An Open-label Study to Assess the Long-term Safety, Tolerability, and Efficacy of KarXT in De Novo Subjects With DSM-5 Schizophrenia
Phase: PHASE3
Conditions: Schizophrenia
Sponsor: Karuna Therapeutics, Inc., a Bristol Myers Squibb company

Official Title of Study: 
An Open-label Study to Assess the Long-term Safety, Tolerability, and Efficacy 
of KarXT in De Novo Subjects With DSM-5 Schizophrenia 
 
NCT Number: NCT04820309 
Document Date (Date in which document was last revised): 26 Sep 2023 
 
 
 

Karuna Therapeutics 
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1 
FINAL CLINICAL STUDY PROTOCOL  
Karuna Therapeutics 
Protocol Title: An Open-label Study to Assess the Long-term Safety, Tolerability, and Efficacy 
of KarXT in De Novo Subjects With DSM-5 Schizophrenia 
Protocol Number: KAR-011 
IND Number: 
127471 
EudraCT Number: 
Not applicable 
Name of Investigational Product: 
KarXT 
Phase of Development: 
3 
Indication: 
Schizophrenia 
Sponsor: 
Karuna Therapeutics 
99 High Street 
Floor 26 
Boston, MA 02110 
Tel: (857) 449-2244 
Email: info@karunatx.com 
Protocol Version: 
4.0 
Protocol Date: 
26 Sep 2023 
-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 Study to Assess the Long-term Safety, Tolerability, 
and Efficacy of KarXT in De Novo Subjects With DSM-5 
Schizophrenia 
Protocol Number: 
KAR-011 
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 
Date (DD-Mmm-YYYY) 
 
 
Karuna Therapeutics 
Date (DD-Mmm-YYYY) 
 
 Clinical Scientist 
Karuna Therapeutics 
Date (DD-Mmm-YYYY) 
Karuna Therapeutics 
Date (DD-Mmm-YYYY) 
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Contract Research Organization Signatory  
 
Syneos Health 
Date (DD-Mmm-YYYY) 
Biostatistician 
 
 
Veristat 
Date (DD-Mmm-YYYY) 
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INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
An Open-label Study to Assess the Long-term Safety, Tolerability, and 
Efficacy of KarXT in De Novo Subjects With DSM-5 Schizophrenia 
Protocol Number: 
KAR-011 
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 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 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 Study to Assess the Long-term Safety, Tolerability, and 
Efficacy of KarXT in De Novo Subjects With DSM-5 Schizophrenia 
Protocol Number: 
KAR-011 
Investigators/Study Sites: 
Approximately 60 sites in the United States 
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 
evaluate plasma concentrations of xanomeline and trospium following 
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) score 
• 
To evaluate the reduction in PANSS negative score  
• 
To evaluate the reduction in PANSS Marder Factor negative 
symptoms score 
• 
To evaluate the percentage of subjects who exhibit a 30% reduction in 
PANSS total score 
Study Endpoint(s): 
Primary Safety Endpoint:  
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The primary safety endpoint is the incidence of treatment-emergent adverse 
events (TEAEs). 
Secondary Endpoints: 
Safety: 
The secondary safety endpoints of the study are: 
• 
Incidence of serious TEAEs 
• 
Incidence of TEAEs leading to withdrawal 
Efficacy: 
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 
• 
CGI-S score at Week 52 
• 
Percentage of PANSS responders (a 30% reduction in PANSS 
total score) at Week 52  
Other Endpoints:  
Other Safety endpoints: 
The other safety endpoints of the study are: 
• 
Spontaneously reported adverse events of special interest (AESIs) 
• 
Spontaneously reported anticholinergic and procholinergic 
symptoms 
• 
Change from baseline in Simpson-Angus Rating Scale (SAS) 
• 
Change from baseline in Barnes Akathisia Rating Scale (BARS) 
• 
Change from baseline in Abnormal Involuntary Movement Scale 
(AIMS) 
• 
Change from baseline in body weight, body mass index (BMI), 
and 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 examinations  
• 
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 
 
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Study Design: 
This is a Phase 3, multicenter, 52-week, outpatient, open-label study to 
evaluate the long-term safety, tolerability, and efficacy of KarXT in 
de novo subjects, defined as those who did not have prior exposure to 
KarXT, who meet DSM-5 criteria for schizophrenia. The study consists of a 
screening phase of up to 14 days (up to a 7-day screening extension is 
permitted with medical monitor approval), a baseline phase of up to 5 days, 
a 52-week open-label treatment phase, and a 7-day safety follow-up/end of 
study (EOS) visit following the last dose of KarXT for subjects who 
complete the treatment phase and those who prematurely discontinue from 
the study 
Screening Phase: 
A suitable number of subjects will be screened to enroll approximately 
600 subjects (aged 18 to 65 years) with schizophrenia who are 
psychiatrically stable and can be adequately managed in an outpatient 
setting across approximately 60 study sites in the United States. The 
screening phase will last up to 14 days (up to a 7-day screening extension is 
permitted with medical monitor approval). 
Baseline Phase: 
Subjects who meet the screening criteria will participate in a baseline 
period consisting of two separate visits. The start of the baseline period, 
Baseline Visit A, must be at least 3 days (and no more than 5 days) prior to 
Baseline Visit B. Subjects must continue to meet eligibility criteria 
throughout the baseline period to remain in the study. 
Treatment Phase: 
In this open-label study, all subjects will receive KarXT for up to 52 weeks. 
All subjects will start on a lead-in dose of KarXT 50/20 (50 mg 
xanomeline/20 mg trospium chloride) twice daily (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.
 
 
 
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Additional changes to KarXT dosing (eg, temporary dose reductions) may 
be permitted as clinically indicated upon approval by the medical monitor. 
Interim visits, which can be conducted in-clinic or by telemedicine per 
investigator discretion, will occur between required in-clinic visits (see 
Schedule of Assessments Table 2). Additional Unscheduled study visits 
should be utilized as necessary to facilitate subject retention and ensure 
compliance with study objectives. 
Safety Follow-up/End of Study: 
A safety follow-up/EOS visit (Visit 30/Day 371±3 days) will be performed 
for all subjects after the last dose of KarXT. 
Independent Safety Monitoring Committee: 
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 Criteria: 
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, at screening.
2.
Subject is capable of providing informed consent.
a.
A signed informed consent form (ICF) must be provided
before any study assessments are performed.
b.
Subject must be fluent (oral and written) in the language of
the ICF to consent
3.
Subject has a primary diagnosis of schizophrenia established by
a comprehensive psychiatric evaluation based on the DSM-5
(American Psychiatric Association 2013) criteria and confirmed
by Mini International Neuropsychiatric Interview (MINI) for
Schizophrenia and Psychotic Disorder Studies version 7.0.2.
4.
The subject has not required psychiatric hospitalization, acute
crisis intervention, or other increase in level of care due to
symptom exacerbation within 8-weeks of screening and is
psychiatrically stable in the opinion of the investigator.
5.
PANSS total score of ≤ 80 at screening and Baseline Visit B (Day 0).
6.
CGI-S score of ≤ 4 at screening and Baseline Visit B (Day 0).
7.
At the time of screening, or at any time within the 30 days prior
to screening, the subject must have received an oral
antipsychotic medication daily at a dose and frequency
consistent with the drug label.
8.
In the opinion of the investigator, it is clinically appropriate for
the subject to discontinue current antipsychotic therapy and
initiate experimental treatment with KarXT.
9.
The subject is willing and able, in the opinion of the investigator,
to discontinue all antipsychotic medications prior to baseline
visit.
a. Subjects should discontinue any antipsychotic
medications prior to Baseline Visit A (Day -3). If
clinically necessary, and in consultation with the
medical monitor, antipsychotic medications may be
continued through the baseline period up until the time
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of Baseline Visit B (Day 0). 
b. Antipsychotic down-taper, if clinically appropriate in the
opinion of the investigator, may occur during the
screening phase.
10. Subject has an identified, reliable informant willing and able to address
some questions related to certain study visits, if needed. An informant
may not be necessary if the subject has been the patient of the
investigator for ≥1 year.
13. BMI must be ≥18 and ≤40 kg/m2.
14. Subject resides in a stable living situation and is anticipated to remain
in a stable living situation for the duration of study enrollment, in the
opinion of the investigator.
15. 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: 
1.
Any primary DSM-5 disorder other than schizophrenia within
12 months before screening (confirmed using MINI version 7.0.2
at screening). Exclusionary disorders include but are not limited
to major depressive disorder, bipolar I or II disorder,
schizoaffective disorder, obsessive compulsive disorder, and
posttraumatic stress disorder. Symptoms of mild mood dysphoria
or anxiety are allowed as long as these symptoms are not the
primary focus of treatment.
2.
The subject has a history of moderate to severe alcohol use
disorder or a substance (other than nicotine or caffeine) use
disorder within the past 12 months or a positive urine drug screen
(UDS) for a substance other than cannabis at screening or
baseline.
a.
A subject with mild substance abuse disorder within
the 12 months before screening must be discussed and
agreed upon with the medical monitor before he/she
can be allowed into the study.
b.
Subjects with a positive UDS for cannabis are
permitted to enroll in the study provided that the
subject’s pattern of use is not indicative of a substance
use disorder.
3.
History or presence of clinically significant cardiovascular,
pulmonary, hepatic, renal, hematologic, gastrointestinal,
endocrine, immunologic, dermatologic, neurologic, or oncologic
disease or any other condition that, in the opinion of the
investigator, would jeopardize the safety of the subject or the
validity of the study results.
4.
Subjects with HIV, cirrhosis, biliary duct abnormalities,
hepatobiliary carcinoma, and/or active hepatic viral infections
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based on either medical history or liver function test results. 
5. History or high risk of urinary retention, gastric retention, or 
narrow--angle glaucoma. 
6. History of irritable bowel syndrome (with or without 
constipation) or serious constipation requiring 
treatment within the last 6 months. 
7. Risk for suicidal behavior during the study as determined by the 
investigator’s clinical assessment and C-SSRS as confirmed by 
the following: 
a. 
Answers “Yes” on items 4 or 5 (C-SSRS – ideation) 
with the most recent episode occurring within the 
2 months before screening, or answers “Yes” to any of 
the 5 items (C-SSRS behavior) with an episode 
occurring within the 12 months before screening. 
Nonsuicidal self-injurious behavior is not 
exclusionary. 
8. Clinically significant abnormal finding on the physical 
examination, medical history, ECG, or clinical laboratory 
results at screening. 
 
 
 
 
 
 
 
10. Subject has a history of treatment resistance to schizophrenia 
medications defined as:  
a. Failure to respond to 2 adequate courses of 
pharmacotherapy (a minimum of 4 weeks at an 
adequate dose per the label) within the past 
12 months, OR 
b. Having received clozapine within the past 3 years 
11. Pregnant, lactating, or less than 3 months postpartum. 
12. 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 opinion of the investigator (and/or Sponsor), may 
compromise the safety of the subject or affect their ability to 
adhere to the protocol visit schedule or fulfill visit 
requirements. 
13. Subjects who have tested positive for coronavirus disease 2019 
(COVID-19) within 2 weeks of screening.  
14. Subjects with extreme concerns relating to global pandemics, 
such as COVID-19, that preclude study participation. 
15. Subject has had psychiatric hospitalization(s) for more than 
30 days (cumulative) within the 6 months before screening. 
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16. Subjects with prior exposure to KarXT. 
17. Risk of violent or destructive behavior. 
18. Current involuntary hospitalization or incarceration. 
19. Participation in another clinical study in which the subject received an 
experimental or investigational drug agent within 30 days prior to 
screening. 
Planned Sample Size: 
Approximately 600 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 
chloride) oral (Days 1 to 2) 
2. Fixed dose KarXT 100/20 BID (100 mg xanomeline/20 mg trospium 
chloride) oral (Days 3 to 7) 
3. Fixed dose KarXT 125/30 BID (125 mg xanomeline/30 mg trospium 
chloride) oral (Days 8 to 364, if tolerated)  
Reference Therapy: 
Not applicable. 
Treatment Duration: 
Total study duration is up to approximately 57 weeks, including a screening 
phase of up to 14 days with an extension of up to 7 days, a baseline phase 
of up to 5 days, a 52-week treatment phase and a 7-day follow-up/EOS 
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; IPSS; 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 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. 
Statistical Methods and 
Planned Analyses: 
Study Populations: 
Enrolled population: All subjects who have given informed consent for 
KAR-011 will be included in the Enrolled population. 
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, and at least 1 postbaseline time point 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 of KarXT 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.  
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 ........................................................................................................................5 
3 
TABLE OF CONTENTS ................................................................................................13 
3.1 
List of In-text Tables ..................................................................................................18 
3.2 
List of In-text Figures .................................................................................................19 
4 
LIST OF ABBREVIATIONS .........................................................................................20 
5 
INTRODUCTION ...........................................................................................................22 
5.1 
Background on Schizophrenia ....................................................................................22 
5.2 
Background on KarXT (Xanomeline Tartrate and Trospium Chloride) ....................22 
 
