 
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instructed to ask subjects to provide event date and ensure event is documented as an AE and 
treatment is documented as concomitant medication. Subjects will not be required to collect and 
present their stool sample, nor will clinic staff be required to corroborate the subject assessment. 
Additional attention can be given to other complaints as well including: straining with bowel 
movements, excessive time needed to pass a bowel movement, hard stools, pain with bowel 
movements secondary to straining, abdominal pain, abdominal bloating, and the sensation of 
incomplete bowel evacuation.[27, 30] 
Treatment of constipation depends on the underlying cause and the duration that it has been 
present. For the purposes of constipation complaints during a clinical trial, the use of laxatives of 
a bulk forming agent, osmotic agent, stool softener, or lubricant type may be used. 
As definitions of constipation are typically based on a history of at least a week, site physician 
discretion will be allowed for initiation of such treatments. 
 
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12 EFFICACY ASSESSMENTS 
The Schedule of Assessments (Table 2) outlines the efficacy assessments to be performed 
throughout the study and their timing. 
12.1 Positive and Negative Syndrome Scale 
The PANSS is a clinician-administered scale used for measuring symptom severity of subjects 
with schizophrenia and is widely used in the study of antipsychotic therapy.[31] The PANSS 
rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general 
psychopathology symptom scales. Subjects are rated from 1 to 7 on each symptom scale. The 
positive symptoms in schizophrenia are the excess or distortion of normal function such as 
hallucinations, delusions, grandiosity, and hostility, and the negative symptoms in schizophrenia 
are the diminution or loss of normal functions. It takes approximately 45 to 50 minutes to 
administer. PANSS total score is the sum of all scales with a minimum score of 30 and a 
maximum score of 210.  
It is recommended, if at all possible, that the PANSS assessment should be performed before all 
the other scale assessments for all visits at which it is performed. 
12.2 Clinical Global Impression-Severity 
The CGI-S is a rating scale, completed independently by a clinician that is used to measure 
illness and symptom severity in subjects with mental disorders. It is used to rate the severity of a 
-S modified asks the clinician 1 question: 
 The 
-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 subjects.[32] 
This rating is based upon observed and reported symptoms, behavior, and function in the past 
7 days. As symptoms and behavior can fluctuate over a week, the score should reflect the 
average severity level across the 7 days. 
 
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13
PHARMACOKINETICS
13.1 Pharmacokinetic Sampling
PK Blood Samples and Timing
On Days 8, 14, 84, 168, and 280
scheduled study visit (see Table 2). On Day 8 the PK sample should be drawn within 1 to 2 hours 
post-dose whenever possible.
Approximately 4 mL of blood will be collected at each scheduled time point. The actual date and 
time of each blood sample collection will be recorded. 
A single PK sample may be drawn if a relevant/significant AE is reported or if there is a dose 
adjustment. For ET that is related to an AE, collection of PK blood sample at the ET visit is 
recommended. 
Details of PK blood sample collection, processing, storage, and shipping procedures will be 
provided in a separate laboratory manual.
13.2 Pharmacokinetic Analytical Methodology
The plasma concentration of trospium and xanomeline in PK samples will be measured using a 
validated bioanalytical method. Details of the method validation and sample analysis will be 
included with the final clinical study report.
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14 EXPLORATORY ASSESSMENTS 
The exploratory assessments cognition testing, prolactin levels, digital biomarkers, EMA PRO, 
and EMA VLMT will be performed at scheduled visits or study days, as per the Schedule of 
Assessments (Table 2). 
14.1 Cognition Testing - Cambridge Neuropsychological Test Automated Battery 
The computerized CANTAB provides an objective measure of cognitive function correlated to 
neural networks. A short cognitive battery measuring core cognitive domains of impairment in 
schizophrenia (ie, as per Brief Assessment of Cognition Schizophrenia key cognitive domains) 
will be employed for this study, and it will take approximately 30 minutes to complete. These 
CANTAB tests meet MATRICS workshop criteria.[33] Subjects will perform the test on a 
provisioned iPad with data immediately uploaded to the CANTAB Connect cloud-based 
platform (Wi-Fi permitting). 
Cognition testing should not be done within 8 hours of receiving benzodiazepine or sleep 
medications. 
Table 6. 
Cognitive Tests and Cognitive Domains Assessed by the Cambridge 
Neuropsychological Test Automated Battery 
CANTAB Tests 
MATRICS Cognitive Domain 
Outcome Measures 
Rapid visual information 
processing 
Sustained attention/vigilance 
 Signal detection 
measure of how good the subject is 
at detecting the target sequence 
(string of three numbers); 
regardless of response tendency 
Verbal recognition memory 
Verbal memory and new learning 
Free Recall: The total number of 
words that are correctly recalled 
from the presentation phase by the 
subject during the immediate free 
recall stage 
Spatial Span 
Working memory 
Forward Span Length: The 
longest sequence of boxes 
successfully recalled by the subject 
One-touch stockings of Cambridge  
Executive Function 
Planning/Problem Solving 
Problems Solved on First Choice: 
The total number of assessed trials 
where the subject chose the correct 
answer on their first attempt 
Abbreviation: CANTAB = Cambridge Neuropsychological Test Automated Battery 
 
14.2 Change in Prolactin 
Blood samples to assess the change in prolactin levels will be obtained on scheduled visits as 
specified in Table 2. Prolactin sample is optional when sites are using local labs.  
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14.3 Digital Biomarkers of Schizophrenia (US only)
Study subjects will be performing brief smartphone-based assessments using the AiCure 
application mentioned in Section 10.2.1. Video and audio of participant behavior captured during 
these assessments will be used to calculate visual and auditory markers of schizophrenia 
symptomatology. These digital biomarkers will be used as exploratory efficacy endpoints to 
measure change from baseline in disease severity. The following exploratory endpoints will be 
collected:
Overall emotional expressivity
Positive emotional expressivity 
Negative emotional expressivity
Audio intensity / speech volume Fundamental frequency of voice
Formant frequencies of voice
Vocal jitter
Vocal shimmer
Pause lengths during speech
Lexical diversity
Rate of speech
Euclidean head movement
Rotational head movement
14.4 EMA Wellness Assessments
EMA Wellness EMA PRO (US only)
EMA is an ambulatory data collection technique that allows the real-time in vivo assessment of 
functioning behaviors. In the present study, EMA Patient Reported Outcomes (PRO) will be 
g associated to negative symptoms and psychotic 
symptoms in schizophrenia through the use of smartphones for subjects enrolled at US sites only. 
EMA PRO surveys
alone or with others, and activities and moods in the last hour. A pop-up visualization will signal 
participants, 3 times per day for 7 days, to respond to very brief (e.g., 3 minutes) questionnaires 
about their activities, mood, and symptom experiences during the last hour, per the Schedule of 
Assessments (Table 2). An abbreviated EMA PRO survey, collecting only information on the 
for 3 days starting on Day 4 and Day 15. Daily assessment times will be adjusted to 
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EMA Wellness - VLMT (US only)
Cognitive insight assessment will be conducted through testing on the Verbal Learning and 
Memory Test (VLMT), which will be completed by subjects enrolled at US sites only. This 
assessment will be performed at home on a cellular device 1 time per day for 2 days every 
28 days beginning on Day 32. During each VLMT administration, subjects will be presented 
with a list of 6- or 12-words over in 2 separate trials each lasting 30 seconds. Immediately 
following each exposure to the list, subjects will be shown target and recognition foil words 
one-by-one and asked to indicate whether or not the word appeared on the list. 
In order to examine response bias and the ability to self-evaluate memory performance, 
immediately after each recognition trial, the subjects will be asked to indicate how many words 
they believe that they got correct. They will also be asked how well they did as compared to the 
previous trial and at the end of the 2 trials they will be asked if they improved over the 2 learning 
trials.
Data Collected on EMAW Platform
Data are encrypted and uploaded to secure servers whenever the phone is connected to Wi-Fi or 
if cellular data is available. If a Wi-Fi and cellular data are unavailable, EMA response data will 
be transferred during in-clinic visits.
During each EMA PRO, subjects will be asked about their location (home vs away and where if 
away); they will also be asked if they are alone or with others, and about their activities, 
symptoms of schizophrenia, and moods in the last hour. 
Data collected during the VLMT include the identification of target words and rejections of foils. 
The participants will also provide an immediate estimate of their memory task performance as 
soon as each recognition trial is over.
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15 STATISTICAL ANALYSIS 
A statistical analysis plan (SAP) will be prepared after the protocol is approved. This document 
will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. The SAP will serve as a complement to the protocol 
and supersedes it in case of differences. 
The statistical evaluation will be performed using SAS® software version 9.4 or higher 
(SAS Institute, Cary, NC). All data will be listed, and summary tables will be provided. 
Summary statistics will be presented by dose group. For continuous variables, data will be 
summarized with the number of subjects (N), mean, standard deviation, median, minimum, and 
maximum by treatment group. For categorical variables, data will be tabulated with the number 
and proportion of subjects for each category by treatment group. No statistical hypothesis testing 
will be performed. 
15.1 Determination of Sample Size 
As the primary objective of this study is to assess the long-term safety and tolerability of KarXT, 
the number of subjects anticipated is based on the number of subjects recruited into and 
completing the acute studies (KAR-007, KAR-009) and meeting the eligibility requirements for 
KAR-008. 
15.2 Analysis Populations 
Enrolled population: All subjects who have given informed consent for KAR-008. 
Safety population: All subjects who receive at least 1 dose of KarXT during the current study 
will be included in the safety population and will be used in the safety analysis. 
Modified ITT (mITT) population: All subjects who are enrolled, received at least 1 dose of 
KarXT, and have a valid PANSS assessment at KAR-008 baseline will be included in the mITT 
population and will be used in the efficacy analysis. 
PK population: All subjects who have received at least 1 dose of KarXT and have at least 
1 measurable plasma concentration of KarXT will be included in the PK population. 
15.3 Safety Analysis 
Safety endpoints will be summarized for all subjects in the Safety population. The presentation 
of safety data will be based on the treatment received in KAR-008. 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 22.1 or higher. The incidence of TEAEs (defined as events with an onset 
date on or after the first dose of KarXT) will be summarized by System Organ Class and 
Preferred Term. All AEs will be listed by subject, along with information regarding onset, 
duration, relationship and severity to KarXT, action taken with KarXT, treatment of event, and 
outcome. 
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Orthostatic vital signs, clinical laboratory data, prolactin levels, ECG parameters, and physical 
examinations will be summarized using descriptive statistics, including observed and change 
from baseline values, as well as numbers of subjects with values outside limits of the normal 
range at each time point. Similar descriptive summaries will be provided for C-SSRS, SAS, 
BARS, AIMS, body weight, BMI, and waist circumference. 
15.4 Efficacy Analysis 
Efficacy analyses will be summarized based on the mITT population. The summaries described 
in this section will provide data on maintenance of effect of open-label KarXT over 52 weeks. 
As these variables are summarized over time and the initial values can be impacted by the 
treatment received in the acute study, the presentation will use a combination of acute/extension 
study treatment groups, which is intended to provide perspective on the change in these values 
from the acute study through the treatment period of KAR-008. Tabular presentations will 
display descriptive statistics for Baseline of the acute study and the observed and change from 
baseline study results by scheduled visit for KAR-008. 
Responder efficacy variables (PANSS responders) will be summarized descriptively. Response 
will be derived relative to the acute study Baseline assessment. 
Continuous efficacy variables based on the change from baseline (PANSS, CGI-S) will be 
summarized using descriptive statistics by scheduled visit. Tabular presentations will display 
descriptive statistics for the Baseline of the acute study and the observed and change from 
baseline results by scheduled visit for KAR-008. Figures for selected variables will also be 
generated in order to demonstrate the kinetics of response over time. 
15.5 Pharmacokinetic Analysis 
The PK evaluation will rely on an existing population PK model for KarXT in subjects with 
schizophrenia. The plasma concentrations of xanomeline and trospium measured in this study 
will be overlaid onto distributions of concentrations predicted by the population PK model 
developed from KAR-007 and KAR-009 data. Percentages of measured concentrations in the 
current study that lie within, above, and below the 90% prediction interval of concentrations 
predicted by the model will be calculated.   
Details of the PK analysis will be described in the SAP.   
15.6 Exploratory Analysis 
The following will be summarized using descriptive statistics: change in cognition using 
CANTAB; digital biomarkers of schizophrenia; EMA PRO and EMA VLMT.  
Further details will be provided in the SAP. 
15.7 Interim Analysis 
No interim analysis is planned for this study. 
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15.8 Handling of Missing Data 
For responder efficacy variables (PANSS responders), missing data may be handled by 
non-responder imputation, meaning that subjects who discontinue early or who have missing 
data at a given time point are imputed as though they did not achieve the given response. 
Supportive summaries will be based on observed case data. 
For continuous efficacy variables based on the change from baseline (PANSS, CGI-S), 
summaries will be based on observed case data.  
Additional methods of missing data imputation may be explored and will be outlined in the SAP. 
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16
STUDY MANAGEMENT
16.1 Approval and Consent
Regulatory Guidelines
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki and/or all relevant regulations, as set forth in Parts 50, 56, 312, Subpart D, of Title 21 of 
the US Code of Federal Regulations (CFR), in compliance with International Council for 
Harmonisation (ICH) and good clinical practice (GCP) guidelines, and all applicable local, state 
and federal government regulations and laws.
Institutional Review Board/Independent Ethics Committee
Conduct of the study must be approved by an appropriately constituted IEC/IRB. Approval is 
required for the study protocol, protocol amendments (if applicable), IB, ICFs, recruitment 
material and subject information sheets and other subject-facing material.
Informed Consent
For each study subject, written informed consent will be obtained before any protocol-related 
activities. As part of this procedure, the PI or designee must explain orally and in writing the 
nature of the study, its purpose, procedures, expected duration, alternative therapy available, and 
the benefits and risks involved in study participation. The subject should be informed that they
may withdraw from the study at any time, and the subject will receive all information that is 
required by local regulations and guidelines for ICH. The PI will provide the Sponsor or its 
representative with a copy of the IEC-/IRB-approved ICF before the start of the study.
The ICF should be revised whenever there are substantial changes to procedures or when new 
information becomes available that may affect the willingness of the subject to participate. 
Revisions to the consent form required during the study must be approved by the Sponsor and 
IEC/IRB, and a copy of the revised consent form is provided to the Sponsor. For any updated or 
revised consent forms, the subjects must be re-consented for continued participation in the study.
A pregnant partner consent form should be obtained before collecting any data from a female 
pregnant partner of a male subject, if she becomes pregnant during the course of the study or 
within 1 week of the last dose of KarXT.
A caregiver consent must be obtained (Ukraine only) before collecting any data from a caregiver 
pertaining to him or her and the subject.
Subject Registry (US only)
Clinical trial registries, such as clinical trial subject database (CTSdatabase) and Verified 
Clinical Trials (VCT) seek to reduce duplicate enrollment by identifying potential protocol 
violations and duplicate subjects before randomization. At the time of providing the informed 
consent for the initial KAR-007 or -009 study (US Only), the investigator or designee will have 
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explained the IRB/IEC-approved Subject Database Authorization to the subject and witnessed 
the signature. That executed authorization form remains in effect for KAR-007 and KAR-008 or 
KAR-009 and KAR-008 study participation. 
At the beginning of screening for KAR-007 or KAR-009 (US only), following consents 
execution and subject number assignment and before other study procedures, site staff that had 
received training and login information access (www.subjectregistry.com) to the database 
entered the subject study ID number and authorized subject identifiers. Two reports, one from 
CTS and one from VCT, detailing any potential protocol violations or dual enrollment attempts 
were generated and were printed for source documentation. The reports detailed each protocol 
violation detected and specific washout period dates where applicable.  
Throughout the initial KAR-007 or KAR-009 study, and during this open label extension study, 
tracking of actively enrolled subjects will continue based on updates by coordinators in the 
interactive response system.  At the last subject contact, CTSdatabase and VCT staff will 
automatically close out the subject (safety follow-up, ET, or completer) based on interactive 
response system (IXRS). 
16.2 Data Handling 
Any data to be recorded directly on the eCRFs (to be considered as source data) will be 
identified at the start of the study. Data reported on the eCRF that are derived from source 
documents should be consistent with the source documents, or the discrepancies must be 
explained. See also Section 16.3.  
Clinical data will be entered by site personnel on eCRFs for transmission to the Sponsor. Data on 
eCRFs transmitted via the web-based data system must correspond to and be supported by source 
documentation maintained at the study site unless the study site makes direct data entry to the 
databases for which no other original or source documentation is maintained. In such cases, the 
study site should document which eCRFs are subject to direct data entry and should have in 
place procedures to obtain and retain copies of the information submitted by direct data entry. 
All study forms and records transmitted to the Sponsor must only include coded identifiers such 
that directly identifying personal information is not transmitted. The primary method of data 
transmittal is via the secure, internet-based electronic data capture (EDC) system maintained by 
Syneos Health. Access to the EDC system is availa
secure internet web site, where a user unique assigned username and password are required for 
access. 
Any changes made to data after collection will be made through the use of the EDC system. 
Electronic CRFs will be considered complete when all missing and/or incorrect data have been 
resolved. 
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16.3 Source Documents 
Source documents are considered to be all information in original records and certified copies of 
original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. The investigator will provide direct 
access to source documents and/or source data in the facilitation of trial-related monitoring, 
audits, review by IECs/IRBs, and regulatory inspections. 
The investigator/institution should maintain adequate and accurate source documents and trial 
subjects. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, not obscure the original entry, and be explained if necessary. 
Data recorded on source documents will be transcribed onto eCRFs. Copies of completed eCRFs 
will be provided to the Sponsor and the sites at the end of the study. The completed eCRFs will 
be retained by the investigator. 
16.4 Record Retention 
Study records and source documents must be preserved for at least 15 years after the completion 
or discontinuation of/withdrawal from the study, at least 2 years after the drug being studied has 
received its last approval for sale, or at least 2 years after the drug development has stopped, and 
in accordance with the applicable local privacy laws, whichever is the longer time period. 
The investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subject health information, including, but not limited to, the 
Standards for Individually Identifiable Health Information, 45 CFR, Parts 160 and 164 (the 
HIPAA of 1996 Privacy Regulation). The investigator shall ensure that study subjects authorize 
the use and disclosure of protected health information in accordance with HIPAA Privacy 
Regulation and in a form satisfactory to the Sponsor. 
16.5 Monitoring 
The study will be monitored according to the KAR-008 monitoring plan to ensure that it is 
conducted and documented properly according to the protocol, GCP, and all applicable 
regulatory requirements. 
Monitoring visits may include on-site or remote visits and may also utilize periodic telephone 
contacts. The PI will assure they and adequate site personnel are available throughout the study 
to collaborate with clinical monitors. Clinical monitors must have direct access to source 
documentation in order to check the completeness, clarity, and consistency of the data recorded 
in the eCRFs for each subject. 
The investigator will make available to the clinical monitor all source documents and medical 
records necessary to review protocol adherence and eCRFs. In addition, the investigator will 
work closely with the clinical monitor and as needed, provide them appropriate evidence that the 
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study is being conducted in accordance with the protocol, applicable regulations, and GCP
guidelines.
16.6 Quality Control and Quality Assurance
The Sponsor or its designee will perform the quality assurance and quality control activities of 
this study; however, responsibility for the accuracy, completeness, security, and reliability of the 
study data presented to the Sponsor lies with the investigator generating the data.
The Sponsor or its designee will arrange audits as part of the implementation of quality 
assurance to ensure that the study is being conducted in compliance with the protocol, standard 
operating procedures, GCP, and all applicable regulatory requirements. Audits will be 
independent of and separate from the routine monitoring and quality control functions. Quality 
assurance procedures will be performed at study sites and during data management to assure that 
safety and efficacy data are adequate and well documented.
16.7 Protocol Amendment and Protocol Deviation
Protocol Amendment
Amendments to the protocol that entail corrections of typographical errors, clarifications of 
confusing wording, changes in study personnel, and minor modifications that have no effect on 
the safety of subjects or the conduct of the study will be classed as administrative amendments 
and will be submitted to the IEC/IRB for information only. Syneos Health will ensure that 
acknowledgement is received and filed. Amendments that are classed as substantial amendments 
must be submitted to the appropriate regulatory authorities and the IECs/IRBs for approval and 
will not be implemented at sites until such approvals are received, other than in the case of an 
urgent safety measure.
Protocol Deviations
Should a protocol deviation occur, the Sponsor must be informed as soon as possible. Protocol 
deviations and/or violations and the reasons they occurred will be included in the clinical study 
report. Reporting of protocol deviations to the IEC/IRB and in accordance with applicable 
All protocol deviations will be tracked in the Clinical Trial Management System.
Deviations considered major will be identified as such before study unblinding during 
medical monitor periodic review.
Major protocol deviations will be tabulated including the frequency and percentage of subjects 
with each type of deviation by treatment group.
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16.8 Ethical Considerations 
This study will be conducted in accordance with this protocol, the accepted version of the 
Declaration of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, 
Subpart D, of Title 21 of the CFR; and in compliance with GCP guidelines. 
IECs/IRBs will review and approve this protocol and the ICF. All subjects and/or caregivers 
(Ukraine only) are required to give written informed consent before participation in the study. 
16.9 Financing and Insurance 
Before the study commences, the Sponsor (or its designee) and the investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study. This agreement will 
be documented in a financial agreement that will be signed by the investigator (or the institution 
signatory) and the Sponsor (or its designee). 
The investigator is required to have adequate current insurance to cover claims for negligence 
and/or malpractice (US only). The Sponsor will provide no-exclusion insurance coverage for the 
clinical study as required by national regulations. 
16.10 Publication Policy/Disclosure of Data 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Intellectual property rights (and related matters) generated by the investigator and others 
performing the clinical study will be subject to the terms of a clinical study agreement that will 
be agreed between the institution and the Sponsor or their designee. With respect to such rights, 
the Sponsor or its designee will solely own all rights and interests in any materials, data, and 
intellectual property rights developed by investigators and others performing the clinical study 
described in this protocol, subject to the terms of any such agreement. In order to facilitate such 
ownership, investigators will be required to assign all such inventions either to their institution or 
directly to the Sponsor or its designee, as will be set forth in the clinical study agreement. 
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17 REFERENCES 
1. Patel KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: overview and treatment options. P 
T. 2014;Sep 39(9):638-645. 
2. van Os J, Kapur S. Schizophrenia. Lancet. 2009 Aug 22;374(9690):635-645. 
3. Wu EQ, Shi L, Birnbaum H, Hudson T, Kessler R. Annual prevalence of diagnosed 
schizophrenia in the USA: a claims data analysis approach. Psychol Med. 2006 
Nov;36(11):1535-1540. 
4. Crismon L, Argo TR, Buckley PF. Schizophrenia. In: DiPiro JT, Talbert RL, Yee GC, et al., 
editors. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, New York: 
McGraw-Hill; 2014:1019-1046. 
5. Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome 
in schizophrenia: implications for MATRICS. Schizophr Res. 2004;72(1):41-51. 
6. Huhn M, Nikolakopoulou A, Schnider-Thoma J, et al. Comparative efficacy and tolerability 
of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a 
systematic review and network meta-analysis. Lancet. 2019;394(10202):939-951. 
7. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients 
with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223. 
8. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 
15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 
2013;382(9896):951-962. 
9. Emsley R, Chiliza B, Asmal L, Harvey BH. The nature of relapse in schizophrenia. BMC 
Psychiatry. 2013;13:50. 
10. Kahn RS, Sommer IE, Murray RM, et al. Schizophrenia. Nat Rev Dis Primers. 
2015;1:15067. 
11. Sellin AK, Shad M, Tamminga, C. Muscarinic agonists for the treatment of cognition in 
schizophrenia. CNS Spectr. 2008 Nov;13(11):985-996. 
12. Wess J, Eglen RM, Gautam D. Muscarinic acetylcholine receptors: mutant mice provide new 
insights for drug development. Nat Rev Drug Discov. 2007 Sep;6:(9):721-733. 
13. Mirza NR, Peters D, Sparks RG. Xanomeline and the antipsychotic potential of muscarinic 
receptor subtype selective agonists. CNS Drug Rev. 2003 Summer;9(2):159-186. 
14. Thorn CA, Moon J, Bourbonais CA, et al. Striatal, hippocampal, and cortical networks are 
differentially responsive to the M4- and M1-muscarinic acetylcholine receptor mediated 
effects of xanomeline. ACS Chem Neurosci. 2019;10(8):3910. 
15. Farde L, Suhara T, Halldin C, et al. PET study of the M1-agonists [11C]xanomeline and 
[11C]butylthio-TZTP in monkey and man. Dementia. 1996;7(4):187-195. 
16. Bodick NC, Offen WW, Levey AI, et al. Effect of xanomeline, a selective muscarinic 
receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch 
Neurol. 1997;54(4):465-473. 
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17. Bodick NC, Offen WW, Shannon HE, et al. The selective muscarinic agonist xaqnomeline 
Alzheimer Dis Assoc Disord. 1997; 11 Suppl 4:S16-22. 
18. Shekhar A, Potter WZ, Lightfoot J, et al. Selective muscarinic receptor agonist xanomeline 
as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008 Aug;165(8):1033-
1039. 
19. Staskin D, Sand P, Zinner N, Dmochowski R, Trospium Study Group. Once daily trospium 
chloride is effective and well tolerated for the treatment of overactive bladder; results from a 
multicenter phase III trial. J Urol. 2007;178(3 Pt 1):978-983; discussion 983-984. 
20. Scheife R, Takeda M. Central nervous system safety of anticholinergic drugs for the 
treatment of overactive bladder in the elderly. Clin Ther. 2005;27(2):144-153. 
21. Brannan SK, Paul SM and Breier A. Xanomeline plus trospium: A novel strategy to enhance 
pro-muscarinic efficacy and mitigate peripheral side effects. Proceedings of the ASCP annual 
meeting 2019. 
22. [HMA] Heads of Medicines Agencies. Clinical Trial Facilitation Group page. 
Recommendations related to contraception and pregnancy testing in clinical trials. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
September 15, 2014. Accessed 27 Mar 2020. 
23. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989 
May;154 (5):672-676. 
24. Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm 
of Suicide Assessment (C-
suicidal risk analysis of antidepressants. Am J Psychiatry. 2007 Jul;164(7):1035-1043. 
25. Chatoor D, Emmanuel A. Constipation and evacuation disorders. Best Pract Res Clin 
Gastroenterol. 2009;23(4):517-530. 
26. Constipation. National Institute of Diabetes and Digestive and Kidney Diseases. 
https://www.niddk.nih.gov/health-information/digestive-diseases/constipation/all-content. 
February 2015. Accessed 28 Mar 2020. 
27. American Gastroenterological Association, Bharucha AE, Dorn SD, Lembo A, Pressman A. 
American Gastroenterological Association medical position statement on constipation. 
Gastroenterology. 2013 Jan;144(1):211-217. 
28. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional 
bowel disorders. Gastroenterology. 2006 Apr;130(5):1480-1491. 
29. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol. 1997 Sep;32(9):920-924. 
30. Locke GR III, Pemberton JH, Phillips SF. American Gastroenterological Association 
Medical Position Statement: guidelines on constipation. Gastroenterology. 2000 
Dec;119(6):1761-1766. 
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31. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr Bull. 1987;13(2):261-276. 
32. Guy W. EDCEU Assessment Manual for Psychopharmacology  Revised. Rockville, MD, 
US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug 
Abuse, and Mental Health Administration, NIMH Psychopharmacology Research Branch, 
Division of Extramural Research Programs, 1976:534-7. DHEW Publication No ADM 
76-338. 
33. Buchanan RW, Davis M, Goff D, et al. A summary of the FDA-NIMH-MATRICS workshop 
on clinical trial design for neurocognitive drugs for schizophrenia. Schizophrenia Bulletin. 
2005 Jan;31(1):5-19. 
 
