Conditions: Schizophrenia Schizophrenia; Psychosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 256
Healthy volunteers: no

Brief summary:
This is a Phase 3, randomized, double-blind, parallel-group, placebo-controlled, multicenter inpatient study to examine the efficacy and safety of KarXT in adult subjects who are acutely psychotic with a Diagnostic and Statistical Manual Fifth Edition (DSM-5) diagnosis of schizophrenia. The primary objective of the study is to assess the efficacy of KarXT (a fixed combination of xanomeline 125 mg and trospium chloride 30 mg twice daily \[BID\]) versus placebo in reducing Positive and Negative Syndrome Scale (PANSS) total scores in adult inpatients with a DSM-5 diagnosis of schizophrenia. The secondary objectives of the study are to evaluate improvement in disease severity and symptoms, safety and tolerability, and pharmacokinetics in adult inpatients with a DSM-5 diagnosis of schizophrenia.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Xanomeline and Trospium Chloride Capsules intervention 2: Placebo
Intervention descriptions: intervention 1: Oral xanomeline 50 mg/trospium 20 mg BID on days 1-2 followed by xanomeline 100 mg/trospium 20 mg BID on days 3-7. The dose is increased to xanomeline 125 mg/trospium 30 mg BID on days 8-35 unless the subject is experiencing adverse events from the xanomeline 100 mg/ trospium 20 mg dose. Subjects who were increased to xanomeline 125 mg/trospium 30 mg will have the option to return to xanomeline 100 mg/ trospium 20 mg depending on clinical response and tolerability. intervention 2: Placebo Capsules

Protocol document:
Prot_SAP_000.pdf: 
Official Title of Study: 
A Phase 3, Randomized, Double-blind, Parallel-group, Placebo-controlled, 
Multicenter Study to Evaluate the Efficacy and Safety of KarXT in Acutely Psychotic 
Hospitalized Adults with DSM-5 Schizophrenia 
 
NCT Number: NCT04738123 
Document Date (Date in which document was last revised): 09 August 2021 
 
 


KAR-009 
KarXT 
5.3.5.1 Clinical Study Report 
Karuna Therapeutics Inc. 
Confidential 
Page 1 of 1 
16.1.1. 
Protocol and Protocol Amendments 
KAR-009 Protocol version 1.0 had two versions, one dated 05 Aug 2020 and one dated 
27 Aug 2020. There were minor changes made to the 05 Aug 2020 Protocol version 1.0 to match 
the KAR-007 protocol that resulted in the 27 Aug 2020 Protocol version 1.0. and it was decided 
by Karuna to keep the same version number. This initial protocol, dated 27 Aug 2020, was 
amended 2 times. The changes in each amendment are summarized in Section 9.8.1.1 and 
Section 9.8.1.2. 
Protocols listed below are attached: 
•
Protocol version 1.0, initial protocol, dated 05 Aug 2020
(Note to File, dated 11 Apr 2023)
•
Protocol version 1.0, initial protocol, dated 27 August 2020
•
Protocol version 1.1, Protocol Amendment 1, dated 23 November 2020
•
Protocol version 1.2, Protocol Amendment 2, dated 09 August 2021
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1 
FINAL CLINICAL STUDY PROTOCOL 
 
Karuna Therapeutics 
Protocol Title: A Phase 3, Randomized, Double-blind, Parallel-group, Placebo-controlled, 
Multicenter Study to Evaluate the Efficacy and Safety of KarXT in Acutely Psychotic 
Hospitalized Adults with DSM-5 Schizophrenia 
Protocol Number: KAR-009 
 
IND Number: 
127471 
EudraCT Number: 
Not applicable 
Name of Investigational Product: 
KarXT 
Phase of Development: 
Phase 3 
Indication: 
Schizophrenia 
Sponsor: 
Karuna Therapeutics 
33 Arch Street 
Suite 3110 
Boston, MA 02110 
Tel: 
 
Email: 
 
Protocol Version:  
1.0 
Protocol Date: 
05 August 2020 
 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to Karuna Therapeutics (previously known 
as Karuna Pharmaceuticals). Any unauthorized copying or use of this document is prohibited. 
 
 
 
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PROTOCOL APPROVAL SIGNATURES 
Protocol Title: 
A Phase 3, Randomized, Double-blind, Parallel-group, 
Placebo-controlled, Multicenter Study to Evaluate the Efficacy and 
Safety of KarXT in Acutely Psychotic Hospitalized Adults with 
DSM-5 Schizophrenia 
Protocol Number: 
KAR-009 
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Council for Harmonisation (ICH) guidelines for current Good 
Clinical Practice (GCP) and applicable regulatory requirements. 
Sponsor Signatory 
 
 
Karuna Therapeutics 
Signature 
Date (DD-Mmm-YYYY) 
 
 
Karuna Therapeutics 
Signature 
Date (DD-Mmm-YYYY) 
Contract Research Organization 
Signatory 
Syneos Health 
Signature 
Date (DD-Mmm-YYYY) 
Biostatistician 
 
Kavanagh Statistical Consulting, LLC 
Signature 
Date (DD-Mmm-YYYY) 
8/6/2020
8/10/2020
8/7/2020
8/6/2020
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INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
A Phase 3, Randomized, Double-blind, Parallel-group, Placebo-controlled, 
Multicenter Study to Evaluate the Efficacy and Safety of KarXT in Acutely 
Psychotic Hospitalized Adults with DSM-5 Schizophrenia 
Protocol Number: 
KAR-009 
 Confidentiality and Current Good Clinical Practice (GCP)/E6(R2) Compliance Statement 
 I, the undersigned, have reviewed this protocol (and amendments, including appendices, 
and I will conduct the study as described in compliance with this protocol (and 
amendments) and relevant International Council for Harmonisation (ICH) guidelines 
including GCP and applicable regulatory requirements. 
 I am thoroughly familiar with the appropriate use of the study drug, 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 
IEC/IRB, I will not modify this protocol without obtaining prior approval of Karuna 
Therapeutics and of the IEC/IRB. I will submit the protocol amendments and/or any 
informed consent form modifications to Karuna Therapeutics and the IEC/IRB, and 
approval will be obtained before any amendments are implemented. 
 I ensure that all persons or party assisting me with the study are adequately qualified and 
informed about the Karuna Therapeutics study drug 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. 
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<Name> 
<Title> 
Investigator Signature 
Date (DD-Mmm-YYYY) 
Institution 
 
 
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2 
SYNOPSIS 
Title of Study: 
A Phase 3, Randomized, Double-blind, Parallel-group, Placebo-controlled, 
Multicenter Study to Evaluate the Efficacy and Safety of KarXT in Acutely 
Psychotic Hospitalized Adults with DSM-5 Schizophrenia 
Protocol Number: 
KAR-009 
Study Sites: 
Approximately 10 sites in the United States and 10 sites in Ukraine 
Phase of Development: 
Phase 3 
Objectives: 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of KarXT (a 
fixed combination of xanomeline and trospium chloride [xanomeline 
125 mg/trospium 30 mg] twice daily [BID]) versus placebo in reducing 
Positive and Negative Syndrome Scale (PANSS) total scores in adult 
inpatients with a Diagnostic and Statistical Manual‒Fifth Edition (DSM-5) 
diagnosis of schizophrenia. 
Secondary Objectives: 
The secondary objectives of the study are: 
 
To evaluate the reduction of PANSS positive score in subjects 
treated with KarXT versus placebo 
 
To evaluate the improvement in Clinical Global Impression-Severity 
(CGI-S) results in subjects treated with KarXT versus placebo 
 
To evaluate the reduction of PANSS negative score in subjects 
treated with KarXT versus placebo 
 
To evaluate the reduction of PANSS Marder Factor negative 
symptoms score in subjects treated with KarXT versus placebo 
 
To evaluate the safety and tolerability of KarXT 
 
To assess the pharmacokinetics (PK) of xanomeline and trospium 
after administration of KarXT in adults who are acutely psychotic 
with a DSM-5 diagnosis of schizophrenia 
Exploratory Objective: 
The exploratory objective of the study is to evaluate the single nucleotide 
polymorphisms (SNPs) regarding schizophrenia subtypes and SNPs related to 
drug metabolism. 
Study Endpoints: 
Primary Endpoint:  
 
Change from baseline in PANSS total score at Week 5 
Secondary Endpoints:  
Efficacy Endpoints 
 
Change from baseline in PANSS positive score at Week 5 
 
Change from baseline in PANSS negative score at Week 5 
 
Change from baseline in PANSS Negative Marder Factor score at 
Week 5  
 
Change from baseline in CGI-S score at Week 5 
 
Percentage of PANSS responders (a 30% change in PANSS total 
score) at Week 5  
Safety Endpoints 
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 
Spontaneously reported adverse events (AEs) 
 
Spontaneously reported cholinergic symptoms 
 
Simpson-Angus Scale (SAS) 
 
Barnes Akathisia Rating Scale (BARS) 
 
Abnormal Involuntary Movement Scale (AIMS) 
 
Body weight, body mass index, waist circumference 
 
Orthostatic vital signs (supine and standing after 2 minutes): blood 
pressure (systolic and diastolic) and heart rate 
 
Clinical laboratory evaluations: hematology, clinical chemistry, 
coagulation, urinalysis, and drug screen 
 
12-lead electrocardiogram (ECG) 
 
Physical examination 
 
Suicidal ideation scale with the use of Columbia Suicide Severity 
Rating Scale (C-SSRS) 
Pharmacokinetic Endpoints 
 
Area under the plasma concentration-time curve (AUC) 
 
Maximum observed plasma concentration (Cmax)  
 
Time to maximum observed plasma concentration (Tmax) 
Exploratory Endpoint 
 
Change in cognition measuring core domains of impairment in 
schizophrenia using the Cambridge Neuropsychological Test 
Automated Battery (CANTAB) 
 
Change from baseline in prolactin levels at Week 5 
 
Prediction of response based on SNP schizophrenia subtypes, and 
SNPs related to KarXT metabolism for both efficacy and tolerability 
 