Nonclinical Studies ............................................................................................24 
 
Completed Clinical Studies ................................................................................27 
5.3 
Clinical Risks/Benefits of KarXT and Study Rationale .............................................37 
6 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................39 
6.1 
Study Objectives .........................................................................................................39 
 
Primary Objective ..............................................................................................39 
 
Secondary Objective ..........................................................................................39 
...........................................................................39 
6.2 
Study Endpoints..........................................................................................................40 
 
Primary Safety Endpoint ....................................................................................40 
 
Secondary Endpoints ..........................................................................................40 
6.2.2.1 
Safety Endpoints ..........................................................................................40 
6.2.2.2 
Efficacy Endpoints .......................................................................................40 
 
Other Endpoints .................................................................................................40 
6.2.3.1 
Other Safety Endpoints ................................................................................40 
6.2.3.2 
Pharmacokinetic Endpoint ...........................................................................41 
............................................................41 
7 
INVESTIGATIONAL PLAN .........................................................................................42 
7.1 
Description of Overall Study Design and Plan ...........................................................42 
7.2 
Discussion of Study Design........................................................................................45 
7.3 
End of Study ...............................................................................................................45 
7.4 
Independent Safety Monitoring Committee ...............................................................45 
8 
SELECTION OF STUDY POPULATION .....................................................................47 
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8.1 
Inclusion Criteria ........................................................................................................47 
8.2 
Exclusion Criteria .......................................................................................................48 
8.3 
Rescreening ................................................................................................................49 
8.4 
Study Withdrawal, Removal, and Replacement of Subjects ......................................50 
 
Pregnancy ...........................................................................................................51 
8.5 
Completion of the Study or Lost to Follow-up ..........................................................52 
8.6 
Study Termination ......................................................................................................52 
9 
TREATMENTS ...............................................................................................................53 
9.1 
Details of Study Treatments .......................................................................................53 
 
Identity of Study Treatments ..............................................................................53 
 
Packaging and Labeling .....................................................................................53 
 
KarXT Storage ...................................................................................................54 
 
KarXT Retention ................................................................................................54 
9.2 
Dosage Schedule ........................................................................................................54 
 
Day 0/Baseline Visit B .......................................................................................54 
 
Visit 1/Day 1 Dosing ..........................................................................................55 
 
Visit 2/Day 3 Dosing ..........................................................................................55 
 
Visit 3/Day 8 Dosing ..........................................................................................55 
 
Visit 4/Day 14 Dosing ........................................................................................55 
 
Visits 5 to 8 (Days 28 to 70) Dosing ..................................................................56 
 
Visits 9 to 29 (Days 84 to 364) Dosing ..............................................................56 
9.3 
Measures to Minimize Bias: Study Treatment Assignment .......................................56 
 
Method of Study Treatment Assignment ...........................................................56 
 
Blinding 56 
9.4 
Dosage Modification ..................................................................................................56 
.57 
9.5 
Treatment Accountability and Compliance ................................................................57 
9.6 
Prior and Concomitant Therapy .................................................................................57 
 
Prior and Concomitant Medications ..................................................................57 
 
Concomitant Medications for Anxiety and/or Sleep Aid ...................................58 
10 
STUDY PROCEDURES .................................................................................................59 
10.1 Informed Consent .......................................................................................................67 
10.2 Study Procedures ........................................................................................................67 
..67 
11 
SAFETY ASSESSMENTS .............................................................................................70 
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11.1 Demographics, Medical History, and Psychiatric History .........................................70 
11.2 Vital Signs ..................................................................................................................70 
11.3 Complete/Targeted Physical Examination .................................................................70 
11.4 Weight, Height, Body Mass Index, and Waist Circumference ..................................71 
11.5 Electrocardiograms .....................................................................................................71 
11.6 Laboratory Assessments .............................................................................................71 
.73 
11.7 Adverse Events ...........................................................................................................74 
 
Adverse Events ..................................................................................................74 
 
Adverse Events of Special Interest ....................................................................75 
 
Serious Adverse Events .....................................................................................76 
 
Serious Adverse Event Reporting ......................................................................76 
 
Drug-Induced Liver Injury .................................................................................77 
 
Trial Discontinuation Criteria Other than DILI and Pregnancy ........................78 
11.7.6.1 
Individual Stopping Criteria .........................................................................78 
11.7.6.2 
Trial Stopping Rules .....................................................................................78 
 
Suspected Unexpected Serious Adverse Reactions ...........................................79 
 
Pregnancy ...........................................................................................................80 
 
Overdose ............................................................................................................81 
11.8 Simpson-Angus Rating Scale .....................................................................................82 
11.9 Barnes Akathisia Rating Scale ...................................................................................82 
11.10 Abnormal Involuntary Movement Scale ....................................................................82 
11.11 Columbia-Suicide Severity Rating Scale ...................................................................82 
11.12 Functional Constipation Inquiry .................................................................................82 
11.13 International Prostate Symptom Score (IPSS) ...........................................................83 
12 
EFFICACY ASSESSMENTS .........................................................................................84 
12.1 Positive and Negative Syndrome Scale ......................................................................84 
12.2 Clinical Global Impression-Severity ..........................................................................84 
13 
PHARMACOKINETICS ................................................................................................85 
13.1 Pharmacokinetic Sampling .........................................................................................85 
 
Blood Samples ...................................................................................................85 
13.2 Bioanalysis of Trospium and Xanomeline .................................................................85 
...86 
...86 
...86 
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....87 
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15 
STATISTICAL ANALYSIS ...........................................................................................90 
15.1 Determination of Sample Size ....................................................................................90 
15.2 Analysis Populations ..................................................................................................90 
15.3 Safety Analysis ...........................................................................................................90 
15.4 Efficacy Analysis........................................................................................................91 
15.5 Pharmacokinetic Analysis ..........................................................................................91 
 ..................................................................................................91 
15.7 Interim Analysis .........................................................................................................91 
15.8 Handling of Missing Data ..........................................................................................92 
16 
STUDY MANAGEMENT ..............................................................................................93 
16.1 Approval and Consent ................................................................................................93 
 
Regulatory Guidelines ........................................................................................93 
 
Institutional Review Board/Independent Ethics Committee ..............................93 
 
Informed Consent ...............................................................................................93 
16.2 Data Handling .............................................................................................................94 
16.3 Source Documents ......................................................................................................94 
16.4 Record Retention ........................................................................................................95 
16.5 Monitoring ..................................................................................................................95 
16.6 Quality Control and Quality Assurance .....................................................................95 
16.7 Protocol Amendment and Protocol Deviation ............................................................96 
 
Protocol Amendment .........................................................................................96 
 
Protocol Deviations ............................................................................................96 
16.8 Ethical Considerations ................................................................................................96 
16.9 Financing and Insurance .............................................................................................96 
16.10 Publication Policy/Disclosure of Data........................................................................97 
17 
REFERENCES ................................................................................................................98 
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APPENDICES ...............................................................................................................101 
APPENDIX 1. CONTRACEPTION GUIDELINES .............................................................102 
APPENDIX 2. FUNCTIONAL CONSTIPATION INQUIRY .............................................103 
 
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3.1 
List of In-text Tables 
Table 1. Study Drug Dosing Scheme ....................................................................................44 
Table 2. Schedule of Assessments ........................................................................................60 
Table 3. Laboratory Assessments..........................................................................................72 
Table 4. Classification of Adverse Events by Intensity ........................................................75 
Table 5. Classification of Adverse Events by Relationship to KarXT..................................75 
 
.........................................................86 
 
 
 
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3.2 
List of In-text Figures 
Figure 1. Change From Baseline in PANSS Total Scores (KAR-004) ..................................32 
Figure 2. Change From Baseline in PANSS-Positive Scores (KAR-004) .............................33 
Figure 3. Change From Baseline in CGI-S (KAR-004) .........................................................34 
Figure 4. Change From Baseline in PANSS-Negative Scores (KAR-004) ............................35 
 
 
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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 
AUC0-24 
area under the plasma concentration-time curve from 0 to 24 hours 
BARS 
Barnes Akathisia Rating Scale 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
 
 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression‒Severity 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTS 
clinical trial subject 
DSM-5 
Diagnostic and Statistical Manual‒Fifth Edition 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
 
 
EOS 
end of study 
EOT 
end of treatment 
EPS 
extrapyramidal symptoms 
 
 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transpeptidase 
GI 
Gastrointestinal 
HIPAA 
Health Insurance Portability Accountability Act 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IPSS 
International Prostate Symptom Score  
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Abbreviation 
Definition 
IRB 
Institutional Review Board 
ISMC 
Independent Safety Monitoring Committee 
LFT 
liver function test 
 
 
MCC 
microcrystalline cellulose 
MINI 
Mini International Neuropsychiatric Interview 
mITT 
modified intent-to-treat 
 
 
 
  
 
 
PANSS 
Positive and Negative Syndrome Scale 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
 
 
 
 
 
  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson-Angus Rating Scale 
 
 
 
 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TID 
3 times daily 
 
 
 
  
US 
United States 
VAS 
visual analog scale 
VCT 
Verified Clinical Trials 
vs 
Versus 
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 (US) population.[2] Moreover, a claims analysis has estimated that 
the annual prevalence of diagnosed schizophrenia in the United States 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 APDs 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, which 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 that 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 M4 receptors in the CNS, which is thought to be responsible for the drug’s potential 
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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 (vs) 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 that 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 
Therapeutics (hereafter, Karuna) hypothesized that the addition of trospium would mitigate 
peripheral procholinergic side effects (nausea, vomiting, diarrhea, sweating, and excess 
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 remaining cholinergic AEs were generally 
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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, multicenter 
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, tolerability, and efficacy of 
KarXT (xanomeline 125 mg/trospium chloride 30 mg) administered twice daily (BID) in adult 
outpatients with Diagnostic and Statistical Manual‒Fifth Edition (DSM-5) diagnosis of 
schizophrenia.   
Xanomeline is currently not approved or marketed in any country. Trospium is marketed in the 
United States 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). 
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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 using xanomeline with trospium. 
 
 
 
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 subjects with schizophrenia 
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 
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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 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). AEs 
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 to date includes 3 completed Phase 1, 
clinical pharmacology studies in healthy volunteers (KAR-001, KAR-002, and KAR-003) and 1 
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 3 times daily (TID), alone, at a total daily dose of 
225 mg in 1 arm; 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 if this dosing regimen would reduce the cholinergic side 
effects of xanomeline by coadministration 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 reductions in VAS scores for 
the xanomeline + trospium treatment arm were 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 
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(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-001 (≥20% of subjects 
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. 
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 All TEAEs were mild or moderate in 
severity, and there were no SAEs or deaths. TEAEs 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 chloride, 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 
chloride 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) 
vs 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 
1 dose of study drug and had at least 1 postbaseline PANSS assessment (modified intent-to-treat 
[mITT] 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 AE (2 [2.2%] placebo; 3 [3.3%] KarXT). 
TEAEs 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 constipation, nausea, dry mouth, 
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dyspepsia, and vomiting, and were more common (≥5% higher or twice that of placebo) in the 
KarXT group than in the placebo group.   
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 common (≥5% higher or twice that of placebo) 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 this study of 
subjects with schizophrenia 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 APDs. 
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 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 change from baseline 
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 (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 vs 
28.9% of KarXT subjects (see Figure 3). 
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Figure 3. 
Change From Baseline in CGI-S (KAR-004) 
 
Abbreviation: CGI-S = Clinical Global Impression‒Severity. 
 