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18 APPENDICES 
Appendix 1: Contraception Guidelines 
Female subjects of childbearing potential with a non-sterilized male sexual partner must agree to 
use at least 1 highly effective method of contraception (eg, hormonal or double barrier method of 
birth control, or intrauterine device) beginning >30 days before receiving study drug on Day 1 
and continuing until 30 days after the End of Study (EOS) Visit. If oral contraceptives are used, 
the subject must have been on a stable dose for 6 months. 
 
A woman is considered to be WOCBP following menarche and until becoming postmenopausal, 
unless she is permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy [22]. Female subjects who are postmenopausal, 
which is defined as 12 consecutive months with no menses without an alternative medical cause, 
must have been postmenopausal for >1 year if they wish to not use contraceptives. 
-stimulating hormone 
(FSH) level which must be elevated and consistent with postmenopausal levels (ie, >40 IU/L); 
otherwise, these subjects must agree to use contraceptives listed below. Female subjects who are 
surgically sterile (ie, hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) will not 
need to undergo the FSH level test. 
 
A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
Highly effective methods of contraception are those that have a failure rate of <1% (when 
implemented consistently and correctly) and include the following: 
 combined (containing estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation (administration may be oral, intravaginal, or transdermal) 
 progestogen-only hormonal contraception associated with inhibition of ovulation 
(administration may be oral, injectable, or implantable) 
 intrauterine device 
 intrauterine hormone-releasing system 
 bilateral tubal ligation or occlusion 
 vasectomy (provided that the male has a medical assessment of surgical success) 
All subjects will be strongly advised that they (or the female partners of male subjects) should 
not become pregnant before receiving study drug on Day 1 and continuing until 30 days after the 
End of Study Visit. A female subject will be advised that she must report immediately to the 
study site for pregnancy testing and appropriate management in the event that she may be 
pregnant. 
 
 
 
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Appendix 2: Functional Constipation Inquiry 
 
 
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1 
FINAL CLINICAL STUDY PROTOCOL  
 
Karuna Therapeutics 
Protocol Title: An Open-label Extension Study to Assess the Long-term Safety, 
Tolerability, and Efficacy of KarXT in Subjects with DSM-5 Schizophrenia 
 
Protocol Number: KAR-008 
 
IND Number: 
127471 
EudraCT Number: 
Not applicable 
Name of Investigational Product: 
KarXT 
Phase of Development: 
Phase 3 
Indication: 
Schizophrenia 
Sponsor: 
Karuna Therapeutics 
99 High St. 
Floor 26 
Boston, MA 02110 
Tel: 
 
Email: 
 
Protocol Version:  
Version 4.0 
Protocol Date: 
11 Jan 2022 
 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to Karuna Therapeutics. Any unauthorized 
copying or use of this document is prohibited. 
 
 
 
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PROTOCOL APPROVAL SIGNATURES
Protocol Title:
An Open-label Extension Study to Assess the Long-term Safety,
Tolerability, and Efficacy of KarXT in Subjects with DSM-5 
Schizophrenia
Protocol Number:
KAR-008
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Council for Harmonisation (ICH) guidelines for 
current Good Clinical Practice (GCP), and applicable regulatory requirements.
Sponsor Signatory
Karuna Therapeutics
Signature
Date
Karuna Therapeutics
Signature
Date (DD-Mmm-YYYY)
Contract Research Organization Signatory 
Syneos Health
Signature
Date 
Biostatistician
Veristat
Signature
Date (DD-Mmm-YYYY)
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INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
An Open-label Extension Study to Assess the Long-term Safety, Tolerability, 
and Efficacy of KarXT in Subjects with DSM-5 Schizophrenia 
Protocol Number: 
KAR-008 
Confidentiality and Current Good Clinical Practice (GCP)/E6(R2) Compliance Statement  
 I, the undersigned, have reviewed this protocol (and amendments), including appendices, 
and I will conduct the study as described in compliance with this protocol (and 
amendments), and relevant International Council for Harmonisation (ICH) guidelines 
including GCP and applicable regulatory requirements. 
 I am thoroughly familiar with the appropriate use of the KarXT, as described in this 
protocol and any other information provided by Karuna Therapeutics including, but not 
limited to, the current investigator
. 
 Prior to initiating the trial, I will provide the independent ethics committee 
(IEC)/institutional review board (IRB) all items subject to review and will obtain a 
written and dated approval/favorable opinion. Once the protocol has been approved by 
the IEC/IRB, I will not modify this protocol without obtaining prior approval of Karuna 
Therapeutics and of the IEC/IRB. I will submit the protocol amendments and/or any 
informed consent form modifications to Karuna Therapeutics and the IEC/IRB, and 
approval will be obtained before any amendments are implemented. 
 I ensure that all persons or party assisting me with the study are adequately qualified and 
informed about the Karuna Therapeutics KarXT and of their delegated study-related 
duties and functions as described in the protocol. I will supervise these delegated persons 
or parties in the conduct of this trial. 
 I ensure that source documents and trial records that include all pertinent observations on 
utable, legible, contemporaneous, original, 
accurate, and complete.  
 I understand that all information obtained during the conduct of the study with regard to 
the 
 state of health will be regarded as confidential. No 
 names will be 
disclosed. All subjects will be identified by assigned numbers on all case report forms, 
laboratory samples, or source documents forwarded to the Sponsor. Clinical information 
may be reviewed by the Sponsor or its agents or regulatory agencies. Agreement must be 
obtained from the subject before disclosure of subject information to a third party. 
 Information developed in this clinical study may be disclosed by Karuna Therapeutics to 
other clinical investigators, regulatory agencies, or other health authority or government 
agencies as required. 
<Name> 
 
<Title> 
Investigator Signature 
 
 
 
Date (DD-Mmm-YYYY) 
 
 
Institution 
 
 
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2 
SYNOPSIS 
Title of Study: 
An Open-label Extension Study to Assess the Long-term Safety, 
Tolerability, and Efficacy of KarXT in Subjects with DSM-5 Schizophrenia 
Protocol Number: 
KAR-008 
Investigators/Study Sites: 
Approximately 30 study sites in the United States and 10 study sites in 
Ukraine 
Phase of Development: 
Phase 3 
Objective(s): 
Primary Objective: 
The primary objective of the study is to assess the long-term safety and 
tolerability of KarXT in subjects with a Diagnostic and Statistical 
Manual-Fifth Edition (DSM-5) diagnosis of schizophrenia. 
Secondary Objectives: 
The secondary objective of this study is to assess the long-term efficacy and 
evaluate plasma concentrations of xanomeline and trospium after 
administration of KarXT in adults with a DSM-5 diagnosis of 
schizophrenia: 
 
To evaluate the reduction in Positive and Negative Syndrome Scale 
(PANSS) total score 
 
To evaluate the reduction in PANSS positive score  
 
To evaluate the improvement in Clinical Global Impression Severity 
(CGI-S) results  
 
To evaluate the reduction in PANSS negative score  
 
To evaluate the reduction in PANSS Marder Factor negative 
symptoms score 
 
Exploratory Objectives: 
The exploratory objectives of this study are: 
 
To evaluate cognition with the Cambridge Neuropsychological Test 
Automated Battery (CANTAB) 
 
To evaluate prolactin levels after administration of KarXT 
 
To characterize outcomes obtained from digital biomarkers, 
ecological momentary assessment administered patient reported 
outcomes (EMA PRO), and an EMA administered verbal learning and 
memory test (EMA VLMT) in schizophrenia 
Study Endpoints: 
Primary safety endpoint:  
The primary safety endpoint is the incidence of treatment-emergent adverse 
events (TEAEs) 
 
Secondary safety endpoints: 
The secondary safety endpoints of the study are: 
 
Incidence of serious TEAEs 
 
Incidence of TEAEs leading to withdrawal 
 
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Secondary efficacy endpoints:
The secondary efficacy endpoints of the study are: 
 
Change from baseline in PANSS total score at Week 52 
 
Change from baseline in PANSS positive score at Week 52 
 
Change from baseline in PANSS negative score at Week 52 
 
Change from baseline in PANSS Negative Marder Factor score at 
Week 52 
 
Change from baseline in CGI-S score at Week 52 
 
Percentage of PANSS responders (a 30% reduction in PANSS total 
score) at Week 52  
Other Endpoints:  
Safety endpoints: 
The other safety endpoints of the study are: 
 
Spontaneously reported adverse events of special interest (AESIs) 
 
Spontaneously reported procholinergic and anticholinergic symptoms 
 
Change from baseline in Simpson-Angus Rating Scale (SAS) 
 
Change from baseline in Barnes Rating Scale for Akathisia (BARS) 
 
Change from baseline in Abnormal Involuntary Movement Scale 
(AIMS) 
 
Change from baseline in body weight, body mass index (BMI), waist 
circumference  
 
Change from baseline in orthostatic vital signs (supine and standing 
after 2 minutes): blood pressure (systolic and diastolic) and heart rate 
 
Change from baseline in clinical laboratory assessments (hematology, 
clinical chemistry, coagulation, urinalysis, and drug screen) 
 
Change from baseline in 12-lead electrocardiogram (ECG)  
 
Change from baseline in physical examination  
 
Suicidal ideation scale with the use of Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
Pharmacokinetic Endpoint: 
 
Comparison of the plasma concentrations of xanomeline and trospium 
measured in this study to the plasma concentrations predicted by a 
population pharmacokinetic (PK) model of studies KAR-007 and 
KAR-009 
Exploratory Endpoints: 
The exploratory endpoints of the study are:  
 
Change from baseline in cognition measuring core domains of 
impairment in schizophrenia using CANTAB 
 
Change from baseline in prolactin levels 
 
Observed digital biomarkers of schizophrenia (US only) 
 
Observed EMA PRO in schizophrenia (US only) 
 
Observed cognitive insight using EMA VLMT in schizophrenia (US 
only) 
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Study Design:
This is a Phase 3 multicenter, 53-week, outpatient, open-label extension 
(OLE) study to evaluate the long-term safety, tolerability, and efficacy of 
KarXT in subjects with DSM-5 schizophrenia who previously completed 
the treatment period of one of the two Phase 3 double-blind studies, 
KAR-007 or KAR-009. The study consists of a 52-week OLE treatment 
phase and a 7-day (±3 days) safety follow-up/end-of-study visit after the 
last KarXT dose for subjects who complete the treatment phase and those 
who prematurely discontinue from the study.  
After written informed consent, subjects who have completed the KAR-007 
or KAR-009 Phase 3 acute study and received the last dose of the study 
drug in that trial will be rolled over into the current OLE study. The 
assessments performed on Visit 10 (Day 35) of studies KAR-007 or 
KAR-009 will be considered as baseline assessments along with any 
additional procedures that will be performed on Day 0 of the current study. 
Any scheduled Day 0 assessments that were not completed on Day 35 of 
the acute study (KAR-007 or KAR-009) must be completed on Day 0 of the 
current study.  
It is preferable that Baseline/Day 0 procedures of the current study be 
completed on the same day as Day 35 of the acute study after all Visit 10 
(Day 35) procedures of the prior study KAR-007 or KAR-009 have been 
completed. However, with medical monitor approval, an extension of up to 
3 days can be granted to complete Baseline/Day 0 procedures. This 
extension cannot be completed inpatient.  
With medical monitor approval, participants may be permitted to complete 
the first 3 days (Visit 1/Day 1 to Visit 2/Day 3) of KAR-008 on the 
inpatient unit.  
Twice-daily dosing with KarXT will commence in the morning of Day 1. 
Subjects who did not complete the full treatment period, or who early 
terminated study KAR-007 or KAR-009, will not be eligible to enroll in 
this long-term extension study.  
Approximately 350 subjects are planned to be enrolled in this study (aged 
18 to 65 years) across approximately 30 study sites in the United States and 
10 study sites in Ukraine. 
In this OLE study, all subjects will receive KarXT for up to 52 weeks. 
Regardless of treatment assignment in the preceding Phase 3 acute study 
(KAR-007 or KAR-009), all subjects will start on a lead-in dose of KarXT 
50/20 (50 mg xanomeline/20 mg trospium) 2 times per day (BID) for the 
first 2 days (Days 1 and 2), followed by KarXT 100/20 BID for the 
remainder of Week 1 (Days 3 to 7). At Visit 3 (Day 8), dosing will be 
titrated upwards to KarXT 125/30 BID unless the subject is continuing to 
experience adverse events (AEs) from the previous dose of KarXT 100/20 
BID. All subjects who are increased to KarXT 125/30 BID, depending on 
tolerability, will have the option to return to KarXT 100/20 BID. 
Re-escalation to 125/30 BID or re-titration in cases in which the subject has 
been off KarXT for a longer period of time (at least a week) is allowed and 
will require a discussion between the principal investigator and the medical 
monitor. Additional changes to KarXT dosing (e.g., temporary dose 
reductions) may be permitted as clinically indicated upon approval by the 
medical monitor.  
Beginning after Visit 9/Day 84, interim visits will be completed with 
flexibility between in-clinic visits, and approximately once every 4 weeks 
thereafter. Whenever possible, interim visits should be conducted by 
telemedicine; however, sites will have the option to schedule on-site interim 
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visits, and are encouraged to use additional unscheduled visits as necessary, 
to facilitate subject retention and ensure adherence to study objectives. 
A safety follow-up/end-of-study visit (Visit 30/Day 371 ±3 days) will be 
performed for all subjects after the last dose of KarXT. 
An Independent Safety Monitoring Committee will be responsible for 
periodically reviewing the safety data from this study and confirming that 
the study may continue. 
Study Population: 
Inclusion Criteria:  
Individuals must meet all of the following criteria to be included in the 
study: 
1. Subject is aged 18 to 65 years, at time of enrollment into the preceding 
acute study (KAR-007 or KAR-009).  
2. Subject is capable of providing informed consent.  
3. A signed informed consent form must be provided before any study 
assessments are performed. 
 
Subject must be fluent in (oral and written) English (United 
States only) or local language (Ukraine only) to consent. 
4. Subject has completed the treatment period on study drug (through 
Day 35 -2 days) of studies KAR-007 or KAR-009.  
5. Subject resides in a stable living situation, in the opinion of the 
investigator. 
6. Subject has an identified, reliable informant/caregiver willing to be 
able to address some questions related to certain study visits, if 
needed.   An informant/caregiver may not be necessary if the subject 
 
7. Women of childbearing potential (WOCBP) or men whose sexual 
partners are WOCBP must be willing and able to adhere to the 
contraception guidelines as defined in Section 8.4.1 and Appendix 1. 
Exclusion Criteria: 
Subjects will be excluded from the study if 1 or more of the following 
criteria is/are applicable: 
1. 
Risk for suicidal behavior during the study as determined by the 
-SSRS as confirmed by the 
following:  
a. 
Subject answers 
suicidal ideation with some intent to act, without specific 
plan) or Item 5 (active suicidal ideation with specific plan and 
intent) on the C-SSRS.  
b. Nonsuicidal self-injurious behavior is not exclusionary. 
2. 
Any clinically significant abnormality, including any finding(s) from 
the physical examination, vital signs, ECG, or laboratory test at the 
end-of-treatment visit of Studies KAR-007 or KAR-009 that the 
investigator, in consultation with the medical monitor, would consider 
to jeopardize the safety of the subject. 
3. 
Female subject is pregnant, breast feeding or planning to become 
pregnant during the course of the study. 
4. 
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 
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safety of the subject or affect his/her ability to adhere to the protocol 
visit schedule or fulfill visit requirements. 
5. 
Subjects with extreme concerns relating to global pandemics such as 
coronavirus disease 2019 (COVID-19) that preclude study 
participation. 
6. 
Risk of violent or destructive behavior. 
7. 
Subjects participating in another investigational drug or device trial or 
planning on participating in another clinical trial during the course of 
the study. 
Planned Sample Size: 
Approximately 350 subjects are planned to be enrolled in this study.  
Investigational Therapy: 
1. Fixed dose KarXT 50/20 BID (50 mg xanomeline/20 mg trospium) 
oral (Days 1 to 2) 
2. Fixed dose KarXT 100/20 BID (100 mg xanomeline/20 mg trospium) 
oral (Days 3 to 7) 
3. Fixed dose KarXT 125/30 BID (125 mg xanomeline/30 mg trospium) 
oral (Days 8 to 364, if tolerated)  
Reference Therapy: 
Not applicable. 
Treatment Duration: 
Total study duration is up to 53 weeks, including a 52-week treatment 
phase and a 7-day follow-up/end-of-study phase. 
Safety assessments: 
Spontaneous AEs including AESIs; procholinergic and anticholinergic 
symptoms, serious AEs (SAEs) and AEs leading to discontinuation of 
KarXT; SAS; BARS; AIMS; body weight; BMI; waist circumference; 
orthostatic vital signs; clinical laboratory assessments (hematology, clinical 
chemistry, coagulation, urinalysis, and drug screen); 12-lead ECG; physical 
examination; and C-SSRS will be evaluated throughout the study as 
scheduled. 
Efficacy assessments: 
PANSS total score, PANSS positive score, PANSS negative score, PANSS 
Negative Marder Factor score, and CGI-S score will be evaluated at 
scheduled visits. 
Pharmacokinetic assessment: 
Blood samples will be collected at scheduled visits for bioanalysis of 
plasma concentrations of xanomeline and trospium, and will be compared 
to the plasma concentrations predicted by a population pharmacokinetic 
(PK) model of studies KAR-007 and KAR-009. 
Exploratory assessments 
Cognition testing using CANTAB; prolactin levels; digital biomarkers of 
schizophrenia; EMA PRO and EMA VLMT will be evaluated during 
scheduled visits or on specified study days.  
Statistical Methods and 
Planned Analyses: 
Study Populations: 
Enrolled population: All subjects who have given informed consent for 
KAR-008. 
Safety population: All subjects who receive at least 1 dose of KarXT during 
the current study will be included in the safety population and will be used 
in the safety analysis. 
Modified ITT (mITT) population: All subjects who are enrolled, received at 
least 1 dose of KarXT during the current study, have a valid post-baseline 
PANSS assessment will be included in the mITT population and will be 
used in the efficacy analysis. 
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PK population: All subjects who have received at least 1 dose of KarXT 
and have at least 1 measurable plasma concentration in the current study 
will be included in the PK population. 
The primary safety endpoint of the study is the incidence of TEAEs. 
Secondary safety endpoints are the incidence of serious TEAEs and the 
incidence of TEAEs leading to withdrawal of KarXT.  
The secondary efficacy endpoints are change from baseline to Week 52 in 
the PANSS total score, PANSS positive score, PANSS negative score, 
PANSS Negative Marder Factor score, CGI-S score, and the percentage of 
PANSS responders at Week 52.  
The exploratory endpoints of the study are change from baseline in 
cognition (CANTAB), prolactin levels, digital biomarkers, EMA PRO, and 
EMA VLMT. 
Descriptive statistics will be used to provide an overview of the safety and 
efficacy results. For continuous parameters, descriptive statistics will 
include n, mean, median, standard deviation, minimum and maximum; For 
categorical parameters, the number and percentage of subjects in each 
category will be presented. The denominator for percentages will be based 
on the number of subjects appropriate for the purposes of analysis. No 
statistical hypothesis testing will be performed. 
 