Study Design: 
This is a Phase 3 randomized, double-blind, parallel-group, 
placebo-controlled, multicenter inpatient study in adults who are 
acutely psychotic with a DSM-5 diagnosis of schizophrenia. Subjects 
will be randomized (1:1 ratio) to receive either KarXT or placebo for a 
treatment period of 5 weeks. Subjects will start on a lead-in dose of 
KarXT 50/20 (xanomeline 50 mg/trospium 20 mg) BID for the first 
2 days (Days 1 and 2) followed by KarXT 100/20 (xanomeline 
100 mg/trospium 20 mg) BID for the remainder of Week 1 (Days 3 to 
7). On Day 8, dosing will be titrated upwards to KarXT 125/30 BID 
unless the subject is continuing to experience AEs from the previous 
dose increase of KarXT 100/20 BID. All subjects who were increased 
to KarXT 125/30 BID, depending on clinical response and tolerability, 
will have the option to return to KarXT 100/20 BID for the remainder 
of the treatment period. Dosing must not change after Visit 7 (Day 21) 
of the study and may be decreased for tolerability reasons no more than 
once during the study. In addition, dose escalation to KarXT 125/30 
BID may not occur outside of the permitted visit window for 
Visit 5/Day 8. 
A safety follow-up visit (Visit 11/ Day 42 + 5 days) will be performed 
for all those subjects who do not rollover in to the long-term open-label 
study KAR-008.  
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The study is designed to test the hypothesis that treatment with KarXT 
in adult schizophrenia subjects with acute psychosis will result in 
significantly greater reduction (ie, improvement) in the primary and 
secondary endpoints at Week 5 from baseline compared with placebo. 
The endpoints are set up as a hierarchical list and step down through 
the statistical testing of each endpoint using an alpha of 0.05. Statistical 
testing of change from baseline to Week 5 in PANSS positive score, 
PANSS negative score, PANSS Negative Marder Factor score, CGI-S, 
and percentage of PANSS responders will be performed only if the 
primary endpoint is significant at the 0.05 alpha level (P ≤ 0.05), and 
testing would continue through a preordered list of key secondary 
efficacy endpoints. If at any point P > 0.05, then formal statistical 
testing would stop. This will control the overall Type 1 error rate across 
all hypotheses/endpoints being tested. 
Selection of Subjects: 
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 must be provided before 
any study assessments are performed. 
b. Subject must be fluent (oral and written) in English (applicable to 
the US) or local language (Ukrainian or Russian applicable to 
Ukraine) 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 for 
Schizophrenia and Psychotic Disorder Studies (MINI) version 
7.0.2. 
4. Subject is experiencing an acute exacerbation or relapse of 
psychotic symptoms, with onset less than 2 months before 
screening. 
a. 
The subject requires hospitalization for this acute exacerbation or 
relapse of psychotic symptoms. 
b. If already an inpatient at screening, has been hospitalized 
for less than 2 weeks for the current exacerbation at the time 
of screening. 
5. Positive and Negative Syndrome Scale total score between 80 and 120, 
inclusive. 
a. 
Score of ≥4 (moderate or greater) for ≥2 of the following Positive 
Scale (P) items: 
i. Item 1 (P1; delusions) 
ii. Item 2 (P2; conceptual disorganization) 
iii. Item 3 (P3; hallucinatory behavior) 
iv. Item 6 (P6; suspiciousness/persecution) 
6. Subjects with no change (improvement) in PANSS total score between 
screening and baseline (Day -1) of more than 20%. 
7. Subject has a CGI-S score of ≥4 at screening and baseline (Day -1) 
visits. 
8. Subject will have been off lithium therapy for at least 2 weeks 
before baseline and free of all oral antipsychotic medications for at 
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least 5 half-lives or 1 week, whichever is longer, before baseline 
(Day -1). 
9. Subjects taking a long-acting injectable antipsychotic could not 
have received a dose of medication for at least 12 weeks (24 weeks 
for INVEGA TRINZA®) before baseline visit (Day -1). 
10. Subject is willing and able to be confined to an inpatient setting for 
the study duration, follow instructions, and comply with the 
protocol requirements. 
11. Body mass index must be ≥18 and ≤40 kg/m2. 
12. Subject resides in a stable living situation and is anticipated to 
return to that same stable living situation after discharge, in the 
opinion of the investigator. 
13. Subject has an identified reliable informant/caregiver. An 
informant/caregiver is needed at the screening and baseline 
visits as well as at the end of the study for relevant assessments 
(site staff may act as informant while the subject is an inpatient). 
An informant/caregiver may not be necessary if the subject has 
been the patient of the investigator for ≥1 year. 
14. Women of childbearing potential (WOCBP), or men whose 
sexual partners are WOCBP, must be able and willing to use at 
least 1 highly effective method of contraception during the study 
and for 7 days after the last dose of study drug. Sperm donation 
is not allowed for 90 days after the final dose of study drug. A 
female subject is considered to be a WOCBP after menarche and 
until she is in a postmenopausal state for 12 months or otherwise 
permanently sterile (for which acceptable methods include 
hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy). For the definition and list of highly effective 
methods of contraception, see APPENDIX 1. 
Exclusion Criteria: 
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, 
moderate to severe alcohol use disorder (within the past 
12 months), substance (other than nicotine or caffeine) use disorder 
within the past 12 months (use of cannabis at screening will result 
in screen failure with the allowance to rescreen at a later date if no 
moderate to severe substance use disorder is determined), major 
depressive disorder, bipolar I or II disorder, schizoaffective 
disorder, obsessive compulsive disorder, and post-traumatic stress 
disorder. Symptoms of mild mood dysphoria or anxiety are allowed 
as long as these symptoms are not the primary focus of treatment. 
a. 
A screening subject with mild substance abuse disorder within 
the 12 months before screening must be discussed and agreed 
upon with the medical monitor before he/she can be allowed 
into the study. 
2. History or presence of clinically significant cardiovascular, 
pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, 
immunologic, dermatologic, neurologic, or oncologic disease or 
any other condition that, in the opinion of the investigator, would 
jeopardize the safety of the subject or the validity of the study 
results. 
3. Subjects with HIV, cirrhosis, biliary duct abnormalities, 
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hepatobiliary carcinoma, and/or active hepatic viral infections 
based on either medical history or liver function test results. 
4. History or high risk of urinary retention, gastric retention, or 
narrow-angle glaucoma. 
5. History of irritable bowel syndrome (with or without 
constipation) or serious constipation requiring treatment 
within the last 6 months 
6. 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. 
7. Clinically significant abnormal finding on the physical 
examination, medical history, ECG, or clinical laboratory 
results at screening. 
8. Subjects cannot currently (within 5 half-lives or 1 week, 
whichever is longer, before baseline [Day -1]) be receiving oral 
antipsychotic medications; monoamine oxidase inhibitors; 
anticonvulsants (eg, lamotrigine, Depakote); tricyclic 
antidepressants (eg, imipramine, desipramine); selective serotonin 
reuptake inhibitors; or any other psychoactive medications except 
for as needed anxiolytics (eg, lorazepam, chloral hydrate). 
9. Pregnant, lactating, or less than 3 months postpartum. 
10. If, in the opinion of the investigator (and/or Sponsor), subject is 
unsuitable for enrollment in the study or subject has any finding 
that, in the view of the investigator (and/or Sponsor), may 
compromise the safety of the subject or affect his/her ability to 
adhere to the protocol visit schedule or fulfill visit requirements. 
11. Positive test for coronavirus (COVID-19) within 2 weeks before 
screening until Day -1 (baseline).  
12. Subjects with extreme concerns relating to global pandemics, 
such as COVID-19, that preclude study participation. 
13. Subject has had psychiatric hospitalization(s) for more than 
30 days (cumulative) during the 90 days before screening. 
14. Subject has a history of treatment resistance to schizophrenia 
medications defined as failure to respond to 2 adequate courses 
of pharmacotherapy (a minimum of 4 weeks at an adequate dose 
per the label) or required clozapine within the last 12 months. 
15. Subjects with prior exposure to KarXT. 
16. Subjects who experienced any adverse effects due to xanomeline 
or trospium. 
17. Participation in another clinical study in which the subject 
received an experimental or investigational drug agent within 
3 months before screening. 
18. Risk of violent or destructive behavior. 
19. Current involuntary hospitalization or incarceration. 
Planned Sample Size: 
A total of approximately 246 adult subjects (aged 18 to 65 years, inclusive) 
are planned to be randomized in a 1:1 ratio to 2 treatment groups, either 
KarXT or placebo. 
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Investigational Therapy: 
1. Fixed dose KarXT 50/20 BID (50 mg xanomeline/20 mg trospium), 
oral (Days 1 to 2) 
2. Fixed dose KarXT 100/20 BID (100 mg xanomeline/20 mg 
trospium), oral (Days 3 to 7) 
3. Fixed dose KarXT 125/30 BID (125 mg xanomeline/30 mg 
trospium), oral (Days 8 to 35, if tolerated) 
Reference Therapy: 
Matching placebo BID oral 
Treatment Duration: 
Total study duration is up to 8 weeks, including a 7-day screening phase (up 
to a 7-day extension of the screening phase is allowed, if necessary), a 
5-week treatment period, and a 7-day follow-up period (only for subjects who 
do not rollover to KAR-008 study). Subjects completing this study will have 
the option of rolling over into a long-term open-label study (KAR-008) in 
which every subject will receive KarXT. 
Efficacy Assessments: 
PANSS total score, PANSS positive score, PANSS negative score, PANSS 
Negative Marder Factor score, and CGI-S score will be evaluated at 
scheduled visits. 
Safety Assessments: 
Spontaneous AEs, cholinergic symptoms, SAS, BARS, AIMS, body weight, 
body mass index, waist circumference, orthostatic vital signs, ECG, clinical 
laboratory assessments (hematology, clinical chemistry, coagulation, 
urinalysis, and drug screen), prolactin levels, physical examination, and 
C-SSRS will be evaluated throughout the study as scheduled. 
Pharmacokinetic Assessments: 
AUC, Cmax, and Tmax will be estimated at scheduled visits. 
Statistical Methods and 
Planned Analyses: 
Intent-to-treat (ITT) population: All subjects who are randomized to the study 
will be included in the ITT population. 
Modified ITT (mITT) population: All subjects who are randomized, received 
at least 1 dose of study drug, have a baseline PANSS assessment, and at least 
1 postbaseline PANSS assessment will be included in the mITT population 
and will be used in the efficacy analysis. 
Safety population: All subjects who received at least 1 dose of study drug 
will be included in the safety population and will be used in the safety 
analysis. 
PK population: All subjects who have an evaluable PK profile will be 
included in the PK population and will be used in the PK analysis. Subjects 
must have received at least 1 dose of active study drug and have at least 
1 measurable plasma concentration of study drug.  
The primary efficacy endpoint of the study is the change from baseline in 
PANSS total score at Week 5. The difference between KarXT and placebo 
will be estimated using a mixed model for repeated measures. The key 
secondary endpoints are the change from baseline to Week 5 in PANSS 
positive score, PANSS negative score, PANSS Negative Marder Factor 
score, CGI-S score, and percentage of PANSS responders at Week 5. The 
statistical analysis of the primary and key secondary efficacy variables will 
account for multiplicity by using a fixed sequence testing procedure. This 
testing procedure will control the overall Type 1 error rate across all 
hypotheses/endpoints being tested. 
Assuming the treatment difference in the change from baseline in PANSS 
total score at Week 5 is 8 points between KarXT and placebo (standard 
deviation 16), a sample size of approximately 172 subjects (86 evaluable 
subjects per arm) will result in a power of 90.3% for a 2-sided alpha of 0.05 
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(P ≤ 0.05). With an anticipated dropout rate of 30%, a total of 246 subjects 
are estimated to be enrolled.  
 
 
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3 
TABLE OF CONTENTS 
1 
FINAL CLINICAL STUDY PROTOCOL .......................................................................1 
2 
SYNOPSIS ........................................................................................................................5 
3 
TABLE OF CONTENTS ................................................................................................12 
3.1 
List of In-text Tables ..................................................................................................16 
3.2 
List of In-text Figures .................................................................................................17 
4 
LIST OF ABBREVIATIONS .........................................................................................18 
5 
INTRODUCTION ...........................................................................................................20 
5.1 
Background on Schizophrenia ....................................................................................20 
5.2 
Background on KarXT (Xanomeline Tartrate and Trospium Chloride) ....................20 
 
Nonclinical Studies ............................................................................................22 
 
Completed Clinical Studies ................................................................................25 
5.3 
Clinical Risks/Benefits of KarXT and Study Rationale .............................................33 
6 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................35 
6.1 
Study Objectives .........................................................................................................35 
 
Primary Objective ..............................................................................................35 
 
Secondary Objectives .........................................................................................35 
 
Exploratory Objective ........................................................................................35 
6.2 
Study Endpoints..........................................................................................................35 
 
Primary Endpoint ...............................................................................................35 
 
Secondary Endpoints ..........................................................................................35 
6.2.2.1 
Efficacy Endpoints .......................................................................................35 
6.2.2.2 
Safety Endpoints ..........................................................................................36 
 
Pharmacokinetic Endpoints ................................................................................36 
 
Exploratory Endpoints .......................................................................................36 
7 
INVESTIGATIONAL PLAN .........................................................................................37 
7.1 
Description of Overall Study Design and Plan...........................................................37 
7.2 
Discussion of Study Design........................................................................................40 
7.3 
End of Study ...............................................................................................................40 
7.4 
Independent Safety Monitoring Committee ...............................................................40 
8 
SELECTION OF STUDY POPULATION .....................................................................41 
8.1 
Inclusion Criteria ........................................................................................................41 
8.2 
Exclusion Criteria .......................................................................................................42 
8.3 
Rescreening ................................................................................................................44 
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8.4 
Study Withdrawal, Removal, and Replacement of Subjects ......................................44 
 
Pregnancy ...........................................................................................................45 
8.5 
Completion of the Study or Lost to Follow-up ..........................................................46 
8.6 
Study Termination ......................................................................................................46 
9 
TREATMENTS ...............................................................................................................47 
9.1 
Details of Study Treatments .......................................................................................47 
 
Identity of Study Treatments ..............................................................................47 
 
Packaging and Labelling ....................................................................................47 
 
Study Drug Storage ............................................................................................48 
 
Study Drug Retention .........................................................................................48 
9.2 
Dose Schedule ............................................................................................................48 
 
Visit 2b/Day 1 Randomization and Dosing .......................................................48 
 
Visit 3/Day 3 and/or Visits Occurring on Weekends/Holidays .........................49 
 
Visit 5/Day 8 Dosing and PK Considerations and Visit 8/Day 28 PK 
Considerations ....................................................................................................49 
 
Visit 10/Day 35 Dosing ......................................................................................49 
9.3 
Measures to Minimize Bias: Study Treatment Assignment .......................................49 
 
Method of Study Treatment Assignment ...........................................................49 
 
Blinding ..............................................................................................................50 
9.4 
Dose Modification ......................................................................................................51 
9.5 
Treatment Accountability and Compliance ................................................................51 
9.6 
Prior and Concomitant Therapy .................................................................................51 
 
Prior and Concomitant Medications ..................................................................51 
 
Concomitant Medications for Anxiety and/or Sleep aid ....................................52 
10 
STUDY PROCEDURES .................................................................................................53 
10.1 Informed Consent .......................................................................................................59 
10.2 Study Procedures ........................................................................................................59 
11 
EFFICACY ASSESSMENTS .........................................................................................60 
11.1 Positive and Negative Syndrome Scale ......................................................................60 
11.2 Clinical Global Impression‒Severity .........................................................................60 
12 
SAFETY ASSESSMENTS .............................................................................................61 
12.1 Demographics, and Medical and Psychiatric History ................................................61 
12.2 Vital Signs ..................................................................................................................61 
12.3 Physical Examination .................................................................................................62 
12.4 Weight, Height, Body Mass Index, Waist Circumference .........................................62 
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12.5 Electrocardiograms .....................................................................................................62 
12.6 Laboratory Assessments .............................................................................................62 
 
Blood Sampling for Pharmacogenetics ..............................................................64 
12.7 Adverse Events ...........................................................................................................64 
 
Adverse Events ..................................................................................................64 
 
Adverse Events of Special Interest ....................................................................66 
 
Serious Adverse Events .....................................................................................66 
 
Serious Adverse Event Reporting ......................................................................67 
 
Drug-Induced Liver Injury .................................................................................67 
 
Suspected Unexpected Serious Adverse Reactions ...........................................68 
 
Pregnancy ...........................................................................................................70 
 
Overdose ............................................................................................................70 
12.8 Cambridge Neuropsychological Test Automated Battery ..........................................70 
12.9 Simpson-Angus Scale .................................................................................................71 
12.10 Barnes Akathisia Rating Scale ...................................................................................71 
12.11 Abnormal Involuntary Movement Scale ....................................................................72 
12.12 Columbia-Suicide Severity Rating Scale ...................................................................72 
12.13 Functional Constipation Inquiry .................................................................................72 
12.14 Mini International Neuropsychiatric Interview Version 7.0.2 ...................................73 
12.15 Change in Prolactin ....................................................................................................73 
13 
PHARMACOKINETICS ................................................................................................74 
13.1 Pharmacokinetic Sampling .........................................................................................74 
 
Blood Samples ...................................................................................................74 
13.2 Pharmacokinetic Analytical Methodology .................................................................75 
14 
STATISTICAL ANALYSIS ...........................................................................................76 
14.1 Determination of Sample Size ....................................................................................76 
14.2 Analysis Populations ..................................................................................................76 
14.3 General Statistical Considerations ..............................................................................77 
14.4 Efficacy Analysis........................................................................................................77 
 
Analysis of the Primary Efficacy Endpoint .......................................................77 
 
Analysis of Secondary Efficacy Endpoints ........................................................78 
14.5 Safety Analysis ...........................................................................................................78 
14.6 Pharmacokinetic Analysis ..........................................................................................78 
14.7 Interim Analysis .........................................................................................................79 
14.8 Handling of Missing Data ..........................................................................................79 
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15 
STUDY MANAGEMENT ..............................................................................................80 
15.1 Approval and Consent ................................................................................................80 
 
Regulatory Guidelines ........................................................................................80 
 
Independent Ethics Committee/Institutional Review Board ..............................80 
 
Informed Consent ...............................................................................................80 
15.2 Data Handling .............................................................................................................81 
15.3 Source Documents ......................................................................................................82 
15.4 Record Retention ........................................................................................................82 
15.5 Monitoring ..................................................................................................................83 
15.6 Quality Control and Quality Assurance .....................................................................83 
15.7 Protocol Amendment and Protocol Deviation ............................................................83 
 
Protocol Amendment .........................................................................................83 
 
Protocol Deviations ............................................................................................84 
15.8 Ethical Considerations ................................................................................................84 
15.9 Financing and Insurance .............................................................................................84 
15.10 Publication Policy/Disclosure of Data........................................................................84 
16 
REFERENCES ................................................................................................................86 
17 
APPENDICES .................................................................................................................89 
APPENDIX 1. CONTRACEPTION GUIDELINES ............................................................90 
APPENDIX 2. FUNCTIONAL CONSTIPATION INQUIRY ............................................91 
 