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 because of 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 APDs 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 study 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. 
KAR-007 and KAR -009 had similar study designs and were modelled from the first pivotal 
study, KAR-004. Both KAR-007 and KAR-009 were Phase 3, randomized, double-blind, 
placebo-controlled trials to assess the efficacy, safety, and tolerability of KarXT in adults with 
DSM-5 schizophrenia, hospitalized with acute psychosis. Both KAR-007 and KAR-009 were 
identical, except KAR-007 enrolled subjects in the US only whereas KAR-009 enrolled subjects 
in Ukraine and the US. The primary objective of the studies was to assess the efficacy of KarXT 
(125/30 BID) vs placebo in reducing PANSS total scores in adult inpatients with a DSM-5 
diagnosis of schizophrenia. Subjects aged 18 to 65 years old received either KarXT or placebo 
(1:1 ratio) for a treatment period of 5 weeks. 
Both pivotal, Phase 3 studies met their primary endpoint. The primary endpoint in KAR-007 and 
KAR-009 was the change from baseline (CFB) in PANSS total score at week 5. In each of the 
studies, treatment with KarXT led to statistically significant improvements in PANSS total score 
at Week 5 compared with placebo (p < 0.0001 in each study). Cohen’s d effect size was 0.61 in 
KAR-007 and 0.60 in KAR-009. 
Secondary endpoints were analyzed based on a planned hierarchy in a fixed sequence and were 
typically in favor of KarXT. Treatment with KarXT led to statistically significant improvements 
relative to placebo in PANSS positive score at Week 5 in both studies (p < 0.0001 in each study). 
In KAR-007, the improvements in PANSS negative and PANSS Marder factor negative 
subscales were statistically significant in favor of KarXT versus placebo at Week 5 (p ≤ 0.0055 
and p = 0.0022, respectively). In KAR-009, the improvements in PANSS negative and PANSS 
Marder factor negative score at Week 5 was greater in KarXT than placebo but did not reach 
statistical significance at the 2-sided alpha level of 0.05 (p = 0.1224 and p = 0.1957, 
respectively). Analysis of the CFB in CGI-S in both studies demonstrated improvements in CGI-
S scores at Week 5 in favor of KarXT versus placebo (statistically significant over placebo for 
KAR-007, and nominally significant over placebo albeit not formally tested in KAR-009). KAR-
007 and KAR-009 included a Week 5 PANSS responder analysis as a secondary efficacy 
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endpoint (defined as an improvement from baseline of at least 30% at Week 5 in PANSS total 
score). The PANSS responder analysis showed that a greater proportion of subjects on KarXT 
achieved ≥ 30% improvement in PANSS total score at Week 5 compared to those on placebo in 
both KAR-007 (54.8% versus 28.3%, p < 0.0001) and KAR-009 (50.6% versus 25.3%, p = 
0.0056). 
KarXT was well-tolerated and safe in the Phase 3 studies, with the pattern and course of safety 
findings largely consistent with the known safety profile of KarXT. The most common TEAEs 
were associated with the procholinergic or anticholinergic effects of KarXT. The administration 
of KarXT was notably free of many common side effects associated with currently approved 
antipsychotic drugs. 
KAR-008 is an ongoing Phase 3, multicenter, outpatient, open label extension (OLE) study 
designed to evaluate the long-term safety, tolerability, and efficacy of KarXT in adults with 
DSM-5 schizophrenia, which includes subjects who completed KAR-007 or KAR-009. Eligible 
subjects receive KarXT for up to 52 weeks. Enrollment in this study is complete (N=156). 
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 postrandomization 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 postrandomization time points for PANSS positive symptom subscores, 
PANSS negative symptom subscores, PANSS Marder Factor negative symptom subscores, and 
CGI-S scores. 
 
 
 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 
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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 United States for 19 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. 
Findings from one Phase 2 (KAR-004) and two Phase 3 (KAR-007 and KAR-009) pivotal 
placebo-controlled studies were similar. In all three clinical studies, administration of KarXT 
(100/20 and 125/30) for 5 weeks resulted in consistent, significant reductions in symptoms of 
schizophrenia in subjects with acute psychosis and CGI-S compared with placebo. The safety 
and tolerability of KarXT was consistent in 3 successive pivotal placebo-controlled studies 
(KAR-004, KAR-007 and KAR-009). The most common treatment-emergent adverse events 
(TEAEs) by preferred term in the KarXT treatment arm included nausea, dyspepsia, vomiting, 
constipation, headache, hypertension, diarrhea, and insomnia. 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. 
KAR-008 is an ongoing Phase 3, multicenter, outpatient, OLE study designed to evaluate the 
long-term safety, tolerability, and efficacy of KarXT in adults with DSM-5 schizophrenia, which 
includes subjects who completed KAR-007 or KAR-009.  
In the current study, 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 
outpatient setting. All subjects will start with a lead-in dose of KarXT 50/20 (50 mg 
xanomeline/20 mg trospium chloride) 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.
 
 
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 
subjects with schizophrenia 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 evaluate plasma 
concentrations of xanomeline and trospium following administration of KarXT in adults with a 
DSM-5 diagnosis of schizophrenia: 
• To evaluate the reduction in PANSS total score 
• To evaluate the reduction in PANSS positive score  
• To evaluate the improvement in CGI-S score 
• To evaluate the reduction in PANSS negative score  
• To evaluate the reduction in PANSS Marder Factor negative symptoms score 
• To evaluate the percentage of subjects who exhibit a 30% reduction in PANSS total score 
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6.2 
Study Endpoints 
 
Primary Safety Endpoint 
The primary safety endpoint of this study is the incidence of TEAEs. 
 
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 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 
• 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 
Other Safety Endpoints 
The other safety endpoints of the study are: 
• Spontaneously reported adverse events of special interest (AESIs) 
• Spontaneously reported anticholinergic and procholinergic symptoms 
• Change from baseline in Simpson-Angus Rating Scale (SAS) 
• Change from baseline in Barnes Akathisia Rating Scale (BARS) 
• Change from baseline in Abnormal Involuntary Movement Scale (AIMS) 
• Change from baseline in body weight, body mass index (BMI), and 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 examinations  
• Suicidal ideation scale with the use of Columbia-Suicide Severity Rating Scale (C-SSRS) 
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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. 
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7 
INVESTIGATIONAL PLAN 
7.1 
Description of Overall Study Design and Plan 
This is a Phase 3, multicenter, 52week, outpatient, open-label study to evaluate the long-term 
safety, tolerability, and efficacy of KarXT in de novo subjects, defined as not previously 
participated in a study of KarXT, who meet DSM-5 criteria for schizophrenia. The study consists 
of a screening phase of up to 14 days (up to a 7-day screening extension is permitted with 
medical monitor approval), a baseline phase of up to 5 days, a 52-week open-label treatment 
phase, and a 7-day safety follow-up/end of study (EOS) visit following the last dose of KarXT 
for subjects who complete the treatment phase and those who prematurely discontinue from the 
study. 
Screening Phase: 
A suitable number of subjects will be screened to enroll approximately 600 subjects (aged 18 to 
65 years) with schizophrenia who are psychiatrically stable and can be adequately managed in an 
outpatient setting across approximately 60 study sites in the United States. The screening phase 
will last up to 14 days (up to a 7-day screening extension is permitted with medical monitor 
approval). 
Baseline Phase: 
Subjects who meet the screening criteria will participate in a baseline period consisting of two 
separate visits. The start of the baseline period, Baseline Visit A, must be at least 3 days (and no 
more than 5 days) prior to Baseline Visit B. Subjects must continue to meet eligibility criteria 
throughout the baseline period to remain in the study. 
Treatment Phase: 
In this open-label study, all subjects will receive KarXT for up to 52 weeks. All subjects will 
start on a lead-in dose of KarXT 50/20 (50 mg xanomeline/20 mg trospium chloride) 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 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.
 
 Additional changes to KarXT dosing (eg, 
temporary dose reductions) may be permitted as clinically indicated upon approval by the 
medical monitor.  
Interim visits, which can be conducted in-clinic or by telemedicine per investigator discretion, 
will occur between required in-clinic visits (see Schedule of Assessments Table 2). Additional 
Unscheduled study visits should be utilized as necessary to facilitate subject retention and ensure 
compliance with study objectives.  
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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 spontaneously reported 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, IPSS  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 PK samples collected at 
scheduled visits. 
A safety follow-up/EOS (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 Drug Dosing Scheme. 
 
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Table 1. 
Study Drug Dosing Scheme 
Period: 
Open-Label Treatmenta 
EOT/ET 
EOS/UNS 
Day: 
Day 1 
Day 3  
+1 day 
Day 8  
±1 day 
Day 14  
±2 days 
Day 28 
 ±3 days 
Day 56  
±3 days 
Days 70 to 
350 ±3 days 
Day 364  
±3 days 
Day 371 ±3 
days 
Visita: 
Visit 1 
Visit 2f 
Visit 3b 
Visit 4 
Visit 5 
Visit 7 
Visits 8c 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 
completion of 
the EOT or ET 
visit 
Abbreviations: BID = twice daily; EOS = end of study; ET = early termination; EOT = end of treatment; N/A = not applicable; PI = principal investigator; 
UNS = unscheduled. 
* All the KarXT doses are in mg xanomeline/mg trospium chloride. 
a. 
At Visit 1 (Day 1) subjects will initiate dosing with KarXT BID independently at home. Visits 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 2, 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 before escalating to KarXT 125/30 dose. 
c. 
After Visit 9/Day 84, required in-clinic visits will be conducted approximately every 4 weeks. Interim visits will be conducted between required in-clinic 
visits and can be conducted by telemedicine or in-clinic per investigator discretion (see Schedule of Assessments Table 2 for further details).  
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. 
 
. Additional changes to KarXT dosing (eg, temporary dose reductions) may be permitted as 
clinically indicated upon approval by the medical monitor. 
f. 
Visit 2/Day 3 is an interim visit and can be conducted via telemedicine or in-clinic per investigator discretion. 
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7.2 
Discussion of Study Design 
The KarXT clinical development program includes this open-label study to evaluate the 
long-term safety, tolerability, and efficacy data for KarXT in de novo subjects, defined as those 
who did not have prior exposure to KarXT, who meet the DSM-5 criteria for schizophrenia. 
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 Visit 2 (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). 
 
 
Interim visits, which can be conducted in-clinic or by telemedicine per investigator discretion, 
will occur between required in-clinic visits (see Schedule of Assessments Table 2). Additional 
Unscheduled study visits should be utilized as necessary to facilitate subject retention and ensure 
compliance with 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 600 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 
clinical study. 
. 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 
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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, at screening. 
2. Subject is capable of providing informed consent. 
a. A signed informed consent form (ICF) must be provided before any study 
assessments are performed. 
b. Subject must be fluent (oral and written) in the language of the ICF to consent 
3. Subject has a primary diagnosis of schizophrenia established by a comprehensive 
psychiatric evaluation based on the DSM-5 (American Psychiatric Association 2013) 
criteria and confirmed by Mini International Neuropsychiatric Interview (MINI) for 
Schizophrenia and Psychotic Disorder Studies version 7.0.2.  
4. The subject has not required psychiatric hospitalization, acute crisis intervention, or 
other increase in level of care due to symptom exacerbation within 8 weeks of 
screening and is psychiatrically stable in the opinion of the investigator. 
5. PANSS total score of ≤ 80 at screening and Baseline Visit B (Day 0). 
6. CGI-S score of ≤ 4 at screening and Baseline Visit B (Day 0). 
7. At the time of screening, or at any time within the 30 days prior to screening, the 
subject must have received an oral antipsychotic medication daily at a dose and 
frequency consistent with the drug label. 
8. In the opinion of the investigator, it is clinically appropriate for the subject to 
discontinue current antipsychotic therapy and initiate experimental treatment with 
KarXT. 
9. The subject is willing and able, in the opinion of the investigator, to discontinue all 
antipsychotic medications prior to baseline visit. 
a. Subjects should discontinue any antipsychotic medications prior Baseline 
Visit A (Day -3). If clinically necessary, and in consultation with the medical 
monitor, antipsychotic medications may be continued through the baseline 
period up until the time of Baseline Visit B (Day 0). 
b. Antipsychotic down-taper, if clinically appropriate in the opinion of the 
investigator, may occur during the screening phase.  
10. Subject has an identified reliable informant willing and able to address some questions 
related to certain study visits, if needed. An informant may not be necessary if the subject 
has been the patient of the investigator for ≥ 1 year. 
11. 
 
 
12. 
 