 
 
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3
TABLE OF CONTENTS
1
FINAL CLINICAL STUDY PROTOCOL ...................................................................1
2
SYNOPSIS........................................................................................................................4
3
TABLE OF CONTENTS..............................................................................................10
3.1
List of In-text Tables ..................................................................................................14
3.2
List of In-text Figures.................................................................................................14
4
LIST OF ABBREVIATIONS.......................................................................................15
5
INTRODUCTION .........................................................................................................18
5.1
Background on Schizophrenia....................................................................................18
5.2
Background on KarXT (Xanomeline Tartrate and Trospium Chloride)....................18
Nonclinical Studies ............................................................................................20
Completed Clinical Studies................................................................................23
5.3
Clinical Risks/Benefits of KarXT and Study Rationale.............................................32
6
STUDY OBJECTIVES AND ENDPOINTS ...............................................................35
6.1
Study Objectives.........................................................................................................35
Primary Objective ..............................................................................................35
Secondary Objectives.........................................................................................35
Exploratory Objectives ......................................................................................35
6.2
Study Endpoints..........................................................................................................35
Primary Safety Endpoint....................................................................................35
Secondary Endpoints..........................................................................................35
6.2.2.1
Safety Endpoints ..........................................................................................35
6.2.2.2
Efficacy Endpoints .......................................................................................36
Other Endpoints .................................................................................................36
6.2.3.1
Safety Endpoints ..........................................................................................36
6.2.3.2
Pharmacokinetic Endpoint ...........................................................................36
6.2.3.3
Exploratory Endpoints..................................................................................36
7
INVESTIGATIONAL PLAN .......................................................................................38
7.1
Description of Overall Study Design and Plan...........................................................38
7.2
Discussion of Study Design........................................................................................41
7.3
End of Study...............................................................................................................41
7.4
Independent Safety Monitoring Committee ...............................................................42
8
SELECTION OF STUDY POPULATION.................................................................43
8.1
Inclusion Criteria........................................................................................................43
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8.2
Exclusion Criteria.......................................................................................................43
8.3
Safety Laboratory Evaluations for Eligibility ............................................................44
8.4
Study Withdrawal, Removal, and Replacement of Subjects......................................44
Pregnancy...........................................................................................................45
8.5
Completion of the Study or Lost to Follow-up ..........................................................46
8.6
Study Termination......................................................................................................47
9
TREATMENTS .............................................................................................................48
9.1
Details of Study Treatments .......................................................................................48
Identity of Study Treatments..............................................................................48
Packaging and Labeling.....................................................................................48
KarXT Storage ...................................................................................................49
KarXT Retention................................................................................................49
9.2
Dosage Schedule ........................................................................................................49
Day 0..................................................................................................................49
Visit 1/Day 1 Dosing..........................................................................................50
Visit 2/Day 3 Dosing..........................................................................................50
Visit 3/Day 8 ......................................................................................................50
Visit 4/Day 14 Dosing and PK Considerations..................................................51
Visits 5 to 8 (Days 28 to 70) Dosing..................................................................51
Visits 9 to 29 (Days 84 to 364) Dosing..............................................................51
9.3
Measures to Minimize Bias: Study Treatment Assignment .......................................52
Method of Study Treatment Assignment...........................................................52
Blinding..............................................................................................................52
9.4
Dosage Modification ..................................................................................................52
Extended Dosing Interruptions and Re-titration ................................................52
9.5
Treatment Accountability and Compliance................................................................52
9.6
Prior and Concomitant Therapy .................................................................................53
Prior and Concomitant Medications ..................................................................53
Concomitant Medications for Anxiety and/or Sleep Aid...................................53
10
STUDY PROCEDURES...............................................................................................55
10.1
Informed Consent .......................................................................................................62
10.2
Study Procedures........................................................................................................62
AiCure Adherence Technology .........................................................................62
11
SAFETY ASSESSMENTS............................................................................................65
11.1
Demographics, Medical History, and Psychiatric History .........................................65
11.2
Vital Signs ..................................................................................................................65
11.3
Complete/Targeted Physical Examination .................................................................65
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11.4
Weight, Height, Body Mass Index, and Waist Circumference ..................................66
11.5
Electrocardiograms.....................................................................................................66
11.6
Laboratory Assessments.............................................................................................66
11.7
Adverse Events...........................................................................................................68
Adverse Events ..................................................................................................68
Adverse Events of Special Interest ....................................................................70
Serious Adverse Events .....................................................................................70
Serious Adverse Event Reporting......................................................................70
Drug-Induced Liver Injury.................................................................................71
11.7.5.1
Trial Discontinuation Criteria Other than DILI and Pregnancy...................72
11.7.5.2
Individual Stopping Criteria.........................................................................72
11.7.5.3
Trial Stopping Rules.....................................................................................72
Suspected Unexpected Serious Adverse Reactions ...........................................73
Warnings and Precautions..................................................................................73
11.8
Pregnancy ...................................................................................................................74
11.9
Overdose.....................................................................................................................75
11.10 Simpson-Angus Rating Scale.....................................................................................76
11.11 Barnes Rating Scale for Akathisia..............................................................................76
11.12 Abnormal Involuntary Movement Scale ....................................................................76
11.13 Columbia-Suicide Severity Rating Scale ...................................................................76
11.14 Functional Constipation Inquiry.................................................................................76
12
EFFICACY ASSESSMENTS.......................................................................................78
12.1
Positive and Negative Syndrome Scale......................................................................78
12.2
Clinical Global Impression-Severity..........................................................................78
13
PHARMACOKINETICS..............................................................................................79
13.1
Pharmacokinetic Sampling.........................................................................................79
PK Blood Samples and Timing..........................................................................79
13.2
Pharmacokinetic Analytical Methodology.................................................................79
14
EXPLORATORY ASSESSMENTS ............................................................................80
14.1
Cognition Testing - Cambridge Neuropsychological Test Automated Battery .........80
14.2
Change in Prolactin ....................................................................................................80
14.3
Digital Biomarkers of Schizophrenia (US only) ........................................................81
14.4
EMA Wellness Assessments......................................................................................81
EMA Wellness EMA PRO (US only).............................................................81
EMA Wellness - VLMT (US only)....................................................................82
Data Collected on EMAW Platform ..................................................................82
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15
STATISTICAL ANALYSIS.........................................................................................83
15.1
Determination of Sample Size....................................................................................83
15.2
Analysis Populations ..................................................................................................83
15.3
Safety Analysis...........................................................................................................83
15.4
Efficacy Analysis........................................................................................................84
15.5
Pharmacokinetic Analysis ..........................................................................................84
15.6
Exploratory Analysis..................................................................................................84
15.7
Interim Analysis .........................................................................................................84
15.8
Handling of Missing Data ..........................................................................................85
16
STUDY MANAGEMENT ............................................................................................86
16.1
Approval and Consent ................................................................................................86
Regulatory Guidelines........................................................................................86
Institutional Review Board/Independent Ethics Committee..............................86
Informed Consent...............................................................................................86
16.2
Data Handling.............................................................................................................87
16.3
Source Documents......................................................................................................88
16.4
Record Retention........................................................................................................88
16.5
Monitoring..................................................................................................................88
16.6
Quality Control and Quality Assurance .....................................................................89
16.7
Protocol Amendment and Protocol Deviation............................................................89
Protocol Amendment .........................................................................................89
Protocol Deviations............................................................................................89
16.8
Ethical Considerations................................................................................................90
16.9
Financing and Insurance.............................................................................................90
16.10 Publication Policy/Disclosure of Data........................................................................90
17
REFERENCES ..............................................................................................................91
18
APPENDICES................................................................................................................94
Appendix 1:
Contraception Guidelines.................................................................................94
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3.1 
List of In-text Tables 
Table 1. Study Drug Dosing Scheme ....................................................................................40 
Table 2. Schedule of Assessments ........................................................................................56 
Table 3. Laboratory Assessments..........................................................................................67 
Table 4. Classification of Adverse Events by Intensity ........................................................69 
Table 5. Classification of Adverse Events by Relationship to KarXT..................................69 
Table 6. Cognitive Tests and Cognitive Domains Assessed by the Cambridge 
Neuropsychological Test Automated Battery .........................................................80 
 
3.2 
List of In-text Figures 
Figure 1. Change from Baseline in PANSS Total Scores (KAR-004) ...................................28 
Figure 2. Change from Baseline in PANSS-Positive Scores (KAR-004) ..............................29 
Figure 3. Change from Baseline in CGI-S (KAR-004) ..........................................................30 
Figure 4. Change from Baseline in PANSS-Negative Scores (KAR-004).............................31 
 
 
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4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AD 
 
AE 
adverse event 
AESI 
adverse event of special interest 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
alanine aminotransferase 
APD 
antipsychotic drug 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-24 
area under the plasma concentration-time curve from 0 to 24 hours 
BACS 
Brief Assessment of Cognition in Schizophrenia 
BARS 
Barnes Akathisia Rating Scale 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CFR 
Code of Federal Regulations 
CGI-S 
 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSM-5 
 
EDC 
electronic data capture 
ECG 
Electrocardiogram 
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination 
eCRF 
electronic case report form 
EMA 
Ecological Momentary Assessment 
EMAW 
Ecological Momentary Assessment Wellness 
EPS 
extrapyramidal symptoms 
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Abbreviation 
Definition 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HIPAA 
Health Insurance Portability Accountability Act 
IB 
 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
IXRS 
interactive response system 
MCC 
microcrystalline cellulose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini International Neuropsychiatric Interview 
mITT 
modified intent-to-treat 
MMRM 
mixed model repeated measures 
OLE 
open-label extension 
PANSS 
Positive and Negative Syndrome Scale 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PRO 
patient reported outcome  
SAS 
Simpson-Angus Rating Scale 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson Angus Scale 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TID 
thrice daily 
TK 
Toxicokinetic 
Tmax 
time to maximum plasma concentration 
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Abbreviation 
Definition 
ULN 
upper limit of normal  
US 
United States 
VAS 
visual analog scale 
VLMT 
Verbal Learning and Memory Test 
WOCBP 
women of childbearing potential 
 
 
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5 
INTRODUCTION 
5.1 
Background on Schizophrenia 
Schizophrenia is a long-term mental disorder involving a breakdown in the relation between 
thought, emotion, and behavior, and leads to faulty perception, inappropriate actions and 
feelings, withdrawal from reality and personal relationships into fantasy and delusion, and a 
sense of mental fragmentation. Symptoms include delusions, hallucination, disorganized speech 
or behavior, and impaired cognitive ability.[1] The prevalence of schizophrenia is between 0.6% 
and 1.9% in the United States population.[2] Moreover, a claims analysis has estimated that the 
annual prevalence of diagnosed schizophrenia in the United States (US) is 5.1 per 1000 lives.[3] 
It is found equally in males and females, with males usually having an earlier onset of 
symptoms.[4]  
Antipsychotic drugs (APDs) are the mainstay of treatment for schizophrenia.[5] All currently 
available antipsychotics act through blockage of all or subsets of dopamine receptors in the 
brain. First-generation APDs include chlorpromazine and haloperidol; treatment with these 
agents is marked by high rates of parkinsonian extrapyramidal symptoms (EPS) and tardive 
dyskinesia and they consequently have limited use today. The second-generation agents, that 
include risperidone, olanzapine, quetiapine, lurasidone, aripiprazole, and lumateperone, tend to 
have lower levels of EPS or tardive dyskinesia and are currently the most commonly prescribed 
APD class. However, the second-generation drugs also have problematic side effects that include 
significant weight gain, metabolic disturbances, sedation, and akathisia.[6, 7, 8] These side 
effects contribute to poor medication adherence resulting in frequent relapses and 
hospitalizations.[9, 10] Thus, there is a need for medications for schizophrenia which act through 
alternative mechanisms. 
Central muscarinic receptors have been hypothesized to be therapeutic treatments for 
schizophrenia based on several converging lines of evidence including both animal and human 
studies.[11, 12] There are 5 subtypes of muscarinic receptors (M1-M5). The therapeutic effect of 
central muscarinic receptor agonism is thought to be due to agonism of M1 and M4 receptors in 
the central nervous system (CNS).[13] However, compounds that agonize M1 and M4 receptors 
are often not specific enough not to also agonize M2 and M3 receptors outside of the CNS due to 
the highly conserved allosteric binding sites that the receptors share, leading to adverse events 
(AEs) related to activation of these peripheral receptors. Thus, any potential benefit of 
 [AD]) has 
been outweighed by the occurrence of AEs associated with peripheral cholinergic side effects 
(nausea, vomiting, diarrhea, sweating, and excess salivation). 
5.2 
Background on KarXT (Xanomeline Tartrate and Trospium Chloride) 
Xanomeline tartrate is a muscarinic-cholinergic receptor agonist. It has agonistic activity at all 
5 muscarinic receptors, but preferentially stimulates M1 and M4 receptors and binding to M1 and 
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M4 receptors in the CNS, which 
effects (Roth, unpublished data). A recent study reports that xanomeline is a very potent M4 
muscarinic agonist in vivo, measured by various second messenger assays.[14] Xanomeline also 
enters the brain rapidly achieving a brain to plasma ratio of greater than 10 making it an 
attractive CNS drug candidate.[15]  
Xanomeline does not have any direct binding activity on dopaminergic receptors, suggesting that 
its mechanism of action is unrelated to direct dopamine involvement. 
Previous double-blind, placebo-controlled clinical trials have provided strong evidence that 
xanomeline has clinically relevant antipsychotic efficacy. In a multicenter outpatient trial in AD 
(N = 343), 3 doses of xanomeline (up to 225 mg/day) and placebo were assessed for 
26 weeks.[16, 17] Significant dose-dependent improvements in psychotic symptoms relative to 
placebo were observed. Moreover, psychotic symptoms resolved quite rapidly in subjects who 
were symptomatic at baseline and a dose-dependent reduction in the emergence of psychotic 
symptoms versus placebo was also observed. In a completer analysis, cognitive improvement 
was also found suggesting longer treatment intervals may be necessary for cognitive 
enhancement.[16, 17] In a subsequent small (N = 20) double-blind, placebo-controlled inpatient 
trial in treatment-resistant subjects with schizophrenia, xanomeline (225 mg/day) demonstrated 
robust and relatively rapid improvement in psychosis compared to placebo. In addition, 
improvement in both negative symptoms and cognitive impairment was observed.[18] 
In both the AD and schizophrenia trials, as well as in previous healthy volunteer studies, 
dose-
sweating, and hypersalivation. These side effects were frequent and, at the higher doses of 
xanomeline, led 
profile curtailed further development of xanomeline as a single agent.  
It is believed that the procholinergic AEs associated with xanomeline are mediated by 
 stimulation of peripheral rather than central muscarinic receptors, which would 
make these AEs theoretically amenable to counteracting peripheral anticholinergic treatment. 
Trospium chloride is a peripherally acting muscarinic antagonist which binds to and antagonizes 
all 5 muscarinic receptor subtypes.[19] It is a commonly used generic drug approved for over 10 
years by the US Food and Drug Administration (FDA) and by European authorities to treat 
overactive bladder and is generally well tolerated.[19] Several human subject studies have 
demonstrated that trospium does not appreciably cross the blood-brain barrier, consistent with 
20]  
KarXT is a novel combination of xanomeline tartrate and trospium chloride. Karuna 
hypothesized that the addition of trospium would mitigate peripheral procholinergic side effects 
(vomiting, nausea, diarrhea, sweating, and hyper-salivation) and thus provide a strategy to allow 
xanomeline to be administered and stimulate brain muscarinic receptors with a decreased side 
effect burden. Phase 1 studies in healthy volunteers of this combination demonstrated that 
KarXT reduced these side effects by 46% compared to xanomeline alone.[21] Moreover, the 
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remaining cholinergic AEs were generally mild to moderate in severity and transient in nature, 
often lasting a few hours without recurrence and were generally single-episode. In general, 
KarXT was well tolerated in healthy adult volunteers. These encouraging safety data prompted 
further work to assess KarXT for the treatment of schizophrenia and potentially other CNS
disorders.
Karuna has recently completed an adequate and well-controlled, randomized, multi-center 
Phase 2, placebo-controlled, inpatient clinical trial of acute psychosis with schizophrenia in 
182 adult subjects (KAR-004). KarXT demonstrated a statistically significant and clinically 
meaningful 11.6 point mean reduction in total Positive and Negative Syndrome Scale (PANSS) 
at 5 weeks compared to placebo (p <0.0001), with statistical separation at each time point 
assessed (2, 4 and 5 weeks), and also demonstrated good overall safety and tolerability.
The purpose of the current study is to evaluate the long-term safety and tolerability of KarXT 
(xanomeline 125 mg/trospium 30 mg) administered twice daily (BID) in adult outpatients with 
Diagnostic and Statisti
-5) diagnosis of schizophrenia. 
Xanomeline is currently not approved or marketed in any country. Trospium is marketed in the 
US and other regions of the world for the treatment of overactive bladder.
Nonclinical Studies
The following is a summary of the important nonclinical safety and toxicology studies. More 
detailed information can be found in the KarXT 
The acute toxicity of xanomeline tartrate was evaluated in mice and rats. All animals were 
observed for 2 weeks for mortality and clinical signs of intolerance, and then necropsied for 
gross examinations. In-life findings attributed to the test article included excessive 
muscarinic-mediated pharmacology, such as excessive salivation, hypoactivity, ataxia, soft 
stools, exophthalmos, ocular discharge, tremors, and convulsions, with survivors typically 
appearing normal by Day 3 or Day 4. Gross findings at necropsy were generally unremarkable
(eg, gas-distended or mucous-filled gastrointestinal [GI] tracts after oral dosing).
KarXT-301 was a 14-day, repeat dose study of KarXT in rats where relatively high doses of 
xanomeline and trospium were given, with either xanomeline alone or in combination with 
trospium. Seven groups of 10 rats/sex/group were administered either vehicle (reverse osmosis 
water), xanomeline alone at 37, 75, 150, or 300 mg/kg/day (split into BID doses, every 
12 hours), or xanomeline/trospium combination doses of 150/200 mg/kg/day or 
225/400 mg/kg/day, respectively (split into BID doses, every 12 hours). 
Satellite animals were included for the collection of plasma after the first and last doses for the 
determination of drug concentrations of each parent drug in support of toxicokinetic (TK) 
assessments.
There was no target-organ toxicity revealed by clinical pathology or by gross or microscopic 
assessments. All intolerance could be attributed to recognized pharmacology of either test article. 
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No dose-related ophthalmic observations were noted. Findings were not indicative of specific 
target organ toxicity. In short, no new hazard was identified.  
Clinical observations noted in most animals administered 300 mg/kg/day xanomeline included 
hypoactivity, clear oral discharge, dilated pupils, irregular or labored respiration, and rough 
haircoat, among other observations. These findings are generally consistent with the anticipated 
pharmacology of xanomeline.  
Three TK animals in the low-dose combination group died or were euthanized in extremis. It is 
unclear to what extent the combination treatment effects versus the different handling of these 
animals (including 3 plasma samplings per animal) contributed to these deaths. If gavage 
accidents were involved (as happened with some TK animals), then they were not detected at 
gross necropsy. There was no microscopic evidence of toxicity seen in any toxicity animals in 
this group or in the higher-dose combination group. 
Three toxicology and 3 TK animal deaths (total of 6) occurred in the high-dose combination 
group. Two toxicology animals had evidence of gavage accidents. For the third, the cause of 
death was undetermined, and a test article-related effect cannot be ruled out, but esophageal 
muscular degeneration/regeneration is indicated in some dosing-related trauma. If gavage 
accidents were involved, then they were not detected at gross necropsy. There was no evidence 
of target organ microscopic findings in GI tract or any other tissue of any animal, including the 
early death toxicity animals.  
A pharmacodynamics (PD)-mediated reduction in GI motility is consistent with the 
anti-muscarinic effects of trospium on intestinal musculature. Fecal retention, malabsorption, 
cessation of eating, dehydration, and rapid deterioration followed with continued dosing. 
Cessation of dosing in the high-dose combination animals that survived led to rapid recovery, 
implying the deleterious effects had been PD-related. No effects on food consumption were seen 
in any xanomeline-alone group. The lack of microscopic findings in the GI tract of any early 
death or surviving animal implies that the adverse effects were pharmacologically mediated 
rather than direct target organ toxicity. 
Twenty-eight Day Repeat-Dose Studies with Xanomeline in Rats and Monkeys: Rats were fed 
xanomeline tartrate at 0, 0.05, 0.1, or 0.2% daily and monkeys were fed xanomeline tartrate daily 
at 0, 5, 12.5, or 30 mg/kg. All animals survived until necropsy. Safety findings in rats included 
reduced body weight in the high-dose group, increases in gamma-glutamyl-transferase, 
cholesterol, and bilirubin, slight decreases in triglycerides, bile duct hyperplasia, higher serum 
potassium (males), and lower serum globulin (females). Findings in monkeys were dose-related 
and included signs of intolerance such as emesis, salivation, diarrhea, hypoactivity, weight loss, 
and treatment-related tachycardia in the high-dose animals. 
Forty-Day Repeat Dose Study of KarXT in Rats (KarXT-302): Six groups of 15 rats/sex/group 
were given vehicle, xanomeline alone at 75 or 150 mg/kg/day, trospium alone at 100 mg/kg/day, 
or xanomeline/trospium combination at doses of 75/50 mg/kg/day or 150/100 mg/kg/day, with 
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all doses split into BID doses. Satellite rats (TK animals) were included for collection of plasma 
after the first and last doses to determine concentrations of each drug. Dosing was initially 
planned to be 90 days, but was terminated after 40 days because of unexpected deaths in the TK 
animals. No target organ toxicity was seen. Safety findings included pharmacologically mediated 
constipation in the trospium alone and combination groups, and mild biliary hyperplasia in the 
high-dose xanomeline-alone and combination groups. There were 4 unscheduled deaths in TK 
animals; 2 in the high-dose xanomeline-alone group (150 g/kg/day) and 2 in the high-dose 
combination group (150 mg/kg/day xanomeline plus 100 mg/kg/day trospium). Both 
xanomeline-only animals had necropsy gross findings of a gavage accident and cause of death 
could not be determined. All toxicology animals survived to their scheduled sacrifice. The 
Sponsor considers that the volume depletion and trauma of multiple bleeds (3 per animal) 
followed by reduced absorption of fluids and nutrients secondary to reduced GI motility with 
continued BID dosing, explains the greater demise of TK animals relative to toxicity animals.  
Based on the results of the 90-day rat toxicology study, oral administration of trospium chloride 
and xanomeline tartrate alone or in combination to Crl:CD(SD) rats BID (12 hours ±60 minutes 
apart) at dosage levels of 25 and 50 mg/kg/dose trospium chloride, 37 and 75 mg/kg/dose 
xanomeline tartrate and a combination of 37/25, 75/25, and 75/50 mg/kg/dose xanomeline 
tartrate/trospium chloride for a minimum of 90 days resulted in minimal to moderate bile duct 
hyperplasia in the livers of the xanomeline tartrate and combination (xanomeline tartrate and 
trospium chloride) group males.  
Although there were no notable differences in the incidence of bile duct hyperplasia when 
comparing the single vs combination groups, there was an increased severity observed in the 
combination group males (specifically the 75/25 and 75/50 mg/kg/dose combination group 
males) when compared to the xanomeline tartrate group males at the terminal euthanasia. The 
bile duct hyperplasia was considered adverse in the high-dose xanomeline tartrate group males 
and in the 75/25 and 75/50 mg/kg/dose combination group males due to instances of moderate 
severity. Therefore, the no-observed-adverse-effect level was considered to be 50 mg/kg/dose for 
trospium chloride, 37 mg/kg/dose for xanomeline tartrate, and 37/25 mg/kg/dose for the 
combination of xanomeline tartrate/trospium chloride. At these doses for males, mean plasma 
AUC0-24 
 91.  
At these doses for females, mean plasma AUC0-24 
267,000 pg hr/mL for xanomeline, and 16,700 + 171,000 
 + xanomeline, 
respectively, on Day 91. The absence of bile duct hyperplasia in females cannot be explained 
from differences in drug exposure. At the recovery euthanasia, bile duct hyperplasia was still 
present, but was limited to minimal severity and there was a decreased incidence in both the 
xanomeline tartrate and combination group males. There was also no notable difference in 
severity between the single vs combination groups at the recovery euthanasia. Given the 
decreased incidence/severity, in combination with the improved histologic appearance of bile 
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ducts at the recovery euthanasia (ie, smaller/flattened epithelium, non-inflammatory, and an 
absence of portal bridging), changes at the recovery euthanasia were consistent with a partial 
resolution of bile duct hyperplasia. With an absence of correlating serum liver enzyme 
elevations, bile acid alterations or hepatocellular degeneration, necrosis or regeneration, and with 
the apparent reversibility following cessation of treatment, these findings appear to have been 
tolerable by the affected animals. Therefore, the maximum tolerated dose was considered to be 
50 mg/kg/dose for trospium chloride, 75 mg/kg/dose for xanomeline tartrate, and 
75/50 mg/kg/dose for the combination of xanomeline tartrate/trospium chloride. 
For males, corresponding mean plasma AUC0-24
822,000
respectively, on Day 91. For females, corresponding mean plasma AUC0-24 values were 
9230
950,000
tudies revealed the 
familiar exaggerations of systemic and CNS muscarinic effects that had previously been seen 
with xanomeline or trospium at high doses. Target organ findings with xanomeline alone were 
limited to biliary hyperplasia in the 28-day rat study but not the 28-day or 12-month monkey 
study, though similar findings were described in a 6-month monkey study. With KarXT, biliary 
hyperplasia was not observed in the 14-day rat study but was reported in the 40-day rat study. 
Notably, these hyperplastic findings are not thought to represent pre-neoplastic lesions, because 
they were of low severity; no fibrosis or associated hepatocellular changes, and no significant 
effects were seen on hepatobiliary-related serum chemistry.
Completed Clinical Studies
Refer to the IB for complete information regarding previous clinical studies conducted with 
xanomeline by Eli Lilly, and studies KAR-001, KAR-002, KAR-003 and KAR-004 conducted 
by Karuna Therapeutics using xanomeline with trospium.
To date, more than 840 subjects or volunteers have been exposed to xanomeline tartrate (oral 
formulation, either alone, in combination with trospium, or as the combination drug KarXT) in 
19 completed clinical studies conducted either by Eli Lilly or Karuna Therapeutics, some for as
long as 3 years. In those studies, significant improvements in cognition and reduced psychotic 
symptoms were observed.
A study of xanomeline monotherapy in subjects with schizophrenia was reported in 2008.[18] In 
this pilot study, the effects of xanomeline were examined in 20 schizophrenia subjects utilizing a 
double-blind, placebo-controlled, 4-week study design. Subjects treated with xanomeline did 
significantly better than subjects in the placebo group on Brief Psychiatric Rating Scale total 
scores and PANSS total scores (ie, 24-point change over placebo, p = 0.04). In the cognitive test 
battery, subjects in the xanomeline group showed improvements relative to placebo in some of 
the cognitive domains of verbal learning and short-term memory function. These studies 
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demonstrated the potential for xanomeline as a treatment for psychosis and cognition across 
multiple subject populations.  
Study H2Q-EW-E001, conducted by Eli Lilly, had 36 male healthy volunteers in 4 groups of 9, 
who were administered escalating single doses of xanomeline tartrate in increments of 1, 5, 10, 
25, 50, 75, 100 and 150 mg. Each group took 2 ascending doses of xanomeline tartrate and 1 
dose of placebo in a single subject blind manner. There were no serious AEs (SAEs). Adverse 
events included watery diarrhea, nausea, dizziness, sweating, shivering, mild disorientation, 
increased blood pressure (BP), increase(s) in sitting and standing heart rate, slight increase in 
supine systolic BP, and postural hypotension. 
The clinical experience with KarXT initiated by Karuna Therapeutics to date includes 
3 completed Phase 1, clinical pharmacology studies in healthy volunteers (KAR-001, KAR-002, 
and KAR-003) and one completed Phase 2 study (KAR-004) in adult inpatients with DSM-5 
schizophrenia. 
The first study conducted by Karuna, KAR-001 was a Phase 1, double-blind, randomized, 
multiple-dose, pilot study comparing xanomeline administered alone to xanomeline administered 
in combination with trospium chloride in normal healthy volunteers. This study consisted of 
2 arms, in which xanomeline was administered three times daily (TID), alone, at a total daily 
dose of 225 mg in 1 arm, and the second arm received the same dose of xanomeline in 
combination with trospium chloride 20 mg administered BID, a total daily dose of 40 mg. 
Subjects were treated for 7 days. The goal was to determine whether this dosing regimen would 
reduce the cholinergic side effects of xanomeline by co-administration of the muscarinic 
antagonist, trospium. 
Overall, treatment with xanomeline 225 mg daily + trospium 40 mg daily administered over 
7 days was considered safe and well tolerated. The results of key and supportive endpoints 
showed a numerical reduction (although not statistically significant) in visual analog scale (VAS) 
scores for cholinergic events for the xanomeline + trospium treatment arm compared to the 
xanomeline-alone treatment arm. Specifically, consistent numerical reduction in VAS scores for 
the xanomeline + trospium treatment arm was observed for the supportive endpoints of 
maximum weekly individual VAS scores and mean daily maximum composite VAS scores.  
Results of the clinician-administered scales were supportive of a reduction in vomiting, feelings 
of nausea, excess salivation, and sweating that interfered with daily activities in the 
xanomeline + trospium treatment arm compared to the xanomeline-alone treatment arm. 
There were no meaningful differences between treatment groups in heart rate, resting BP, 
orthostatic BP or any electrocardiogram (ECG) parameters including QT. A small subset of 
subjects in both treatment arms had transient increases in heart rate and orthostatic BP changes 
which may have contributed to syncope and postural dizziness in those subjects. Two subjects 
(both in the xanomeline-alone arm) experienced syncope. The incidence of orthostatic AEs in the 
KarXT group was approximately one-half that of subjects in the xanomeline-alone group. 
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The most commonly reported treatment-emergent AEs (TEAEs) in KAR-
in either treatment arm) were hyperhidrosis, salivary hypersecretion, nausea, dizziness postural, 
and diarrhea. Subject incidences of these 5 TEAEs was higher in the xanomeline-alone treatment 
arm (61.8%) compared to the xanomeline + trospium treatment arm (34.3%).  
Overall, treatment with xanomeline 225 mg combined with trospium chloride 40 mg 
administered over 7 days was considered safe and well tolerated. The observed side effect profile 
was consistent with the known safety profile of xanomeline and trospium chloride. The incidence 
of TEAEs and cholinergic TEAEs was lower in the xanomeline + trospium treatment arm 
compared to the xanomeline-alone treatment arm. 
Study KAR-002 was a Phase 1, double-blind, randomized, multiple-dose adaptive design pilot 
study to evaluate the safety and tolerability of KarXT in normal healthy volunteers. Subjects 
received either 100 mg xanomeline + 20 mg trospium BID or placebo. The first cohort of this 
study was stopped after 1.5 days when the FDA put the program on hold due to a preliminary rat 
finding in the 14-day study. This study used a new formulation of KarXT in which xanomeline 
and trospium were combined into a single dose form and given BID. Safety findings included an 
increase in orthostatic complaints. Caution should be used in drawing conclusions from this 
study, as subjects did not have time to reach steady state plasma levels from dosing, as only 
3 doses were given. 
Study KAR-003 was a Phase 1, double-blind, randomized, multiple-dose, adaptive design, 
inpatient pilot study to evaluate the safety and tolerability of KarXT in normal healthy 
volunteers. The primary objective of this study was to assess the safety and tolerability of 7 days 
of daily administration of KarXT at various dose combinations, administered BID. Subjects 
received either KarXT or placebo (3:1 ratio). All subjects on KarXT received 2 days of 50 mg 
xanomeline + 20 mg trospium BID, and then increased to different doses for Days 3 to 7. This 
study also used the new formulation of KarXT in which xanomeline and trospium were 
combined into a single dosage form and given BID.  
There was a relatively high degree of variability in xanomeline and trospium exposures between 
individuals in all cohorts, which is consistent with previous results with KarXT, 
xanomeline-alone, and trospium-alone. Peak plasma concentrations were observed at a median 
time of 2.0 hours for xanomeline and 1.0 hour for trospium across all treatment groups and study 
days.  
Although there was insufficient data to draw a definitive conclusion regarding the impact of 
trospium on the pharmacokinetics (PK) and bioavailability of xanomeline, or the impact of 
xanomeline on the pharmacokinetics and bioavailability of trospium, the PK results suggest that 
neither drug had a meaningful impact on the PK behavior of the other drug. 
During the 2-day lead-
completed dosing were dry mouth, nausea, and constipation. For the treatment groups that 
completed dosing, although the incidence of TEAEs was lower in the KarXT 100/20 BID 
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(66.7%) group compared to KarXT 125/40 group (88.9%), the incidence of cholinergic TEAEs 
(nausea, vomiting, diarrhea, sweating, and excess salivation) was similar between the 2 groups. 
The most commonly reported TEAEs ( 20% of subjects in either treatment group) in these 
groups were dizziness, nausea, dry mouth, headache, vomiting, dyspepsia, somnolence, vision 
blurred, and dysuria. For the treatment groups that did not complete dosing (KarXT 150/20 BID 
group and KarXT 150/40 BID group), the cholinergic TEAEs were generally higher compared to 
the treatment groups that completed dosing.  
Overall, anticholinergic TEAEs appeared to occur primarily in the treatment groups that were 
dosed with 40 mg trospium BID (KarXT 150/40 BID and KarXT 125/40 BID groups), 
particularly when paired with 125 mg xanomeline BID, suggesting to consider slightly lowering 
the trospium dose from 40 mg BID in future studies. All TEAEs were mild or moderate in 
severity, and there were no SAEs or deaths. Treatment-emergent AEs were primarily cholinergic 
or orthostatic (and a few anticholinergic). Doses of 100 mg and 125 mg BID of xanomeline were 
well tolerated when paired with 20 mg and 40 mg BID of trospium, respectively. The safety and 
tolerability profile of KarXT 100/20 BID and KarXT 125/40 BID was acceptable and supports 
further evaluation at similar doses in future studies. Doses of KarXT 150/20 BID and 150/40 
BID were not well tolerated in this study. A pairing of 150 mg xanomeline with 40 mg trospium 
appeared to be better tolerated than 150/20, but some subjects still experienced tolerability 
issues. 
Study KAR-004 was a Phase 2 randomized, double-blinded study to assess the safety, 
tolerability, and efficacy of KarXT in adults with DSM-5 schizophrenia, hospitalized with acute 
psychosis. The primary objective of the study was to assess the efficacy of KarXT (125/30 BID) 
versus placebo in reducing PANSS total scores in adult inpatients with a DSM-5 diagnosis of 
schizophrenia. Subjects received either KarXT or placebo (1:1 ratio) for a treatment period of 
5 weeks. All subjects on KarXT received a lead-in dose of KarXT 50/20 BID for the first 2 days 
followed by KarXT 100/20 BID on Days 3 to 7. On Day 8, dosing was titrated upwards to 
KarXT 125/30 BID unless the subject was continuing to experience AEs from a previous dose 
increase of 100/20 BID.   
A total of 182 subjects were enrolled and randomized (92 placebo; 90 KarXT).  Of these 
subjects, 170 (87 [94.6%] placebo; 83 [92.2%] KarXT) received at least one dose of study drug 
and had at least one post-baseline PANSS assessment (Modified Intent to Treat population used 
for the efficacy analyses).  Discontinuation rates were similar between the 2 treatment groups; 37 
subjects discontinued the study early (19 [20.7%] placebo; 18 [20.0%] KarXT). The most 
common reason for early discontinuation was consent withdrawn (14 [15.2%] placebo; 14 
[15.6%] KarXT) followed by Adverse Event (2 [2.2%] placebo; 3 [3.3%] KarXT). 
Treatment-emergent adverse events (TEAE) were reported in 43.3% of subjects in the placebo 
group and 53.9% of subjects in the KarXT group.  The most commonly reported TEAEs were 
constipa
or twice that of placebo) in the KarXT group than in the placebo group.   
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There were 27.8% and 42.7% of subjects in the placebo and KarXT groups, respectively, who 
experienced at least 1 TEAE related to study drug. The most commonly reported study drug 
related TEAEs for the placebo and KarXT total groups were nausea, constipation, dry mouth, 
in the 
KarXT group than in the placebo group. The majority of the reported TEAEs were mild (27.8% 
placebo; 36.0% KarXT) or moderate (14.4% placebo; 16.9% KarXT) in severity. Two severe 
TEAEs were reported during the study.  One subject in the placebo group had a severe TEAE of 
worsening schizophrenia symptoms, and 1 subject in the KarXT high dose group had a severe 
event of increased psychosis which was reported as an SAE possibly related to KarXT by the 
investigator.  There were no other SAEs reported during the study and there were no deaths 
during the study. 
The pattern and course of safety findings in KAR-004 were consistent with the known safety 
profile from earlier studies of both xanomeline monotherapy and xanomeline combined with 
trospium (KarXT). Even though the qualitative AE profile was consistent with earlier Phase 1 
PK/safety studies in healthy volunteers, the relative tolerability burden was lower in the current 
study of schizophrenia patients receiving KarXT than in the healthy volunteers.  In addition, the 
safety and tolerability of KarXT was favorable and notably free of many common side effects 
associated with current antipsychotic drugs. 
KarXT demonstrated statistically significant and clinically meaningful reduction in total PANSS 
score at all time points over 5 weeks compared to placebo (Figure 1). The primary efficacy 
endpoint result for the study (change from baseline (CFB) in PANSS total score between the 
placebo group and the KarXT group at Visit 9/Week 5) showed a statistically significant 
decrease in PANSS total score (p<0.0001). The statistically significant difference in CFB 
between the treatment groups was there at Visit 6/Week 2 (p<0.0001) and continued to Visit 
8/Week 4 and Visit 9/Week 5. Overall, the decrease from baseline in PANSS total score for the 
KarXT group was statistically significantly greater compared to the placebo group by treatment 
group for Visits 6, 8, and 9 (p<0.0001). 
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Figure 1. 
Change from Baseline in PANSS Total Scores (KAR-004) 
 