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3.1 
List of In-text Tables 
Table 1 
Study Design ...........................................................................................................39 
Table 2. Schedule of Assessments ........................................................................................54 
Table 3. Laboratory Assessments..........................................................................................63 
Table 4. Classification of Adverse Events by Intensity ........................................................65 
Table 5. Classification of Adverse Events by Relationship to Study Drug ..........................66 
Table 6 
Cognitive Tests and Cognitive Domains Assessed by the Cambridge 
Neuropsychological Test Automated Battery .........................................................71 
Table 7 
Statistical Testing Procedure ...................................................................................77 
 
 
 
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3.2 
List of In-text Figures 
Figure 1 Change from Baseline in PANSS Total Scores (KAR-004) ...................................29 
Figure 2 Change from Baseline in PANSS-Positive Scores (KAR-004) ..............................30 
Figure 3 Change from Baseline in CGI-S (KAR-004) ..........................................................31 
Figure 4 Change from Baseline in PANSS-Negative Scores (KAR-004).............................32 
 
 
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4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AD 
Alzheimer’s disease 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
APD 
antipsychotic drug 
AUC 
area under the plasma concentration-time curve 
AUC0-12 
area under the plasma concentration-time curve from 0 to 12 hours 
AUC0-24 
area under the plasma concentration-time curve from 0 to 24 hours 
BARS 
Barnes Akathisia Rating Scale 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression‒Severity 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTS database 
Clinical Trial Subject database 
DSM-5 
Diagnostic and Statistical Manual‒Fifth Edition 
EDC 
electronic data capture 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EPS 
extrapyramidal symptoms 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability Accountability Act 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
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Abbreviation 
Definition 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
MCC 
microcrystalline cellulose 
MINI 
Mini International Neuropsychiatric Interview 
mITT 
modified intent-to-treat 
MMRM 
mixed model for repeated measures 
PANSS 
Positive and Negative Syndrome Scale 
PK 
Pharmacokinetic(s) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson Angus Scale 
SNP 
single nucleotide polymorphism 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TID 
thrice daily 
TK 
toxicokinetic 
Tmax 
Time to maximum observed plasma concentration 
ULN 
upper limit of normal  
US 
United States 
VAS 
visual analog scale 
VCT 
Verified Clinical Trials Registry 
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 US is 5.1 per 1000 lives[3]. It is found 
equally in males and females, with males usually having an earlier onset of symptoms[4].  
The mainstay for treating schizophrenia is antipsychotic drugs (APDs)[5]. All currently available 
antipsychotics act through blockage of all or subsets of dopamine receptors in the brain. First-
generation APDs include chlorpromazine and haloperidol; treatment with these agents is marked 
by high rates of parkinsonian extrapyramidal symptoms (EPS) and tardive dyskinesia, and they 
consequently have limited use today. The second-generation agents that include risperidone, 
olanzapine, quetiapine, lurasidone, aripiprazole, and lumateperone tend to have lower levels of 
EPS or tardive dyskinesia and are currently the most commonly prescribed APD class. However, 
the second-generation drugs also have problematic side effects that include significant weight 
gain, metabolic disturbances, sedation, and akathisia[6, 7, 8]. These side effects contribute to 
poor medication adherence resulting in frequent relapses and hospitalizations[9, 10]. Thus there 
is a need for medications for schizophrenia which act through alternative mechanisms. 
Central muscarinic receptors have been hypothesized to be therapeutic treatments for 
schizophrenia based on several converging lines of evidence including both animal and human 
studies[11,12]. There are 5 subtypes of muscarinic receptors (M1-M5). The therapeutic effect of 
central muscarinic receptor agonism is thought to be due to agonism of M1 and M4 receptors in 
the central nervous system (CNS)[13]. However, compounds that agonize M1 and M4 receptors 
are often not specific enough not to also agonize M2 and M3 receptors outside of the CNS due to 
the highly conserved allosteric binding sites that the receptors share, leading to adverse events 
(AEs) related to activation of these peripheral receptors. Thus, any potential benefit of 
muscarinic agonists in schizophrenia (or other indications such as Alzheimer’s disease [AD]) has 
been outweighed by the occurrence of AEs associated with peripheral cholinergic side effects 
(nausea, vomiting, diarrhea, sweating, and excess salivation).  
5.2 
Background on KarXT (Xanomeline Tartrate and Trospium Chloride) 
Xanomeline tartrate is a muscarinic-cholinergic receptor agonist. It has agonistic activity at all 
5 muscarinic receptors but preferentially stimulates M1 and M4 receptors and binding to M1 and 
M4 receptors in the CNS is thought to be responsible for the drug’s potential therapeutic effects 
(Roth, unpublished data). A recent study reports that xanomeline is a very potent M4 muscarinic 
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agonist in vivo, measured by various second messenger assays[14]. Xanomeline also enters the 
brain rapidly achieving a brain to plasma ratio of greater than 10 making it an attractive CNS 
drug candidate[15]. 
Xanomeline does not have any direct binding activity on dopaminergic receptors, suggesting that 
its mechanism of action is unrelated to direct dopamine involvement. 
Previous double-blind, placebo controlled clinical trials have provided strong evidence that 
xanomeline has clinically relevant antipsychotic efficacy. In a multicenter outpatient trial in AD 
(N = 343), 3 doses of xanomeline (up to 225 mg/day) and placebo were assessed for 
26 weeks[16, 17]. Significant dose-dependent improvements in psychotic symptoms relative to 
placebo were observed. Moreover, psychotic symptoms resolved quite rapidly in subjects who 
were symptomatic at baseline and a dose dependent reduction in the emergence of psychotic 
symptoms versus placebo was also observed. In a completer analysis, cognitive improvement 
was also found suggesting longer treatment intervals may be necessary for cognitive 
enhancement[16, 17]. In a subsequent small (N = 20) double-blind, placebo-controlled inpatient 
trial in treatment resistant subjects with schizophrenia, xanomeline (225 mg/day) demonstrated 
robust and relatively rapid improvement in psychosis compared to placebo. In addition, 
improvement in both negative symptoms and cognitive impairment was observed[18]. 
In both the AD and schizophrenia trials, as well as in previous healthy volunteer studies, dose 
dependent “cholinergic” AEs were also reported, namely vomiting, nausea, diarrhea, sweating 
and hypersalivation. These side effects were frequent and, at the higher doses of xanomeline led 
to significant rates of discontinuation in the AD studies. This “pro-cholinergic” AE profile 
curtailed further development of xanomeline as a single agent.  
It is believed that the procholinergic AEs associated with xanomeline are mediated by 
xanomeline’s stimulation of peripheral rather than central muscarinic receptors, which would 
make these AEs theoretically amenable to counteracting peripheral anticholinergic treatment. 
Trospium chloride is a peripherally acting muscarinic antagonist which binds to and antagonizes 
all five muscarinic receptor subtypes[19]. It is a commonly used generic drug approved for over 
10 years by the Food and Drug Administration (FDA) and by European authorities to treat 
overactive bladder and is generally well tolerated[19]. Several human subject studies have 
demonstrated that trospium does not appreciably cross the blood brain barrier, consistent with the 
drug’s quaternary ammonium structure[20].  
KarXT is a novel combination of xanomeline tartrate and trospium chloride. Karuna 
hypothesized that the addition of trospium would mitigate peripheral procholinergic side effects 
(vomiting, nausea, diarrhea, sweating and hyper-salivation) and thus provide a strategy to allow 
xanomeline to be administered and stimulate brain muscarinic receptors with a decreased side 
effect burden. Phase 1 studies in healthy volunteers of this combination demonstrated that 
KarXT reduced these side effects by 46% compared to xanomeline alone[21]. Moreover, the 
remaining cholinergic AEs were generally mild to moderate in severity and transient in nature, 
often lasting a few hours without recurrence and were generally single-episode. In general, 
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KarXT was well tolerated in healthy adult volunteers. These encouraging safety data prompted 
further work to assess KarXT for the treatment of schizophrenia and potentially other CNS 
disorders. 
Karuna has recently completed an adequate and well-controlled, randomized, multi-center 
Phase 2, placebo-controlled, inpatient clinical trial of acute psychosis with schizophrenia in 
182 adult subjects (KAR-004). KarXT demonstrated a statistically significant and clinically 
meaningful 11.6 point mean reduction in total Positive and Negative Syndrome Scale (PANSS) 
at 5 weeks compared to placebo (P < 0.0001), with statistical separation at each time point 
assessed (2, 4, and 5 weeks) and also demonstrated good overall safety and tolerability. 
The purpose of the current study is to evaluate the safety and efficacy of KarXT (xanomeline 
125 mg/trospium 30 mg) administered twice daily (BID) in adult inpatients with Diagnostic and 
Statistical Manual‒Fifth Edition (DSM-5) diagnosis of schizophrenia. A placebo arm is included 
to provide test sensitivity.  
Xanomeline is currently not approved or marketed in any country. Trospium is marketed in the 
US and other regions of the world for the treatment of overactive bladder. 
 
Nonclinical Studies 
The following is a summary of the important nonclinical safety and toxicology studies. More 
detailed information can be found in the KarXT Investigator’s Brochure (IB). 
The acute toxicity of xanomeline tartrate was evaluated in mice and rats. All animals were 
observed for 2 weeks for mortality and clinical signs of intolerance, and then necropsied for 
gross examinations. In-life findings attributed to the test article included excessive 
muscarinic-mediated pharmacology, such as excessive salivation, hypoactivity, ataxia, soft 
stools, exophthalmos, ocular discharge, tremors, and convulsions, with survivors typically 
appearing normal by Days 3 or 4. Gross findings at necropsy were generally unremarkable (eg, 
gas-distended or mucous-filled gastrointestinal [GI] tracts after oral dosing). 
KarXT-301 was a 14-day, repeat dose study of KarXT in rats where relatively high doses of 
xanomeline and trospium were given, with either xanomeline alone or in combination with 
trospium. Seven groups of 10 rats/sex/group were administered either vehicle (reverse osmosis 
water); xanomeline alone at 37, 75, 150, or 300 mg/kg/day (split into BID doses, every 
12 hours); or xanomeline/trospium combination dosages of 150/200 mg/kg/day or 
225/400 mg/kg/day, respectively (split into BID doses, every 12 hours).  
Satellite animals were included for the collection of plasma after the first and last doses for the 
determination of drug concentrations of each parent drug in support of toxicokinetic (TK) 
assessments.  
There was no target-organ toxicity revealed by clinical pathology or by gross or microscopic 
assessments. All intolerance could be attributed to recognized pharmacology of either test article. 
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No dose-related ophthalmic observations were noted. Findings were not indicative of specific 
target organ toxicity. In short, no new hazard was identified.  
Clinical observations noted in most animals administered 300 mg/kg/day xanomeline included 
hypoactivity, clear oral discharge, dilated pupils, irregular or labored respiration, and rough hair 
coat, among other observations. These findings are generally consistent with the anticipated 
pharmacology of xanomeline.  
Three TK animals in the low-dose combination group died or were euthanized in extremis. It is 
unclear to what extent the combination treatment effects versus the different handling of these 
animals (including 3 plasma samplings per animal) contributed to these deaths. If gavage 
accidents were involved (as happened with some TK animals), then they were not detected at 
gross necropsy. There was no microscopic evidence of toxicity was seen in any toxicity animals 
in this group or in the higher-dose combination group. 
Three toxicology and 3 TK animal deaths (total of 6) occurred in the high-dose combination 
group. Two toxicology animals had evidence of gavage accidents. For the third, the cause of 
death was undetermined, and a test article-related effect cannot be ruled out, but 
degeneration/regeneration of esophageal muscular is indicated some dosing-related trauma. If 
gavage accidents were involved, then they were not detected at gross necropsy. There was no 
evidence of target organ microscopic findings in GI tract or any other tissue of any animal, 
including the early death toxicity animals.  
A pharmacodynamics-mediated reduction in GI motility is consistent with the anti-muscarinic 
effects of trospium on intestinal musculature. Fecal retention, malabsorption, cessation of eating, 
dehydration, and rapid deterioration followed with continued dosing. Cessation of dosing in the 
high dose combination animals that survived led to rapid recovery, implying the deleterious 
effects had been pharmacodynamics-related. No effects on food consumption were seen in any 
xanomeline-alone group. The lack of microscopic findings in the GI tract of any early death or 
surviving animal implies that the adverse effects were pharmacologically mediated rather than 
direct target organ toxicity. 
Twenty-eight Day Repeat-Dose Studies with Xanomeline in Rats and Monkeys: Rats were fed 
xanomeline tartrate at 0%, 0.05%, 0.1%, or 0.2% daily and monkeys were fed xanomeline 
tartrate daily at 0, 5, 12.5, or 30 mg/kg. All animals survived until necropsy. Safety findings in 
rats included reduced body weight in the high dose group, increases in gamma-glutamyl-
transferase, cholesterol, and bilirubin, slight decreases in triglycerides, bile duct hyperplasia, 
higher serum potassium (males), and lower serum globulin (females). Findings in monkeys were 
dose related and included signs of intolerance such as emesis, salivation, diarrhea, hypoactivity, 
weight loss, and treatment-related tachycardia in the high-dose animals. 
Forty-Day Repeat Dose Study of KarXT in Rats (KarXT-302): Six groups of 15 rats/sex/group 
were given vehicle, xanomeline alone at 75 or 150 mg/kg/day, trospium alone at 100 mg/kg/day, 
or xanomeline/trospium combination at doses of 75/50 mg/kg/day or 150/100 mg/kg/day, with 
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all doses split into BID doses. Satellite rats (TK animals) were included for collection of plasma 
after the first and last doses to determine concentrations of each drug. Dosing was initially 
planned to be 90 days but was terminated after 40 days because of unexpected deaths in the TK 
animals. No target organ toxicity was seen. Safety findings included pharmacologically mediated 
constipation in the trospium alone and combination groups and mild biliary hyperplasia in the 
high-dose xanomeline alone and combination groups. There were 4 unscheduled deaths in TK 
animals; 2 in the high-dose xanomeline alone group (150 g/kg/day) and 2 in the high-dose 
combination group (150 mg/kg/day xanomeline plus 100 mg/kg/day trospium). Both 
xanomeline-only animals had necropsy gross findings of a gavage accident, and cause of death 
could not be determined. All toxicology animals survived to their scheduled sacrifice. Sponsor 
considers that the volume depletion and trauma of multiple bleeds (3 per animal), followed by 
reduced absorption of fluids and nutrients secondary to reduced GI motility with continued BID 
dosing explains the greater demise of TK animals relative to toxicity animals.  
Based on the results of the 90-day rat toxicology study, oral administration of trospium chloride 
and xanomeline tartrate alone or in combination to Crl:CD (SD) rats BID (12 hours ± 60 minutes 
apart) at dosage levels of 25 and 50 mg/kg/dose trospium chloride, 37 and 75 mg/kg/dose 
xanomeline tartrate, and a combination of 37/25, 75/25, and 75/50 mg/kg/dose xanomeline 
tartrate/trospium chloride for a minimum of 90 days resulted in minimal to moderate bile duct 
hyperplasia in the livers of the xanomeline tartrate and combination (xanomeline tartrate and 
trospium chloride) group males. Although there were no notable differences in the incidence of 
bile duct hyperplasia when comparing the single vs combination groups, there was an increased 
severity observed in the combination group males (specifically the 75/25 and 75/50 mg/kg/dose 
combination group males) when compared with the xanomeline tartrate group males at the 
terminal euthanasia. The bile duct hyperplasia was considered adverse in the high-dose 
xanomeline tartrate group males and in the 75/25 and 75/50 mg/kg/dose combination group 
males due to instances of moderate severity. Therefore, the no-observed-adverse-effect level was 
considered to be 50 mg/kg/dose for trospium chloride, 37 mg/kg/dose for xanomeline tartrate, 
and 37/25 mg/kg/dose for the combination of xanomeline tartrate/trospium chloride. At these 
doses for males, mean plasma AUC0-24 values were 27,700 pg•hr/mL for trospium, 146,000 
pg•hr/mL for xanomeline, and 4510 + 111,000 pg•hr/mL for trospium + xanomeline, 
respectively, on Day 91. At these dosages for females, mean plasma AUC0-24 values were 9230 
pg•hr/mL for trospium; 267,000 pg•hr/mL for xanomeline; and 16,700 + 171,000 pg•hr/mL for 
trospium + xanomeline, respectively, on Day 91. The absence of bile duct hyperplasia in females 
cannot be explained from differences in drug exposure. At the recovery euthanasia, bile duct 
hyperplasia was still present but was limited to minimal severity, and there was a decreased 
incidence in both the xanomeline tartrate and combination group males. There was also no 
notable difference in severity between the single vs combination groups at the recovery 
euthanasia. Given the decreased incidence/severity, in combination with the improved histologic 
appearance of bile ducts at the recovery euthanasia (i.e., smaller/flattened epithelium, 
noninflammatory, and an absence of portal bridging), changes at the recovery euthanasia were 
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consistent with a partial resolution of bile duct hyperplasia. With an absence of correlating serum 
liver enzyme elevations, bile acid alterations or hepatocellular degeneration, necrosis or 
regeneration, and with the apparent reversibility after cessation of treatment, these findings 
appear to have been tolerable by the affected animals. Therefore, the maximum tolerated dose 
was considered to be 50 mg/kg/dose for trospium chloride, 75 mg/kg/dose for xanomeline 
tartrate, and 75/50 mg/kg/dose for the combination of xanomeline tartrate/trospium chloride. For 
males, corresponding mean plasma AUC0-24 values were 27,700 pg•hr/mL for trospium; 
822,000 pg•hr/mL for xanomeline; and 133,000 + 276,000 pg•hr/mL for trospium + xanomeline, 
respectively, on Day 91. For females, corresponding mean plasma AUC0-24 values were 
9230 pg•hr/mL for trospium; 2,090,000 pg•hr/mL for xanomeline; and 17,600 + 
950,000 pg•hr/mL for trospium + xanomeline, respectively, on Day 91. 
In summary, no new findings on the “combination” of xanomeline and trospium (KarXT) were 
discovered; toxicology studies revealed the familiar exaggerations of systemic and CNS 
muscarinic effects that had previously been seen with xanomeline or trospium at high doses. 
Target organ findings with xanomeline alone were limited to biliary hyperplasia in the 28-day rat 
study but not the 28-day or 12-month monkey study, though similar findings were described in a 
6-month monkey study. With KarXT, biliary hyperplasia was not observed in the 14-day rat 
study but was reported in the 40-day rat study. Notably, these hyperplastic findings are not 
thought to represent pre-neoplastic lesions, because they were of low severity; no fibrosis or 
associated hepatocellular changes, and no significant effects were seen on hepatobiliary-related 
serum chemistry.  
 