 
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13. BMI must be ≥ 18 and ≤ 40 kg/m2. 
14. Subject resides in a stable living situation and is anticipated to remain in a stable living 
situation for the duration of study enrollment, in the opinion of the investigator. 
15. 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 one or more of the following criteria is/are 
applicable: 
1. Any primary DSM-5 disorder other than schizophrenia within 12 months before 
screening (confirmed using MINI version 7.0.2 at screening). Exclusionary disorders 
include but are not limited to major depressive disorder, bipolar I or II disorder, 
schizoaffective disorder, obsessive compulsive disorder, and posttraumatic stress 
disorder. Symptoms of mild mood dysphoria or anxiety are allowed as long as these 
symptoms are not the primary focus of treatment. 
2. The subject has a history of moderate to severe alcohol use disorder or a substance 
(other than nicotine or caffeine) use disorder within the past 12 months or a positive 
urine drug screen (UDS) for a substance other than cannabis at screening or baseline. 
a. A subject with mild substance abuse disorder within the 12 months before 
screening must be discussed and agreed upon with the medical monitor 
before he/she can be allowed into the study. 
b. Subjects with a positive UDS for cannabis are permitted to enroll in the study 
provided that the subject’s pattern of use is not indicative of a substance use 
disorder. 
3. History or presence of clinically significant cardiovascular, pulmonary, hepatic, 
renal, hematologic, GI, endocrine, immunologic, dermatologic, neurologic, or 
oncologic disease or any other condition that, in the opinion of the investigator, 
would jeopardize the safety of the subject or the validity of the study results. 
4. Subjects with HIV, cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma, 
and/or active hepatic viral infections based on either medical history or liver function 
test (LFT) results. 
5. History or high risk of urinary retention, gastric retention, or narrow--angle glaucoma. 
6. History of irritable bowel syndrome (with or without constipation) or 
serious constipation requiring treatment within the last 6 months 
7. Risk for suicidal behavior during the study as determined by the investigator’s 
clinical assessment and C-SSRS as confirmed by the following: 
a. Answers “Yes” on items 4 or 5 (C-SSRS – ideation) with the most recent 
episode occurring within the 2 months before screening, or answers “Yes” 
to any of the 5 items (C-SSRS behavior) with an episode occurring within 
the 12 months before screening. Nonsuicidal self-injurious behavior is not 
exclusionary. 
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8. Clinically significant abnormal finding on the physical examination, medical 
history, ECG, or clinical laboratory results at screening. 
9. 
 
 
 
 
 
 
 
 
 
 
 
 
.   
10. Subject has a history of treatment resistance to schizophrenia medications defined 
as:  
a. Failure to respond to 2 adequate courses of pharmacotherapy (a minimum 
of 4 weeks at an adequate dose per the label) within the past 12 months, 
OR, 
b. Having received clozapine within the past 3 years 
11. Pregnant, lactating, or less than 3 months postpartum. 
12. 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 opinion of the 
investigator (and/or Sponsor), may compromise the safety of the subject or affect 
their ability to adhere to the protocol visit schedule or fulfill visit requirements. 
13. Subjects who have tested positive for coronavirus disease 2019 (COVID-19) 
within 2 weeks of screening.  
14. Subjects with extreme concerns relating to global pandemics, such as COVID-19, 
that preclude study participation. 
15. Subject has had psychiatric hospitalization(s) for more than 30 days (cumulative) 
within the 6 months before screening. 
16. Subjects with prior exposure to KarXT. 
17. Risk of violent or destructive behavior. 
18. Current involuntary hospitalization or incarceration. 
19. Participation in another clinical study in which the subject received an experimental or 
investigational drug agent within 30 days prior to screening. 
8.3 
Rescreening 
Individuals who sign the ICF to participate in the study but who do not subsequently meet all the 
requirements and therefore do not enroll (screen failures) may be allowed to rescreen up to 
1 time in consultation with the medical monitor. Participants who screen failed due to elevated 
LFTs are not eligible for rescreening.  
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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 (after receiving at least 1 dose of the study drug) 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 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 
• 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 investigator’s clinical judgement; 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 11.7.8.  
• Sponsor’s decision to discontinue study 
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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 EOS 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 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). 
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 at Screening, Baseline Visit B (Day 0) 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 treatment with 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 KarXT. The investigator must notify the Sponsor or their designee of any female 
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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 11.7.8 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 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 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 IRB will be informed about the reason for such action. Similarly, if 
the Sponsor terminates the study, it will inform the investigators, the IRB, and the subjects of the 
reason for such an action. Similar notifications will be sent by the 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 is loaded 
with trospium chloride. In addition to the active ingredients, the xanomeline beads contain 
microcrystalline cellulose (MCC), ascorbic acid, and talc. In addition to MCC, trospium beads 
contain lactose monohydrate and talc. 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 mg BID for a total daily dose of 100/40 mg, 
followed by 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 (Day 8), dosing may be increased to 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.
 
  
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 50/20 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, opaque, and hydroxypropyl methylcellulose hard capsule. 
KarXT 100/20 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, opaque, and hydroxypropyl methylcellulose hard capsule. 
KarXT 125/30 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, opaque, and 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 Catalent Pharma Solutions, located in 
Philadelphia, Pennsylvania. All packaging and labeling operations will be performed according 
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to Good Manufacturing Practice for Medicinal Products and the relevant regulatory 
requirements. 
Blister packaged investigational product is labeled with the name of the drug, recommended 
storage conditions, the name and address of the manufacturer, and the Investigational Use 
Statement “Caution: New Drug - Limited by Federal (or United States) law to investigational 
use.” 
Further details on the investigational product label will be provided in the Pharmacy Manual. 
Complete details on study medication dispensing can be found in the Pharmacy Manual.  
 
KarXT Storage 
KarXT must be stored at room temperature 15 °C to 25 °C. 
 
KarXT Retention 
KarXT must be retained until completion or termination of the study. All unused and used 
KarXT must be destroyed at the site or returned to a drug-destruction facility for destruction, as 
specified by Sponsor through written authorization. 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 and/or return to drug destruction facility are documented and 
maintained. No used or unused KarXT may be disposed until fully accounted for by the study 
monitor. 
9.2 
Dosage Schedule 
The first dose of KarXT will be administered in the morning of Day 1 and the last dose will be 
administered in the morning of end of treatment (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). Administration of KarXT will be supervised by study site personnel (during in-
clinic visits) and 
 monitor administration of KarXT in between clinic 
visits to ensure compliance 
. 
 
Day 0/Baseline Visit B 
• 
Sites will provide the subjects with a titration blister card wallet containing sufficient 
KarXT doses for the first week of study participation. Subjects will be instructed 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 return the titration blister card wallet at their next visit.  
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Visit 1/Day 1 Dosing 
• Initiate BID dosing with KarXT 50/20. 
• All subjects should receive 4 doses of KarXT 50/20 before dose escalation to KarXT 
100/20 BID. Subjects should contact the investigator in the event they did not take all 
4 doses of KarXT 50/20 during the first 2 days of dosing. 
 
Visit 2/Day 3 Dosing 
• Initiate BID dosing with KarXT 100/20. 
• All the subjects should receive at least 8 doses of KarXT 100/20 before dose escalation to 
KarXT 125/30 BID. Subjects should contact the investigator in the event they do not take 
at least 8 doses of KarXT 100/20 during the first week of dosing. 
• Remind the subject to return the titration blister card wallet at their next visit.  
 
Visit 3/Day 8 Dosing 
• If dose escalation to the KarXT 125/30 level is confirmed by investigator order, site staff 
will provide subjects with a single 125/30 maintenance blister card wallet.  
• The first dose of 125/30 is to be self-administered in the evening at home by the subject. 
If the subject has not yet received their morning dose of 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. 
• Remind the subject to return the maintenance blister card wallet at their next visit.  
In the event that the subject is not escalated to KarXT 125/30, in accordance with investigator 
order, dispense a single 100/20 maintenance blister card wallet. 
 
Visit 4/Day 14 Dosing  
• If dose of KarXT 125/30 BID was confirmed by investigator order, site staff will provide 
subjects with two 125/30 maintenance blister card wallets, which will provide sufficient 
doses until the subject’s next study 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 return the maintenance blister card wallets at their next visit.  
In the event that the subject was not escalated to KarXT 125/30, in accordance with investigator 
order, sites should provide subjects with two 100/20 maintenance blister card wallets.  
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Visits 5 to 8 (Days 28 to 70) Dosing  
• At each study visit, site staff will provide subjects with two 125/30 or 100/20 
maintenance blister card wallets based on the investigator-confirmed dose in order to 
provide sufficient quantities of KarXT until the subject’s next clinic visit.   
• Remind the subject to return the maintenance blister card wallets at their next visit.  
 
Visits 9 to 29 (Days 84 to 364) Dosing  
• At each scheduled in-clinic study visit, site staff will provide subjects with four 125/30 or 
100/20 maintenance blister card wallets based on the investigator-confirmed dose in 
order to provide sufficient quantities of KarXT until the subject’s 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. 
• Remind the subject to return the maintenance blister card wallets at their next in-clinic 
visit.  
9.3 
Measures to Minimize Bias: Study Treatment Assignment 
 
Method of Study Treatment Assignment 
At screening, the interactive web response system (IWRS) will assign a unique subject 
identification number to the subject known as the Subject Number. This number will be 
associated with the subject throughout the study. Every subject who signs an ICF must be 
entered into the IWRS regardless of eligibility in order to obtain a Subject Number. This 9-digit 
number will consist of a 3-digit study code and a 3-digit site identification, followed by a 3-digit 
number assigned sequentially within each site, starting at 
. 
 
Blinding 
This is an open-label study; therefore, blinding is not applicable. 
9.4 
Dosage Modification 
Subjects will self-administer 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).  
Additional changes to KarXT dosing (eg, temporary dose reductions) may be permitted as 
clinically indicated upon approval by the medical monitor. 
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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 
 monitor administration of KarXT in between clinic visits to ensure 
compliance 
. KarXT will be dispensed in prepackaged blister card wallets. 
The titration wallet will contain 10 days of dosing with 2 days of 50/20 KarXT BID and 8 days 
of 100/20 KarXT BID. After titration, subjects will receive 1 or more wallets each containing 8 
days of BID doses of 125/30 or 100/20 KarXT based on the investigator-confirmed dose. 
Subjects will be advised to return the blister card wallets to the site staff at each in-clinic visit for 
drug accountability. 
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 destroyed or 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 they were taking up to 6 months before 
the study, up to the time of consent. All prior medications will be recorded on the eCRF. 
Restricted prior therapies are provided below. 
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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. 
During the study (i.e., from the time consent until study completion [EOS]), subjects should 
refrain from the use of any new concomitant medications without the approval of the 
investigator. The administration of any other concomitant medications during the study period is 
prohibited without the 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. 
After written informed consent is obtained from the subject, those subjects who are taking the 
following medications must have the minimum washout periods specified below and not take the 
medications for the duration of the study. 
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 
 
 
 
 
 
 
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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 Section 11, Section12, 
Section 13, and Section 14 for additional details regarding safety, efficacy, PK, 
 
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 by telemedicine 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 Day -17 to 
Day -4 
Day -3 
to Day -1 
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 Screening1 
Baseline 
Visit A2 
Baseline 
Visit B  
1 
2a 
3 
4 
5 
6 
7 
8 
9 
10a 
11 
12 
13 
14 
15 
TYPE OF VISIT
C 
C 
C 
 
I 
C 
C 
C 
C 
C 
C 
C 
I 
C 
I 
C 
I 
C 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect demographic 
information (date of 
birth, age, sex, race, 
ethnicity) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject eligibility 
verification process 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, psychiatric, 
and medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(WOCBP only)c 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Urine drugs of abuse 
and alcohol testingd 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Review of 
inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, body weight, 
BMI, waist 
circumferencee 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Complete physical 
examinationf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical 
examinationg 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
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DAY 
 
Day -17 to 
Day -4 
Day -3 
to Day -1 
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 Screening1 
Baseline 
Visit A2 
Baseline 
Visit B  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10a 
11 
12 
13 
14 
15 
TYPE OF VISIT 
C 
C 
C 
 
I 
C 
C 
C 
C 
C 
C 
C 
I 
C 
I 
C 
I 
C 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spontaneous AEsh 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of 
concomitant 
medicationsi 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs: BP and 
HRj 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Resting ECG (12-
lead)k 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Blood samples for 
clinical laboratory 
testsl 
X 
 
 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
Blood sample for 
viral serologym 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Functional 
constipation inquiryn 
 
Xb 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Determination of 
dose titration 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood drawo 
 
 
 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
MINI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PANSSp 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
C-SSRSq 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
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DAY 
 