1. Abbreviations: LS = least squares; mITT = modified intent-to-treat; PANSS = Positive and Negative 
Syndrome Scale; SEM = standard error of the mean. 
A significant reduction in the secondary endpoint of PANSS-positive scores was observed 
(p<0.0001) at Week 5 as well as the 2 earlier time points (ie, Weeks 2 and 4; see Figure 2). 
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Figure 2. 
Change from Baseline in PANSS-Positive Scores (KAR-004) 
 
2. Abbreviations: LS = least squares; mITT = modified intent-to-treat; PANSS = Positive and Negative 
Syndrome Scale; SEM = standard error of the mean. 
 
As regards the Clinical Global Impression  Severity of Illness (CGI-S), subjects in the KarXT 
group overall significantly improved in ratings compared to placebo, with a p-value of <0.001 at 
Week 5. At Week 5, 8% of placebo subjects improved (decreased) their CGI-S ratings at least 
2 levels versus 28.9% of KarXT subjects (see Figure 3). 
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Figure 3. 
Change from Baseline in CGI-S (KAR-004) 
 
3. Abbreviation: CGI-
 
 
A statistically significant reduction in the secondary endpoint of PANSS-negative score was 
observed (p<0.001) at Week 5. Overall, the changes in the KarXT group were statistically 
significantly greater compared to the placebo group at Visits 6, 8, and 9 (p<0.001). The least 
square mean improvement for the placebo group was 1.32 points at Week 5 (Visit 9) and the 
mean improvement for the KarXT group was 3.85 points leading to a mean difference of 
2.53 points at Week 5 (Visit 9; see Figure 4). 
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Figure 4. 
Change from Baseline in PANSS-Negative Scores (KAR-004) 
 
4. Abbreviations: LS = least squares; mITT = modified intent-to-treat; PANSS = Positive and Negative 
Syndrome Scale; SEM = standard error of the mean. 
 
The overall safety/tolerability data were also fairly unambiguous; among the highlights:  
 The overall discontinuation rate on KarXT was 20%, similar to placebo (21%). The number 
of discontinuations due to TEAEs was equal in the KarXT and placebo arms (N = 2 in each 
group) 
 The dose escalation rate on KarXT was high and similar to placebo: 
o 91% of KarXT subjects escalated to 125/30 KarXT (vs 97% on placebo) 
o 4% percent de-escalated back to 100/20 KarXT dose (vs 1% on placebo) 
 The overall TEAE rate on KarXT was 54% vs 43% on placebo: 
o The most common TEAEs were constipation, nausea, dry mouth, dyspepsia, and 
vomiting. None of these TEAEs were severe and none led to discontinuations 
o One SAE occurred in the study (the subject was on KarXT): the subject discontinued 
treatment and subsequently sought hospital care for worsening psychosis, meeting the 
regulatory definition of an SAE.   
o No syncope or mean changes in BP were seen 
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o A 5.5 bpm peak mean placebo adjusted resting heart rate increase with a downward 
trend after Week 2 was seen 
o One subject (on KarXT) was discontinued due to an elevated gamma-glutamyl 
transpeptidase (GGT) 
o There were no new safety findings associated with KarXT that have not been observed 
with either xanomeline alone or trospium alone in previous trials 
 KarXT did not show evidence of many of the kinds of AEs that often occur in currently 
available antipsychotics for the treatment of schizophrenia  
 The rates of the following AEs were similar for KarXT and placebo: somnolence, weight 
gain, and EPS 
 Overall, the KAR-004 results confirm and extend the antipsychotic benefit of xanomeline 
observed in past studies of xanomeline alone and the well tolerated nature of KarXT.  
KAR-004 results support the continued development of KarXT into Phase 3 trials. 
Two randomized, double-blind, placebo-controlled Phase 3 trials (KAR-007 and KAR-009) are 
planned in which the subjects will be exposed to either KarXT or placebo (1:1) for a period of up 
to 5 weeks. Subjects who complete either of these 2 studies will be eligible to roll over into this 
long-term open-label study. 
5.3 
Clinical Risks/Benefits of KarXT and Study Rationale 
The risks and benefits of KarXT in humans are not fully known. KarXT is a fixed dose 
combination of xanomeline and trospium.  
The available clinical trial data indicate that KarXT has robust efficacy and a favorable safety 
profile that appears unique compared to all available APDs. Most of these clinical data were 
setting. Treatment with KarXT is not associated with weight gain, sedation, or meaningful EPS 
changes. In contrast, these serious side-effects pose a significant risk with other APD treatments 
for schizophrenia and can lead to discontinuation of treatment and significant morbidity. A Phase 
2 registration quality pivotal trial in 182 subjects met the primary endpoint with the PANSS total 
score showing a 11.6 point mean improvement compared to placebo with a highly significant 
(p < 0.0001) separation from placebo (-17.4 KarXT vs. -5.9 placebo) at Week 5. KarXT, as 
compared to placebo, demonstrated highly significant reduction in PANSS total scores 
(p < 0.0001) at all post randomization time points (Weeks 2, 4 and, 5) with a calculated effects 
at all post randomization time points for PANSS positive symptom subscores, PANSS negative 
symptom subscores, PANSS Marder Factor negative symptom subscores, and CGI-S scores. 
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Over 840 subjects or volunteers have been exposed to xanomeline tartrate (oral formulation; 
either alone, in combination with trospium, or as the combination drug KarXT) in clinical 
studies. These early clinical studies, as well as nonclinical pharmacology and toxicology studies, 
have not revealed any specific contraindications to the use of xanomeline. The most common 
side effects/symptoms are the cholinergic related effects: nausea, vomiting, excess salivation, 
excess sweating, and diarrhea. In addition, subjects treated with xanomeline alone have reported 
both syncope and orthostatic dizziness. The addition of trospium decreases the peripheral 
cholinergic effect of xanomeline creating a better tolerated therapy. In addition, a titration phase 
also increases the tolerability of KarXT. 
Trospium chloride has been marketed in the US for 12 years. The most frequently reported AEs 
reported in pivotal trials were dry mouth, constipation, abdominal pain, headache, urinary 
retention, and abnormal vision and accommodation. For additional information, the package 
insert for trospium chloride tablets for oral use can be found in the IB. 
In a Phase 2 (KAR-004) clinical study, KarXT (100/20 and 125/30) significantly reduced the 
symptoms of schizophrenia in subjects with acute psychosis after treatment for 28 days. KarXT 
also showed an acceptable safety profile with the most common TEAEs being constipation, 
nausea, dry mouth, dyspepsia, and vomiting. All the reported TEAEs were mild or moderate in 
intensity. One SAE (psychotic disorder) was reported by a single subject and no deaths were 
reported in the study. KarXT was generally well-tolerated and found to be safe in this patient 
population. 
KarXT represents a novel approach to the treatment of patients with schizophrenia that will 
provide an important and meaningful alternative to current therapies. The current tolerability and 
AE profile and the efficacy of KarXT justify further development of KarXT in this patient 
population by advancing to Phase 3 trials. Two such Phase 3 trials (KAR-007 and KAR-009) are 
planned where the subjects will receive the study drug (KarXT or placebo) for 5 weeks.  
In the current study, regardless of treatment assignment in the preceding Phase 3 study 
(KAR-007 or KAR-009), all subjects will receive KarXT for a period of approximately 52 weeks 
with the primary objective of assessing the long-term safety and tolerability profile of KarXT in 
an out-patient setting. All subjects will start with a lead-in dose of KarXT 50/20 BID for Days 1 
to 2 and then the dose will be titrated to 100/20 BID for Days 3 to 7, allowing the subject to 
adjust to KarXT before receiving a higher dose of 125/30 BID starting on Visit 3 (Day 8), unless 
the subject is continuing to experience AEs from the previous dose increase of KarXT 100/20 
BID. All subjects who are increased to KarXT 125/30 BID, depending on tolerability, will have 
the option to return to KarXT 100/20 BID. Re-escalation to 125/30 BID or re-titration in cases 
where subject has been off KarXT for a longer period of time (at least a week) is allowed and 
will require a discussion between the principal investigator (PI) and the medical monitor.  
Dosing will occur every 12 ±4.5 hours each day, during waking hours. KarXT should be dosed 
on an empty stomach (ie, at least 1 hour before a meal or 2 to 3 hours after a meal).  
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The current study is designed to demonstrate that long-term treatment with KarXT in adult 
schizophrenia subjects is safe and tolerable.  
 
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6
STUDY OBJECTIVES AND ENDPOINTS
6.1
Study Objectives
Primary Objective
The primary objective of the study is to assess the long-term safety and tolerability of KarXT in 
subjects with a DSM-5 diagnosis of schizophrenia.
Secondary Objectives
The secondary objective of this study is to assess the long-term efficacy and evaluate plasma 
concentrations of xanomeline and trospium after administration of KarXT in adults with a 
DSM-5 diagnosis of schizophrenia:
To evaluate the reduction in PANSS total score
To evaluate the reduction of PANSS positive score 
To evaluate the improvement in Clinical Global Impression Severity (CGI-S) results 
To evaluate the reduction of PANSS negative score 
To evaluate the reduction of PANSS Marder Factor negative symptoms score
Exploratory Objectives
The exploratory objectives of this study are:
To evaluate cognition with the Cambridge Neuropsychological Test Automated Battery 
(CANTAB)
To evaluate prolactin levels after administration of KarXT
To characterize outcomes obtained from digital biomarkers, ecological momentary 
assessment administered patient reported outcomes (EMA PRO), and an EMA 
administered verbal learning and memory test (EMA VLMT) in schizophrenia (US only)
6.2
Study Endpoints
Primary Safety Endpoint
The primary safety endpoint of this study is the incidence of treatment-emergent AEs (TEAE).
Secondary Endpoints
6.2.2.1
Safety Endpoints
The secondary safety endpoints of this study are: 
Incidence of serious TEAEs
Incidence of TEAEs leading to withdrawal
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6.2.2.2
Efficacy Endpoints
The secondary efficacy endpoints of this study are:
Change from baseline in PANSS total score at Week 52
Change from baseline in PANSS positive score at Week 52
Change from baseline in PANSS negative score at Week 52
Change from baseline in PANSS Negative Marder Factor score at Week 52
Change from baseline in CGI-S score at Week 52
Percentage of PANSS responders (a 30% reduction in PANSS total score) at Week 52
Other Endpoints
6.2.3.1
Safety Endpoints
Spontaneously reported adverse events of special interest (AESIs)
Spontaneously reported procholinergic and anticholinergic symptoms
Change from baseline in Simpson-Angus Rating Scale (SAS)
Change from baseline in Barnes Rating Scale for Akathisia (BARS)
Change from baseline in Abnormal Involuntary Movement Scale (AIMS)
Change from baseline in body weight, body mass index (BMI), waist circumference 
Change from baseline in orthostatic vital signs (supine and standing after 2 minutes): BP 
(systolic and diastolic) and heart rate
Change from baseline in clinical laboratory assessments (hematology, clinical chemistry, 
coagulation, urinalysis, and drug screen)
Change from baseline in 12-lead ECG 
Change from baseline in physical examination 
Suicidal ideation scale with the use of Columbia-Suicide Severity Rating Scale (C-SSRS)
6.2.3.2
Pharmacokinetic Endpoint
Comparison of the plasma concentrations of xanomeline and trospium measured in this 
study to the plasma concentrations predicted by a population pharmacokinetic (PK)
model of studies KAR-007 and KAR-009
6.2.3.3
Exploratory Endpoints
The exploratory endpoints of this study are: 
Change from baseline in cognition measuring core domains of impairment in 
schizophrenia using CANTAB
Change from baseline in prolactin levels
Observed digital biomarkers of schizophrenia (US only)
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 Observed ecological momentary assessment administered patient reported outcomes 
(EMA PRO) in schizophrenia (US only) 
 Observed cognitive insight using an EMA administered verbal learning and memory test 
(EMA VLMT) in schizophrenia (US only) 
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7 
INVESTIGATIONAL PLAN 
7.1 
Description of Overall Study Design and Plan 
This is a Phase 3 multicenter, 53-week, outpatient, open-label extension (OLE) study to evaluate 
the long-term safety, tolerability, and efficacy of KarXT in subjects with DSM-5 schizophrenia 
who previously completed the treatment period of one of the two Phase 3 double-blind studies, 
KAR-007 or KAR-009. The study consists of a 52-week OLE treatment phase and a 7-day 
(±3 days) follow-up/end-of-study (EOS) visit after the last KarXT dose for subjects who 
complete the treatment phase and those who prematurely discontinue from the study.  
After written informed consent, subjects who have completed either the KAR-007 or KAR-009 
Phase 3 acute study and received the last dose of the study drug in that trial will be rolled over 
into the current OLE study. The assessments performed on Visit 10 (Day 35) of studies 
KAR-007 or KAR-009 will be considered as baseline assessments along with any additional 
procedures that will be performed on Day 0 of the current study. Any scheduled Day 0 
assessments that were not completed on Day 35 of the acute study (KAR-007 or KAR-009) must 
be completed on Day 0 of the current study.  
It is preferable that Baseline/Day 0 procedures of the current study be completed on the same day 
as Day 35 of the acute study after all Visit 10 (Day 35) procedures of the prior study KAR-007 
or KAR-009 have been completed. However, with medical monitor approval, an extension of up 
to 3 days can be granted to complete Baseline/Day 0 procedures. This extension cannot be 
completed inpatient.  
With medical monitor approval, participants may be permitted to complete the first 3 days (Visit 
1/Day 1 to Visit 2/Day 3) of KAR-008 on the inpatient unit. 
Subjects who did not complete the full treatment period, or who early terminated studies KAR-
007 or KAR-009, will not be eligible to enroll in this long-term extension study.   
Approximately 350 subjects are planned to be enrolled in this study (aged 18 to 65 years at time 
of enrollment into the preceding acute study) across approximately 30 study sites in the United 
States and 10 study sites in Ukraine.  
In this OLE study, all subjects will receive KarXT for up to 52 weeks. Regardless of treatment 
assignment in the preceding Phase 3 acute study (KAR-007 or KAR-009), all subjects will start 
on a lead-in dose of KarXT 50/20 BID for the first 2 days (Days 1 and 2), followed by 
KarXT 100/20 BID for the remainder of Week 1 (Days 3 to 7). On Visit 3 (Day 8), dosing will 
be titrated upwards to KarXT 125/30 BID unless the subject is continuing to experience AEs 
from the previous dose of KarXT 100/20 BID. All subjects who are increased to KarXT 125/30 
BID, depending on tolerability, will have the option to return to KarXT 100/20 BID for the 
remainder of the treatment period. Re-escalation to 125/30 BID or re-titration in cases in which 
the subject has been off KarXT for a longer period of time (at least a week) is allowed and will 
require a discussion between the PI and the medical monitor. Additional changes to KarXT 
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dosing (e.g., temporary dose reductions) may be permitted as clinically indicated upon approval 
by the medical monitor. 
Beginning after Visit 9/Day 84, interim visits will be completed with flexibility between in-clinic 
visits, approximately once every 4 weeks. Whenever possible, interim visits should be conducted 
by telemedicine; however, sites will have the option to schedule on-site interim visits, and are 
encouraged to use additional unscheduled as necessary, to facilitate subject retention and ensure 
adherence to study objectives. . 
All subjects will have questionnaires administered throughout the study (see Schedule of 
Assessments Table 2). Analyses of change from baseline in diagnostic measures will be 
performed. 
Safety will be assessed through spontaneous AEs including AESIs, procholinergic and 
anticholinergic symptoms; SAEs and AEs leading to discontinuation of KarXT; SAS; BARS; 
AIMS; body weight; BMI; waist circumference; orthostatic vital signs; clinical laboratory 
assessments (hematology, clinical chemistry, coagulation, urinalysis, and drug screen), 12-lead 
ECG; physical examination; and C-SSRS will be evaluated throughout the study as scheduled. 
Section 11 provides complete details on these safety assessments. 
Efficacy will be assessed through PANSS total score, PANSS-positive score, PANSS-negative 
score, PANSS Negative Marder Factor score, and CGI-S score at scheduled visits. Refer to 
Section 12 for more details. 
Plasma concentrations of xanomeline and trospium will be evaluated. Details are provided in 
Section 13. 
Exploratory assessments include cognition testing using CANTAB; prolactin levels; digital 
biomarkers of schizophrenia (US Only); Ecological Momentary Assessment (EMA) Patient 
Reported Outcomes (PRO; US Only) and EMA Verbal Learning and Memory Test (VLMT; US 
Only). Smartphone-based assessments (i.e., digital biomarkers of schizophrenia, EMA PRO, 
EMA VLMT and AiCure technology) will be optional. Exploratory assessments will be 
evaluated during scheduled visits or on specified study days. See Section 14 for more details.  
A safety follow-up/end of study (EOS) visit  (Visit 30/Day 371) will be performed for all 
subjects after the last dose of KarXT for subjects who complete the treatment phase and those 
who prematurely discontinue from the study. 
An Independent Safety Monitoring Committee (ISMC) will be responsible for periodically 
reviewing the safety data from this study and confirming that the study may continue. 
Table 1 presents the Study Drug Dosing Scheme. 
 