Completed Clinical Studies 
Refer to the IB for complete information regarding previous clinical studies conducted with 
xanomeline by Eli Lilly, and studies KAR-001, KAR-002, KAR-003, and KAR-004 conducted 
by Karuna Therapeutics using xanomeline with trospium. 
To date, more than 750 subjects or volunteers have been exposed to xanomeline tartrate (oral 
formulation, either alone, in combination with trospium, or as the combination drug KarXT) in 
18 completed clinical studies conducted either by Eli Lilly or Karuna Therapeutics, some for as 
long as 3 years. In those studies, significant improvements in cognition and reduced psychotic 
symptoms were observed.  
A study of xanomeline monotherapy in subjects with schizophrenia was reported in 2008[18]. In 
this pilot study, the effects of xanomeline were examined in 20 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 
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. 
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These studies demonstrated the potential for xanomeline as a treatment for psychosis and 
cognition across multiple subject populations.  
Study H2Q-EW-E001, conducted by 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 mg, 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 in sitting and standing heart rate, slight increase in supine systolic 
BP, and postural hypotension. 
The clinical experience with KarXT initiated by Karuna Therapeutics to date includes 
3 completed Phase 1, clinical pharmacology studies in healthy volunteers (KAR-001, KAR-002, 
and KAR-003) and one completed Phase 2 study (KAR-004) in adult inpatients with DSM-5 
schizophrenia. 
The first study conducted by Karuna, KAR-001 was “A Phase 1, double-blind, randomized, 
multiple-dose, pilot study comparing xanomeline administered alone to xanomeline administered 
in combination with trospium chloride in normal healthy volunteers.” This study consisted of 
2 arms, in which xanomeline was administered TID, alone, at a total daily dose of 225 mg in one 
arm, and the second arm received the same dose of xanomeline in combination with trospium 
chloride 20 mg administered BID, a total daily dose of 40 mg. Subjects were treated for 7 days. 
The goal was to determine whether this dosing regimen would reduce the cholinergic side effects 
of xanomeline by co-administration of the muscarinic antagonist, trospium.  
Overall, treatment with xanomeline 225 mg daily + trospium 40 mg daily administered over 
7 days was considered safe and well tolerated. The results of key and supportive endpoints 
showed a numerical reduction (although not statistically significant) in visual analog scale (VAS) 
scores for cholinergic events for the xanomeline + trospium treatment arm compared to the 
xanomeline alone treatment arm. Specifically, consistent numerical reduction in VAS scores for 
the xanomeline + trospium treatment arm was observed for the supportive endpoints of 
maximum weekly individual VAS scores and mean daily maximum composite VAS scores.  
Results of the clinician-administered scales were supportive of a reduction in vomiting, feelings 
of nausea, excess salivation, and sweating that interfered with daily activities in the 
xanomeline + trospium treatment arm compared to the xanomeline alone treatment arm. 
There were no meaningful differences between treatment groups in heart rate, resting BP, 
orthostatic BP or any electrocardiogram (ECG) parameters including QT. A small subset of 
subjects in both treatment arms had transient increases in heart rate and orthostatic BP changes 
which may have contributed to syncope and postural dizziness in those subjects. Two subjects 
(both in the xanomeline alone arm) experienced syncope. The incidence of orthostatic AEs in the 
KarXT group was approximately one-half that of subjects in the xanomeline alone group. 
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The most commonly reported treatment-emergent AEs (TEAEs) in KAR-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. 
Study KAR-002 was a Phase 1, double-blind, randomized, multiple-dose adaptive design pilot 
study to evaluate the safety and tolerability of KarXT in normal healthy volunteers. Subjects 
received either 100 mg xanomeline + 20 mg trospium BID or placebo. The first cohort of this 
study was stopped after 1.5 days when the US FDA put the program on hold due to a preliminary 
rat finding in the 14-day study. This study used a new formulation of KarXT in which 
xanomeline and trospium were combined into a single dose form and given BID. Safety findings 
included an increase in orthostatic complaints. Caution should be used in drawing conclusions 
from this study, as subjects did not have time to reach steady state plasma levels from dosing, as 
only 3 doses were given. 
Study KAR-003 was a Phase 1, double-blind, randomized, multiple-dose, adaptive design, 
inpatient pilot study to evaluate the safety and tolerability of KarXT in normal healthy 
volunteers. The primary objective of this study was to assess the safety and tolerability of 7 days 
of daily administration of KarXT at various dose combinations, administered BID. Subjects 
received either KarXT or placebo (3:1 ratio). All subjects on KarXT received 2 days of 50 mg 
xanomeline + 20 mg trospium BID, and then increased to different doses for Days 3 to 7. This 
study also used the new formulation of KarXT in which xanomeline and trospium were 
combined into a single dosage form and given BID.  
There was a relatively high degree of variability in xanomeline and trospium exposures between 
individuals in all cohorts, which is consistent with previous results with KarXT, 
xanomeline-alone, and trospium-alone. Peak plasma concentrations were observed at a median 
time of 2.0 hours for xanomeline and 1.0 hour for trospium across all treatment groups and study 
days.  
Although there was insufficient data to draw a definitive conclusion regarding the impact of 
trospium on the pharmacokinetics (PK) and bioavailability of xanomeline, or the impact of 
xanomeline on the PK and bioavailability of trospium, the PK results suggest that neither drug 
had a meaningful impact on the PK behavior of the other drug. 
During the 2-day lead-in phase, the most common AEs (≥20% of subjects) when all the subjects 
completed dosing were dry mouth, nausea, and constipation. For the treatment groups that 
completed dosing, although the incidence of TEAEs was lower in the KarXT 100/20 BID 
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(66.7%) group compared to KarXT 125/40 group (88.9%), the incidence of cholinergic TEAEs 
(nausea, vomiting, diarrhea, sweating, and excess salivation) was similar between the 2 groups. 
The most commonly reported TEAEs (20% of subjects in either treatment group) in these 
groups were dizziness, nausea, dry mouth, headache, vomiting, dyspepsia, somnolence, vision 
blurred, and dysuria. For the treatment groups that did not complete dosing (KarXT 150/20 BID 
group and KarXT 150/40 BID group), the cholinergic TEAEs were generally higher compared to 
the treatment groups that completed dosing.  
Overall, anticholinergic TEAEs appeared to occur primarily in the treatment groups that were 
dosed with 40 mg trospium BID (KarXT 150/40 BID and KarXT 125/40 BID groups), 
particularly when paired with 125 mg xanomeline BID, suggesting to consider slightly lowering 
the trospium dose from 40 mg BID in future studies. All TEAEs were mild or moderate in 
severity, and there were no SAEs or deaths. Treatment-emergent AEs were primarily cholinergic 
or orthostatic (and a few anticholinergic). Doses of 100 mg and 125 mg BID of xanomeline were 
well tolerated when paired with 20 mg and 40 mg BID of trospium, respectively. The safety and 
tolerability profile of KarXT 100/20 BID and KarXT 125/40 BID was acceptable and supports 
further evaluation at similar doses in future studies. Doses of KarXT 150/20 BID and 
150/40 BID were not well tolerated in this study. A pairing of 150 mg xanomeline with 40 mg 
trospium appeared to be better tolerated than 150/20, but some subjects still experienced 
tolerability issues. 
Study KAR-004 was a Phase 2 randomized, double-blinded study to assess the safety 
tolerability, and efficacy of KarXT in adults with DSM-5 schizophrenia, hospitalized with acute 
psychosis. The primary objective of the study was to assess the efficacy of KarXT 125/30 BID 
versus placebo in reducing PANSS total scores in adult inpatients with a DSM-5 diagnosis of 
schizophrenia. Subjects received either KarXT or placebo (1:1 ratio) for a treatment period of 
5 weeks. All subjects on KarXT received a lead-in dose of KarXT 50/20 BID for the first 2 days 
followed by KarXT 100/20 BID on Days 3 to 7. On Day 8, dosing was titrated upwards to 
KarXT 125/30 BID unless the subject was continuing to experience AEs from previous dose 
increase of 100/20 BID. The clinical portion of this study was completed and clinical study 
report is in progress. No new safety concerns have arisen during this study. 
The KAR-004 trial results are unambiguous regarding efficacy, where not only the primary 
outcome measure showed a robust separation from placebo, but the additional sensitivity and 
secondary outcome measures were consistently robust as well.  
KarXT demonstrated statistically significant and clinically meaningful mean reductions in total 
PANSS scores at 5 weeks compared to placebo (P < 0.0001) in the modified intent-to-treat 
(mITT) population. The KarXT group showed an adjusted mean improvement of 17.40 points at 
Week 5 compared to an adjusted mean 5.85 point improvement in the placebo group for a 
difference of 11.56 points in the total PANSS score (Figure 1). Substantial significant differences 
were also seen between KarXT and placebo at Weeks 2 and 4; moreover, the difference appears 
to be widening with each successive timepoint. In addition, sensitivity analyses of the primary 
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outcome measure all showed the same strong differences from placebo attesting to the robustness 
of the finding in Completer, last observation carried forward, and Per Protocol populations (all 
with p < 0.0001). Also, analyses exploring missingness via imputation for missing data at 
random or not missing at random also showed strong separation (both with p < 0.0001). The 
Cohen’s d effect size observed in this trial was 0.75. 
Figure 1 
Change from Baseline in PANSS Total Scores (KAR-004) 
 