Day -17 to 
Day -4 
Day -3 
to Day -1 
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 Screening1 
Baseline 
Visit A2 
Baseline 
Visit B  
1 
2a 
3 
4 
5 
6 
7 
8 
9 
10a 
11 
12 
13 
14 
15 
TYPE OF VISIT 
C 
C 
C 
 
I 
C 
C 
C 
C 
C 
C 
C 
I 
C 
I 
C 
I 
C 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGI-S scale 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
SAS 
 
Xb 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
BARS 
 
Xb 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
AIMS 
 
Xb 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
KarXT dispenseds  
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Subject self-
administration of 
KarXT BID using 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IPSSw 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
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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
I 
C 
I 
C 
I 
C 
I 
C 
I 
C 
I 
C 
I 
C 
C 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(WOCBP only)c 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Urine drugs of abuse and 
alcohol testingd 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Body weight, BMI, waist 
circumferencee 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Complete physical 
examinationf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Targeted physical 
examinationg 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Spontaneous AEsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
Review of concomitant 
medicationsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
Vital signs: BP and HRj 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
12-lead resting ECGk 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Blood samples for clinical 
laboratory testsl 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Functional constipation 
inquiryn 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
PK blood drawo 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
PANSSp 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
C-SSRSq 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X3 
CGI-S scale 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
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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
I 
C 
I 
C 
I 
C 
I 
C 
I 
C 
I 
C 
I 
C 
C 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAS 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
BARS 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
AIMS 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
KarXT dispenseds 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Subject self-administration of 
KarXT BID 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
IPSSw 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Abbreviations: AE = adverse event; AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; BMI = body mass index; 
BID = twice daily; BP = blood pressure; C= Clinic visit; 
; CGI-S = Clinical Global 
Impression‒Severity scale; C-SSRS = Columbia-Suicide Severity Rating Scale; d = day; 
; ECG = electrocardiogram; 
 
 EOS = end of study; EOT = end of treatment; ET = early termination; HR = heart rate; I = Interim visit; IPSS = 
International Prostate Symptom Score, MINI = Mini International Neuropsychiatric Interview; 
; PANSS = Positive 
and Negative Syndrome Scale; PK = pharmacokinetic; 
; 
 QTcF = QT 
interval corrected by Fridericia; SAS = Simpson-Angus Rating Scale; 
; UNS = unscheduled visit; WOCBP = women of 
childbearing potential. 
1. Up to a 7-day screening extension can be granted with medical monitor approval 
2. Baseline Visit A must be completed no less than 3 days and no more than 5 days before Baseline Visit B. 
3. Unscheduled (UNS) visits may be conducted as needed to facilitate retention and ensure compliance with study objectives. UNS visits must include at a 
minimum a review of concomitant medications, assessment of any new or ongoing AEs, and a C-SSRS. Other assessments may be performed as needed. 
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a. 
At Visit 2/Day 3, and beginning again on Visit 10/Day 98 and every 4 weeks thereafter, interim visits will be completed between the required in-clinic 
visits. Interim visits will be conducted by site staff and can be completed using telemedicine (audio only, or audio + video) or in-clinic, per investigator 
discretion. 
b. This procedure may be completed at either Baseline Visit A or Baseline Visit B. 
c. 
A urine pregnancy test for WOCBP should be performed at scheduled visits. In case of positive urine pregnancy test result, a serum sample should be sent 
to central laboratory for confirmation of the result. 
d. 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 locally at scheduled visits. A sample should be sent to the central lab at screening. 
Thereafter, if positive, with the exception of cannabinoids or marijuana, a sample should be sent to the central laboratory for confirmation of the result.  
e. 
Height is recorded at screening only. 
f. 
A complete physical examination includes body temperature (°C), 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. 
g. 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. 
h. AEs as reported by subjects or observed by clinical staff and occurs after dosing. For interim visits, spontaneous AEs will be collected by telemedicine.  
i. 
For interim visits, concomitant medications will be collected by telemedicine. 
j. 
Vital signs measurements should be taken at scheduled in-clinic visits, while the subject is supine and standing after 2 minutes. Includes systolic and 
diastolic BP and is to be taken in the same arm for the duration of the study. During clinic visits, orthostatic vital signs should occur 2 (±1) hours after 
morning dosing whenever possible.  
k. ECG should be obtained within 1 to 2 hours after the morning dose and before blood withdrawal for any safety laboratory tests whenever possible. During 
the ECG, ventricular rate (bpm), PR (msec), QRS (msec), QT (msec), and QTcF (msec) measurements should be obtained. 
l. 
Refer to Section 11.6 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. 
m. All subjects must have the following viral serology tests completed at Screening: anti-HCV antibody, HBV surface antigen, HBV core antibody, HIV-1 
antibody, and HIV-2 antibody. If the subject tests positive for anti-HCV antibody, then HCV RNA via polymerase chain reaction should be performed to 
confirm or rule out active infection. 
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. PK blood samples will be collected on Days 8, 14, 84, 168, and 280. On Day 8 the PK sample should be drawn within 1 to 2 hours post-dose whenever 
possible. Note: 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. 
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p. It is recommended that the PANSS assessment should be performed before all the other scale assessments for all visits at which it is performed, except for 
the screening visit (MINI conducted first). The PANSS assessment includes the Marder Factor. 
q. C-SSRS past 12-months version will be utilized at screening; the “since last visit” version will be conducted at all other scheduled study visits. At the 
Unscheduled visit, the C-SSRS should be performed to monitor subjects for suicidality. 
 
. 
s. 
See Pharmacy Manual for details on KarXT dispensing and compliance evaluation. 
w. IPSS will be administered monthly only in male subjects ≥45 years of age at the time of signing the informed consent. IPSS assessment administration will 
start from Visit 11 (at the time of this amendment, study enrollment has been completed, and all enrolled subjects have completed Visit 9). 
 
 
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10.1 Informed Consent 
Informed consent forms must be approved for use by the reviewing 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 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; 
12-lead 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. 
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 should include at a 
minimum the C-SSRS and an assessment of concomitant medications and any new or ongoing 
adverse events. 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. 
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11 SAFETY ASSESSMENTS 
Safety assessments (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, 12-lead ECG, IPSS, 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 will be collected for all subjects at screening. The information to be captured 
includes date of birth (alternatively year of birth if full date of birth is not allowed to be collected 
for legal reasons), age, sex, race and ethnicity, which will be obtained from the subject and 
recorded in the eCRF. 
Medical, psychiatric, and medication history will be recorded at screening. Investigators should 
document the occurrence, signs, and symptoms of the subject’s preexisting conditions, including 
all baseline symptoms, ongoing illnesses, other chronic conditions, and surgical history at 
screening. Medical history will also include history of drug, substance, or alcohol 
abuse/dependence within 1 year before Screening. 
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 the time of consent or described in the past medical history and identified 
as clinically significant 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. BP measurements are to be taken in the same arm 
for the duration of the study. During treatment 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 
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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 
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. 
11.4 Weight, Height, Body Mass Index, and Waist Circumference 
Height (screening only), 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 whenever possible 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 
whenever possible. 
ECGs will be transmitted electronically to a central reader at the central reading facility 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 in the eCRF. ECGs will be 
repeated if clinically significant abnormalities are observed or artifacts are present. 
At screening, the investigator will examine the ECG traces for signs of cardiac disease that could 
exclude the subject from the study. An assessment of normal or abnormal will be recorded; if the 
ECG is considered abnormal, the abnormality will be documented in 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 
Urinalysis (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) 
 
 
Coagulation 
Serologya 
PT 
Activated PTT 
Fibrinogen 
HBV 
HCV 
HIV 
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 central laboratory 
to confirm the result. 
Full and microscopic urinalysis:  
Chemical exam: SG, pH, bilirubin, urobilinogen, protein, glucose, ketone, hemoglobin, leukocyte esterase, 
nitrite.  
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; Hb = hemoglobin; HBV = Hepatitis B; Hct = 
hematocrit; HCV = Hepatitis C; HDL = high density lipoprotein; HIV = Human Immunodeficiency virus; 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; SG = specific gravity; WBC = white blood cell; WOCBP = women of 
childbearing potential. 
a The following viral serology tests completed at Screening: anti-HCV antibody, HBV surface antigen, HBV core 
antibody, HIV 1 antibody, and HIV-2 antibody. If the subject tests positive for anti-HCV antibody, then HCV 
RNA via polymerase chain reaction should be performed to confirm or rule out active infection. 
 
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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 of urine 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, when indicated) will be analyzed at a central 
laboratory facility. Urine samples will first be analyzed at investigator site by dipstick. If the 
results of the dipstick indicates 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 in the 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 at the scheduled visits.  A sample should be sent to the central lab at screening. 
Thereafter, if positive, with the exception of cannabinoids or marijuana, a sample should be 
sent to the central laboratory for confirmation of the result. 
• Alcohol testing will be performed using a breathalyzer or urine alcohol test.  
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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 the time of consent, 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 the time of consent will be documented in the medical history eCRF. Changes 
in these conditions and new symptoms, physical signs, syndromes, or diseases should be noted in 
the AE eCRF during the rest of the study. Clinically significant vital signs and 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 in the 
appropriate page of the eCRF. AEs will be elicited by asking the subject a nonleading question, 
for example, “Have you experienced any new or changed symptoms since we last 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 in 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 in the eCRF. 
For the purposes of this study, the period of observation for collection of AEs extends from the 
time of consent until EOS. 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. 
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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 
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 
LFT elevations as outlined in 11.7.5 inclusive of drug-induced liver injury (DILI) and 
symptomatic orthostasis including syncope (a transient loss of consciousness or fainting) is to be 
captured as an AESI and reported as such. Non symptomatic orthostasis will not be reported as 
an AESI. Any such AESI due to any cause, whether or not related to KarXT, must be reported 
within 24 hours of occurrence or when the investigator becomes aware of the event. Notification 
can be made using email. 
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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 in 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. SAEs 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. 
 
Serious Adverse Event Reporting 
An SAE occurring from the time of informed consent until EOS 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 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: Safety@catalystcr.com 
The event must be recorded in 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 
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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 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 
Drug-Induced Liver Injury (DILI) should be reported as an AESI anytime the subject exhibits: 
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Trial Discontinuation Criteria Other than DILI and Pregnancy 
11.7.6.1 
Individual Stopping Criteria 
Based on NCI CTCAE v5.0, study drug will be discontinued in any subject who has a ≥ 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. 
11.7.6.2 
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 
c. Terminate the study. 
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Suspected Unexpected Serious Adverse Reactions 
AEs 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 Independent Ethics 
Committee (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 AD 
patients. It is notable, however, that the hepatic enzyme elevations were not observed in the 
Phase 1 studies in healthy volunteers and that the LFT 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 AD 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 >2 × upper limit of reference range in either the 
xanomeline or KarXT datasets. 
 
Pregnancy 
WOCBP must have a negative pregnancy test at Screening and Baseline Visit B (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 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. 
 
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 BP 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). Epinephrine 0.1 to 1.0 mg subcutaneous may be of value in overcoming severe 
cardiovascular or bronchoconstrictor responses. 
AEs associated with overdoses should be reported in 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 Akathisia Rating Scale  
The BARS 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 known 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. 
11.11 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 
version will be completed; for all subsequent visits the “Since Last Visit” version of the C-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.[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 all in-clinic visits, 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. 
11.13 International Prostate Symptom Score (IPSS) 
The Internal Prostate Symptom Score (IPSS) is administered by a clinician [38]. The IPSS is 
based on the answers to seven questions concerning urinary symptoms and one question 
concerning quality of life. Each question concerning urinary symptoms allows the patient to 
choose one out of six answers indicating increasing severity of the particular symptom. The 
answers are assigned points from 0 (not at all) to 5 (almost always). The total score can therefore 
range from 0 to 35 (asymptomatic to very symptomatic)[39]. 
The questions assess following urinary symptoms: (1) Incomplete emptying, (2) frequency, (3) 
intermittency, (4) urgency, (5) weak stream, (6) straining and (7) Nocturia. 
Question 8 of the IPSS refers to the patient’s perceived quality of life. The score on question 8 is 
not included in the total score calculation. 
If a subject has an IPSS score of 5 (almost always) on items 1, 3, 5, or 6, OR a sum of scores on 
IPSS items 1, 3, 5, and 6 of ≥ 9 during the treatment period, the subject should be referred to a 
urologist. The urologist, in collaboration with the study Investigator and the medical monitor, 
should determine whether the subject should be discontinued from study treatment and/or the 
study. Study drug should be temporarily interrupted until the subject is seen by the urologist. 
 