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Table 1. 
Study Drug Dosing Scheme   
 
Period: 
Open-Label Extension Treatmenta 
EOT/ET 
EOS/UNS 
Day: 
Day 1 
Day 3 
+1 day 
Day 8b  
±1 day 
Day 14 
±2 days 
Days 28-70  
±3 days 
Days 84-350 
±3 days 
Day 364 
±3 days 
 
Day 371  
±3 days 
Visit: 
Visit 1 
Visit 2 
Visit 3 b 
Visit 4 
Visits 5-8 
Visits 9c -28 
Visit 29 
 
Visit 30 
Xanomeline/ 
trospium 
chloride 
(KarXT)*: 
50/20 BID 
100/20 BID 
125/30 BID 
(Option: 
100/20 
BID)d 
125/30 BID 
(Option: 
100/20 
BID)d,e 
125/30 BID 
(Option: 
100/20 
BID)d,e 
125/30 BID 
(Option: 
100/20 BID)d,e 
125/30 BID 
(Option: 
100/20 BID) 
d,e 
N/A 
Comment(s): 
2-day 
lead-in 
dose 
Upward 
titration 
of dose 
Upward 
titration 
of dose 
 
7 (±3) days after 
completion of the 
EOT or ET visit 
Abbreviations: 
BID = twice daily; EOS = end of study; EOT = end of treatment; ET = early termination; N/A = not applicable; 
PI = principal investigator; UNS = unscheduled. 
* All the KarXT doses are in mg xanomeline/mg trospium. 
a. At Visit 1 (Day 1) subjects will initiate dosing with KarXT BID.  Visits 2, 3, 4, 5, 6, 7, 8, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, and 30 are in-clinic/on-site 
visits. Visits 10, 12, 14, 16, 18, 20, 22, 24, 26, and 28 are interim visits and can be conducted via telemedicine or on-site. 
b. Subject to receive at least 8 doses of KarXT 100/20 prior to escalating to the KarXT 125/30 dose.  
c. Beginning after Visit 9/Day 84, interim visits will be completed with flexibility between in-clinic visits, approximately once every 4 weeks.  
d. All subjects who are increased to KarXT 125/30, depending on tolerability, will have the option to return to KarXT 100/20 BID. 
e. Re-escalation to 125/30 BID or re-titration in cases where subject has been off KarXT for a longer period of time (at least a week) is allowed and will require 
a discussion between the PI and the medical monitor. Additional changes to KarXT dosing (e.g., temporary dose reductions) may be permitted as clinically 
indicated upon approval by the medical monitor. 
 
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7.2 
Discussion of Study Design 
The KarXT clinical development program includes this open-label extension study to evaluate 
the long-term safety, tolerability, and efficacy of KarXT in subjects with schizophrenia who 
participated in either of the 2 Phase 3 double-blind clinical studies and completed the treatment 
period. 
This study will allow subjects that were randomized into a preceding Phase 3 study (KAR-007 or 
KAR-009) to reinstitute (or initiate treatment if a placebo subject) KarXT therapy. Subjects will 
receive KarXT (with the same lead-in dose of KarXT 50/20 BID), regardless of treatment 
assignment from the preceding Phase 3 study. Thus, subjects who received placebo during the 
preceding Phase 3 study who may not have demonstrated clinical benefit, nonetheless, may be 
considered appropriate for the current study, as all subjects will receive KarXT.  
The dosing plan for this study has been established and follows the earlier studies. All eligible 
subjects will receive the same lead-in doses of KarXT (KarXT 50/20 BID). Dosing will be 
titrated to 100/20 BID on Day 3 and further titrated to 125/30 BID on Visit 3 (Day 8), unless the 
subject continues to experience AE(s) from the previous dose increase of KarXT.  
During the study, all subjects who are increased to the highest dose of KarXT, depending on 
tolerability, will have the option to return to the next lower dose of KarXT (100/20 BID). 
Re-escalation to 125/30 BID or re-titration in cases where subject has been off KarXT for a 
longer period of time (at least a week) is allowed and will require a discussion between the PI 
and the medical monitor.  
Beginning after Visit 9/Day 84, interim visits will be completed with flexibility between in-clinic 
visits, approximately once every 4 weeks thereafter. Whenever possible, interim visits should be 
conducted by telemedicine; however, sites will have the option to schedule on-site interim visits, 
and are encouraged to use additional unscheduled visits as necessary to facilitate subject 
retention and ensure adherence to study objectives.  
A 52-week treatment phase is considered to be sufficient to demonstrate the long-term safety and 
tolerability of KarXT. A sample size of approximately 350 subjects is also determined to be an 
appropriate number of evaluable subjects to assess the long-term safety of KarXT administration. 
Section 5.2 details the nonclinical and clinical background information available on KarXT, 
including dose rationale.  
7.3 
End of Study 
A subject will have fulfilled the requirements for study completion if/when the subject has 
completed the study treatment, including the EOS visit or the last scheduled visit as indicated in 
the Schedule of Assessments (Table 2) in accordance with the protocol. 
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7.4 
Independent Safety Monitoring Committee 
For the purpose of this study, the ISMC is an independent group of individuals with pertinent 
expertise that reviews on a regular basis accumulating safety and tolerability data from the 
clinical study. The ISMC will include 3 clinicians and a reporting statistician. This committee 
will be responsible, on a periodic basis, for confirming the safety and tolerability of KarXT 
throughout the study, with particular focus on assessing for any new or long-term toxicities that 
might be involved with KarXT. 
The reviews will allow a comparison of event rates and detection of safety signals, and to 
identify important safety information. The ISMC charter will contain the details of the types of 
data to be reviewed, the defined triggers for review, the minimum frequency of meetings (timed, 
if no triggers), and the communication plan for disseminating review recommendations. 
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8 
SELECTION OF STUDY POPULATION 
Section 7.1 provides information regarding the number of subjects planned to be enrolled. 
8.1 
Inclusion Criteria 
Individuals must meet all of the following criteria to be included in the study: 
1. Subject is aged 18 to 65 years, at time of enrollment into the preceding acute study 
(KAR-007 or KAR-009).  
2. Subject is capable of providing informed consent. 
a. A signed informed consent form must be provided before any study assessments 
are performed. 
b. Subject must be fluent in (oral and written) English (United States only) or local 
language (Ukraine only) to consent. 
3. Subject has completed the treatment period on study drug (through Day 35 -2 days) of 
Studies KAR-007 or KAR-009.  
4. Subject resides in a stable living situation, in the opinion of the investigator. 
5. Subject has an identified, reliable informant/caregiver willing to be able to address some 
questions related to certain study visits, if needed. An informant/caregiver may not be 
 
6. Women of childbearing potential (WOCBP) or men whose sexual partners are WOCBP 
must be willing and able to adhere to the contraception guidelines as defined in Section 
8.4.1 and Appendix 1. 
 
8.2 
Exclusion Criteria 
Subjects will be excluded from the study if 1 or more of the following criteria is/are applicable: 
1. Risk for suicidal behavior during the study as determined by the inve
assessment and C-SSRS as confirmed by the following:  
a. 
Subject answers Y
some intent to act, without specific plan) or Item 5 (active suicidal ideation with 
specific plan and intent) on the C-SSRS assessment. 
b. 
Nonsuicidal self-injurious behavior is not exclusionary. 
2. Any clinically significant abnormality including any finding(s) from the physical 
examination, vital signs, ECG, or laboratory test at the end-of-treatment visit of studies 
KAR-007 or KAR-009 that the investigator, in consultation with the medical monitor, 
would consider to jeopardize the safety of the subject. 
3. Female subject is pregnant, breast feeding or planning to become pregnant during the 
course of the study.  
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4. 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 his/her ability to adhere to 
the protocol visit schedule or fulfill visit requirements. 
5. Subjects with extreme concerns relating to global pandemics such as coronavirus disease 
2019 (COVID-19) that preclude study participation. 
6. Risk of violent or destructive behavior. 
7. Subjects participating in another investigational drug or device trial or planning on 
participating in another clinical trial during the course of the study. 
 
8.3 
Safety Laboratory Evaluations for Eligibility 
Subjects may be enrolled into KAR-008 prior to receipt of the results from the safety laboratory 
evaluations collected on Visit 10 of the preceding acute study.  These subjects will be dosed on 
Day 1 of KAR-008; however, subjects may be withdrawn from KAR-008 depending upon the 
clinical significance of the results of the Visit 10 safety laboratory evaluations at the discretion of 
the PI in consultation with the medical monitor. Abnormal lab values deemed clinically 
significant must be recorded as AEs.  Subjects with elevated liver function tests (LFTs) per the 
DILI criteria must be withdrawn from further participation in KAR-008.  Retesting of labs is 
allowed once, with the exception of elevated LFTs. 
8.4 
Study Withdrawal, Removal, and Replacement of Subjects 
If a subject discontinues study treatment and is withdrawn from the study for any reason, the 
study site must immediately notify the medical monitor. The date and the reason for study 
discontinuation must be recorded on the electronic case report form (eCRF). Subjects who 
complete or discontinue early from the study will be asked to return to the study site within 
7 (±3) days of the EOT or ET visit to complete EOS assessments as indicated in the Schedule of 
Assessments (Table 2). 
In the event that a subject discontinues prematurely from the study because of a treatment 
emergent AE (TEAE) or serious TEAE, the TEAE or serious TEAE will be followed up until it 
resolves (returns to normal or baseline values) or stabilizes, or until it is judged by the 
investigator to no longer be clinically significant. 
Once a subject is withdrawn from the study, the subject may not re-enter the study. 
A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons 
including, but not limited to, the following: 
 progressive disease 
 unacceptable toxicity or AE 
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subject withdrawal of consent: at any time, a subject's participation in the study may be 
terminated at his/her request or on the basis of the 
clinical judgment; the 
reason for subject withdrawal will be noted on the eCRF
intercurrent illness: a condition, injury, or disease unrelated to the primary diagnosis that 
became apparent during treatment and necessitated the subject s termination from the 
study
general or specific changes in the subject's condition that renders them ineligible for 
further treatment according to the inclusion/exclusion criteria (eg, subject has need for a 
medication prohibited by the protocol)
subject fails to adhere to the protocol requirements (eg, drug noncompliance [if a subject 
is off KarXT for >7 consecutive days])
violation of entry criteria, ie, enrolled subjects who are later discovered not to meet 
eligibility criteria
development of suicidal or assaultive behavior
alcohol abuse or illegal drug use
pregnancy, as indicated in Section 11.8
Subjects who withdraw from the study will be encouraged to complete the same final evaluations 
as subjects completing the study according to this protocol, particularly safety evaluations. The 
aim is to record data in the same way as for subjects who completed the study.
Reasonable efforts will be made to contact subjects who are lost to follow-up. A subject will be 
considered lost to follow-up if he or she repeatedly fails to return for scheduled visits and is 
unable to be contacted by the study center. 
file. Subjects with AEs ongoing at end of study will be followed until the AE is resolved or the 
subject is considered to be in stable condition.
The Sponsor has the right to terminate the study at any time in case of SAEs or if special 
circumstances concerning the KarXT become known, making further treatment of subjects 
impossible. In this event, the investigator(s) will be informed of the reason for study termination.
Pregnancy
No evidence of mutagenicity, or treatment effects on reproduction, fertility, or fetal parameters 
have been demonstrated in animals following administration of xanomeline, but there are no 
adequate and well-controlled studies in pregnant women (FDA Pregnancy Category B). Animal 
reproduction studies of trospium chloride have shown an adverse effect on the fetus, but 
potential benefits may warrant the use of the drug in pregnant women despite the risk (FDA 
Pregnancy Category C).
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Therefore, WOCBP in this study must be willing to use a highly effective method of birth 
control (see Appendix 1 for a list of acceptable highly effective methods of contraception) during 
the study and for 30 days after the last dose of KarXT. WOCBP will have a urine pregnancy test 
on Day 0 (before receiving KarXT) and thereafter, as designated at other scheduled visits 
(Table 2). In case of positive urine pregnancy test result, a serum sample should be sent to the 
central laboratory to confirm the result. Pregnant women are excluded from this study because 
the effects of KarXT on the developing human fetus are unknown with the potential for 
teratogenic or abortifacient effects. 
Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment 
of the mother with KarXT, women who become pregnant must discontinue KarXT immediately. 
The effects of KarXT on sperm are unknown. Male subjects whose sexual partners are WOCBP 
must agree to use a highly effective method of birth control (see Appendix 1 for a list of 
acceptable highly effective methods of contraception) and must not impregnate a sexual partner 
during or for 30 days after the last dose of KarXT. They must also agree to refrain from sperm 
donation for 30 days after the last dose of KarXT. 
WOCBP will be instructed that known or suspected pregnancy occurring during the study should 
be confirmed and reported to the investigator. If a female subject becomes pregnant, the 
investigator must withdraw her from the study without delay. The subject must not receive any 
further doses of the KarXT. The investigator must notify the Sponsor or their designee of any 
female subject or female partner of a male subject that becomes pregnant while participating in 
the study. If the female subject or the female partner of the male subject is willing and able to 
consent to pregnancy follow-up, she will be followed until her pregnancy reaches term. Only 
those procedures that would not expose the pregnant female patient to undue risk will be 
performed. See Section 11.8 for further reporting and monitoring details. 
Full details of the pregnancy will be recorded on the withdrawal page (exit form) of the eCRF, or 
a Pregnancy Reporting Form will be completed if the subject has completed the study. 
Notification of the pregnancy should be submitted via the Pregnancy Reporting Form within 
24 hours of knowledge of the pregnancy. Pregnancy is not to be considered an AE; however, it 
must be reported using the same procedure as described for reporting SAEs, Section 11.7.4. 
8.5 
Completion of the Study or Lost to Follow-up 
The study will be completed when all subjects have completed their study-related procedures in 
accordance with the protocol. 
Every reasonable effort will be made to contact subjects who are lost to follow-up to obtain EOS 
information. Details regarding follow-up efforts are to 
records/source documentation. 
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8.6 
Study Termination 
The availability of any new adverse safety information related to KarXT may result in stopping 
the study. An investigator, Sponsor, or Institutional Ethics Committee (IEC)/Institutional Review 
Board (IRB) may take such actions. If the study is terminated for safety reasons, subjects will be 
notified immediately and assured that appropriate treatment and follow-up will be available. If an 
investigator terminates the study, the Sponsor, subjects, and IEC/IRB will be informed about the 
reason for such action. Similarly, if the Sponsor terminates the study, it will inform the 
investigators, the IEC/IRB, and the subjects of the reason for such an action. Similar 
notifications will be sent by the IEC/IRB if it takes such an action. 
 
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9
TREATMENTS
9.1
Details of Study Treatments
KarXT is formulated as hard hydroxypropyl methylcellulose oral capsules containing 2 distinct 
populations of drug beads, 1 of which is loaded with xanomeline tartrate and the other of which 
is loaded with trospium chloride. Each capsule contains the free base equivalent of xanomeline 
and trospium according to the desired dosage strength. In addition to the active ingredients, the 
drug beads contain microcrystalline cellulose (MCC). The beads are not coated and are 
formulated for immediate release of the active ingredients.
Identity of Study Treatments
Active study agents for treatment group will be size 0, Swedish orange, opaque, and 
hydroxypropyl methylcellulose hard capsules. For the 2-day lead-in period (Days 1 and 2), 
subjects will receive capsule strength KarXT 50/20 BID, followed by 2 capsules of KarXT 
50/10 mg BID or a dosage of 100/20 mg BID for a total daily dose of 200/40 mg for the 
remainder of Week 1 (Days 3 to 7). At the beginning of Visit 3 (Day 8), dosing may be increased 
to 2 capsules of KarXT 62.5/15 mg or a dosage of 125/30 mg BID for a total daily dose of 
250/60 mg, depending on tolerability. Investigators have the option to return a subject to KarXT 
100/20 mg BID. Re-escalation to 125/30 BID or re-titration in cases where subject has been off 
KarXT for a longer period of time (at least a week) is allowed and will require a discussion 
between the PI and the medical monitor.
Additional changes to KarXT dosing (e.g., temporary dose reductions) may be permitted as 
clinically indicated upon approval by the medical monitor (see also Section 9.4).
KarXT 50/10 mg is composed of 44.4% xanomeline tartrate, 5.8% trospium chloride, excipients 
37.59% MCC, 11.5% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a size 0, 
Swedish orange, hydroxypropyl methylcellulose hard capsule.
KarXT 50/20 mg is composed of 33.4% xanomeline tartrate, 8.7% trospium chloride, excipients 
39.8% MCC, 17.3% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a size 0, Swedish 
orange, hydroxypropyl methylcellulose hard capsule.
KarXT 62.5/15 mg is composed of 41.7% xanomeline tartrate, 6.5% trospium chloride, 
excipients 38.1% MCC, 12.9% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a 
size 0, Swedish orange, hydroxypropyl methylcellulose hard capsule.
All investigational agents are to be stored according to requirements as specified on the 
Investigational Product label.
Packaging and Labeling
The study packaging and labeling will be performed by Corealis Pharma, located in Laval, 
Quebec, Canada and Catalent Pharma Solutions, located in Winchester, Kentucky (labelling for 
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the US sites), and Catalent Pharma Solutions, located in Philadelphia, Pennsylvania (labelling for 
Ukrainian sites). All packaging and labeling operations will be performed according to Good 
Manufacturing Practice for Medicinal Products and the relevant regulatory requirements.
Bulk supply bottles are labeled with the name of the drug, recommended storage conditions, the 
name and address of the manufacturer and the Investigational Use Statement (for the US sites: 
and for the 
).
Further details on labeling of investigational product will be provided in the Pharmacy Manual.
KarXT Storage
Prior to dispensing KarXT to the subjects, it must be stored at controlled room temperature
15°C-25°C.
KarXT Retention
KarXT must be retained until completion or termination of the study, and written authorization 
from the Sponsor has been received. All unused and used KarXT must be destroyed at the site or 
ity to ensure that the Sponsor 
has provided written authorization prior to return or destruction, and that appropriate records of 
the disposal are documented and maintained. No used or unused KarXT may be disposed until 
fully accounted for by the study monitor.
9.2
Dosage Schedule
Subjects who roll over into KAR-008 will start dosing with KarXT on Day 1 of the current 
study. Baseline/Day 0 procedures must be completed prior to Day 1 and preferably on the same 
day as Visit 10 (Day 35) of the preceding acute study KAR-007 or KAR-009. The assessments 
performed on Visit 10 (Day 35) of studies KAR-007 or KAR-009 will be considered as baseline 
assessments along with any additional procedures that must be performed up to Day 1 of the 
current study. 
The first dose of the KarXT will be self-administered in the morning of Day 1 and the last dose 
will be self-administered in the morning of EOT Visit (Day 364). KarXT should be administered 
daily BID on an empty stomach (ie, at least 1 hour before a meal or 2 to 3 hours after a meal). 
Some considerations for dosing and PK blood withdrawals are provided in the subsections 
below. As described in Section 10.2, subjects may opt to utilize AiCure Technology to monitor 
KarXT dosing adherence. 
Day 0
The site pharmacist will prefill 2 child resistant pill bottles with sufficient quantities of
50mg/20mg of KarXT for the first 2 days of dosing and a sufficient quantity of 
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50mg/10mg pills to accommodate subsequent BID dosing of KarXT at 100/20 level until 
Visit 3/Day 8.
Sites will send the subject home with instruction to begin self-administration of KarXT 
BID in the morning of Day 1. 
For all KarXT doses, the first dose is to be self-administered in the morning and the 
evening dose will be self-administered at 12 (±4.5) hours after the morning dose. 
Remind the subject to bring their pill bottles to the next clinic visit.
Visit 1/Day 1 Dosing
Initiate BID dosing with KarXT 50/20.
All subjects must have taken 4 doses of the KarXT 50/20 before dose escalation to 
KarXT 100/20 BID. Subjects should be instructed to contact the investigator in the event 
they did not take all 4 doses of KarXT 50/20 prior to Visit 2/Day 3.
Visit 2/Day 3 Dosing
Initiate BID dosing with KarXT 100/20. Subjects who have not taken their morning dose 
of 50/20 KarXT at the time of the study visit should receive their first dose of KarXT 
100/20 at the time of the study visit. 
Subjects who plan to utilize AiCure to track adherence must have completed AiCure 
training and registration prior to dosing.
All the subjects must have taken at least 8 doses of the KarXT 100/20 before dose 
escalation to KarXT 125/30 BID. Subjects should be instructed to contact the investigator
in the event they did not take at least 8 doses of KarXT 100/20 prior to Visit 3/Day 8.
Remind the subject to bring their pill bottles to the next clinic visit.
Visit 3/Day 8
If dose escalation to the KarXT 125/30 level is confirmed by investigator order, the site 
pharmacist will prefill 1 child resistant bottle with a sufficient quantity of 62.5 mg/15 mg
pills to accommodate BID dosing of KarXT at 125/30 level until the next clinic visit.
If the subject has not yet taken their morning dose of 100/20 KarXT at the time of the 
study visit, the subject should receive their first dose of KarXT 125/30 at the time of the 
study visit. 
A single PK sample should be drawn at Visit 3/Day 8, and the dose of KarXT and time of 
most recent dosing should be recorded. Whenever possible, the PK sample should be 
obtained within 1 to 2 hours of dosing.
Remind the subject to bring their pill bottle to the next clinic visit.
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In the event that the subject is not escalated to KarXT 125/30, in accordance with investigator 
order, dispense sufficient quantities of 50 mg/10 mg pills to continue BID dosing of KarXT at 
the 100/20 level until next clinic visit.
Visit 4/Day 14 Dosing and PK Considerations
If dose of KarXT 125/30 BID was confirmed by investigator order, the site pharmacist 
will prefill 1 child resistant bottle with a sufficient quantity of 62.5 mg/15mg pills to 
accommodate BID dosing of KarXT at 125/30 level until the next clinic visit.
A single PK sample should be drawn at Visit 4/Day 14, and the dose of KarXT and time 
of most recent dosing should be recorded.
Remind the subject to bring their pill bottle to the next clinic visit.
If dose of KarXT 100/20 BID was confirmed by investigator order, dispense sufficient quantities 
of 50 mg/10 mg pills to continue BID dosing of KarXT at the 100/20 level until next clinic visit.
Visits 5 to 8 (Days 28 to 70) Dosing 
If dose of KarXT 125/30 BID was confirmed by investigator order, the site pharmacist 
will prefill 1 child resistant bottle with a sufficient quantity of 62.5 mg/15 mg pills to 
accommodate BID dosing of KarXT at the 125/30 level until the next clinic visit.
Remind the subject to bring their pill bottle to the next clinic visit.
If dose of KarXT 100/20 BID was confirmed by investigator order, dispense sufficient quantities 
of 50 mg/10 mg pills to continue BID dosing of KarXT at the 100/20 level until next clinic visit.
Visits 9 to 29 (Days 84 to 364) Dosing 
If dose of KarXT 125/30 BID was confirmed by investigator order, the site pharmacist 
will prefill two child resistant bottles with a sufficient quantity of 62.5 mg/15 mg pills to 
accommodate BID dosing of KarXT at the 125/30 level until the next clinic visit.
For Days 84, 168, and 280, a single PK sample will be collected and the dose of KarXT 
and time of most recent dosing should be recorded.
See Section 9.4.1 for management of KarXT dose changes and PK sampling.
Remind the subject to bring their pill bottles to the next clinic visit.
If dose of KarXT 100/20 BID was confirmed by investigator order, dispense sufficient quantities 
of 50 mg/10 mg pills to continue BID dosing of KarXT at the 100/20 level until next clinic visit.
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9.3
Measures to Minimize Bias: Study Treatment Assignment
Method of Study Treatment Assignment
The 9-digit Subject Number previously assigned to the subject in the study KAR-007/KAR-009 
will continue to be used in the current study KAR-008. This number will be associated with the 
subject throughout the current study.
Blinding
This is an open-label study; therefore, blinding is not applicable.
9.4
Dosage Modification
Subjects will self-administer the KarXT as described in Section 7.1 and in accordance with the 
Schedule of Assessments (Table 2). The KarXT doses were selected based on the previous 
preclinical and clinical studies (see Section 5.2). Per the protocol, subjects will be evaluated for 
dose adjustments starting at Visit 3 through the remainder of the treatment period (see 
Section 9.2).
Additional changes to KarXT dosing (e.g., temporary dose reductions) may be permitted as 
clinically indicated upon approval by the medical monitor.
Extended Dosing Interruptions and Re-titration
Re-escalation to 125/30 BID or re-titration in cases where subject has been off the KarXT for a 
longer period of time (at least a week) is allowed and will require a discussion between the 
principal investigator (PI) and the medical monitor.
All subjects approved by the PI and medical monitor will resume KarXT by repeating the lead-in 
dosing scheme used at the start of study. Subjects will start with a lead-in dose of KarXT 
50/20 BID for the first 2 days after restarting study drug. Then the dose will be titrated to 100/20 
BID for at least the next 4 days, allowing the subject to adjust to KarXT before receiving a 
higher dose of 125/30 BID after restarting study drug, unless the subject is continuing to 
experience AEs from the previous dose, in which case the subject will remain on 
KarXT 100/20 BID.
9.5
Treatment Accountability and Compliance
The pharmacist or other designated individual will maintain records of study treatment delivered 
to the study site, the inventory at the study site, the distribution to each subject, and the return of 
materials to the Sponsor or designee for storage or disposal. These records should include dates, 
quantities, batch/serial numbers, expiration dates, temperature log, and unique code numbers 
assigned to the product and study subjects.
Administration of KarXT will be supervised by study site personnel (during in-clinic visits). The 
pharmacist (or designee) will be responsible for dispensing KarXT into labeled child-resistant 
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pill bottles for subjects use when at home. The quantity of KarXT capsules dispensed should be 
sufficient to cover the period (including visit window) until next planned study visit.  Please refer 
to the Schedule of Assessments in Section 10 and the study Pharmacy Manual for details. 
Investigators will maintain records that adequately document that the subjects were provided 
with the correct study treatment supply and reconcile the usage of the study drug. Investigational 
product will not be returned to the Sponsor or designee or destroyed until accountability has been 
fully monitored through the end of the study. KarXT accountability will be assessed periodically 
by the assigned study monitor.
9.6
Prior and Concomitant Therapy
Prior and Concomitant Medications
Concomitant medications ongoing as of Visit 10/Day 35 of the preceding acute study (KAR-007 
or KAR-009) will be captured in the eCRF as baseline therapy. Thereafter, all medications and 
other treatments taken by the subject during the study, including those treatments initiated before
the start of the study drug administration, must be recorded on the KAR-008 eCRF.
Restricted prior therapies are provided below.
During the study (ie, from the time of enrollment at baseline visit [Day 0] until study completion
(EOS), subjects should refrain from the use of any new concomitant medications without the 
prior approval of the investigator. The administration of any other concomitant medications 
during the study period is prohibited without the prior approval of the investigator unless its use 
is deemed necessary in a medical emergency. Any medication or therapy that is taken by or 
administered to the subject during the course of the study must be recorded in the eCRF. The 
entry must include the dose, regimen, route, indication, and dates of use.
All the subjects enrolled into the study must not take the below mentioned prohibited 
medications for the duration of the treatment period.
Oral or long-acting injectable antipsychotic medications, monoamine oxidase inhibitors, 
mood stabilizers (ie, lithium), anticonvulsants (eg, lamotrigine, Depakote), tricyclic 
antidepressants (eg, imipramine, desipramine), selective serotonin reuptake inhibitors, or 
any other psychoactive medications except for anxiolytics that were taken on an as 
needed basis (eg, lorazepam, chloral hydrate). 
Note: Please direct questions relating to prohibited medications to the medical monitor.
Concomitant Medications for Anxiety and/or Sleep Aid
Subjects are allowed to take benzodiazepines (up to 4 mg lorazepam/day or equivalent) for 
anxiety, agitation, and insomnia on a PRN basis. Subjects may also use non-benzodiazepine 
medications (eg, zolpidem, zaleplon) as a sleep aid, also on a PRN basis. Study sites must record 
the use of such medications in the eCRF and 
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Note: Cognition testing should not be done within 8 hours of receiving a benzodiazepine or sleep 
medication. 
 