Abbreviations: LS = least squares; mITT = modified intent-to-treat; PANSS = Positive and Negative Syndrome 
Scale; SEM = standard error of the mean. 
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 timepoints (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. 
In regards to the Clinical Global Impression – Severity of Illness (CGI-S), subjects in the KarXT 
group overall significantly improved in ratings compared with placebo, with a P value of <0.001 
at Week 5. At Week 5, 8% of subjects on placebo improved (decreased) their CGI-S ratings by 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 with 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 
 Most common TEAEs were constipation, nausea, dry mouth, dyspepsia, and vomiting. 
None of these TEAEs were rated as severe, and none led to discontinuations 
 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.  
 No syncope or mean changes in BP were seen 
 A 5.5 bpm peak mean placebo adjusted resting heart rate increase with a downward trend 
after week 2 was seen 
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 One subject (on KarXT) was discontinued due to an elevated gamma-glutamyl 
transpeptidase 
 There were no new safety findings associated with KarXT that have not been observed 
with either xanomeline-alone or trospium-alone in previous trials 
 KarXT did not show evidence of many of the kinds of AEs that often occur in currently 
available antipsychotics for the treatment of schizophrenia.  
 The rates of the following AEs were similar for KarXT and placebo: somnolence, weight 
gain, and extrapyramidal symptoms. 
Another Phase 3 study (KAR-007) is planned at approximately 20 study sites in the US. 
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 with all available 
APDs. 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 with placebo, demonstrated highly significant reduction in PANSS total scores 
(P < 0.0001) at all post randomization time points (Weeks 2, 4, and, 5) with a calculated effects 
size (Cohen’s d) of 0.75. KarXT, as compared to placebo, demonstrated significant improvement 
at all post randomization time points for PANSS positive symptom subscores, PANSS negative 
symptom subscores, PANSS Marder Factor negative symptom subscores, and CGI-S scores. 
More than 750 subjects or volunteers have been exposed to xanomeline tartrate (oral 
formulation, either alone, in combination with trospium, or as the fixed dose combination drug 
KarXT) in clinical studies. These early clinical studies, as well as nonclinical pharmacology and 
toxicology studies, have not revealed any specific contraindications to the use of xanomeline. 
The most common side effects/symptoms are the cholinergic related effects: nausea, vomiting, 
excess salivation, excess sweating, and diarrhea. In addition, subjects treated with xanomeline 
alone have reported both syncope and orthostatic dizziness. The addition of trospium decreases 
the peripheral cholinergic effect of xanomeline creating a better tolerated therapy. In addition, a 
titration phase also increases the tolerability of KarXT. 
Trospium chloride has been marketed in the US for 12 years. The most frequently reported AEs 
reported in pivotal trials were dry mouth, constipation, abdominal pain, headache, urinary 
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retention, and abnormal vision and accommodation. For additional information, the package 
insert for trospium chloride tablets for oral use can be found in the IB. 
In a Phase 2 (KAR-004) clinical study, KarXT (100/20 and 125/30) significantly reduced the 
symptoms of schizophrenia in subjects with acute psychosis after treatment for 28 days. KarXT 
also showed an acceptable safety profile with the most common TEAEs being constipation, 
nausea, dry mouth, dyspepsia, and vomiting. All the reported TEAEs were mild or moderate in 
intensity. One SAE (psychotic disorder) was reported by a single subject and no deaths were 
reported in the study. KarXT was generally well-tolerated and found to be safe in this patient 
population. 
KarXT represents a novel approach to the treatment of patients with schizophrenia that will 
provide an important and meaningful alternative to current therapies. The current tolerability and 
AE profile and the efficacy of KarXT justify further development of KarXT in this patient 
population by advancing to Phase 3 trials. 
Subjects assigned to active study drug may benefit by improvement in schizophrenia symptoms. 
Since subjects will be having an acute psychotic event, subjects will be hospitalized where the 
clinical staff is available to help them 24 hours a day. In addition, the inpatient setting represents 
an important venue for research, examining the effects of KarXT and helps to eliminate or 
reduce to the extent possible, subjectivity and bias. Furthermore, this inpatient setting will also 
enhance measurable quality standards as well as increased adherence. 
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6 
STUDY OBJECTIVES AND ENDPOINTS 
6.1 
Study Objectives 
 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of KarXT 125/30 BID versus 
placebo in reducing PANSS total scores in adult inpatients with a DSM-5 diagnosis of 
schizophrenia. 
 
Secondary Objectives 
The secondary objectives of the study are: 
 To evaluate the reduction of PANSS positive score in subjects treated with KarXT versus 
placebo 
 To evaluate the improvement in CGI-S results in subjects treated with KarXT versus 
placebo 
 To evaluate the reduction of PANSS negative score in subjects treated with KarXT 
versus placebo 
 To evaluate the reduction of PANSS Marder Factor negative symptoms score in subjects 
treated with KarXT versus placebo 
 To evaluate the safety and tolerability of KarXT 
 To assess the PK of xanomeline and trospium after administration of KarXT in adults 
who are acutely psychotic with a DSM-5 diagnosis of schizophrenia 
 
Exploratory Objective 
The exploratory objective of the study is to evaluate the single nucleotide polymorphisms (SNPs) 
regarding schizophrenia subtypes and SNPs related to drug metabolism. 
6.2 
Study Endpoints 
 
Primary Endpoint 
The primary endpoint of this study is change from baseline in PANSS total score at Week 5 
 
Secondary Endpoints 
6.2.2.1 
Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
 Change from baseline in PANSS positive score at Week 5 
 Change from baseline in PANSS negative score at Week 5 
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 Change from baseline in PANSS Negative Marder Factor score at Week 5 
 Change from baseline in CGI-S score at Week 5 
 Percentage of PANSS responders (a 30% change in PANSS total score) at Week 5  
6.2.2.2 
Safety Endpoints 
The safety endpoints of this study are as follows: 
 Spontaneously reported AEs 
 Spontaneously reported cholinergic symptoms 
 Simpson-Angus Scale (SAS) 
 Barnes Akathisia Rating Scale (BARS) 
 Abnormal Involuntary Movement Scale (AIMS) 
 Body weight, body mass index (BMI), waist circumference 
 Orthostatic vital signs (supine and standing after 2 minutes): BP (systolic and diastolic) 
and heart rate 
 Clinical laboratory evaluations: hematology, clinical chemistry, coagulation, urinalysis, 
and drug screen 
 12-lead ECG 
 Physical examination 
 Suicidal ideation scale with the use of Columbia Suicide Severity Rating Scale (C-SSRS) 
 
Pharmacokinetic Endpoints 
The PK endpoints of this study are as follows: 
 Area under the plasma concentration-time curve (AUC) 
 Maximum observed plasma concentration (Cmax) 
 Time to maximum observed plasma concentration (Tmax) 
 
Exploratory Endpoints 
 Change in cognition measuring core domains of cognitive impairment in schizophrenia 
using the Cambridge Neuropsychological Test Automated Battery (CANTAB) 
 Change from baseline in prolactin levels at Week 5 
 Prediction of response based on SNP schizophrenia subtypes, and SNPs related to KarXT 
metabolism for both efficacy and tolerability 
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7 
INVESTIGATIONAL PLAN 
7.1 
Description of Overall Study Design and Plan 
This Phase 3, randomized, double-blind, parallel-group, placebo-controlled, multicenter, 
inpatient clinical study in adults who are acutely psychotic with a DSM-5 diagnosis of 
schizophrenia is designed to test the hypothesis that treatment with KarXT will result in 
significantly greater reduction (ie, improvement) in the primary and secondary endpoints at 
Week 5 from baseline compared with placebo. Total study duration is up to 8 weeks, including a 
7-day screening phase (up to a 7-day extension of the screening phase is allowed, if necessary), a 
5 week treatment period, and a 7-day follow-up period (only for subjects who do not rollover to 
KAR-008 study). Subjects completing this study will have the option of rolling over into a 
long-term open-label study (KAR-008) in which every subject will receive KarXT. 
Screening Period:  
Screening of subjects will take place in 7 days or less before Day -1 (Days -8 to -2). Up to a 
7-day extension of the screening time is allowed, if necessary. 
A suitable number of subjects will be screened to randomize approximately 246 subjects across 
approximately 10 sites in the US and 10 sites in Ukraine. Subjects will be randomized through 
the IWRS in a 1:1 ratio to receive either KarXT or placebo for a treatment duration of 5 weeks. 
Treatment Period:  
In the treatment period, all subjects assigned to KarXT will start on a lead-in dose of 
KarXT 50/20 (xanomeline 50 mg/trospium 20 mg) BID for the first 2 days (Days 1 and 2) 
followed by KarXT 100/20 (xanomeline 100 mg/trospium 20 mg) BID for the remainder of 
Week 1 (Days 3 to 7). On Day 8, dosing will be titrated upwards to KarXT 125/30 BID unless 
the subject is continuing to experience AEs from the previous dose of KarXT 100/20 BID. All 
subjects who are increased to KarXT 125/30 BID, depending on clinical response and 
tolerability, will have the option to return to KarXT 100/20 BID for the remainder of the 
treatment period. Dosing must not change after Visit 7 (Day 21) of the study and may be 
decreased for tolerability reasons no more than once during the study. In addition, dose 
escalation to KarXT 125/30 BID may not occur outside of the permitted visit window for 
Visit 5/Day 8.  
All randomized 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. 
Efficacy assessments (PANSS scores and CGI-S score) will be assessed at scheduled visits. 
Refer to Section 11 for more details. 
Safety will be assessed through spontaneous AEs, cholinergic symptoms, cognition testing, SAS, 
BARS, AIMS, body weight, BMI, waist circumference, orthostatic vital signs, ECG, clinical 
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laboratory assessments (hematology, clinical chemistry, coagulation, urinalysis, and drug 
screen), prolactin levels, physical examination, and C-SSRS will be evaluated throughout the 
study as scheduled. Section 12 provides complete details on these safety assessments. 
Details on PK assessments are provided in Section 13. 
Safety Follow-up Period: 
A safety follow-up visit (Visit 11/ Day 42 + 5 days) will be performed for all those subjects who 
do not rollover into the long-term open-label study KAR-008. 
An Independent Safety Monitoring Committee (ISMC) will be responsible for reviewing on a 
periodic basis the safety data from this study and confirming that the study may continue. 
Table 1 presents the study design.
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Table 1 
Study Design 
 
Phase: 
Screening 
Inpatient Treatment 
End of 
Treatment 
Safety 
Follow-up 
Day: 
Days -8 
to -2 
Day -1 
Day 1 
Day 3 + 
1 day 
Day 7 ± 
2 days 
Day 8 ± 
2 days 
Day 14 ± 2 
days 
Day 21 ± 2 
days 
Day 28 
± 2 days 
Day 32 
+ 1 
day 
Day 35  
- 2 daysc 
Day 42 + 
5 days 
Visit: 
Visit 1 
Visit 2a 
Visit 
2b 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Xanomeline
/ trospium 
(KarXT)*: 
N/A 
 
50/20 
BID 
100/20 
BID 
100/20 
BID 
125/30 
BID 
(Option: 
100 /20 
BID)a 
125/30 BID 
(Option: 
100 /20 
BID)a 
125/30 BID 
(Option: 
100/20 
BID)a 
125/30 
BIDb 
125/30 
BIDb 
N/A 
 
Comment: 
Up to a 
7-day 
extension 
to the 
screening 
phase is 
allowed. 
Baseline 
2-day 
lead-in 
dose 
Upward 
titration 
of dose 
 
Upward 
titration 
of dose 
Downward dose 
adjustment allowed 
according to clinical 
response/tolerability 
No dose 
adjustment 
allowed (after 
Day 21) 
 
For 
subjects 
who do 
not enter 
in to 
rollover 
Study 
(KAR-
008) 
Abbreviation: BID = twice daily. 
* All the KarXT doses are in mg. 
a. 
All subjects who are increased to KarXT 125/30, depending on clinical response and tolerability, will have the option to return to KarXT 100/20 BID for 
the remainder of the treatment period. 
b. No dose adjustment will be allowed after Visit 7. All subjects will continue taking the doses chosen for KarXT at Visit 7. 
c. 
For subjects rolling over in to KAR-008 study, the last dose of study drug will be administered the evening of Visit 10. For the subjects who do not rollover 
in to KAR-008 study, the last dose will be administered the evening before Visit 10. 
 