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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 scheduled assessments for all visits at which it is performed, except during screening 
when the MINI should be conducted first. 
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 
 
Blood Samples 
On Days 8, 14, 84, 168, and 280, a single sample will be collected during the subject’s regularly 
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 Bioanalysis of Trospium and Xanomeline 
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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15 STATISTICAL ANALYSIS 
An 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 Statistical Analysis System ® 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.  
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. 
15.1 Determination of Sample Size 
No formal sample size calculations were done. A sample size of up to 600 was deemed sufficient 
to provide 6- and 12-month safety data on subjects exposed to KarXT. 
15.2 Analysis Populations 
Enrolled population: All subjects who have given informed consent for KAR-011 will be 
included in the Enrolled population. 
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. 
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, and at least 1 postbaseline time point 
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 in the current study will be included in the PK 
population. 
15.3 Safety Analysis 
Safety endpoints will be summarized for all subjects in the Safety population. 
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, 
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duration, relationship and severity to KarXT, action taken with KarXT, treatment of event, and 
outcome. 
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, IPSS, 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. 
Tabular presentations will display descriptive statistics for baseline and change from baseline 
study results by scheduled visit. 
Responder efficacy variables (PANSS responders) will be summarized descriptively.  
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 and change from baseline results by scheduled visit. 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.   
15.7 Interim Analysis  
No interim analysis is planned for this study. 
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15.8 Handling of Missing 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 7 days of the last dose of KarXT. 
Subject Registry: 
Clinical trial registries, such as clinical trial subject (CTS) database (CTS database) 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 study, the investigator or designee will explain the IRB-approved Subject 
Database Authorization to the subject and witness the signature. 
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At the beginning of screening visit, following consent execution and subject number assignment 
and before other study procedures, site staff that have received training and login information 
access (www.subjectregistry.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.  
Throughout the study, tracking of actively enrolled subjects will continue based on updates by 
coordinators in the interactive response system. At the last subject contact, CTS database and 
VCT staff will automatically close out the subject (safety follow-up, ET, or completer) based on 
IWRS. 
16.2 Data Handling 
Any data to be recorded directly in the eCRFs (to be considered as source data) will be identified 
at the start of the study. Data reported in 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 in eCRFs for transmission to the Sponsor. Data in 
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 website, 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. 
eCRFs 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. 
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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 into 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-011 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 investigators will assure them 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. 
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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. 
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 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 
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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. 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;39(9):638-645. 
2. van Os J, Kapur S. Schizophrenia. Lancet. 2009;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;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 
. 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;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;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;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-S22. 
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;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. 
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;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;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;144(1):211-217. 
28. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional 
bowel disorders. Gastroenterology. 2006;130(5):1480-1491. 
29. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol. 1997;32(9):920-924. 
30. Locke GR III, Pemberton JH, Phillips SF. American Gastroenterological Association 
Medical Position Statement: guidelines on constipation. Gastroenterology. 
2000;119(6):1761-1766. 
31. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr Bull. 1987;13(2):261-276. 
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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. 
38. Barry MJ, Fowler FJ, Chang Y, et al. The American Urological Association symptom index: 
does mode of administration affect its psychometric properties? The Journal of urology. 
1995;154(3):1056-1059. 
39. Barry MJ F, Jr. FJ, O'Leary MP, et al. The American Urological  Association Symptom 
Index for Benign Prostatic Hyperplasia. The J of Urology. 1992 November;148:1549-1557. 
 
 
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18 APPENDICES 
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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 last dose of study drug. If oral contraceptives are used, the 
subject must have been on a stable dose for ≥6 months. 
 
A woman of child-bearing potential (WOCBP) is any woman who has experienced menarche 
and is not yet postmenopausal unless she is permanently sterile (i.e. hysterectomy, bilateral 
salpingectomy, bilateral tubal ligation, or bilateral oophorectomy). Women who have 
experienced menarche but are not yet postmenopausal, and who are permanently sterile by one 
of the methods described above are not required to undergo pregnancy testing at study visits, and 
it is not considered a protocol deviation to skip pregnancy testing for these individuals.  
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) 
• double barrier method consisting of a physical (e.g., condom, diaphragm) and chemical 
barrier (e.g., spermicide) 
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 30 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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APPENDIX 2. FUNCTIONAL CONSTIPATION INQUIRY 
1 
ROME III Diagnostic Criteria for Constipation and Irritable Bowel Syndrome with 
Constipation 
Symptoms ≥3 months; onset ≥6 months before diagnosis 
Functional Constipation 
IBS-C 
Must include ≥ 2 of the following: 
• 
Straininga 
• 
Lumpy or hard stoolsa 
• 
Sensation of incomplete evacuationa 
• 
Sensation of anorectal 
obstruction/blockagea 
• 
Manual maneuvers to facilitate defecation 
(eg, digital evacuation, support of the 
pelvic floor)a 
• 
<3 defecations/week 
IBS: Recurrent abdominal pain/discomfort 
≥ 3 days/month for the past 3 months, 
associated with ≥ 2 of the following: 
• 
Improvement with defecation 
• 
Onset associated with change in stool 
frequency 
• 
Onset associated with change in stool 
form 
• 
Loose stool rarely present without use of 
laxatives 
IBS is subtyped by predominant stool 
pattern 
• 
IBS-C: hard or lumpy stoolsb ≥ 25% of 
defecations; loose or watery stoolsc 
< 25% of defecationsd 
• 
Insufficient criteria for IBS-C 
 
Abbreviation: IBS-C = irritable bowel syndrome with constipation. 
a 
≥ 25% of defecations.  
b 
Bristol Stool Form Scale 1–2: separate, hard lumps like nuts (difficult to pass); or lumpy, sausage-shaped stool.  
c 
Bristol Stool Form Scale 6–7: fluffy pieces of stool with ragged edges; mushy stool; or watery without solid 
pieces (entirely liquid).  
d 
In the absence of use of antidiarrheals or laxatives (Longstreth GF et al. Gastroenterology. 2006;130:1480-
1491, C3 p.1486).  
 
 
 
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2 Bristol Stool Form Scale 
 
 
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1.
TABULAR SUMMARY OF REVISIONS IMPLEMENTED IN THE AMENDED PROTOCOL
The major revisions to Protocol KAR-011 v4.0 include changes to include the International Prostate Symptom Score (IPSS) 
assessment, schedule of assessments, updated Phase 3 study status, administrative and minor editing changes that do not affect the 
content or conduct of the protocol have been incorporated. 
Bolded text indicates new content and strike-through shows deleted text. Only the changed text in a section will be shown. Changes 
to the reference section are not documented. The administrative and minor editing are not elaborated on in this document but are 
found in the tracked change document that accompanies this summary of revisions. 
Section in Amended 
Protocol 
Original Text 
Revised Text 
Rationale for 
Change 
Synopsis, Title Page, 
Sponsor Signature Page, 
Header 
13 December 2021, and Protocol version 3.0 
26-September-2023, and Protocol version 4.0
Corrected date 
and version to 
v4.0 issue 
Synopsis/Study 
Design/ Section 7.2 
De novo subjects, defined as not previously 
participated in a study of KarXT, who meet 
DSM-5 criteria for schizophrenia. 
De novo subjects, defined as those who did not 
have prior exposure to KarXT, who meet DSM-5 
criteria for schizophrenia. 
To be consistent 
with exclusion 
criteria number 16, 
updated de novo 
subject’s definition. 
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Section in Amended 
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Synopsis/Safety 
assessments/Section 7.1/ 
Section 11/Section 15.3 
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. 
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; IPSS; and 
C-SSRS will be evaluated throughout the study as 
scheduled. 
, 
monthly reporting 
of IPSS assessment 
for male subjects ≥ 
45 has been added 
to safety 
assessments.  
List of Abbreviations 
IPSS: International Prostate Symptom Score 
Updated 
abbreviations list. 
Section 5.2.2 
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. Also, a Phase 3 open-
label, roll-over trial (KAR-008) is planned in 
which the subjects rolled-over from KAR-007 
and KAR-009 will be treated with KarXT for 
a period of up to 52 weeks in an outpatient 
setting. 
KAR-007 and KAR -009 had similar study 
designs and were modelled from the first 
pivotal study, KAR-004. Both KAR-007 and 
KAR-009 were Phase 3, randomized, double-
blind, placebo-controlled trials to assess the 
efficacy, safety, and tolerability of KarXT in 
adults with DSM-5 schizophrenia, 
hospitalized with acute psychosis. Both KAR-
007 and KAR-009 were identical, except 
KAR-007 enrolled subjects in the US only 
whereas KAR-009 enrolled subjects in 
Ukraine and the US. The primary objective 
of the studies was to assess the efficacy of 
KarXT (125/30 BID) vs placebo in reducing 
PANSS total scores in adult inpatients with a 
Added KAR-007 
and KAR-009 
study status and 
results. 
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DSM-5 diagnosis of schizophrenia. Subjects 
aged 18 to 65 years old received either 
KarXT or placebo (1:1 ratio) for a treatment 
period of 5 weeks. 
Both pivotal, Phase 3 studies met their 
primary endpoint. The primary endpoint in 
KAR-007 and KAR-009 was the change from 
baseline (CFB) in PANSS total score at week 
5. In each of the studies, treatment with 
KarXT led to statistically significant 
improvements in PANSS total score at Week 
5 compared with placebo (p < 0.0001 in each 
study). Cohen’s d effect size was 0.61 in 
KAR-007 and 0.60 in KAR-009. 
Secondary endpoints were analyzed based on 
a planned hierarchy in a fixed sequence and 
were typically in favor of KarXT. Treatment 
with KarXT led to statistically significant 
improvements relative to placebo in PANSS 
positive score at Week 5 in both studies (p < 
0.0001 in each study). In KAR-007, the 
improvements in PANSS negative and 
PANSS Marder factor negative subscales 
were statistically significant in favor of 
KarXT versus placebo at Week 5 (p ≤ 0.0055 
and p = 0.0022, respectively). In KAR-009, 
the improvements in PANSS negative and 
PANSS Marder factor negative score at 
Week 5 was greater in KarXT than placebo 
but did not reach statistical significance at the 
2-sided alpha level of 0.05 (p = 0.1224 and p = 
0.1957, respectively). Analysis of the CFB in 
CGI-S in both studies demonstrated 
improvements in CGI-S scores at Week 5 in 
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favor of KarXT versus placebo (statistically 
significant over placebo for KAR 007, and 
nominally significant over placebo albeit not 
formally tested in KAR-009). KAR-007 and 
KAR-009 included a Week 5 PANSS 
responder analysis as a secondary efficacy 
endpoint (defined as an improvement from 
baseline of at least 30% at Week 5 in PANSS 
total score). The PANSS responder analysis 
showed that a greater proportion of subjects 
on KarXT achieved ≥ 30% improvement in 
PANSS total score at Week 5 compared to 
those on placebo in both KAR-007 (54.8% 
versus 28.3%, p < 0.0001) and KAR 009 
(50.6% versus 25.3%, p = 0.0056). 
KarXT was well-tolerated and safe in the 
Phase 3 studies, with the pattern and course 
of safety findings largely consistent with the 
known safety profile of KarXT. The most 
common TEAEs were associated with the 
procholinergic or anticholinergic effects of 
KarXT. The administration of KarXT was 
notably free of many common side effects 
associated with currently approved 
antipsychotic drugs. 
KAR-008 is an ongoing Phase 3, multicenter, 
outpatient, open label extension (OLE) study 
designed to evaluate the long-term safety, 
tolerability, and efficacy of KarXT in adults 
with DSM-5 schizophrenia, which includes 
subjects who completed KAR-007 or KAR-
009. Eligible subjects receive KarXT for up to 
52 weeks. Enrollment in this study is 
complete (N=156). 
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Section 5.3 
Trospium chloride has been marketed in 
the United States for 12 years. 
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. 
Trospium chloride has been marketed in the 
United States for 19 years. 
Findings from one Phase 2 (KAR-004) and 
two Phase 3 (KAR-007 and KAR-009) pivotal 
placebo-controlled studies were similar. In all 
three clinical studies, administration of 
KarXT (100/20 and 125/30) for 5 weeks 
resulted in consistent, significant reductions 
in symptoms of schizophrenia in subjects 
with acute psychosis and CGI-S compared 
with placebo. The safety and tolerability of 
KarXT was consistent in 3 successive pivotal 
placebo-controlled studies (KAR-004, KAR-
007 and KAR-009). The most common 
treatment-emergent adverse events (TEAEs) 
by preferred term in the KarXT treatment 
arm included nausea, dyspepsia, vomiting, 
constipation, headache, hypertension, 
diarrhea, and insomnia. 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 
 