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10 STUDY PROCEDURES 
Table 2 outlines the timing of procedures and assessments to be performed throughout the study. 
Section 11.6 specifies laboratory assessment samples to be obtained. See Sections 11, 12, 13, and 
14 for additional details regarding efficacy, safety, PK, and exploratory assessments, 
respectively. 
COVID-19 testing will be completed in accordance with clinical site standard operating 
procedures. If a subject tests positive for COVID-19 during the study, they may be quarantined 
as needed and any scheduled visits should be rescheduled or conducted via telemedicine per the 
discretion of the investigator. If the subject requires hospitalization, an SAE should be reported, 
and the subject should be followed up as outlined in Section 11.7.3. 
 
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Table 2. 
Schedule of Assessments  
DAY 
 
 
0 
 
1 
 
3 
(+1d) 
8 
(± 1d) 
14 
(± 2d) 
28 
(± 3d) 
42 
(± 3d) 
56 
(± 3d) 
70 
(± 3d) 
84 
(± 3d) 
98 
(± 3d) 
112 
(± 3d) 
126 
(± 3d) 
140 
(± 3d) 
154 
(± 3d) 
168 
(± 3d) 
WEEK 
 
1 
 
 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
VISIT Baseline1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10a 
11 
12 
13 
14 
15 
TYPE OF VISIT Clinic 
  
Clinic Clinic Clinic Clinic Clinic Clinic Clinic Clinic Interim Clinic Interim Clinic Interim Clinic 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject eligibility verification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (WOCBP 
only)b 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Urine drugs of abuse and alcohol 
testingc 
 
 
 
 
 
X 
 
 
Review of inclusion/exclusion 
criteria 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, body weight, BMI, waist 
circumferenced  
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Complete physical examinatione 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical examinationf 
Spontaneous AEsg 
X 
  
 
 
 
 
 
 
Review of concomitant 
medicationsh 
 
 
 
 
 
 
 
Vital signs: BP and HRi 
 
 
 
 
 
 
 
Resting ECG (12-lead)j 
X 
   
 
 
X 
 
 
 
 
 
 
X 
Blood samples for clinical 
laboratory testsk 
X 
 
 
 
X 
X 
 
 
X 
 
 
X 
Blood sample for prolactinl  
X 
 
 
 
X 
 
 
 
 
 
 
X 
Functional constipation inquirym 
X 
 
 
 
 
 
X 
 
Determination of dose titration 
 
 
PK blood drawn 
PANSSo 
C-SSRSp 
 
CGI-S scale 
Cognition testingq 
 
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DAY 
 
 
0 
 
1 
 
3 
(+1d) 
8 
(± 1d) 
14 
(± 2d) 
28 
(± 3d) 
42 
(± 3d) 
56 
(± 3d) 
70 
(± 3d) 
84 
(± 3d) 
98 
(± 3d) 
112 
(± 3d) 
126 
(± 3d) 
140 
(± 3d) 
154 
(± 3d) 
168 
(± 3d) 
WEEK 
 
1 
 
 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
VISIT Baseline1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10a 
11 
12 
13 
14 
15 
TYPE OF VISIT Clinic 
  
Clinic Clinic Clinic Clinic Clinic Clinic Clinic Clinic Interim Clinic Interim Clinic Interim Clinic 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAS 
BARS 
AIMS 
KarXT dispensed 
Subject self-administration of 
KarXT  
OPTIONAL 
AiCure registration and trainingr 
EMA registration and trainings 
EMA PROt 
EMA VLMTu 
Digital biomarkers using AiCure 
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Table 2 
Schedule of Assessments (Continued from Visits 16 to 30) 
DAY 
 
182 
(± 3d) 
196 
(± 3d) 
210 
(± 3d) 
224 
(± 3d) 
238 
(± 3d) 
252 
(± 3d) 
266 
(± 3d) 
280 
(± 3d) 
294 
(± 3d) 
308 
(± 3d) 
322 
(± 3d) 
336 
(± 3d) 
350 
(± 3d) 
364 
(± 3d) 
371 
(± 3d) 
WEEK 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52 
53 
VISIT 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
(EOT/
ET) 
30 
(EOS/ UNS)3 
TYPE OF VISIT Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic 
Clinic 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(WOCBP only)b 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Urine drugs of abuse and 
alcohol testingc 
Height, body weight, BMI, 
waist circumferenced 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Complete physical 
examinatione 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Targeted physical 
examinationf 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Spontaneous AEsg 
Review of concomitant 
medicationsh 
Vital signs: BP and HRi 
Resting ECG (12-lead)j 
 
 
 
 
 
X 
 
 
 
Blood samples for clinical 
laboratory testsk 
 
X 
 
 
 
X 
 
 
 
Blood sample for 
prolactinl 
 
 
 
 
 
X 
 
 
 
Functional constipation 
inquirym 
PK blood drawn 
PANSSo 
C-SSRSp 
CGI-S scale 
Cognition testingq 
SAS 
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DAY 
 
182 
(± 3d) 
196 
(± 3d) 
210 
(± 3d) 
224 
(± 3d) 
238 
(± 3d) 
252 
(± 3d) 
266 
(± 3d) 
280 
(± 3d) 
294 
(± 3d) 
308 
(± 3d) 
322 
(± 3d) 
336 
(± 3d) 
350 
(± 3d) 
364 
(± 3d) 
371 
(± 3d) 
WEEK 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52 
53 
VISIT 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
(EOT/
ET) 
30 
(EOS/ UNS)3 
TYPE OF VISIT Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic Interim Clinic 
Clinic 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BARS 
AIMS 
KarXT dispensed 
Subject self-administration 
of KarXT  
OPTIONAL 
AiCure adherence 
technologyr 
EMA PROt 
EMA VLMTu 
Digital biomarkers using 
AiCure appv 
Abbreviations: AE = adverse event; AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; BL = baseline; BMI = body 
mass index; BP = blood pressure; CGI-
-SSRS = Columbia-Suicide Severity Rating Scale; d = day; 
ECG = electrocardiogram; EMAW = EMA Wellness; EOS = end of study; EOT = end of treatment; ET = early termination; HR = heart rate; PANSS = Positive 
and Negative Syndrome Scale; PK = pharmacokinetic; QTcF = QT interval corrected by Fridericia; SAS = Simpson-Angus Rating Scale; UNS = unscheduled 
visit. 
1. Baseline Day 0 assessments should be rolled over from Day 35/Visit 10 of the preceding study (KAR-007 or KAR-009) whenever possible (exception: 
cognition which should be rolled over from Day 32).  Includes pregnancy testing, complete physical exam, vital signs, ECG, safety laboratory evaluations, 
functional constipation inquiry, PANSS, C-SSRS, CGI-S, SAS, AIMS and BARS. 
2. (X) = Optional and to be completed only if Day 0 visit does not take place on the same day of Day 35/Visit 10 of the preceding study. See footnotes for 
additional details. 
3. Unscheduled (UNS) visits may be conducted as needed to facilitate retention and ensure adherence to study objectives. Other assessments may be 
performed as needed. 
4. This procedure is optional and should only be performed for participants who have terminated early; PK draw is recommended if termination is due to AE. 
 
 
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a. 
Beginning after Visit 9/Day 84, and every 4 weeks thereafter, interim visits will be completed with flexibility between the in-clinic visits. Interim visits 
should be conducted by site staff using telemedicine (audio only, or audio + video); however, sites will have the option to schedule in-clinic visits as needed 
to ensure subject retention and support study objectives. 
b. A urine pregnancy test for WOCBP should be performed at scheduled visits. If a urine pregnancy test is positive, a serum sample should be sent to central 
laboratory for confirmation of the result. A new urine pregnancy test should be performed on Day 0 visit only if subject left the inpatient unit after 
completion of Visit 10 of the preceding acute study but prior to completion of the Day 0 procedures of the current study. 
c. 
A National Institute on Drug Abuse-5 (NIDA-5) urine drug screen (cannabinoids or marijuana, phencyclidine, amphetamines, opiates, and cocaine) and test 
for alcohol (breathalyzer or urine alcohol level) will be performed at the indicated scheduled visits.  Should be performed on Day 0 visit only if subject left 
the inpatient unit after completion of Visit 10 of the preceding acute study but prior to completion of the Day 0 procedures of the current study. 
d. Baseline height is recorded from Study KAR-007/KAR-009 Screen visit.  Baseline body weight, BMI and waist circumference recorded from KAR-007/-
009 Visit 10. At the indicated study visits, body weight and waist circumference will be measured and BMI calculated.  
e. 
A complete physical examination includes body temperature (°C), general appearance, head/eyes/ears/nose/throat (HEENT), examination of thorax and, 
assessment of cardiac, musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited neurological examination. 
f. 
A targeted physical examination includes at a minimum body temperature, a check of general appearance, as well as examination of organ systems that are 
 These also include symptom-
driven physical examinations which will be performed as clinically indicated at any study visit. A targeted physical examination at Day 0 is optional, and 
only required if the subject has reported a new AE in the time since completing Visit 10 of the preceding acute study. 
g. Adverse events as reported by subjects or observed by clinical staff. Adverse events ongoing as of Visit 10 of the preceding acute study will be recorded in 
the KAR-008 Medical History eCRF. Adverse events occurring after dosing with KarXT in the current study will be recorded in the KAR-008 AE eCRF. 
One PK blood sample may be drawn if a relevant/significant AE (based on medical judgment) is reported during a scheduled visit or if there is a dose 
titration or a relevant/significant AE reported during an unscheduled visit (no multiple draws). For interim visits, spontaneous AEs will be collected by 
telemedicine or during in-clinic visits. 
h. Concomitant medications ongoing as of Visit 10/Day 35 of the preceding acute study will be captured in the eCRF as baseline therapy.  Thereafter, all 
medications and other treatments taken by the subject during the study, including those treatments initiated before the start of the study, must be recorded 
on the KAR-008 eCRF. For interim visits, concomitant medications will be collected by telemedicine or during in-clinic visits. 
i. 
Vital signs measurements should be taken at all in-clinic visits, while the subject is supine and standing after 2 minutes. BP includes systolic and diastolic 
BP and is to be taken in the same arm for the duration of the study. During in-clinic visits orthostatic vital signs should occur 2 (±1) hours after morning 
dose of KarXT whenever possible.   
j. 
ECG should be obtained within 1 to 2 hours post morning dose whenever possible. ECG at all indicated visits should be performed before blood withdrawal 
for any safety laboratory tests and/or PK analysis. ECGs will be transmitted electronically to a central reader for determination of ventricular rate (bpm), PR 
(msec), QRS (msec), QT (msec), and QTcF (msec) measurements. 
k. Refer to Section 11.6 for individual laboratory tests. For urinalysis, a urine dipstick will be performed at the site. In the event of abnormalities, the sample 
will be sent to the central laboratory for full microscopic urinalysis.  
l. 
Prolactin sample is optional when using local labs. 
m. Functional constipation inquiry: At specified visits, subjects will be asked whether they have experienced constipation (per the ROME III criteria and 
Bristol Stool Form Scale; see Appendix 2) since the last visit and if yes, whether the constipation required intervention. If the subject answers yes, sites are 
instructed to ask subjects to provide event date and ensure the event is documented as an AE and treatment is documented as concomitant medication.  
n. PK blood samples will be collected on Days 8, 14, 84, 168, and 280. At Day 8 the PK sample should be obtained within 1 to 2 hours post dose whenever 
possible. In cases of dose reduction, re-escalation, re-titration, or a relevant/significant AE is reported, an additional PK sample may be collected per 
investigator discretion in consultation with the medical monitor. 
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o. It is recommended, if at all possible, that the PANSS assessment should be performed before all the other scale assessments for all visits at which it is 
performed.  
p. 
 should be used for C-SSRS administration. At the Unscheduled visit, the C-SSRS should be performed to monitor subjects for 
suicidality. 
q. Cognition testing is performed using CANTAB. Cognition testing should not be done within 8 hours of receiving a benzodiazepine or sleep medication.  
r. 
Participation in AiCure technology is optional. For subjects who opt to utilize it, AiCure should be used to self-administer KarXT beginning on Day 1 
whenever possible, and no later than Visit 2, Day 3. Refer to the Study Operations Manual for details. 
s. 
Participation in EMA is optional and is used in the US Only. See Study Operations Manual for additional details. 
t. 
Participation in EMA PRO is optional. For subjects who opt to utilize it, EMA PRO (US Only) will be completed by the subject at home on a cellular 
device 3 times per day for 7 days every 28 days, beginning on Day 29. An abbreviated version of the assessment will be utilized on Days 4-6 and 15-17 to 
familiarize subjects with the process. Refer to Study Operational Manual for details. 
u. Participation in EMA Wellness technology is optional. For subjects who opt to utilize it, cognitive insight (US Only) will be assessed using the EMA 
VLMT.  The assessment will be completed by the subject at home on a cellular device 1 time per day for 2 days every 28 days beginning on Day 32. Refer 
to Study Operational Manual for details. 
v. Participation in digital biomarkers using the AiCure app is optional. For subjects who opt to utilize it, digital biomarkers of schizophrenia (US Only) will be 
calculated through completion of a smartphone-based assessment daily by the subject for 3 days collected initially on Days 4-6, 9-11, and 15-17. 
Subsequently subjects will complete assessments daily for 3 days every 28 days, beginning on Day 29. Refer to Study Operational Manual for details. 
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10.1 Informed Consent
Informed consent forms must be approved for use by the reviewing Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB). Before performing any study-related 
procedures, the investigator (or designee) will obtain written informed consent from the subject
and/or caregiver (Ukraine only).
10.2 Study Procedures
Assessments and their timing are to be performed as outlined in the Schedule of Assessments 
(Table 2). Section 11.6 specifies laboratory assessment samples to be obtained. 
Safety assessments are described in Section 11 and include spontaneous AEs including AESIs;
procholinergic and anticholinergic symptoms, SAEs and AEs leading to discontinuation of the 
KarXT; SAS; BARS; AIMS; body weight; BMI; waist circumference; orthostatic vital signs; 
ECG; clinical laboratory assessments (hematology, clinical chemistry, coagulation, urinalysis, 
and drug screen); physical examination; and C-SSRS.
Efficacy assessments are described in Section 12 and include PANSS and CGI-S scores.
PK assessments are described in Section 13.
Exploratory assessments are described in Section 14 and include cognition testing using 
CANTAB; prolactin levels; digital biomarkers of schizophrenia (optional); EMA PRO
(optional); and EMA VLMT (optional).
The investigator may, at his/her discretion, arrange for a subject to have an unscheduled 
assessment, especially in the case of AEs that require follow-up or are considered by the 
investigator to be possibly related to the use of KarXT. The unscheduled visit page in the eCRF 
must be completed. The assessments and procedures that may be performed during an 
unscheduled visit are outlined in the Schedule of Assessments (Table 2). Additional assessments 
can be performed as needed, at the discretion of the investigator, and following discussion with 
the medical monitor.
Study discontinuation procedures are described in Section 8.4 and Section 8.6.
AiCure Adherence Technology
Smartphone-based technology including AiCure will be optional for all subjects. Subjects may 
opt out at the beginning of the study or at any point during the treatment period. AiCure 
technology can be used to monitor study medication adherence in all subjects, both in the US and 
the Ukraine. Subjects must complete registration and training to begin utilizing AiCure 
technology no later than Visit 2/Day 3, prior to escalating from 50/20 to 100/20 KarXT. See 
Operations Manual for additional details. Additionally, the AiCure technology may be used to 
capture Digital Biomarker Assessment of schizophrenia symptoms of subjects in the US only.
Medication Adherence (US and Ukraine):
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In subjects who opt to use smartphone-based technology, this study will employ a medication 
adherence monitoring platform (herein after referred to as Platform). The Platform uses artificial 
intelligence on smartphones to confirm medication ingestion. In addition, built-in reminders and 
a communication system allow real-time intervention in case of drug interruptions.  
Use of this Platform will in no way supersede or replace the physician and/or prescribed 
medication protocol of the subjects. Because the Platform does not change the medication 
protocol of the subjects, but rather encourages adherence to the predefined protocol, use of this 
Platform presents minimal risk to the subjects. Use of the Platform will be optional for all 
subjects in the study. 
The monitoring Platform requires that all subjects take each dose of the medication while using a 
smartphone. Participants will download the AiCure application on their personal smartphone 
device; for participants who do not have a smartphone or do not wish to use their personal 
smartphone but still wish to do smartphone-based assessments, site personnel will provide the 
participant with one of the preloaded backup provisioned devices. 
When at home, study subjects will receive a medication reminder at a time within a predefined 
window. This notification reminds subjects to take their medication dose while using the 
Platform. Subjects will follow a series of prescribed steps in front of the front-facing webcam to 
visually confirm their ingestion of the medication. The application on the smartphone will make 
an automated determination of whether the subject has properly taken their medication at the 
prescribed time. There is no need for a healthcare provider to review the administration, nor 
would a healthcare provider need to be available at the time the subject takes their medication. 
The amount of guidance that the device provides to the subject is automatically reduced as the 
subject becomes more proficient at using the application. 
Digital Biomarker Assessment (US only): 
For subjects enrolled at US sites and who opt to use smartphone-based technology, subjects will 
be performing brief smartphone-based assessments using the AiCure application. Video and 
audio of participant behavior captured during these assessments will be used to calculate visual 
and auditory markers of schizophrenia symptomatology. These digital biomarkers will be used as 
exploratory efficacy endpoints to measure change from baseline in disease severity. See Section 
14.4 for endpoint discussion. The material will be presented to subjects in one of two ways. In 
the first, material will be presented to subjects, and will include questionnaires provided at 
regular intervals during the study. Images may also be shown to subjects, and they will be asked 
to describe each image in a few sentences to the camera of the smartphone.   
Data Collected on the AiCure Platform: 
After the device confirms proper medication ingestion, video recordings will be encrypted and 
transmitted to a secure centralized location for further analysis, including testing for duplicate 
enrollment. Video and audio recordings from the Digital Biomarker assessments will be 
encrypted and transmitted in a similar manner. The captured data and video are reviewable 
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through a roles and rules restricted system ensuring privacy of the information. The system is 
compliant with applicable US and European data privacy laws, including General Data 
Protection Regulation (GDPR) (EU) 2016/679 the Health Insurance Portability and 
Accountability Act (HIPAA), which protects the privacy and security of healthcare information. 
Phone numbers of the patients may also be collected and stored in an encrypted manner. Storing 
the phone numbers will allow for direct communication with patients, including automated 
messaging from the Platform device and contact by healthcare providers or other monitoring 
personnel. At no time is the phone number visible to healthcare providers or monitoring 
personnel. Individuals outside the clinical sites will not be provided with patient names, nor will 
they be given access to patient medical records. 
The Platform may provide significant benefits to study subjects as well as to the other 
stakeholders in the trial. Subjects will benefit from rapid and tailored intervention in case of 
non-adherence (drug interruptions) without having to visit the clinic for unscheduled visits. 
Healthcare providers will have access to real-time and continuous adherence data without having 
to rely on self-reported data or frequent study visits by patients. Subjects who regularly fail to 
take their medication will be contacted by healthcare providers or other study monitoring 
personnel for retraining. 
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11 SAFETY ASSESSMENTS 
Safety assessments (spontaneous AEs including AESIs; procholinergic and anticholinergic 
symptoms; SAEs and AEs leading to discontinuation of the KarXT; SAS; BARS; AIMS; body 
weight; BMI; waist circumference; orthostatic vital signs; ECG; clinical laboratory assessments 
[hematology, clinical chemistry, coagulation, urinalysis, and drug screen]; physical examination; 
and C-SSRS) will be performed at protocol-specified visits, as specified in the Schedule of 
Assessments (Table 2).  
11.1 Demographics, Medical History, and Psychiatric History 
Demographic data, and medical and psychiatric history will be recorded from the Phase 3, 
double-blind, acute study (KAR-007/KAR-009).  
Illnesses first occurring or detected during the study and/or worsening of a concomitant illness 
during the study are to be documented as AEs on the eCRF in accordance with Section 11.7. All 
changes that are not present at baseline or described in the past medical history and identified as 
clinically noteworthy must be recorded as AEs. 
11.2 Vital Signs 
Orthostatic vital signs (systolic and diastolic BP and heart rate measurements) will be evaluated 
at all scheduled visits indicated in the Schedule of Assessments (Table 2). All vital signs will be 
measured supine and standing after 2 minutes. Blood pressure measurements are to be taken in 
the same arm for the duration of the study. During in-clinic visits, beginning with Visit 2 
(Day 3), orthostatic vital signs should occur 2 (±1) hours after morning dosing, whenever 
possible.   
Vital sign measurements will be repeated if clinically significant or machine/equipment errors 
occur. Out-of-range BP, or heart rate m
discretion. Any confirmed, clinically significant vital sign measurements must be recorded as 
AEs. 
11.3 Complete/Targeted Physical Examination 
A complete physical examination (body temperature, general appearance, 
head/eyes/ears/nose/throat [HEENT], examination of thorax and abdomen, assessment of 
cardiac, musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited 
neurological examination) will be performed at visits as specified in Table 2. Physical 
examinations will be performed by a physician or qualified designee. 
A targeted physical examination includes at a minimum body temperature, a check of general 
appearance, as well as examination of organ systems that are relevant to the investigator, based 
These also include symptom-driven physical examinations which will be performed as clinically 
indicated at any study visit. 
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11.4 Weight, Height, Body Mass Index, and Waist Circumference 
The baseline height measurement will be recorded from the lead-in Study KAR-007 or KAR-009 
Screen visit. The baseline body weight, BMI and waist circumference measurements will be 
recorded from the KAR-007 or KAR-009 Visit 10. At the indicated visits of the current study 
(Table 2), body weight and waist circumference will be measured and BMI calculated. All 
findings should be recorded in the eCRF. 
11.5 Electrocardiograms 
A 12-lead, resting ECG should be obtained within 1 to 2 hours post morning dose at the visits 
indicated in the Schedule of Assessments (Table 2), whenever possible. ECG at all scheduled 
visits should be performed before blood withdrawal for any safety laboratory tests and/or PK 
analysis. 
ECGs will be transmitted electronically to a central reader for determination of ventricular 
rate (bpm), PR (msec), QRS (msec), QT (msec), and QTcF (msec) measurements. An assessment 
of normal or abnormal will be recorded; if the ECG is considered abnormal, the abnormality will 
be documented on the eCRF. ECGs will be repeated if clinically significant abnormalities are 
observed or artifacts are present. 
11.6 Laboratory Assessments 
Laboratory assessment samples (Table 3) are to be obtained at designated visits as detailed in the 
Schedule of Assessments (Table 2). 
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Table 3. 
Laboratory Assessments 
Hematology 
Serum Chemistry 
Urine Analysis (Dipstick) 
Full and differential blood count 
Hct 
Hb 
MCH 
MCHC 
MCV 
Platelet count 
RBC count 
WBC count with differential 
 