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7.2 
Discussion of Study Design 
A randomized, double-blind, parallel-group, placebo-controlled study design is suitable for 
conducting any interventional studies. This design will minimize bias and provide reference data 
for comparison of efficacy and safety parameters of the investigational drug. 
Schizophrenia is a long-term mental disorder which requires a chronic therapy. A 5-week 
treatment duration is considered an acceptable treatment duration to observe clinically significant 
response (ie. primary endpoint can be achieved). The 5-week treatment duration is substantiated 
by the statistically significant outcome of the KAR-004 study of the same duration.  
7.3 
End of Study 
A subject will have fulfilled the requirements for study completion when the subject has 
completed all study periods, including the End of Study visit (Visit 10/Day 35 (End of 
Treatment) for subjects who roll over into KAR-008 or Visit 11/Day 42 (Follow-up) for subjects 
who do not roll over into the KAR-008 study) as indicated in the Schedule of Assessments 
(Table 2) in accordance with the protocol. 
Subjects completing this study will have the option of rolling over into a long-term open-label 
study (KAR-008) in which every subject will receive KarXT. 
Note: A safety follow-up visit will be performed 1 week after the End of Study visit for subjects 
who do not rollover in to the long-term open-label study. 
7.4 
Independent Safety Monitoring Committee 
For the purpose of this study, the ISMC is an independent group of individuals with pertinent 
expertise that reviews on a regular basis accumulating safety data from the clinical study. This 
committee will be responsible, on a periodic basis, for confirming the safety of KarXT 
throughout the study, with particular focus on assessing for any new toxicities that might be 
involved with KarXT. 
The reviews will be of unblinded data to allow a comparison of event rates and detection of 
safety signals across treatment groups to identify important safety information. The ISMC 
charter will contain the details of the types of data to be reviewed, the defined triggers for 
review, the minimum frequency of meetings (timed, if no triggers), and the communication plan 
for disseminating review recommendations. 
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8 
SELECTION OF STUDY POPULATION 
Section 7.1 provides information regarding number of subjects planned to be randomized. 
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 must be provided before any study assessments are 
performed. 
b. Subject must be fluent (oral and written) in English (applicable to the US) or local 
language (Ukrainian or Russian applicable to Ukraine) 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 for 
Schizophrenia and Psychotic Disorder Studies (MINI) version 7.0.2. 
4. Subject is experiencing an acute exacerbation or relapse of psychotic symptoms, 
with onset less than 2 months before screening. 
a. The subject requires hospitalization for this acute exacerbation or relapse of psychotic 
symptoms. 
b. If already an inpatient at screening, has been hospitalized for less than 2 weeks for 
the current exacerbation at the time of screening. 
5. Positive and Negative Syndrome Scale total score between 80 and 120, inclusive. 
a. Score of ≥4 (moderate or greater) for ≥2 of the following Positive Scale (P) items: 
i. Item 1 (P1; delusions) 
ii. Item 2 (P2; conceptual disorganization) 
iii. Item 3 (P3; hallucinatory behavior) 
iv. Item 6 (P6; suspiciousness/persecution) 
6. Subjects with no change (improvement) in PANSS total score between screening and 
baseline (Day -1) of more than 20%. 
7. Subject has a CGI-S score of ≥4 at screening and baseline (Day -1) visits. 
8. Subject will have been off lithium therapy for at least 2 weeks before baseline and free 
of all oral antipsychotic medications for at least 5 half-lives or 1 week, whichever is 
longer, before baseline (Day -1). 
9. Subjects taking a long-acting injectable antipsychotic could not have received a dose of 
medication for at least 12 weeks (24 weeks for INVEGA TRINZA®) before baseline 
visit (Day -1). 
10. Subject is willing and able to be confined to an inpatient setting for the study duration, 
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follow instructions, and comply with the protocol requirements. 
11. BMI must be ≥18 and ≤40 kg/m2. 
12. Subject resides in a stable living situation and is anticipated to return to that same stable 
living situation after discharge, in the opinion of the investigator. 
13. Subject has an identified reliable informant/caregiver. An informant/caregiver is 
needed at the screening and baseline visits as well as at the end of the study for 
relevant assessments (site staff may act as informant while the subject is an inpatient). 
An informant/caregiver may not be necessary if the subject has been the patient of the 
investigator for ≥1 year. 
14. Women of childbearing potential (WOCBP), or men whose sexual partners are 
WOCBP, must be able and willing to use at least 1 highly effective method of 
contraception during the study and for 7 days after the last dose of study drug. Sperm 
donation is not allowed for 90 days after the final dose of study drug. A female 
subject is considered to be a WOCBP after menarche and until she is in a 
postmenopausal state for 12 months or otherwise permanently sterile (for which 
acceptable methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy)[22]. For the definition and list of highly effective methods of 
contraception, see APPENDIX 1.  
8.2 
Exclusion Criteria 
Individuals meeting any of the following criteria at screening or baseline are ineligible to 
participate in this study: 
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, moderate to severe alcohol use disorder (within the past 
12 months), substance (other than nicotine or caffeine) use disorder within the past 
12 months (use of cannabis at screening will result in screen failure with the allowance 
to rescreen at a later date if no moderate to severe substance use disorder is determined), 
major depressive disorder, bipolar I or II disorder, schizoaffective disorder, obsessive 
compulsive disorder, and post-traumatic stress disorder. Symptoms of mild mood 
dysphoria or anxiety are allowed as long as these symptoms are not the primary focus of 
treatment. 
a. A screening subject with mild substance abuse disorder within the 12 months before 
screening must be discussed and agreed upon with the medical monitor before he/she 
can be allowed into the study. 
2. 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. 
3. Subjects with HIV, cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma, and/or 
active hepatic viral infections based on either medical history or liver function test 
results. 
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4. History or high risk of urinary retention, gastric retention, or narrow-angle glaucoma. 
5. History of irritable bowel syndrome (with or without constipation) or serious 
constipation requiring treatment within the last 6 months. 
6. 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. 
7. Clinically significant abnormal finding on the physical examination, medical history, 
ECG, or clinical laboratory results at screening. 
8. Subjects cannot currently (within 5 half-lives or 1 week, whichever is longer, before 
baseline [Day -1]) be receiving oral antipsychotic medications; monoamine oxidase 
inhibitors; anticonvulsants (eg, lamotrigine, Depakote); tricyclic antidepressants (eg, 
imipramine, desipramine); selective serotonin reuptake inhibitors; or any other 
psychoactive medications except for as needed anxiolytics (eg, lorazepam, chloral 
hydrate). 
9. Pregnant, lactating, or less than 3 months postpartum. 
10. If, in the opinion of the investigator (and/or Sponsor), subject is unsuitable for 
enrollment in the study or subject has any finding that, in the view of the investigator 
(and/or Sponsor), may compromise the safety of the subject or affect his/her ability to 
adhere to the protocol visit schedule or fulfill visit requirements. 
11. Positive test for coronavirus (COVID-19) within 2 weeks before screening until 
Day -1 (baseline). 
12. Subjects with extreme concerns relating to global pandemics, such as COVID-19, that 
preclude study participation. 
13. Subject has had psychiatric hospitalization(s) for more than 30 days (cumulative) 
during the 90 days before screening. 
14. Subject has a history of treatment resistance to schizophrenia medications defined as 
failure to respond to 2 adequate courses of pharmacotherapy (a minimum of 4 weeks 
at an adequate dose per the label) or required clozapine within the last 12 months. 
15. Subjects with prior exposure to KarXT. 
16. Subjects who experienced any adverse effects due to xanomeline or trospium. 
17. Participation in another clinical study in which the subject received an experimental or 
investigational drug agent within 3 months before screening. 
18. Risk of violent or destructive behavior. 
19. Current involuntary hospitalization or incarceration. 
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8.3 
Rescreening 
Individuals who sign the informed consent form (ICF) to participate in the study but who do not 
subsequently meet all the requirements for safety laboratory assessments and therefore do not 
enroll (screen failures) may be rescreened, upon approval of the medical monitor on a case by 
case basis. Such individuals may be allowed to rescreen up to 1 time. When re-testing within the 
same screening procedure, only the exclusionary laboratory tests will be repeated once in case 
the exclusionary laboratory result was not due to a pathological condition and was occasional 
(except for individuals who have positive serology results).  
8.4 
Study Withdrawal, Removal, and Replacement of Subjects 
If a subject discontinues study treatment and is withdrawn from the study for any reason, the 
study site must immediately notify the medical monitor. The date and the reason for study 
discontinuation must be recorded on the electronic case report form (eCRF). Subjects who 
complete or discontinue early from the study will be discharged from the study site, if clinically 
warranted after completing all the Visit 10/early termination assessments as indicated in the 
Schedule of Assessments (Table 2). 
Note: A safety follow-up visit will be performed 1 week after the End of Study visit for those 
subjects who do not roll over into the long-term open-label study KAR-008. 
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 will 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 the investigator’s clinical judgment. The 
reason for subject withdrawal will be noted on the eCRF. 
 intercurrent illness: a condition, injury, or disease unrelated to the primary diagnosis that 
became apparent during treatment and necessitated the subject’s termination from the 
study 
 general or specific changes in the subject’s condition that renders him/her ineligible for 
further treatment according to the inclusion/exclusion criteria (eg, subject has need for a 
medication prohibited by the protocol) 
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 subject fails to adhere to the protocol requirements (eg, drug noncompliance [if a study 
subject is off study drug for >5 days in a row])  
 violation of entry criteria; ie, subjects who are enrolled but are later discovered not to 
meet entry criteria 
 development of suicidal or assaultive behavior 
 alcohol or illegal drug use 
 pregnancy, as indicated in Section 12.7.7. Any study subject who becomes pregnant 
while participating in the study will be unblinded to study treatment randomization. If she 
is found to be on active treatment assignment, she will be followed until her pregnancy 
reaches term. 
 Sponsor’s decision to discontinue study. 
Subjects withdrawing 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 leave the unit or are lost to follow-up. 
These efforts must be documented in the subject’s file. Subjects with AEs ongoing at end of 
study will be followed until the AE is resolved (regardless of whether they enroll in the 
long-term open-label study KAR-008) or the subject is considered to be in stable condition. 
The Sponsor has the right to terminate the study at any time in case of SAEs or if special 
circumstances concerning the study drug 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, women of childbearing potential in this study must be willing to use a highly effective 
method of birth control (see APPENDIX 1 for a list of acceptable highly effective methods of 
contraception) during the study and for 7 days after the last dose of study drug. Females of 
childbearing potential will have a serum pregnancy test at screening and a urine pregnancy test 
on Day 1 (before receiving KarXT) and Day 35.  
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. 
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Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment 
of the mother with KarXT, women who are breastfeeding must not be enrolled in the study. 
The effects of study drug on sperm are unknown. Men who are willing to participate in the study 
must agree to use a highly effective method of birth control (see APPENDIX 1 for a list of 
acceptable highly effective methods of contraception) and must not impregnate a sexual partner 
during or for 90 days after the last dose of study drug. They must also agree to refrain from 
sperm donation for 90 days after the last dose of study drug. 
Female subjects of child-bearing potential will be instructed that known or suspected pregnancy 
occurring during the study should be confirmed and reported to the investigator. If a female 
subject becomes pregnant, the investigator must withdraw her from the study without delay. The 
subject must not receive any further doses of the study drug. Upon discontinuation from the 
study, only those procedures that would not expose the pregnant female subject to undue risk 
will be performed. See Section 12.7.7 for further reporting and monitoring details. 
Full details of the pregnancy will be recorded on the withdrawal page (exit form) of the eCRF, or 
a pregnancy report will be completed if the subject has completed the study. Notification of the 
pregnancy should be submitted on 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 SAE (Section 12.7.4). 
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 leave the facility and are lost to 
follow-up to obtain end of study 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 Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB) may take such actions. If the study is terminated for safety reasons, subjects 
will be notified immediately and assured that appropriate treatment and follow-up will be 
available. If an investigator terminates the study, the Sponsor, subjects, and IEC/IRB will be 
informed about the reason for such action. Similarly, if the Sponsor terminates the study, it will 
inform the investigators, the IEC/IRB, and the subjects of the reason for such an action. Similar 
notifications will be sent by the IEC/IRB if it takes such an action. 
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9 
TREATMENTS 
9.1 
Details of Study Treatments 
KarXT is formulated as hard hydroxypropyl methylcellulose oral capsules containing 2 distinct 
populations of drug beads, one of which is loaded with xanomeline tartrate and the other of 
which is loaded with trospium chloride. Each capsule contains the freebase equivalent of 
xanomeline and trospium according to the desired dose strength. In addition to the active 
ingredients, the drug beads contain microcrystalline cellulose (MCC). The beads are not coated 
and are formulated for immediate release of the active ingredients. 
 
Identity of Study Treatments 
Active study agents for treatment group will be size 0, Swedish orange-white, opaque, and 
hydroxypropyl methylcellulose hard capsules. Placebo will be prepared in matching capsules; 
therefore, an unblinded pharmacist will be required to dispense study agent at each day of 
dosing. For the 2-day lead-in period (Days 1 and 2), subjects randomized to active drug will 
receive capsule strength KarXT 50/20 BID, followed by 2 capsules of KarXT 50/10 mg BID or a 
dosage of 100/20 BID for a total daily dosage of 200/40 mg xanomeline/trospium chloride for 
the remainder of Week 1 (Days 3 to 7). At the beginning of Week 2, dosing may be increased to 
2 capsules of KarXT 62.5/15 mg or a dosage of 125/30 BID for a total daily dosage of 
250/60 mg xanomeline/trospium chloride, depending on clinical response and tolerability. 
Investigators have the option to return a subject to KarXT 100/20 BID for the remainder of the 
treatment period, but dosing must not change after Visit 7 of the study.  
KarXT 50/10 mg is composed of 44.4% xanomeline tartrate, 5.8% trospium chloride, excipients 
37.59% MCC, 11.5% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a size 0, 
Swedish orange, hydroxypropyl methylcellulose hard capsule. 
KarXT 50/20 mg is composed of 33.4% xanomeline tartrate, 8.7% trospium chloride, excipients 
39.8% MCC, 17.3% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a size 0, Swedish 
orange, hydroxypropyl methylcellulose hard capsule. 
KarXT 62.5/15 mg is composed of 41.7% xanomeline tartrate, 6.5% trospium chloride, 
excipients 38.1% MCC, 12.9% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a 
size 0, Swedish orange, hydroxypropyl methylcellulose hard capsule. 
Placebo is composed of sugar spheres pf011, 850/1000 suglets, 99.05% colorcon, and 10.05% 
talc in a size 0, Swedish orange, an opaque white hydroxypropyl methylcellulose hard capsule. 
All investigational agents are to be stored according to requirements. 
 
Packaging and Labelling 
The study packaging and labelling will be performed by Corealis Pharma, located in Laval, 
Quebec, Canada, Catalent Pharma Solutions, located in Winchester, Kentucky (labelling for the 
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US sites), and Catalent Pharma Solutions, located in Philadelphia, Pennsylvania (labelling for 
Ukrainian sites). All packaging and labelling operations will be performed according to Good 
Manufacturing Practice for Medicinal Products and the relevant regulatory requirements. 
Bulk supply bottles are labeled with the name of the drug, recommended storage conditions, the 
name and address of the manufacturer, and the Investigational Use Statement (“Caution: New 
Drug – Limited by Federal [US] Law to Investigational Use”). 
Further details on labelling of investigational products will be provided in the Pharmacy Manual.  
 
Study Drug Storage 
KarXT and placebo must be stored at controlled room temperature 15°C-25°C in a secured 
location with no access to unauthorized personnel. 
 
Study Drug Retention 
Study drug not used in KAR-009 may be used for the long-term extension study (KAR-008). 
Therefore, unused study drug for this particular study must be retained until completion or 
termination of the KarXT program, and written authorization from the Sponsor has been 
received. All unused and used study drug must be destroyed at the site or returned, as specified 
by Sponsor. It is the investigator’s responsibility to ensure that the Sponsor has provided written 
authorization prior to return or destruction, and that appropriate records of the disposal are 
documented and maintained. No used or unused study drug may be disposed until fully 
accounted for by the study monitor. 
9.2 
Dose Schedule 
The first dose of the study drug will be administered in the morning of Day 1. For subjects who 
roll over to Study KAR-008, the last dose will be administered in the evening of Visit 10 
(Day 35 -2 days). Subjects who do not rollover to Study KAR-008 study will have the last dose 
of the study drug administered in the evening before Visit 10 (Day 35 -2 days). The study drug 
should be administered daily BID on an empty stomach (ie, at least 1 hour before a meal) or 2 to 
3 hours after a meal. Some considerations for dosing and PK blood withdrawals are provided in 
the subsections below. 
 
Visit 2b/Day 1 Randomization and Dosing 
 
The first dose will be administered in the morning, and the evening dose will be 
administered 12 ± 0.5 hours after the morning dose.  
 
All subjects must be administered 4 dosages of the KarXT 50/20 or placebo before dose 
escalation to KarXT 100/20 BID. 
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Visit 3/Day 3 and/or Visits Occurring on Weekends/Holidays 
 
When Day 3 occurs on a weekend, it is expected that the complete Visit 3 will be 
performed, and the subject’s dose will be escalated on Day 3. 
 
If completion of the visit is not possible on Day 3, the +1-day visit window may be used. 
In this instance, the dose will not be escalated until the study visit occurs. In all cases, 
the subject must have had at least 4 doses of KarXT 50/20 or placebo before escalating 
to KarXT 100/20 or placebo. 
 
This may result in only 4 days of the KarXT 100/20 or placebo dose at Visit 5/Day 8, 
which is acceptable. 
 