 
 
 
 
 
Updated safety 
findings from 
completed Phase 3 
studies (KAR-007 
and KAR-009) and 
provided a status 
update from 
ongoing OLE 
study (KAR-008). 
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current therapies. 
KAR-008 is an ongoing Phase 3, 
multicenter, outpatient, OLE study 
designed to evaluate the long-term 
safety, tolerability, and efficacy of 
KarXT in adults with DSM-5 
schizophrenia, which includes subjects 
who completed KAR-007 or KAR-009. 
Section 11.7.2 
AESIs will be monitored and include 
orthostasis and LFT elevations as outlined in 
11.7.5 inclusive of drug-induced liver injury 
(DILI) and symptomatic orthostasis including 
syncope (a transient loss of consciousness or 
fainting) is to be captured as an AESI and 
reported as such. 
LFT elevations as outlined in 11.7.5 inclusive of 
drug-induced liver injury (DILI) and symptomatic 
orthostasis including syncope (a transient loss of 
consciousness or fainting) is to be captured as an 
AESI and reported as such. Non symptomatic 
orthostasis will not be reported as an AESI. Any 
such AESI due to any cause, whether or not 
related to KarXT, must be reported within 24 
hours of occurrence or when the investigator 
becomes aware of the event. Notification can be 
made using email. 
Updated criteria 
for AESI to include 
Syncope and DILI, 
and clarified 
reporting 
requirements. 
Section 11.7.5 
Drug-Induced Liver Injury (DILI) should be 
reported as an AESI anytime the subject exhibits: 
Updated section to 
clarify when DILI 
should be reported as an 
AESI. 
 
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Section 11.7.9 
Supportive treatment should be used as 
indicated (artificial respiration, maintenance 
of airway, oxygen, etc). Atropine sulfate 
should be available for intravenous 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. 
Supportive treatment should be used as 
indicated (artificial respiration, maintenance of 
airway, oxygen, etc). Epinephrine 0.1 to 1.0 mg 
subcutaneous may be of value in overcoming 
severe cardiovascular or bronchoconstrictor 
responses. 
Clarified language 
to be consistent 
with IB. 
Section 11.13 
The Internal Prostate Symptom Score (IPSS) is 
administered by a clinician [38]. The IPSS is 
based on the answers to seven questions 
concerning urinary symptoms and one question 
concerning quality of of life. Each question 
concerning urinary symptoms allows the patient 
to choose one out of six answers indicating 
increasing severity of the particular symptom. 
The answers are assigned points from 0 (not at all) 
to 5 (almost always). The total score can therefore 
range from 0 to 35 (asymptomatic to very 
symptomatic) [39]. 
The questions assess following urinary symptoms: 
(1) Incomplete emptying, (2) frequency, (3) 
intermittency, (4) urgency, (5) weak stream, (6) 
straining and (7) Nocturia. 
Question 8 of the IPSS refers to the patient’s 
perceived quality of life. The score on question 8 is 
not included in the total score calculation. 
If a subject has an IPSS score of 5 (almost always) 
on items 1, 3, 5, or 6, OR a sum of scores on IPSS 
items 1, 3, 5, and 6 of ≥ 9 during the treatment 
, 
monthly reporting 
of IPSS assessment 
for male subjects   
≥ 45 has been 
added to this 
protocol. This 
section describes 
the IPSS 
assessment and 
follow-up. 
 
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period, the subject should be referred to a 
urologist.The urologist, in collaboration with the 
study Investigator and the medical monitor, 
should determine whether the subject should be 
discontinued from study treatment and/or the 
study. Study drug should be temporarily 
interrupted until the subject is seen by the 
urologist. 
Section 15.4 
Responder efficacy variables (PANSS 
responders) will be summarized descriptively. 
Responses will be derived relative to the acute 
study baseline assessments. 
Responder efficacy variables (PANSS 
responders) will be summarized descriptively.  
The omitted 
sentence is not 
applicable to this 
trial. 
Appendix 1 
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. 
Postmenopausal status must be confirmed by a 
test of the subject’s follicle-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. 
A woman of child-bearing potential (WOCBP) is 
any woman who has experienced menarche and is 
not yet postmenopausal unless she is permanently 
sterile (i.e. hysterectomy, bilateral salpingectomy, 
bilateral tubal ligation, or bilateral 
oophorectomy). Women who have experienced 
menarche but are not yet postmenopausal, and 
who are permanently sterile by one of the 
methods described above are not required to 
undergo pregnancy testing at study visits, and it is 
not considered a protocol deviation to skip 
pregnancy testing for these individuals. 
Updated language 
to clarify the 
contraception 
guidelines of 
WOCBP. 
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Original Text 
Revised Text 
Rationale for 
Change 
Female subjects who are surgically sterile (ie, 
hysterectomy, bilateral salpingectomy, or 
bilateral oophorectomy) will not need to 
undergo the FSH level test. 
 
 
Summary of Changes to Table 2 (Schedule of Assessment) 
 
Change 
Rationale 
Added IPSS assessment at Visit 11, Visit 13, Visit 15, Visit 17, Visit 19, Visit 
21, Visit 23, Visit 25, Visit 27, Visit 29, and End of Study/unscheduled 
Visit. 
 
, implemented monthly reporting of IPSS assessment for male 
subjects ≥ 45 at these visits.  
 
w. IPSS will be administered monthly only in male subjects ≥45 years of age 
at the time of signing the informed consent. IPSS assessment 
administration will start from Visit 11 (at the time of this amendment, 
study enrollment has been completed, and all enrolled subjects have 
completed Visit 9). 
 
Added footnote to clarify the IPSS administration specifications. 
 
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1. 
TABULAR SUMMARY OF REVISIONS IMPLEMENTED IN THE AMENDED PROTOCOL 
The major revisions to Protocol KAR-011 v3.0 include changes to inclusion criteria, schedule of assessments, and number of sites 
and subjects. Administrative and minor editing changes that do not affect the content or conduct of the protocol has been 
incorporated. 
Bolded text indicates new content, strike-through shows deleted text. Only the changed text in a section will be shown. An ellipsis, or 
series of dots (…), is used to indicate that unchanged text before and/or after the addition or revision is not shown. For changes that 
affect multiple sections of the protocol, the change is listed once at the first instance below, and each subsequent protocol section 
incorporating that change is also listed at that point. Changes to the reference section are not documented. The administrative and 
minor editing are not elaborated on in this document but are found in tracked change document, that accompanies this summary of 
revisions. 
 
 
 
 
 
 
Section in Amended 
Protocol 
Original Text 
Revised Text 
Rationale for 
Change 
Synopsis, Title Page, 
Sponsor Signature Page, 
Header 
31-August-2021 
20-December-2021 
Corrected date to 
v3.0 issue 
Synopsis/ 
Investigators/Study 
Sites 
 
Approximately 40 sites in the United States 
Approximately 60 sites in the United States 
Change in total 
number of study 
participants will 
require more study 
sites. 
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Section in Amended 
Protocol 
Original Text 
Revised Text 
Rationale for 
Change 
 
 
 
 
 
 
 
  
 
 
 
 
 
Synopsis / Study 
Endpoints / 
Secondary 
Endpoints / 
Efficacy 
Section 6.2.2.2 
Percentage of PANSS responders (a 30% 
change in PANSS total score) at Week 52 
Percentage of PANSS responders (a 30% 
reduction in PANSS total score) at Week 52 
Response is defined 
as a reduction in 
PANSS scores (i.e., 
30% worsening is not 
response) 
 
 
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Section in Amended 
Protocol 
Original Text 
Revised Text 
Rationale for 
Change 
 
 
 
 
 
 
 
 
 
 
Synopsis / Study Design / 
Screening Phase 
 
Section 7.1 
A suitable number of subjects will be screened to 
enroll approximately 400 subjects (aged 18 to 65 
years) with schizophrenia who are psychiatrically 
stable and can be adequately managed in an 
outpatient setting across approximately 40 study 
sites in the United States. The screening phase will 
last up to 14 days (up to a 7-day screening 
extension is permitted with medical monitor 
approval) and will end upon the start of the study 
baseline phase 
 
A suitable number of subjects will be screened to 
enroll approximately 600 subjects (aged 18 to 65 
years) with schizophrenia who are psychiatrically 
stable and can be adequately managed in an 
outpatient setting across approximately 60 study sites 
in the United States. The screening phase will last up 
to 14 days (up to a 7-day screening extension is 
permitted with medical monitor approval). 
 
Study size increased 
to ensure adequate 6 
and 12 month 
exposures. 
Unnecessary text 
removed. 
Synopsis / Study Design / 
Baseline Phase 
Section 7.1 
Table 2 
Subjects who meet the screening criteria will 
participate in a baseline period consisting of two 
separate visits and lasting no more than 5 days 
during which, subjects will complete 3 days of at-
home assessments 
. 
 
Subjects who meet the screening criteria will 
participate in a baseline period consisting of two 
separate visits. The start of the baseline period, 
Baseline Visit A, must be at least 3 days (and no 
more than 5 days) prior to Baseline Visit B. 
Subjects must continue to meet eligibility criteria 
throughout the baseline period to remain in the 
study. 
 
Clarification of 
baseline period 
duration and 
requirements 
Synopsis / Study Design / 
Treatment Phase 
Section 7.1 
Section 7.2 
Table 2 
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 compliance with study 
objectives. Additional unscheduled study visits 
may be conducted as needed. 
 
Interim visits, which can be conducted in-
clinic or by telemedicine per investigator 
discretion, will occur between required in-
clinic visits (see Schedule of Assessments 
Table 2). Additional Unscheduled study visits 
should be utilized as necessary to facilitate 
subject retention and ensure compliance with 
study objectives. 
Clarification of 
interim visits and 
their use. 
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Section in Amended 
Protocol 
Original Text 
Revised Text 
Rationale for 
Change 
Synopsis / Study Criteria / 
Inclusion Criteria 
Section 8.1 
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 (oral and 
written) in English to consent 
2. Subject is capable of providing informed 
consent. 
a. 
A signed informed consent form 
(ICF) must be provided before any 
study assessments are performed. 
b. Subject must be fluent (oral and 
written) in the language of the 
ICF to consent 
 
Permit use of non-
english ICF for 
native Spanish 
speakers 
Synopsis / Study Criteria / 
Inclusion Criteria 
Section 8.1 
5. PANSS total score of ≤ 80 at screening 
6. CGI-S score of ≤ 4 at screening 
7. PANSS total score of ≤ 80 at screening and 
Baseline Visit B (Day 0). 
8. CGI-S score of ≤ 4 at screening and Baseline 
Visit B (Day 0). 
Ensure participants 
remain stable and 
safe to manage in 
outpatient setting 
Synopsis / Study Criteria / 
Inclusion Criteria 
Section 8.1 
7. At the time of screening, the subject 
must be receiving an oral antipsychotic 
medication daily as maintenance 
therapy. 
 