ALT 
ALP 
AST 
Albumin 
Uric acid 
BUN or urea 
Carbon dioxide 
Creatinine 
Creatine kinase and subtypes 
Electrolytes (sodium, 
potassium, chloride, calcium, 
phosphorus) 
GGT 
Glucose 
LDH 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
HDL 
LDL 
Triglycerides 
Total protein 
Appearance 
pH 
Protein 
Glucose 
Ketone bodies 
Indicators of blood and WBCs 
Specific gravity 
Urobilinogen 
Occult blood 
WBCs 
HbA1c (glycated Hb test) 
Prolactin 
  
Coagulation 
PT 
Activated PTT 
Fibrinogen 
Pregnancy test: A urine pregnancy test for WOCBP should be performed per the schedule of assessments 
(Table 2).  In case of positive urine pregnancy test result, a serum sample should be sent to the central 
laboratory to confirm the result. 
Full and microscopic urinalysis:  
Chemical exam: SG, pH, bilirubin, urobilinogen, protein, glucose, ketone, hemoglobin, leukocyte esterase, 
nitrite, ascorbic acid 
Microscopic exam: RBCs, WBCs, epithelial cells, bacteria, yeasts, parasites, casts, crystals 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; GGT = gamma-glutamyl transpeptidase; HCG = human 
chorionic gonadotropin; Hb = hemoglobin; Hct = hematocrit; HDL = high density lipoprotein; LDH = lactate 
dehydrogenase; LDL = low density lipoprotein; MCH = mean corpuscular hemoglobin; MCHC = mean 
corpuscular hemoglobin concentration; MCV = mean corpuscular volume; PT = prothrombin time; 
PTT = partial thromboplastin time; RBC = red blood cell; WBC = white blood cell; WOCBP = women of 
childbearing potential. 
 
Venous blood of approximately 12 to 20 mL will be withdrawn for the tests listed above at 
scheduled time points as per Table 2.  
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A minimum volume of 10 mL will be obtained to perform urinalysis (if abnormalities observed 
on dipstick) and urine drug screen at scheduled time points as per Table 2. 
Blood and urine samples (microscopic analysis) will be analyzed at a central laboratory facility. 
Urine samples will first be analyzed by dipstick at the site. If the results of the dipstick indicate 
abnormalities to be further investigated, the sample will be sent to the central laboratory and a 
microscopic analysis will be performed. All laboratory reports must be reviewed, signed, and 
dated by the investigator. A legible copy of all reports must be filed with both the 
eCRF 
and medical record (source document) for that visit. Any laboratory test result considered by the 
investigator to be clinically significant should be considered an AE (clinically significant AEs 
include those that require an intervention). Clinically significant abnormal values occurring 
during the study will be followed up until repeat test results return to normal, stabilize, or are no 
longer clinically significant.
All the study subjects will be closely monitored for the drug-induced liver toxicity (detailed in
Section 11.7.5), during the study.
Other Laboratory Assessments:
A National Institute on Drug Abuse-5 (NIDA-5) urine drug screen (cannabinoids or 
marijuana, phencyclidine, amphetamines, opiates, and cocaine) will be performed using a 
dipstick throughout the study. 
Alcohol testing will be performed using a breathalyzer or urine alcohol test. 
11.7 Adverse Events
Adverse Events
An AE is any symptom, physical sign, syndrome, or disease that either emerges during the study 
or, if present at screening/baseline, worsens during the study, regardless of the suspected cause 
of the event. All medical and psychiatric conditions (except those related to the indication under 
study) present at screening/baseline will be documented in the medical history eCRF. Changes in 
these conditions and new symptoms, physical signs, syndromes, or diseases should be noted on 
the AE eCRF during the rest of the study. Clinically significant laboratory abnormalities should 
also be recorded as AEs. Surgical procedures that were planned before the subject enrolled in the 
study are not considered AEs if the conditions were known before study inclusion; the medical 
condition should be reported in the 
medical history.
In accordance with the protocol, the investigator and/or study staff will elicit AEs and 
intercurrent illness during and at the end of the study period and these will be recorded on the 
appropriate page of the eCRF. Adverse events will be elicited by asking the subject a nonleading 
tudy as soon as the results of the final lab 
tests are available.
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Each AE is to be documented on the eCRF with reference to date of onset, duration, frequency, 
severity, relationship to KarXT, action taken with KarXT, treatment of event, and outcome. 
Furthermore, each AE is to be classified as being serious or nonserious. Changes in AEs and 
resolution dates are to be documented on the eCRF. 
For the purposes of this study, the period of observation for collection of AEs extends from the 
time of consent until the EOS or ET. Follow-up of the AE, even after the date of therapy 
discontinuation, is required if the AE persists until the event resolves or stabilizes at a level 
acceptable to the investigator. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the event should be noted. If the intensity category changes over a number of days, 
then those changes should be recorded separately (with distinct onset dates). 
The severity of AEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0 (Grades 1 through 5). 
Specific guidelines for classifying AEs by intensity and relationship to KarXT are given in 
Table 4 and Table 5. 
Table 4. 
Classification of Adverse Events by Intensity 
MILD: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with 
everyday activities. 
MODERATE: An event that is sufficiently discomforting to interfere with normal everyday activities. 
SEVERE: An event that prevents normal everyday activities. 
 
Table 5. 
Classification of Adverse Events by Relationship to KarXT 
UNRELATED: This category applies to those AEs that are clearly and incontrovertibly due to extraneous 
causes (disease, environment, etc). 
UNLIKELY: This category applies to those AEs that are judged to be unrelated to the test drug but for which 
no extraneous cause may be found. An AE may be considered unlikely to be related to KarXT if or when it 
meets 2 of the following criteria: (1) it does not follow a reasonable temporal sequence from administration of 
the test drug; (2) it could readily have been produced by the 
 clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; (3) it does not follow a known pattern of 
response to the test drug; or (4) it does not reappear or worsen when the drug is readministered. 
POSSIBLY: This category applies to those AEs for which a connection with the test drug administration 
appears unlikely but cannot be ruled out with certainty. An AE may be considered possibly related if or when 
it meets 2 of the following criteria: (1) it follows a reasonable temporal sequence from administration of the 
drug; (2) it could not readily have been produced by the 
 clinical state, environmental or toxic factors, 
or other modes of therapy administered to the subject; or (3) it follows a known pattern of response to the test 
drug. 
PROBABLY: This category applies to those AEs that the investigator feels with a high degree of certainty are 
related to the test drug. An AE may be considered probably related if or when it meets 3 of the following 
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
reasonably explained by the known characteristics of the 
 clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; (3) it disappears or decreases on cessation or 
reduction in dose (note that there are exceptions when an AE does not disappear upon discontinuation of the 
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drug, yet drug-relatedness clearly exists; for example, as in bone marrow depression, fixed drug eruptions, or 
tardive dyskinesia); or (4) it follows a known pattern of response to the test drug.
DEFINITELY: This category applies to those AEs that the investigator feels are incontrovertibly related to test 
drug. An AE may be assigned an attribution of definitely related if or when it meets all of the following
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
reasonably explained by the known characteristics of the 
clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; (3) it disappears or decreases on cessation or 
reduction in dose and recurs with re-exposure to drug (if rechallenge occurs); and (4) it follows a known 
pattern of response to the test drug.
5.
Abbreviation: AE = adverse event.
Adverse Events of Special Interest
The AEs of special interest will be monitored and include orthostasis and liver function test 
elevations inclusive of drug-induced liver injury (DILI).
Serious Adverse Events
An SAE is any untoward medical occurrence, in the view of either the investigator or Sponsor, 
that:
results in death,
is life-threatening,
results in inpatient hospitalization or prolongation of existing hospitalization (however, 
hospitalization for elective treatment of a pre-existing non-worsening condition is not 
considered an SAE; the details of such hospitalizations must be recorded on the medical 
history or physical examination page of the eCRF),
results in persistent or significant disability/incapacity, and/or
is a congenital anomaly/birth defect.
Other important medical events that may not be immediately life-threatening or result in death or 
hospitalization, based upon appropriate medical judgment, are considered SAEs if they are 
thought to jeopardize the subject and/or require medical or surgical intervention to prevent 1 of 
the outcomes defining an SAE. Serious AEs are critically important for the identification of 
t. If either the Sponsor or the investigator believes that an event is 
serious, the event must be considered serious and evaluated by the Sponsor for expedited 
reporting.
Serious Adverse Event Reporting
An SAE occurring from the time of informed consent until EOS or ET must be reported to the 
Catalyst Clinical Research Pharmacovigilance group and will be communicated to the Sponsor. 
Any such SAE due to any cause, whether or not related to the KarXT, must be reported within 24 
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hours of occurrence or when the investigator becomes aware of the event. Notification can 
be made using email.
Catalyst Clinical Research Pharmacovigilance email address: 
The event must be recorded on the standard AE eCRF. Preliminary reports of SAEs must be 
followed up by detailed descriptions later on, including clear and anonymized photocopies of 
hospital case reports, consultant reports, autopsy reports, and other documents when requested 
and applicable. SAE reports must be made whether or not the investigator considers the event to 
be related to the investigational drug.
Appropriate remedial measures should be taken to treat the SAE, and the response should be 
recorded. Clinical, laboratory, and diagnostic measures should be employed as needed in order to 
determine the etiology of the problem. The investigator must report all additional follow-up 
evaluations to the Catalyst Clinical Research Pharmacovigilance group within 24 hours of 
becoming aware of the additional information or as soon as is practicable. All SAEs will be 
followed up until the investigator and Sponsor agree the event is satisfactorily resolved.
Any SAE that is not resolved by the end of the study or upon discontinuation of the 
participation in the study is to be followed up until it either resolves, stabilizes, returns to 
baseline values (if a baseline value is available), or is shown to not be attributable to the KarXT
or procedures.
After EOS, any SAE that the Investigator considers related to study drug must be reported to 
Catalyst Clinical Safety or the Sponsor/designee.
Drug-Induced Liver Injury
The sponsor has incorporated the following for monitoring of drug-induced liver injuries:
An increase of serum alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) to >3 × ULN should be followed by repeat testing within 48 to 72 hours of all 4 of 
the usual serum measures (ALT, AST, ALP, and total bilirubin) to confirm the 
abnormalities and to determine if they are increasing or decreasing. An inquiry should be 
made about the symptoms (eg, fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, and rash).
Close observation should be initiated with ALT or AST >3 × ULN:
o
Repeat liver enzyme and serum bilirubin tests 2 or 3 times weekly. The frequency of 
retesting can decrease to once per week or less if abnormalities stabilize or the trial 
drug has been discontinued and the subject is asymptomatic.
o
Obtain a more detailed history of symptoms and prior or concurrent diseases.
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o Obtain a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug 
use, and special diets. 
o Rule out acute viral hepatitis types A, B, C, D, and E, autoimmune or alcoholic 
hepatitis, non-alcoholic steatohepatitis, hypoxic/ischemic hepatopathy, and biliary 
tract disease. 
o Obtain a history of exposure to environmental chemical agents. 
o Obtain additional tests to evaluate liver function, as appropriate (eg, international 
normalized ratio, and/or direct bilirubin). 
o Consider gastroenterology or hepatology consultations. 
 Discontinuation of treatment should be considered if: 
o ALT or AST >8 × ULN 
o ALT or AST >5 × ULN for more than 2 weeks 
o ALT or AST >3 × ULN and (total bilirubin >2 × ULN or international normalized 
ratio >1.5) 
o ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or eosinophilia (>5%) 
 Hepatic adjudication of cases should include an evaluation for alternative causes such as 
viral, autoimmune, alcohol, hepatobiliary disorders, non-alcoholic steatohepatitis, 
concomitant medications, etc. 
 Follow-up to resolution of elevated liver enzymes. 
 Gamma-glutamyl transferase elevations alone should not prompt drug discontinuation.  
Subjects must be monitored closely. If close monitoring is not possible, the study drug should be 
discontinued. 
11.7.5.1 
Trial Discontinuation Criteria Other than DILI and Pregnancy 
11.7.5.2 
Individual Stopping Criteria 
Based on NCI CTCAE v5.0, study drug will be 
 Grade 4 
AE. Discontinuation or reduction in the dosage of the study drug for Grade 3 AEs other than 
DILI AEs (see Section 11.7.5) will be at the discretion of the investigator. 
11.7.5.3 
Trial Stopping Rules 
The safety and tolerability aspects of KarXT will be overseen by an ISMC. The ISMC will meet 
periodically and review the unblinded data and will be responsible for advising the sponsor on 
ways to safeguard the interests of the clinical study subjects. The committee is expected to 
recommend sponsor whether to: 
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a.
Continue the clinical study without modification; or
b. Continue the clinical study with modification (listing the specific modifications 
recommended); or
c.
Terminate the study.
Suspected Unexpected Serious Adverse Reactions
Adverse events that meet all of the following criteria will be classified as suspected unexpected 
serious adverse reactions (SUSARs) and reported to the appropriate regulatory authorities in 
accordance with applicable regulatory requirements for expedited reporting:
serious
unexpected (ie, the event is not consistent with the safety information in the IB or 
package insert of generic trospium)
there is at least a reasonable possibility that there is a causal relationship between the event 
and the study treatment
The investigator will assess whether an event is causally related to study treatment. The Sponsor 
meets the criteria for being reportable as a 7-day or 15-day safety report. SUSARs that are fatal 
or life-threatening must be reported to the regulatory authorities and the IEC/IRBs (where 
required) within 7 days after the Sponsor (or Syneos Health) has first knowledge of them, with a 
follow-up report submitted within a further 8 calendar days. Other SUSARs must be reported to 
the relevant regulatory authorities and the IEC/IRBs within 15 calendar days after the Sponsor 
(or Syneos Health) first has knowledge of them.
The Sponsor (or Syneos Health) is responsible for reporting SUSARs and any other events 
required to be reported in an expedited manner to the regulatory authorities and for informing 
investigators of reportable events, in compliance with applicable regulatory requirements within 
specific timeframes. Investigators will notify the relevant IEC/IRBs of reportable events within 
the applicable timeframes.
Warnings and Precautions
Risk of Urinary Retention:
Trospium chloride tablets should be administered with caution to subjects with clinically 
significant bladder outflow obstruction because of the risk of urinary retention.
Angioedema:
Angioedema of the face, lips, tongue, and/or larynx has been reported with trospium chloride, the 
active ingredient in trospium chloride tablets. In one case, angioedema occurred after the first 
dose of trospium chloride. Angioedema associated with upper airway swelling may be 
life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, trospium chloride 
should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a 
patent airway should be promptly provided.
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Decreased Gastrointestinal Motility: 
Trospium should be administered with caution to subjects with GI obstructive disorders because 
of the risk of gastric retention. Trospium chloride, like other antimuscarinic agents, may decrease 
GI motility and should be used with caution in subjects with conditions such as ulcerative colitis, 
intestinal atony, and myasthenia gravis. 
Controlled Narrow-angle Glaucoma: 
In subjects being treated for narrow-angle glaucoma, trospium chloride should only be used if 
the potential benefits outweigh the risks and in that circumstance only, with careful monitoring. 
Central Nervous System Effects: 
Trospium chloride is associated with anticholinergic CNS effects. A variety of CNS 
anticholinergic effects have been reported, including dizziness, confusion, hallucinations, and 
somnolence. Subjects should be monitored for signs of anticholinergic CNS effects, particularly 
after beginning treatment or increasing the dose. Advise subjects not to drive or operate heavy 
machinery until they know how trospium chloride affects them. If a subject experiences 
anticholinergic CNS effects, dose reduction or drug discontinuation should be considered. 
Anticholinergic Adverse Reactions in Subjects with Moderate Renal Impairment: 
Trospium is substantially excreted by the kidney. The effects of moderate renal impairment on 
systemic exposure are not known but systemic exposure is likely increased. Therefore, 
anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract 
infection, and urinary retention) are expected to be greater in subjects with moderate renal 
impairment. 
Elevation of liver enzymes: 
Elevated liver enzymes have been reported in previous studies of xanomeline alone in 
e, however, that the hepatic enzyme elevations were not 
observed in the Phase 1 studies in healthy volunteers and that the liver function test elevations 
observed in the Phase 2 schizophrenia study (KAR-004) with KarXT (a combination of 
xanomeline and trospium) were quite limited in contrast to the effects observed with xanomeline 
experienced more hepatic enzyme elevations, the data demonstrate reversibility even with 
continued xanomeline treatment in those patients where there was sufficient follow-up data. 
limit of reference range in either the xanomeline or KarXT datasets. 
11.8 Pregnancy 
WOCBP must have a negative pregnancy test at baseline (Day 0).  
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The investigator must notify the Sponsor (or designee) of any female subject or female partner of 
a male subject that becomes pregnant while participating in the study. Any known cases of 
pregnancy will be reported until the subject completes or withdraws from the study.  
The pregnancy will be reported immediately by faxing/emailing a completed pregnancy report to 
the Sponsor (or designee) within 24 hours of knowledge of the event. The pregnancy will not be 
processed as an SAE; however, the investigator will follow-up with the subject until completion 
of the pregnancy and must assess the outcome in the shortest possible time, but not more than 
30 days after completion of the pregnancy.  
If a female subject becomes pregnant, the investigator must withdraw her from the study without 
delay. The subject must not receive any further doses of the KarXT. Upon discontinuation from 
the study, only those procedures that would not expose the subject to undue risk will be 
performed. 
If the female subject or the female partner of the male subject is willing and able to consent to 
pregnancy follow-up, she will be followed until her pregnancy reaches term. Information 
regarding the pregnancy must only be submitted after obtaining written consent from the 
pregnant partner. The investigator will arrange counseling for the pregnant partner by a specialist 
to discuss the risks of continuing with the pregnancy and the possible effects on the fetus. 
The investigator should notify the Sponsor (or designee) of the pregnancy outcome by 
submitting a follow-up pregnancy report. If the outcome of the pregnancy involved spontaneous 
or therapeutic abortion (any congenital anomaly detected in an aborted fetus is to be 
documented), stillbirth, neonatal death, or congenital anomaly, the investigator will report the 
event by faxing/emailing a completed pregnancy report form to the Sponsor (or designee) within 
24 hours of knowledge of the event. This event is considered as an SAE. 
The investigator should also be notified of pregnancy occurring during the study but confirmed 
after completion of the study. In the event that a subject is subsequently found to be pregnant 
after inclusion in the study, any pregnancy will be followed to term, and the status of mother and 
child will be reported to the Sponsor after delivery. 
11.9 Overdose 
The investigator must immediately notify the Sponsor of any occurrence of overdose with 
KarXT (total daily dose greater than 250/60 mg). 
Signs and symptoms of overdose may vary considerably. They are usually manifested by 
increasing GI stimulation with epigastric distress, abdominal cramps, diarrhea and vomiting, 
excessive salivation, pallor, cold sweating, urinary urgency, blurring of vision, and eventually 
fasciculation and paralysis of voluntary muscles. Miosis, increases or decreases in blood pressure 
with or without bradycardia, and severe anxiety and panic may occur. 
Supportive treatment should be used as indicated (artificial respiration, maintenance of airway, 
oxygen, etc.). Atropine sulfate should be available for IV or intramuscular administration. 
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Several doses ranging from 0.5 to 2.0 mg may be required. Epinephrine 0.1 to 1.0 mg 
subcutaneous may also be of value in overcoming severe cardiovascular or bronchoconstrictor 
responses. 
Adverse events associated with overdoses should be reported on the eCRF. 
11.10 Simpson-Angus Rating Scale 
The SAS is an established instrument to measure drug-related extrapyramidal syndromes. It is a 
10-item testing instrument used to assess gait, arm dropping, shoulder shaking, elbow rigidity, 
wrist rigidity, leg pendulousness, head dropping, glabella tap, tremor, and salivation. The range 
of scores is from 0 to 40 with increased scores indicating increased severity. 
11.11 Barnes Rating Scale for Akathisia 
The Barnes Rating Scale for akathisia is a rating scale used to assess the severity of drug-induced 
akathisia, or restlessness, involuntary movements, and inability to sit still. The range of scores is 
0 to 14, with higher scores indicating greater severity.[23] 
11.12 Abnormal Involuntary Movement Scale 
The AIMS is a rating scale that is used to measure involuntary movements know as tardive 
dyskinesia, which can sometimes develop as a side effect of long-term treatment with 
antipsychotic medications. It is a 12-item scale to assess orofacial, extremity, and truncal 
movements as well as the overall severity, incap
the movements. Items are scored from 0 (none) to 4 (severe). A higher score indicates more 
severe dyskinesia. 
11.13 Columbia-Suicide Severity Rating Scale 
The C-SSRS is a tool designed to systematically assess and track suicidal AEs (suicidal behavior 
and suicidal ideation) throughout the study.[24] The strength of this suicide classification system 
is in its ability to comprehensively identify suicidal events while limiting the over-identification 
of suicidal behavior. The scale takes approximately 5 minutes to administer. The C-SSRS will be 
administered by a trained rater at the site. 
11.14 Functional Constipation Inquiry 
Constipation refers to bowel movements that are infrequent or hard to pass.[25] The stool is 
often hard and dry.[26] Other symptoms may include abdominal pain, bloating, and feeling as if 
one has not completely passed the bowel movement.[27] The normal frequency of bowel 
movements in adults is between 3 per day and 3 per week.[25] Constipation will be defined per 
the Rome III criteria, as less than 3 bowel movements per week, Appendix 2 
(Longswreth,1486,C3).[28] 
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The Bristol Stool Form Scale has been correlated with a change in intestinal function, and has 
been shown to be a useful tool in clinical practice and research.[29] A sample Bristol Stool Form 
Scale is located in Appendix 2. 
As a measure of anticholinergic effects, at specified visits (Table 2), subjects will be asked 
whether they have experienced constipation per the ROME III criteria since the last visit, and if 
yes, whether the constipation required intervention. If the subject answers yes, sites are 
instructed to ask subjects to provide event date and ensure event is documented as an AE and 
treatment is documented as concomitant medication. Subjects will not be required to collect and 
present their stool sample, nor will clinic staff be required to corroborate the subject assessment. 
Additional attention can be given to other complaints as well including: straining with bowel 
movements, excessive time needed to pass a bowel movement, hard stools, pain with bowel 
movements secondary to straining, abdominal pain, abdominal bloating, and the sensation of 
incomplete bowel evacuation.[27, 30] 
Treatment of constipation depends on the underlying cause and the duration that it has been 
present. For the purposes of constipation complaints during a clinical trial, the use of laxatives of 
a bulk forming agent, osmotic agent, stool softener, or lubricant type may be used. 
As definitions of constipation are typically based on a history of at least a week, site physician 
discretion will be allowed for initiation of such treatments. 
 