All subjects must be administered 8 doses of the KarXT 100/20 or placebo before dose 
escalation to KarXT 125/30 BID. 
 
Visit 5/Day 8 Dosing and PK Considerations and Visit 8/Day 28 PK 
Considerations 
 
If dose escalation to the KarXT 125/30 or placebo level is confirmed by investigator 
order on Visit 5/Day 8, that dose is to be administered in the morning (after the predose 
PK blood draw) to allow for serial postdose PK blood draws per protocol (Table 2, 
Footnote p). 
 
Should the use of visit windows be necessary, serial PK sampling must accompany the 
actual day of dose escalation for Visit 5.  
 
For Visit 8, serial PK sampling is meant to capture the PK profile of the subject’s final 
KarXT dose level (125/30 or 100/20) after multiple doses; therefore, Visit 8 should 
occur at least 7 days after Visit 7 is completed, and there must be no changes in dose for 
at least 7 days leading up to Visit 8. PK sampling must accompany the actual day of 
Visit 8 if a window is used. 
 
Visit 10/Day 35 Dosing 
 Subjects willing to rollover in to Study KAR-008 will continued to be dosed at 
Visit 10/Day 35, and their last dose will be the evening of Visit 10. These subjects will 
start their at-home dosing on Day 1 of Study KAR-008. 
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 
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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 t3-digit study code and a 3-digit site identification followed by a 3-digit 
number assigned sequentially within each site, starting at 
. 
On Day -1, all eligible subjects will be randomly assigned in a 1:1 ratio to either KarXT or 
placebo groups. Subjects will be assigned a randomization number through the IWRS, in 
accordance with the randomization code generated by the authorized personnel at VERISTAT. 
At the study site, the randomization schedule will only be accessible to authorized unblinded 
pharmacy personnel or designee. Once a randomization number is allocated to one subject, it 
may not be assigned to another subject even if the former discontinued the study. 
 
Blinding 
An IWRS will allocate treatment based on a prespecified randomization list generated by 
VERISTAT. Active and placebo study drug will be provided in bulk to each site participating in 
the study. For each dose, study drug and packaging will be identical in size, shape, color, and 
appearance (see Section 9.1.2). No other study site personnel (except the pharmacist or other 
designated unblinded individual), subjects, informants/caregivers, Sponsor personnel, or Sponsor 
designees (eg, Sponsor’s Medical Monitor) will be unblinded to treatment assignment throughout 
the duration of the study unless unblinding is required. Both active study drug and placebo will 
be supplied as identical matching capsules. This prevents bias on the part of the study staff and 
the subject to influence the results of the study.  
If an investigator becomes unblinded to a given subject’s study treatment, that subject will be 
discontinued from the study unless there are ethical reasons for that subject not to be 
discontinued; approval from the Sponsor/medical monitor must be obtained in such instances. 
VERISTAT will generate and maintain the security of the randomization code. In the event that 
emergency unblinding is required for a given subject because of AEs or concerns for the 
subject’s safety or wellbeing, the investigator may break the randomization code for just that 
subject via the IWRS, by which system the unblinding will be captured after consultation and 
agreement with the medical monitor/Sponsor. The unblinding and its cause will also be 
documented in the eCRF. Unblinding according to the protocol will occur only after completion 
of the study. 
If an AE is thought to be related to the study drug and poses a safety risk, the investigator must 
decide whether to stop investigational treatment and/or treat the subject. Subject withdrawal 
should be avoided, if possible. If discontinuation of treatment occurs, every attempt should be 
made to restart study drug if medically appropriate, whatever the duration of discontinuation. 
When a subject has an AE that requires that the investigator be unblinded, the investigator can 
obtain the treatment assignment from the IWRS system. The site is expected to notify the study 
medical monitor before breaking the study blind unless it is in the subject’s best interest if the 
blind is broken immediately. Note: In most circumstances, it is not necessary to unblind a 
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subject, even if an SAE has occurred. For many drugs there is no specific therapy for AEs. The 
appropriate course of action is to stop the investigational drug and treat the signs and symptoms 
resulting from the AE. 
The members of the ISMC will be unblinded as they review the safety data from the study. 
9.4 
Dose Modification 
Subjects will be dosed as described in Section 7.1 and in accordance with the Schedule of 
Assessments (Table 2). The study drug 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 at Visits 5, 6, and 7 and at unscheduled visits. No dose adjustments are allowed after 
Visit 7. No other dose modifications are permissible in this study except those specified in this 
protocol. 
9.5 
Treatment Accountability and Compliance 
The pharmacist or other designated unblinded 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 study drug will be supervised by study site personnel to ensure compliance. 
Investigators will maintain records that adequately document that the subjects were provided 
with the correct study treatment bulk supply and reconcile the products received from the drug 
dispensing center. Investigational product will not be returned to the Sponsor or designee until 
accountability has been fully monitored through the end of the study. Study drug accountability 
will be assessed periodically by the assigned unblinded study monitor. 
9.6 
Prior and Concomitant Therapy 
 
Prior and Concomitant Medications 
Subjects will be asked for all prior medications he/she were taking up to 6 months before the 
study, up to the time of the first dose of study medication on Day 1. All prior medications will be 
recorded on the eCRF. 
Restricted prior therapies are provided in Section 8.2.  
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 (ie, from the time of enrollment at the screening visit until study completion), 
subjects will refrain from the use of any new concomitant medications without the specific prior 
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approval of the investigator. The administration of any other concomitant medications during the 
study period is prohibited without the prior approval of the investigator unless its use is deemed 
necessary in a medical emergency. Any medication or therapy that is taken by or administered to 
the subject during the course of the study must be recorded in the eCRF. The entry must include 
the dose, regimen, route, indication, and dates of use. 
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. 
 Within 5 half-lives or 1 week, whichever is longer, before baseline (Day -1), subjects 
could not have taken oral antipsychotic medications, MAO inhibitors, mood stabilizers 
(ie, lithium), anticonvulsants (eg, lamotrigine, Depakote), tricyclic antidepressants (eg, 
imipramine, desipramine), selective serotonin reuptake inhibitors, or any other 
psychoactive medications except for anxiolytics that were taken on an as needed basis 
(eg, lorazepam, chloral hydrate).  
 Subjects taking a long acting injectable antipsychotic could not have received a dose of 
medication for at least 12 weeks (24 weeks for INVEGA TRINZA®).  
Note: Please direct questions relating to prohibited medications to the Medical Monitor. 
 
Concomitant Medications for Anxiety and/or Sleep aid 
Subjects are allowed to take benzodiazepines (up to 6 mg lorazepam/day or equivalent) for 
anxiety, agitation, and insomnia. Subjects may also use non-benzodiazepine medications 
(eg, zolpidem, zaleplon) as a sleep aid. Study sites must record the use of rescue medications in 
the eCRF and subject’s source document. Note: Cognition testing should not be done within 
8 hours of receiving a benzodiazepine or sleep medication. 
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10 STUDY PROCEDURES 
Table 2 outlines the timing of procedures and assessments to be performed throughout the study. 
Section 12.6 specifies laboratory assessment samples to be obtained. See Sections 11, 12, and 13 
for additional details regarding efficacy, safety, and PK assessments, respectively. 
  
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Table 2. 
Schedule of Assessments 
PROCEDURE 
SCREENING 
PHASE 
TREATMENT PHASE 
SAFETY 
FOLLOW
-UPt 
Unscheduled 
Visit(s)b 
VISIT 
1 
(Day -8 
to -2)a 
2a 
(Day 
-1) 
2b 
(Day 
1) 
3 
(Day 
3 +1 
day) 
4 
(Day 
7 ±2 
days) 
5 
(Day 
8 ±2 
days) 
6 
(Day 
14 ±2 
days) 
7 
(Day 
21 ±2 
days) 
8 
(Day 
28 ±2 
days)u 
9 
(Day 
32 +1 
day) 
10/ET 
(Day 35 
-2 days) 
11 
(Day 42 
+5 days) 
WEEKS PAST 
RANDOMIZATION 
NA 
0 
 
 
1 
 
2 
3 
4 
 
5 
6 
 
Written informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Collect 
demographic 
information (date of 
birth, sex, race) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(females of 
childbearing 
potential only)c 
X
c 
X
c 
 
 
 
 
 
 
 
 
X
c 
X
c 
 
Urine test for 
drugs of abuse 
and alcohol 
testingd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Review of 
inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Subject eligibility 
verification process 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, 
psychiatric, and 
medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examinatione 
X
e 
 
 
 
 
 
 
 
 
 
X
e 
X 
 
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PROCEDURE 
SCREENING 
PHASE 
TREATMENT PHASE 
SAFETY 
FOLLOW
-UPt 
Unscheduled 
Visit(s)b 
VISIT 
1 
(Day -8 
to -2)a 
2a 
(Day 
-1) 
2b 
(Day 
1) 
3 
(Day 
3 +1 
day) 
4 
(Day 
7 ±2 
days) 
5 
(Day 
8 ±2 
days) 
6 
(Day 
14 ±2 
days) 
7 
(Day 
21 ±2 
days) 
8 
(Day 
28 ±2 
days)u 
9 
(Day 
32 +1 
day) 
10/ET 
(Day 35 
-2 days) 
11 
(Day 42 
+5 days) 
WEEKS PAST 
RANDOMIZATION 
NA 
0 
 
 
1 
 
2 
3 
4 
 
5 
6 
 
Spontaneous AEsf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of 
concomitant 
medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height (Screening 
only) and body 
weight, BMI, waist 
circumference 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Orthostatic vital 
signs: BP and heart 
rateg 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Resting 12-lead ECGh 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
Blood samples for 
hematology, 
coagulation, and 
serum chemistry and 
urine sample for 
urinalysisi 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
COVID-19 
testing 
X 
X 
 
 
 
 
 
 
 
 
 
 
Xj 
Blood sample 
for prolactink 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Blood sample 
for viral 
serologyl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
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PROCEDURE 
SCREENING 
PHASE 
TREATMENT PHASE 
SAFETY 
FOLLOW
-UPt 
Unscheduled 
Visit(s)b 
VISIT 
1 
(Day -8 
to -2)a 
2a 
(Day 
-1) 
2b 
(Day 
1) 
3 
(Day 
3 +1 
day) 
4 
(Day 
7 ±2 
days) 
5 
(Day 
8 ±2 
days) 
6 
(Day 
14 ±2 
days) 
7 
(Day 
21 ±2 
days) 
8 
(Day 
28 ±2 
days)u 
9 
(Day 
32 +1 
day) 
10/ET 
(Day 35 
-2 days) 
11 
(Day 42 
+5 days) 
WEEKS PAST 
RANDOMIZATION 
NA 
0 
 
 
1 
 
2 
3 
4 
 
5 
6 
 
Blood sample 
for DNA testing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Functional 
constipation inquirym 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Admission of subject 
to inpatient unitn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization/
assignment of 
subject 
randomization 
number 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Determination of dose 
adjustment 
 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
Study drug provided 
(randomized, double- 
blind) and 
administered daily 
BIDo 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Blood samples for PK 
analysisp 
 
 
 
 
 
X
p 
 
 
X
p 
 
X
p 
 
X
p 
MINI version 7.0.2q 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Positive and Negative 
Syndrome Scale 
(PANSS) for 
schizophreniar 
X 
X 
 
 
 
 
X 
X 
X 
 
X 
 
 
C-SSRSs 
X 
X 
 
 
X 
 
X 
X 
X 
 
X 
X 
X
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PROCEDURE 
SCREENING 
PHASE 
TREATMENT PHASE 
SAFETY 
FOLLOW
-UPt 
Unscheduled 
Visit(s)b 
VISIT 
1 
(Day -8 
to -2)a 
2a 
(Day 
-1) 
2b 
(Day 
1) 
3 
(Day 
3 +1 
day) 
4 
(Day 
7 ±2 
days) 
5 
(Day 
8 ±2 
days) 
6 
(Day 
14 ±2 
days) 
7 
(Day 
21 ±2 
days) 
8 
(Day 
28 ±2 
days)u 
9 
(Day 
32 +1 
day) 
10/ET 
(Day 35 
-2 days) 
11 
(Day 42 
+5 days) 
WEEKS PAST 
RANDOMIZATION 
NA 
0 
 
 
1 
 
2 
3 
4 
 
5 
6 
 
CGI-S Scale 
X 
X 
 
 
X 
 
X 
X 
X 
 
X 
 
 
Cognition testingt 
X
s 
X 
 
 
 
 
 
X 
 
X 
 
 
 