 
 
 
 
 
 
 
. 
7. At the time of screening, or at any time 
within the 30 days prior to screening, 
the subject must have received an oral 
antipsychotic medication daily at a dose 
and frequency consistent with the drug 
label. 
Subjects who have 
recently 
discontinued 
treatment may be 
eligible if current 
meeting all other 
stability criteria. 
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Section in Amended 
Protocol 
Original Text 
Revised Text 
Rationale for 
Change 
Synopsis / Study Criteria / 
Exclusion Criteria 
Section 8.2 
1. The subject has a history of moderate to 
severe alcohol use disorder or a 
substance (other than nicotine or 
caffeine) use disorder within the past 12 
months 
a. 
A subject with mild substance 
abuse disorder within the 12 
months before screening must 
be discussed and agreed upon 
with the medical monitor 
before he/she can be allowed 
into the study. 
b. Subjects who test positive for 
cannabis at screening may be 
permitted to enroll in 
consultation with the medical 
monitor if the subject’s 
pattern of use is not indicative 
of a substance use disorder. 
2. The subject has a history of moderate to 
severe alcohol use disorder or a substance 
(other than nicotine or caffeine) use 
disorder within the past 12 months or a 
positive urine drug screen (UDS) for a 
substance other than cannabis at 
screening or baseline. 
a. 
A subject with mild 
substance abuse disorder 
within the 12 months before 
screening must be discussed 
and agreed upon with the 
medical monitor before 
he/she can be allowed into 
the study. 
b. Subjects with a positive 
UDS for cannabis are 
permitted to enroll in the 
study subject’s pattern of 
use is not indicative of a 
substance use disorder. 
Clarified that UDS 
will be utilized to 
assess use of non-
protocol permitted 
substances. 
Additional 
discussion w/ 
medical monitor 
not required for 
cannabis provided 
the subject does 
not meet criteria 
for a substance use 
disorder 
Synopsis / Study Criteria / 
Exclusion Criteria 
Section 8.2 
19. Participation in another clinical study in 
which the subject received an 
experimental or investigational drug 
agent within 3 months of to screening. 
19. Participation in another clinical study in 
which the subject received an experimental 
or investigational drug agent within 30 
days prior to screening. 
30 days deemed 
sufficient to ensure 
subject safety 
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Section in Amended 
Protocol 
Original Text 
Revised Text 
Rationale for 
Change 
Synopsis / Sample Size 
Section 7.2 
Approximately 400 subjects (aged 18 to 65 
years) are planned to be enrolled in this 
study. 
Approximately 600 subjects (aged 18 to 65 
years) are planned to be enrolled in this study. 
Sample size 
increased to ensure 
study objectives 
Table 1 
Section 8.4 
7 (±3) days after the last dose or for ET from 
the study or UNS 
7 (±3) days after completion of the EOT or 
ET visit 
Clarified EOS 
study takes place 
w/in 7 days of ET 
or EOT visit 
Table 1 / Footnote a 
At Visit 1 (Day 1) subjects will initiate dosing with 
KarXT BID independently at home. 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 by telemedicine. 
Visits 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 2, 10, 12, 14, 16, 18, 20, 22, 24, 
26, and 28 are interim visits and can be 
conducted via telemedicine or on-site. 
Visit 2 made 
interim (see 
below); all interim 
visits may be 
completed on-site 
or via telemedicine 
per investigator 
discretion 
Table 1 / Footnote c 
Beginning after Visit 9/Day 84, interim visits will 
be completed with flexibility between in-clinic 
visits, approximately once every 4 weeks.  
After Visit 9/Day 84, required in-clinic visits will 
be conducted approximately every 4 weeks. 
Interim visits will be conducted between required 
in-clinic visits and can be conducted by 
telemedicine or in-clinic per investigator 
discretion (see Schedule of Assessments Table 2 
for further details).  
Clarified use of 
interim visits 
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Section in Amended 
Protocol 
Original Text 
Revised Text 
Rationale for 
Change 
Table 1 / Footnote f 
Table 2 
Visit 2/Day 3 is an interim visit and can be 
conducted via telemedicine or in-clinic per 
investigator discretion. 
Visit 2 changed to 
interim to reduce 
study burden and 
increase 
investigator 
flexibility to meet 
study objectives  
Section 9.2.4, 9.2.5 
If dose escalation to the KarXT 125/30 level is 
confirmed by investigator order on Visit 3/Day 8, 
site staff will provide subjects with a single 125/30 
maintenance blister card wallet.  
If dose escalation to the KarXT 125/30 level is 
confirmed by investigator order, site staff will 
provide subjects with a single 125/30 maintenance 
blister card wallet.  
 
Dose is confirmed 
by investigator 
order at each study 
visit. 
Section 9.6.1 
Subjects will be asked to confirm all prior 
medications they were taking up to 6 months 
before the study, up to the time of the Baseline 
Visit A (Day -3). All prior medications will be 
recorded on the eCRF. 
 
Subjects will be asked to confirm all prior 
medications they were taking up to 6 months before 
the study, up to the time of consent. All prior 
medications will be recorded on the eCRF. 
 
Prior medications 
are those taken 
prior to consent 
Section 9.6.1 
During the study (ie, from the time of enrollment at 
the screening visit until study completion (EOS), 
subjects should refrain from the use of any new 
concomitant medications without the approval of 
the investigator. 
During the study (i.e., from the time consent until 
study completion [EOS]), subjects should refrain 
from the use of any new concomitant medications 
without the approval of the investigator. 
Clarified conmeds 
should be managed 
from time of 
consent 
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Section in Amended 
Protocol 
Original Text 
Revised Text 
Rationale for 
Change 
Section 11.1 
Section 11.7.1 
All changes not present at baseline or described in 
the past medical history and identified as clinically 
significant must be recorded as AEs. 
All changes not present at the time of consent or 
described in the past medical history and identified as 
clinically significant must be recorded as AEs. 
AE collection 
begins upon signed 
consent 
Section 11.6 
Table 2 
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 at the 
scheduled visits.  
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 at the scheduled 
visits.  A sample should be sent to the central lab 
at screening. Thereafter, if positive, with the 
exception of cannabinoids or marijuana, a sample 
should be sent to the central laboratory for 
confirmation of the result. 
Urine drug screen 
(UDS) samples 
only need to be 
sent to central lab 
at screening for 
eligibility review 
and thereafter only 
if the on-site test is 
positive for a 
substance other 
than cannabis. 
Negative results 
reported by on-site 
UDS. 
Section 11.7.4 
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… 
An SAE occurring from the time of informed 
consent until EOS must be reported… 
After EOS, any SAE that the Investigator 
considers related to study drug must be reported 
to Catalyst Clinical Safety or the 
Sponsor/designee. 
Clarified SAEs 
occurring at any 
time during the 
study must be 
reported. Any 
SAEs the 
investigator 
becomes aware of 
after EOS must be 
reported 
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Section in Amended 
Protocol 
Original Text 
Revised Text 
Rationale for 
Change 
Appendix 1 
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… 
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… 
Double barrier is 
not highly 
effective; all study 
approved 
contraception 
methods are listed 
within appendix 1 
 
 
Summary of Changes to Table 2 (Schedule of Assessment) 
 
Change 
Rationale 
Removal of AE collection at Visit 1/Day 1 
Visit 1/Day 1 reflects only the beginning of at-home dosing with KarXT and 
any AEs reported will be assessed and collected on an ongoing basis from the 
time of consent  
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Removal of vital signs, constipation inquiry, and C-SSRS at Visit 2/Day 3 
Visit 2/Day 3 changed to interim visit 
Removed PANSS assessment at Visit 4, Visit 17, Visit 21, Visit 25 
These additional assessments are unnecessary to meet study objectives and 
increase participant burden. 
 
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KAR-011 Summary of Changes of Amendment 2 
Page 1 
Updated Karuna Therapeutics address 
Updated Protocol Date 
Section 2, Synopsis 
Synopsis was updated to reflect content changes in the protocol as noted for each section below. 
6.1.2 
Secondary Objective 
Updated to integrate last bullet into general statement 
The secondary objective of this study is to assess the long-term efficacy and evaluate plasma 
concentrations of xanomeline and trospium following administration of KarXT in adults with a DSM-5 
diagnosis of schizophrenia: 
•
To evaluate the reduction in PANSS total score
•
To evaluate the reduction in PANSS positive score
•
To evaluate the improvement in CGI-S score
•
To evaluate the reduction in PANSS negative score
•
To evaluate the reduction in PANSS Marder Factor negative symptoms score
•
To evaluate the percentage of subjects who exhibit a 30% reduction in PANSS total score
6.2.2.2 Efficacy Endpoints 
Changed the secondary efficacy endpoint for CGI-S Score: 
•
CGI-S score at Week 52
6.2.3.2 Pharmacokinetic Endpoint 
Updated Endpoint to add more specific language 
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.   
7.1 Description of Overall Study Design and Plan 
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Updated Language to define “de novo” and extend screening period: 
This is a Phase 3, multicenter, 52 week, outpatient, open-label study to evaluate the long term safety, 
tolerability, and efficacy of KarXT in de novo subjects, defined as not previously participated in a study 
of KarXT, who meet DSM-5 criteria for schizophrenia. The study consists of a screening phase of up to 
14 days (up to a 7-day screening extension is permitted with medical monitor approval), a baseline phase 
of up to 5 days, a 52-week open-label treatment phase, and a 7-day safety follow-up/end of study (EOS) 
visit following the last dose of KarXT for subjects who complete the treatment phase and those who 
prematurely discontinue from the study. 
Screening Phase: 
A suitable number of subjects will be screened to enroll approximately 400 subjects (aged 18 to 65 years) 
with schizophrenia who are psychiatrically stable and can be adequately managed in an outpatient setting 
across approximately 40 study sites in the United States. The screening phase will last up to 14 days (up 
to a 7-day screening extension is permitted with medical monitor approval) and will end upon the start of 
the study baseline phase. 
Table 1 
Moved early termination subjects to Day 364/Visit 29 from Day 371/Visit 30 
7.2 Discussion of Study Design 
Updated Language to define “de novo”: 
The KarXT clinical development program includes this open-label study to evaluate the 
long-term safety, tolerability, and efficacy data for KarXT in de novo subjects, defined as not 
previously participated in a study of KarXT, who meet the DSM-5 criteria for schizophrenia. 
8.1 Inclusion Criteria 
Updated language to direct reader to contraception guidelines section: 
15. 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 
Added new exclusion criteria 
19. Participation in another clinical study in which the subject received an experimental or
investigational drug agent within 3 months before screening.
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9.1.1 Identity of Study Treatments 
Added new statement 
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). 
9.2.4 
Visit 3/Day 8 Dosing 
Removed specific visit language 
In the event that the subject is not escalated to KarXT 125/30, in accordance with investigator order, 
dispense a single 100/20 maintenance blister card wallet. 
9.2.5 
Visit 3/Day 8 Dosing 
Removed specific visit language 
In the event that the subject is not escalated to KarXT 125/30, in accordance with investigator order, 
dispense a single 100/20 maintenance blister card wallet. 
9.2.7 Visits 9 to 29 (Days 84 to 364) Dosing  
Changed day of PK draw 
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. 
9.4 Dosage Modification 
Changed evaluation for dose adjustments to start at Visit 3, not Visit 4 
Subjects will self-administer 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). 
9.6.1 
Prior and Concomitant Medications 
Removed Language 
During the study (ie, from the time of enrollment at the screening visit until study completion (EOS), 
subjects should refrain from the use of any new concomitant medications without the approval of the 
investigator. 
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10. Study Procedures
Removed and updated language 
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 Section 11, Section12, Section 13, and 
Section 14 for additional details regarding safety, efficacy, PK, 
 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 by telemedicine 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. 
Table 2. Schedule of Assessments 
Updated footnotes for clarification 
Moved the Early Termination visit from Day 371/Visit 30 to Day 364/Visit 29 
Moved a PK sample collection from Day 364/Visit 29 to Day 280/Visit 40 
 
. 
Added blood sample for Viral serology at screening 
10.2  Study Procedures 
Removed language 
PK assessments are described in Section 13. 
11.3 
Complete/Targeted Physical Examination 
Added language 
Physical examinations will be performed by a physician or qualified designee. 
11.5 
Electrocardiograms 
Updated language 
A 12-lead, resting ECG should be obtained whenever possible 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 whenever possible. 
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Table 3 Laboratory Assessments 
Removed Albumin from Serum Chemistry 
 
HbA1c added (glycated Hb test) 
Added viral serology and associated footnotes 
11.6 
Laboratory Assessments 
Corrected language 
•
Alcohol testing will be performed using a breathalyzer or urine alcohol test.
11.7.8 Pregnancy 
Added language for clarity 
WOCBP must have a negative pregnancy test at Baseline Visit B (Day 0). 
13.1.1 Blood Samples 
On Days 8, 14, 84, 168, and 364280, a single sample will be collected during the subject’s regularly 
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.  
Note: 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 
Bioanalysis of Trospium and Xanomeline 
Administrative update to language 
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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15.5 
Pharmacokinetic Analysis 
Updated language to add more specific details 
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.   
APPENDIX 1. CONTRACEPTION GUIDELINES 
Updated language for clarity 
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. Postmenopausal status must be 
confirmed by a test of the subject’s follicle 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. 
Deleted reference: 
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-
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About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. September 15, 2014. 
Accessed April 8, 2020. 
APPENDIX 3. ALTERNATIVE PROCEDURES DURING COVID-19 PANDEMIC-RELATED 
PHYSICAL DISTANCING 
Deleted Appendix 3 – removed the alternative procedure schedule in event of required physical distancing 
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