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12 EFFICACY ASSESSMENTS 
The Schedule of Assessments (Table 2) outlines the efficacy assessments to be performed 
throughout the study and their timing. 
12.1 Positive and Negative Syndrome Scale 
The PANSS is a clinician-administered scale used for measuring symptom severity of subjects 
with schizophrenia and is widely used in the study of antipsychotic therapy.[31] The PANSS 
rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general 
psychopathology symptom scales. Subjects are rated from 1 to 7 on each symptom scale. The 
positive symptoms in schizophrenia are the excess or distortion of normal function such as 
hallucinations, delusions, grandiosity, and hostility, and the negative symptoms in schizophrenia 
are the diminution or loss of normal functions. It takes approximately 45 to 50 minutes to 
administer. PANSS total score is the sum of all scales with a minimum score of 30 and a 
maximum score of 210.  
It is recommended, if at all possible, that the PANSS assessment should be performed before all 
the other scale assessments for all visits at which it is performed. 
12.2 Clinical Global Impression-Severity 
The CGI-S is a rating scale, completed independently by a clinician that is used to measure 
illness and symptom severity in subjects with mental disorders. It is used to rate the severity of a 
-S modified asks the clinician 1 question: 
 The 
-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 subjects.[32] 
This rating is based upon observed and reported symptoms, behavior, and function in the past 
7 days. As symptoms and behavior can fluctuate over a week, the score should reflect the 
average severity level across the 7 days. 
 
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13
PHARMACOKINETICS
13.1 Pharmacokinetic Sampling
PK Blood Samples and Timing
On Days 8, 14, 84, 168, and 280
scheduled study visit (see Table 2). On Day 8 the PK sample should be drawn within 1 to 2 hours 
post-dose whenever possible.
Approximately 4 mL of blood will be collected at each scheduled time point. The actual date and 
time of each blood sample collection will be recorded. 
A single PK sample may be drawn if a relevant/significant AE is reported or if there is a dose 
adjustment. For ET that is related to an AE, collection of PK blood sample at the ET visit is 
recommended. 
Details of PK blood sample collection, processing, storage, and shipping procedures will be 
provided in a separate laboratory manual.
13.2 Pharmacokinetic Analytical Methodology
The plasma concentration of trospium and xanomeline in PK samples will be measured using a 
validated bioanalytical method. Details of the method validation and sample analysis will be 
included with the final clinical study report.
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14 EXPLORATORY ASSESSMENTS 
The exploratory assessments cognition testing, prolactin levels, digital biomarkers, EMA PRO, 
and EMA VLMT will be performed at scheduled visits or study days, as per the Schedule of 
Assessments (Table 2). 
14.1 Cognition Testing - Cambridge Neuropsychological Test Automated Battery 
The computerized CANTAB provides an objective measure of cognitive function correlated to 
neural networks. A short cognitive battery measuring core cognitive domains of impairment in 
schizophrenia (ie, as per Brief Assessment of Cognition Schizophrenia key cognitive domains) 
will be employed for this study, and it will take approximately 30 minutes to complete. These 
CANTAB tests meet MATRICS workshop criteria.[33] Subjects will perform the test on a 
provisioned iPad with data immediately uploaded to the CANTAB Connect cloud-based 
platform (Wi-Fi permitting). 
Cognition testing should not be done within 8 hours of receiving benzodiazepine or sleep 
medications. 
Table 6. 
Cognitive Tests and Cognitive Domains Assessed by the Cambridge 
Neuropsychological Test Automated Battery 
CANTAB Tests 
MATRICS Cognitive Domain 
Outcome Measures 
Rapid visual information 
processing 
Sustained attention/vigilance 
 Signal detection 
measure of how good the subject is 
at detecting the target sequence 
(string of three numbers); 
regardless of response tendency 
Verbal recognition memory 
Verbal memory and new learning 
Free Recall: The total number of 
words that are correctly recalled 
from the presentation phase by the 
subject during the immediate free 
recall stage 
Spatial Span 
Working memory 
Forward Span Length: The 
longest sequence of boxes 
successfully recalled by the subject 
One-touch stockings of Cambridge  
Executive Function 
Planning/Problem Solving 
Problems Solved on First Choice: 
The total number of assessed trials 
where the subject chose the correct 
answer on their first attempt 
6. Abbreviation: CANTAB = Cambridge Neuropsychological Test Automated Battery 
 
14.2 Change in Prolactin 
Blood samples to assess the change in prolactin levels will be obtained on scheduled visits as 
specified in Table 2. Prolactin sample is optional when sites are using local labs.  
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14.3 Digital Biomarkers of Schizophrenia (US only)
Study subjects may be performing brief smartphone-based assessments using the AiCure 
application mentioned in Section 10.2.1. Video and audio of participant behavior captured during 
these assessments will be used to calculate visual and auditory markers of schizophrenia 
symptomatology. These digital biomarkers will be used as exploratory efficacy endpoints to 
measure change from baseline in disease severity. The following exploratory endpoints will be 
collected:
Overall emotional expressivity
Positive emotional expressivity 
Negative emotional expressivity
Audio intensity / speech volume Fundamental frequency of voice
Formant frequencies of voice
Vocal jitter
Vocal shimmer
Pause lengths during speech
Lexical diversity
Rate of speech
Euclidean head movement
Rotational head movement
The collection of digital biomarkers via the AiCure application is optional for all subjects.
14.4 EMA Wellness Assessments
EMA Wellness EMA PRO (US only)
EMA is an ambulatory data collection technique that allows the real-time in vivo assessment of 
functioning behaviors. In the present study, EMA Patient Reported Outcomes (PRO) may be 
symptoms in schizophrenia through the use of smartphones for subjects enrolled at US sites only. 
EMA PRO surveys ar
alone or with others, and activities and moods in the last hour. A pop-up visualization will signal 
participants, 3 times per day for 7 days, to respond to very brief (e.g., 3 minutes) questionnaires 
about their activities, mood, and symptom experiences during the last hour, per the Schedule of 
Assessments (Table 2). An abbreviated EMA PRO survey, collecting only information on the 
for 3 days starting on Day 4 and Day 15. Daily assessment times will be adjusted to 
The collection of EMA Wellness 
variables via the EMA PRO application is optional for all subjects.
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EMA Wellness - VLMT (US only)
Cognitive insight assessment will be conducted through testing on the Verbal Learning and 
Memory Test (VLMT), which will be completed by subjects enrolled at US sites only. This 
assessment will be performed at home on a cellular device 1 time per day for 2 days every 
28 days beginning on Day 32. During each VLMT administration, subjects will be presented 
with a list of 6- or 12-words over in 2 separate trials each lasting 30 seconds. Immediately 
following each exposure to the list, subjects will be shown target and recognition foil words 
one-by-one and asked to indicate whether or not the word appeared on the list. 
In order to examine response bias and the ability to self-evaluate memory performance, 
immediately after each recognition trial, the subjects will be asked to indicate how many words 
they believe that they got correct. They will also be asked how well they did as compared to the 
previous trial and at the end of the 2 trials they will be asked if they improved over the 2 learning 
trials.
The collection of EMA Wellness VLMT is optional for all subjects.
Data Collected on EMAW Platform
Data are encrypted and uploaded to secure servers whenever the phone is connected to Wi-Fi or 
if cellular data is available. If a Wi-Fi and cellular data are unavailable, EMA response data will 
be transferred during in-clinic visits.
During each EMA PRO, subjects will be asked about their location (home vs away and where if 
away); they will also be asked if they are alone or with others, and about their activities, 
symptoms of schizophrenia, and moods in the last hour. 
Data collected during the VLMT include the identification of target words and rejections of foils. 
The participants will also provide an immediate estimate of their memory task performance as 
soon as each recognition trial is over.
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15 STATISTICAL ANALYSIS 
A statistical analysis plan (SAP) will be prepared after the protocol is approved. This document 
will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. The SAP will serve as a complement to the protocol 
and supersedes it in case of differences. 
The statistical evaluation will be performed using SAS® software version 9.4 or higher 
(SAS Institute, Cary, NC). All data will be listed, and summary tables will be provided. 
Summary statistics will be presented by dose group. For continuous variables, data will be 
summarized with the number of subjects (N), mean, standard deviation, median, minimum, and 
maximum by treatment group. For categorical variables, data will be tabulated with the number 
and proportion of subjects for each category by treatment group. No statistical hypothesis testing 
will be performed. 
15.1 Determination of Sample Size 
As the primary objective of this study is to assess the long-term safety and tolerability of KarXT, 
the number of subjects anticipated is based on the number of subjects recruited into and 
completing the acute studies (KAR-007, KAR-009) and meeting the eligibility requirements for 
KAR-008. 
15.2 Analysis Populations 
Enrolled population: All subjects who have given informed consent for KAR-008. 
Safety population: All subjects who receive at least 1 dose of KarXT during the current study 
will be included in the safety population and will be used in the safety analysis. 
Modified ITT (mITT) population: All subjects who are enrolled, received at least 1 dose of 
KarXT, and have a valid post-baseline PANSS assessment will be included in the mITT 
population and will be used in the efficacy analysis. 
PK population: All subjects who have received at least 1 dose of KarXT and have at least 
1 measurable plasma concentration of KarXT will be included in the PK population. 
15.3 Safety Analysis 
Safety endpoints will be summarized for all subjects in the Safety population. The presentation 
of safety data will be based on the treatment received in KAR-008. 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 22.1 or higher. The incidence of TEAEs (defined as events with an onset 
date on or after the first dose of KarXT) will be summarized by System Organ Class and 
Preferred Term. All AEs will be listed by subject, along with information regarding onset, 
duration, relationship and severity to KarXT, action taken with KarXT, treatment of event, and 
outcome. 
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Orthostatic vital signs, clinical laboratory data, ECG parameters, and physical examinations will 
be summarized using descriptive statistics, including observed and change from baseline values, 
as well as numbers of subjects with values outside limits of the normal range at each time point. 
Similar descriptive summaries will be provided for C-SSRS, SAS, BARS, AIMS, body weight, 
BMI, and waist circumference. 
15.4 Efficacy Analysis 
Efficacy analyses will be summarized based on the mITT population. The summaries described 
in this section will provide data on maintenance of effect of open-label KarXT over 52 weeks. 
As these variables are summarized over time and the initial values can be impacted by the 
treatment received in the acute study, the presentation will use a combination of acute/extension 
study treatment groups, which is intended to provide perspective on the change in these values 
from the acute study through the treatment period of KAR-008. Tabular presentations will 
display descriptive statistics for Baseline of the acute study and the observed and change from 
baseline study results by scheduled visit for KAR-008. 
Responder efficacy variables (PANSS responders) will be summarized descriptively. Response 
will be derived relative to the acute study Baseline assessment. 
Continuous efficacy variables based on the change from baseline (PANSS, CGI-S) will be 
summarized using descriptive statistics by scheduled visit. Tabular presentations will display 
descriptive statistics for the Baseline of the acute study and the observed and change from 
baseline results by scheduled visit for KAR-008. Figures for selected variables will also be 
generated in order to demonstrate the kinetics of response over time. 
15.5 Pharmacokinetic Analysis 
The PK evaluation will rely on an existing population PK model for KarXT in subjects with 
schizophrenia. The plasma concentrations of xanomeline and trospium measured in this study 
will be overlaid onto distributions of concentrations predicted by the population PK model 
developed from KAR-007 and KAR-009 data. Percentages of measured concentrations in the 
current study that lie within, above, and below the 90% prediction interval of concentrations 
predicted by the model will be calculated.   
Details of the PK analysis will be described in the SAP.   
15.6 Exploratory Analysis 
The following will be summarized using descriptive statistics: change in cognition using 
CANTAB; prolactin levels, digital biomarkers of schizophrenia; EMA PRO and EMA VLMT.  
Further details will be provided in the SAP. 
15.7 Interim Analysis 
No interim analysis is planned for this study. 
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15.8 Handling of Missing Data 
For continuous efficacy variables based on the change from baseline (PANSS, CGI-S), 
summaries will be based on observed case data.  
Additional methods of missing data imputation may be explored and will be outlined in the SAP. 
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16
STUDY MANAGEMENT
16.1 Approval and Consent
Regulatory Guidelines
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki and/or all relevant regulations, as set forth in Parts 50, 56, 312, Subpart D, of Title 21 of 
the US Code of Federal Regulations (CFR), in compliance with International Council for 
Harmonisation (ICH) and good clinical practice (GCP) guidelines, and all applicable local, state 
and federal government regulations and laws.
Institutional Review Board/Independent Ethics Committee
Conduct of the study must be approved by an appropriately constituted IEC/IRB. Approval is 
required for the study protocol, protocol amendments (if applicable), IB, ICFs, recruitment 
material and subject information sheets and other subject-facing material.
Informed Consent
For each study subject, written informed consent will be obtained before any protocol-related 
activities. As part of this procedure, the PI or designee must explain orally and in writing the 
nature of the study, its purpose, procedures, expected duration, alternative therapy available, and 
the benefits and risks involved in study participation. The subject should be informed that they
may withdraw from the study at any time, and the subject will receive all information that is 
required by local regulations and guidelines for ICH. The PI will provide the Sponsor or its 
representative with a copy of the IEC-/IRB-approved ICF before the start of the study.
The ICF should be revised whenever there are substantial changes to procedures or when new 
information becomes available that may affect the willingness of the subject to participate. 
Revisions to the consent form required during the study must be approved by the Sponsor and 
IEC/IRB, and a copy of the revised consent form is provided to the Sponsor. For any updated or 
revised consent forms, the subjects must be re-consented for continued participation in the study.
A pregnant partner consent form should be obtained before collecting any data from a female 
pregnant partner of a male subject, if she becomes pregnant during the course of the study or 
within 1 week of the last dose of KarXT.
A caregiver consent must be obtained (Ukraine only) before collecting any data from a caregiver 
pertaining to him or her and the subject.
Subject Registry (US only)
Clinical trial registries, such as clinical trial subject database (CTSdatabase) and Verified 
Clinical Trials (VCT) seek to reduce duplicate enrollment by identifying potential protocol 
violations and duplicate subjects before randomization. At the time of providing the informed 
consent for the initial KAR-007 or -009 study (US Only), the investigator or designee will have 
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explained the IRB/IEC-approved Subject Database Authorization to the subject and witnessed 
the signature. That executed authorization form remains in effect for KAR-007 and KAR-008 or 
KAR-009 and KAR-008 study participation. 
At the beginning of screening for KAR-007 or KAR-009 (US only), following consents 
execution and subject number assignment and before other study procedures, site staff that had 
received training and login information access (www.subjectregistry.com) to the database 
entered the subject study ID number and authorized subject identifiers. Two reports, one from 
CTS and one from VCT, detailing any potential protocol violations or dual enrollment attempts 
were generated and were printed for source documentation. The reports detailed each protocol 
violation detected and specific washout period dates where applicable.  
Throughout the initial KAR-007 or KAR-009 study, and during this open label extension study, 
tracking of actively enrolled subjects will continue based on updates by coordinators in the 
interactive response system.  At the last subject contact, CTSdatabase and VCT staff will 
automatically close out the subject (safety follow-up, ET, or completer) based on interactive 
response system (IXRS). 
16.2 Data Handling 
Any data to be recorded directly on the eCRFs (to be considered as source data) will be 
identified at the start of the study. Data reported on the eCRF that are derived from source 
documents should be consistent with the source documents, or the discrepancies must be 
explained. See also Section 16.3.  
Clinical data will be entered by site personnel on eCRFs for transmission to the Sponsor. Data on 
eCRFs transmitted via the web-based data system must correspond to and be supported by source 
documentation maintained at the study site unless the study site makes direct data entry to the 
databases for which no other original or source documentation is maintained. In such cases, the 
study site should document which eCRFs are subject to direct data entry and should have in 
place procedures to obtain and retain copies of the information submitted by direct data entry. 
All study forms and records transmitted to the Sponsor must only include coded identifiers such 
that directly identifying personal information is not transmitted. The primary method of data 
transmittal is via the secure, internet-based electronic data capture (EDC) system maintained by 
Syneos Health. Access to the EDC system is availa
secure internet web site, where a user unique assigned username and password are required for 
access. 
Any changes made to data after collection will be made through the use of the EDC system. 
Electronic CRFs will be considered complete when all missing and/or incorrect data have been 
resolved. 
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16.3 Source Documents 
Source documents are considered to be all information in original records and certified copies of 
original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. The investigator will provide direct 
access to source documents and/or source data in the facilitation of trial-related monitoring, 
audits, review by IECs/IRBs, and regulatory inspections. 
The investigator/institution should maintain adequate and accurate source documents and trial 
subjects. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, not obscure the original entry, and be explained if necessary. 
Data recorded on source documents will be transcribed onto eCRFs. Copies of completed eCRFs 
will be provided to the Sponsor and the sites at the end of the study. The completed eCRFs will 
be retained by the investigator. 
16.4 Record Retention 
Study records and source documents must be preserved for at least 15 years after the completion 
or discontinuation of/withdrawal from the study, at least 2 years after the drug being studied has 
received its last approval for sale, or at least 2 years after the drug development has stopped, and 
in accordance with the applicable local privacy laws, whichever is the longer time period. 
The investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subject health information, including, but not limited to, the 
Standards for Individually Identifiable Health Information, 45 CFR, Parts 160 and 164 (the 
HIPAA of 1996 Privacy Regulation). The investigator shall ensure that study subjects authorize 
the use and disclosure of protected health information in accordance with HIPAA Privacy 
Regulation and in a form satisfactory to the Sponsor. 
16.5 Monitoring 
The study will be monitored according to the KAR-008 monitoring plan to ensure that it is 
conducted and documented properly according to the protocol, GCP, and all applicable 
regulatory requirements. 
Monitoring visits may include on-site or remote visits and may also utilize periodic telephone 
contacts. The PI will assure they and adequate site personnel are available throughout the study 
to collaborate with clinical monitors. Clinical monitors must have direct access to source 
documentation in order to check the completeness, clarity, and consistency of the data recorded 
in the eCRFs for each subject. 
The investigator will make available to the clinical monitor all source documents and medical 
records necessary to review protocol adherence and eCRFs. In addition, the investigator will 
work closely with the clinical monitor and as needed, provide them appropriate evidence that the 
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study is being conducted in accordance with the protocol, applicable regulations, and GCP
guidelines.
16.6 Quality Control and Quality Assurance
The Sponsor or its designee will perform the quality assurance and quality control activities of 
this study; however, responsibility for the accuracy, completeness, security, and reliability of the 
study data presented to the Sponsor lies with the investigator generating the data.
The Sponsor or its designee will arrange audits as part of the implementation of quality 
assurance to ensure that the study is being conducted in compliance with the protocol, standard 
operating procedures, GCP, and all applicable regulatory requirements. Audits will be 
independent of and separate from the routine monitoring and quality control functions. Quality 
assurance procedures will be performed at study sites and during data management to assure that 
safety and efficacy data are adequate and well documented.
16.7 Protocol Amendment and Protocol Deviation
Protocol Amendment
Amendments to the protocol that entail corrections of typographical errors, clarifications of 
confusing wording, changes in study personnel, and minor modifications that have no effect on 
the safety of subjects or the conduct of the study will be classed as administrative amendments 
and will be submitted to the IEC/IRB for information only. Syneos Health will ensure that 
acknowledgement is received and filed. Amendments that are classed as substantial amendments 
must be submitted to the appropriate regulatory authorities and the IECs/IRBs for approval and 
will not be implemented at sites until such approvals are received, other than in the case of an 
urgent safety measure.
Protocol Deviations
Should a protocol deviation occur, the Sponsor must be informed as soon as possible. Protocol 
deviations and/or violations and the reasons they occurred will be included in the clinical study 
report. Reporting of protocol deviations to the IEC/IRB and in accordance with applicable 
All protocol deviations will be tracked in the Clinical Trial Management System.
Deviations considered major will be identified as such before study unblinding during 
medical monitor periodic review.
Major protocol deviations will be tabulated including the frequency and percentage of subjects 
with each type of deviation by treatment group.
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16.8 Ethical Considerations 
This study will be conducted in accordance with this protocol, the accepted version of the 
Declaration of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, 
Subpart D, of Title 21 of the CFR; and in compliance with GCP guidelines. 
IECs/IRBs will review and approve this protocol and the ICF. All subjects and/or caregivers 
(Ukraine only) are required to give written informed consent before participation in the study. 
16.9 Financing and Insurance 
Before the study commences, the Sponsor (or its designee) and the investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study. This agreement will 
be documented in a financial agreement that will be signed by the investigator (or the institution 
signatory) and the Sponsor (or its designee). 
The investigator is required to have adequate current insurance to cover claims for negligence 
and/or malpractice (US only). The Sponsor will provide no-exclusion insurance coverage for the 
clinical study as required by national regulations. 
16.10 Publication Policy/Disclosure of Data 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Intellectual property rights (and related matters) generated by the investigator and others 
performing the clinical study will be subject to the terms of a clinical study agreement that will 
be agreed between the institution and the Sponsor or their designee. With respect to such rights, 
the Sponsor or its designee will solely own all rights and interests in any materials, data, and 
intellectual property rights developed by investigators and others performing the clinical study 
described in this protocol, subject to the terms of any such agreement. In order to facilitate such 
ownership, investigators will be required to assign all such inventions either to their institution or 
directly to the Sponsor or its designee, as will be set forth in the clinical study agreement. 
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17 REFERENCES 
1. Patel KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: overview and treatment options. P 
T. 2014;Sep 39(9):638-645. 
2. van Os J, Kapur S. Schizophrenia. Lancet. 2009 Aug 22;374(9690):635-645. 
3. Wu EQ, Shi L, Birnbaum H, Hudson T, Kessler R. Annual prevalence of diagnosed 
schizophrenia in the USA: a claims data analysis approach. Psychol Med. 2006 
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18 APPENDICES 
Appendix 1: Contraception Guidelines 
Female subjects of childbearing potential with a non-sterilized male sexual partner must agree to 
use at least 1 highly effective method of contraception beginning >30 days before receiving 
study drug on Day 1 and continuing until 30 days after the End of Study (EOS) Visit. If oral 
contraceptives are used, the subject must have been on a stable dose for 6 months. 
 
A woman is considered to be WOCBP following menarche and until becoming postmenopausal, 
unless she is permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy [22]. Female subjects who are postmenopausal, 
which is defined as 12 consecutive months with no menses without an alternative medical cause, 
must have been postmenopausal for >1 year if they wish to not use contraceptives. 
-stimulating hormone 
(FSH) level which must be elevated and consistent with postmenopausal levels (ie, >40 IU/L); 
otherwise, these subjects must agree to use contraceptives listed below. Female subjects who are 
surgically sterile (ie, hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) will not 
need to undergo the FSH level test. 
 
A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
Highly effective methods of contraception are those that have a failure rate of <1% (when 
implemented consistently and correctly) and include the following: 
 combined (containing estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation (administration may be oral, intravaginal, or transdermal) 
 progestogen-only hormonal contraception associated with inhibition of ovulation 
(administration may be oral, injectable, or implantable) 
 intrauterine device 
 intrauterine hormone-releasing system 
 bilateral tubal ligation or occlusion 
 vasectomy (provided that the male has a medical assessment of surgical success) 
All subjects will be strongly advised that they (or the female partners of male subjects) should 
not become pregnant before receiving study drug on Day 1 and continuing until 30 days after the 
End of Study Visit. A female subject will be advised that she must report immediately to the 
study site for pregnancy testing and appropriate management in the event that she may be 
pregnant. 
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Appendix 2: Functional Constipation Inquiry 
 
 
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