Simpson-Angus 
Rating Scale 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Barnes Rating Scale 
for Akathisia 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Abnormal 
Involuntary 
Movement Scale 
(AIMS) 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Abbreviations: AE = adverse event; BID = twice daily; BMI = body mass index; BP = blood pressure; CGI-S = Clinical Global Impression‒Severity scale; 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ET = early termination; ID = identification; MINI = Mini International 
Neuropsychiatric Interview; PK = pharmacokinetic; QTcF = QT interval corrected by Fridericia. 
a. 
Up to a 7-day extension of the screening phase is allowed, if needed. 
b. 
Other assessments as needed. 
c. 
A serum pregnancy test for females of childbearing potential should be done at screening, and urine pregnancy tests should be done at other visits. 
d. 
A National Institute on Drug Abuse-5 urine drug screen (cannabinoids or marijuana, phencyclidine, amphetamines, opiates, and cocaine) will be 
performed at screening and at Visit 2a (baseline). If a subject leaves the study site, he/she should have a urine drug screen and test for alcohol 
(breathalyzer or blood alcohol level) upon returning to the study site.  
e. 
A complete physical examination includes body temperature (°C), general appearance, head/eyes/ears/nose/throat, examination of thorax and 
abdomen, assessment of cardiac, musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited neurological 
examination. 
f. 
AEs as reported by subjects or observed by clinical staff and occurs from Day -1. One PK blood sample may be drawn if a relevant/significant AE 
(based on medical judgement) is reported during a scheduled visit or if there is a dose adjustment or a relevant/significant AE reported during an 
unscheduled visit (no multiple draws). 
g. 
Vital signs taken supine and standing after 2 minutes. BP includes systolic and diastolic BP and is to be taken in the same arm for the duration of the 
study. Heart rate is measured in beats/minute. During treatment, beginning with Day 1, orthostatic vital signs should occur 2 (±1) hours after morning 
dosing. Orthostatic vital signs are only required after the morning dose of the specified visit days, but additional orthostatic vital sign monitoring is 
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allowed at the investigator’s discretion. It would be acceptable, for example, to do orthostatic vital signs BID after dosing increases for a day or 2 for 
subjects where it seems warranted, but this should not be done automatically. 
h. 
ECG on Day 1 will be done at 2 hours + 15 minutes post morning dose. ECGs at all other scheduled visits will be performed before blood withdrawal for 
any safety laboratory tests and/or PK analysis. During the ECG, ventricular rate (bpm), PR (msec), QRS (msec), QT (msec), and QTcF (msec) 
measurements should be obtained.  
i. 
Refer to Table 3 for individual laboratory tests. 
j. 
Optional COVID-19 test may be performed at unscheduled visits based on the Investigator’s discretion. 
k. 
Blood sample for prolactin must be obtained before the morning dose of the study drug at scheduled visits (except at Visit 2a). 
l. 
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. 
m. Functional constipation inquiry: At specified visits, subjects will be asked whether they have experienced constipation (per the ROME III criteria and 
Bristol Stool Form scale; see APPENDIX 2) since the last visit and if yes, whether the constipation required intervention. If the subject answers yes, 
sites are instructed to ask subjects to provide event date and ensure the event is documented as an AE and treatment is documented as concomitant 
medication.  
n. 
If an eligible subject is not already an inpatient, the subject should be admitted to the inpatient unit. 
o. 
Starting on Day 1, study drug is administered daily BID (first dose of study will be administered in the morning of Day 1, and evening dose will be 
administered 12 ± 0.5 hours after the morning dose and after last PK sampling [for Visits 5 and 8] is completed), on an empty stomach (ie, at least 
1 hour before a meal) or 2 to 3 hours after a meal by the study staff, with the last dose administered on the evening before Visit 10 for subjects who do 
not enter Study KAR-008. For subjects rolling over to Study KAR-008, the last dose will be administered on the evening of Visit 10. All subjects must 
receive at least 4 dosages of the 50/20 BID before dose escalation to KarXT 100/20 BID. 
p. 
For Visit 5/Day 8 and Visit 8/Day 28, 7 PK blood draws are required: before the morning dose, and at 0.5 hour ± 5 minutes, 1 hour ± 5 minutes, 
2 hours ± 10 minutes, 4 hours ± 10 minutes, 8 hours ± 10 minutes, and 12 hours ± 10 minutes after the morning dose (Note: The 12-hour samples must 
be collected before administration of the evening dose). PK blood draws at Visit 5 must be drawn in relation to the first dose of KarXT 125/30 for 
subjects who are escalated in the morning of Visit 5/Day 8 ± 2 days. PK blood must also be drawn in relation to the morning dose for subjects who are 
not escalated at Visit 5/Day 8 ± 2 days. For Visit 10/ET, a single PK blood sample should be drawn before discharge (preferably in the morning) for 
completed (and early termination) subjects. One PK blood sample may also be drawn if a relevant/ significant AE is reported during a scheduled visit 
or if there is a dose adjustment or a relevant/significant AE reported during an unscheduled visit (no multiple draws). For an ET Visit that is related to 
an AE, the collection of a PK blood sample is not optional and should be drawn before discharge. 
q. 
It should be performed before PANSS assessment. 
r. 
It is recommended, if at all possible, that the PANSS assessment should be performed before all the other scale assessments for all visits at 
which it is performed. The PANSS assessment includes the Marder Factor. 
s. 
C-SSRS first time use lifetime, other times use “Since Last Visit” version. At the Unscheduled visit, the C-SSRS should be performed to monitor subjects 
for suicidality. 
t. 
During screening, subjects will complete each of the CANTAB tests for familiarization purposes. These same tests will then be administered on Visits 
2a, 7, and 9. Note: Cognition testing cannot be done within 8 hours of receiving benzodiazepine or sleep medications. 
u. 
Safety follow-up visit will be performed 1 week (Day 42 +5 days) after the end of study visit for subjects who did not rollover in to the long-term 
open-label study KAR-008. 
v. 
Visit 8 must occur at least after 7 days after completion of Visit 7, and there must be no changes in dose for at least 7 days leading up to Visit 8. 
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10.1 Informed Consent 
Informed consent forms must be approved for use by the reviewing IEC/IRB. Before performing 
any study-related procedures, the investigator (or designee) will obtain written informed consent 
from the subject.  
10.2 Study Procedures 
Assessments and their timings are to be performed as outlined in the Schedule of Assessments 
(Table 2). Section 12.6 specifies laboratory assessment samples to be obtained.  
Assessments and procedures scheduled at a visit where study drug is administered should be 
performed before administration of treatment unless otherwise indicated in the Schedule of 
Assessments (Table 2). 
Efficacy assessments are described in Section 11 and include PANSS and CGI-S scores. 
Safety assessments are described in Section 12 and include spontaneous AEs; cholinergic 
symptoms; cognition testing (CANTAB); SAS; BARS; AIMS; body weight; BMI; waist 
circumference; orthostatic vital signs; ECG; clinical laboratory assessments (hematology, clinical 
chemistry, coagulation, urinalysis, and drug screen); prolactin levels; physical examination; and 
C-SSRS. 
PK assessments are described in Section 13 and include estimation of AUC, Cmax, and Tmax. 
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 study drug. 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 after discussion with the 
medical monitor. 
Study discontinuation procedures are described in Section 8.4 and 8.6. 
 
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11 EFFICACY ASSESSMENTS 
The Schedule of Assessments (Table 2) outlines the efficacy assessments to be performed 
throughout the study and their timing. 
11.1 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[23]. 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. The PANSS assessment includes the Marder Factor. 
It is recommended, if at all possible, that the PANSS assessment should be performed before all 
the other scale assessments for all visits at which it is performed.  
11.2 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 modified CGI-S 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[24]. 
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 previous 7 days. 
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12 SAFETY ASSESSMENTS 
Safety assessments (spontaneous AEs; cholinergic symptoms; cognition testing [CANTAB]; 
SAS; BARS; AIMS; body weight; BMI; waist circumference; orthostatic vital signs; ECG; 
clinical laboratory assessments [hematology, clinical chemistry, coagulation, urinalysis, 
prolactin, and drug screen]; physical examination; and C-SSRS) are to be performed at 
protocol-specified visits, as specified in the Schedule of Assessments (Table 2).  
12.1 Demographics, and Medical 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 and psychiatric 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 12.7. All 
changes not present at baseline or described in the past medical history and identified as 
clinically noteworthy must be recorded as AEs. 
12.2 Vital Signs 
Orthostatic vital signs (systolic and diastolic BP and heart rate measurements) will be evaluated 
at the 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, beginning with Day 1, orthostatic vital signs should 
occur 2 (±1) hours after morning dosing. Orthostatic vital signs are only required after the 
morning dose of the specified visit days, but additional orthostatic vital sign monitoring is 
allowed at the investigator’s discretion. 
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. 
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12.3 Physical Examination 
A complete physical examination (body temperature, general appearance, 
head/eyes/ears/nose/throat, examination of thorax and abdomen, assessment of cardiac, 
musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited 
neurological examination) will be performed at visits as specified in Table 2. Physical 
examinations will be performed by a physician. 
12.4 Weight, Height, Body Mass Index, 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. 
12.5 Electrocardiograms 
A 12-lead, resting ECG will be obtained at the visits indicated in the Schedule of Assessments 
(Table 2). During the ECG, ventricular rate (bpm), PR (msec), QRS (msec), QT (msec), and 
QTcF (msec) measurements will be obtained. ECG at Day 1 will be performed 2 hours (+ 
15 minutes) post morning dose. ECGs at all other scheduled visits will be performed before 
blood withdrawal for any safety laboratory tests and/or PK analysis. 
All the ECGs obtained will be interpreted by experienced independent blinded reader(s) at the 
central laboratory. 
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 on the eCRF. ECGs will be 
repeated if clinically significant abnormalities are observed or artifacts are present. 
12.6 Laboratory Assessments 
Laboratory assessment samples (Table 3) are to be obtained at designated visits as detailed in the 
Schedule of Assessments (Table 2). 
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Table 3. 
Laboratory Assessments 
Hematology 
Serum Chemistry 
Urine Analysis (Dipstick) 
Full and differential blood count 
Hct 
Hb 
MCH 
MCHC 
MCV 
Platelet count 
RBC count 
WBC count with differential 
 
Albumin 
ALT 
ALP 
AST 
Albumin 
Uric acid 
BUN or urea 
Carbon dioxide 
Creatinine 
Creatine kinase and subtypes 
Electrolytes (sodium, 
potassium, chloride, calcium, 
phosphorus) 
GGT 
Glucose 
LDH 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Triglycerides 
Total protein 
Appearance 
pH 
Protein 
Glucose 
Ketone bodies 
Indicators of blood and WBCs 
Specific gravity 
Urobilinogen 
Occult blood 
WBCs 
 
Prolactin 
Coagulation 
Serologya 
COVID-19 
PT 
Activated PTT 
Fibrinogen 
HBV 
HCV 
HIV 
 
Pregnancy test: A serum pregnancy test will be performed on all women of childbearing potential at 
screening and a urine pregnancy test (urine HCG) will be performed at other scheduled visits.  
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; GGT = gamma-glutamyl transpeptidase; Hb = hemoglobin; HBV = Hepatitis B; 
HCG = human chorionic gonadotropin; Hct = hematocrit; HCV = Hepatitis C; HIV = Human Immunodeficiency 
virus; LDH = lactate dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular 
hemoglobin concentration; MCV = mean corpuscular volume; PT = prothrombin time; PTT = partial 
thromboplastin time; RBC = red blood cell; WBC = white blood cell. 
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. 
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 urine volume of 10 mL will be obtained to perform urinalysis and urine drug screen 
at scheduled time points as per Table 2.  
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Blood and urine samples will be analyzed at a central laboratory facility. Urine samples will be 
analyzed by dipstick, and a microscopic analysis will be performed if the results of dipstick 
indicate abnormalities to be further investigated. All laboratory reports must be reviewed, signed, 
and dated by the investigator. A legible copy of all reports must be filed with both the subject’s 
eCRF and medical record (source document) for that visit. Any laboratory test result considered 
by the investigator to be clinically significant should be considered an AE (clinically significant 
AEs include those that require an intervention). Clinically significant abnormal values occurring 
during the study will be followed up with until repeat test results return to normal, stabilize, or 
are no longer clinically significant.  
All the study subjects will be closely monitored for drug-induced liver toxicity, detailed in 
Section 12.7.5, during the study. 
Other Laboratory Assessments: 
 A National Institute on Drug Abuse-5 urine drug screen (cannabinoids or marijuana, 
phencyclidine, amphetamines, opiates, and cocaine) will be performed at screening and at 
Visit 2a (baseline).  
 Alcohol testing is performed using a breathalyzer or blood alcohol test.  
 If a subject leaves the study site, he/she should have a urine drug screen test and test for 
alcohol (breathalyzer or blood alcohol test) upon returning to the study site. 
 
Blood Sampling for Pharmacogenetics 
A blood sample may be collected at baseline (Day -1) for exploratory pharmacogenetic analysis. 
Approximately 9 mL of blood may be collected for subsequent DNA extraction. The samples 
will be stored at a central laboratory facility, where DNA will be extracted and retained. The 
collection, storage, shipping, processing of the blood samples, and the analytical methods to be 
used will be detailed in the laboratory manual.  
The genetic variants to be analyzed may include SNPs and any other variants as deemed 
necessary by the Sponsor.  
The details on the statistical analysis will be provided either in the statistical analysis plan (SAP) 
or the clinical study report. 
12.7 Adverse Events 
 
Adverse Events 
An AE is any symptom, physical sign, syndrome, or disease that either emerges during the study 
or, if present at screening, 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) 
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present at screening will be documented in the medical history eCRF. Changes in these 
conditions and new symptoms, physical signs, syndromes, or diseases should be noted on the AE 
eCRF during the rest of the study. Clinically significant laboratory abnormalities should also be 
recorded as AEs. Surgical procedures that were planned before the subject enrolled in the study 
are not considered AEs if the conditions were known before study inclusion; the medical 
condition should be reported in the subject’s medical history. 
In accordance with the protocol, the investigator and/or study staff will elicit AEs and 
intercurrent illness during and at the end of the study period, and these will be recorded on the 
appropriate page of the eCRF. 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 laboratory tests 
are available. 
Each AE is to be documented on the eCRF with reference to date of onset, duration, frequency, 
severity, relationship to study drug, action taken with study drug, treatment of event, and 
outcome. Furthermore, each AE is to be classified as being serious or nonserious. Changes in 
AEs and resolution dates are to be documented on the eCRF. 
For the purposes of this study, the period of observation for collection of AEs extends from the 
time immediately after the administration of study drug on Day 1 until the End of Study (Visit 10 
for subjects who roll over and Visit 11 for subjects who do not roll over to Study KAR-008 
study) or early termination. Follow up of the AE, even after the date of therapy discontinuation, 
is required if the AE persists until the event resolves or stabilizes at a level acceptable to the 
investigator. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the event should be noted. If the intensity category changes over a number of days, 
then those changes should be recorded separately (with distinct onset dates). 
The severity of AEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events, version 5.0 (Grades 1 through 5). 
Specific guidelines for classifying AEs by intensity and relationship to study drug are given in 
Table 4 and Table 5. 
Table 4. 
Classification of Adverse Events by Intensity 
MILD: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with 
everyday activities. 
MODERATE: An event that is sufficiently discomforting to interfere with normal everyday activities. 
SEVERE: An event that prevents normal everyday activities. 
 
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Table 5. 
Classification of Adverse Events by Relationship to Study Drug 
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 study drug 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 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 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 reexposure to drug (if rechallenge occurs); and (4) it follows a known pattern 
of response to the test drug. 
Abbreviation: AE, adverse event. 
 
 
Adverse Events of Special Interest 
The AEs of special interest will be monitored. AE of special interest is orthostasis. 
AEs of special interest should be recorded as AEs and reported as SAEs when appropriate. 
 
Serious Adverse Events 
A, 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 
(hospitalization for elective treatment of a pre-existing, nonworsening condition is not, 
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however, considered an SAE; the details of such hospitalizations must be recorded on the 
medical history or physical examination page of the eCRF), 
 results in persistent or significant disability/incapacity, and/or 
 is a congenital anomaly/birth defect. 
Other important medical events that may not be immediately life-threatening or result in death or 
hospitalization, based upon appropriate medical judgment, are considered SAEs if they are 
thought to jeopardize the subject and/or require medical or surgical intervention to prevent one 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 first dose of the study drug is administered, during the study, or 
within 1 week of stopping the treatment must be reported to the Catalyst Clinical Research 
Pharmacovigilance group and will be communicated to the Sponsor. Any such SAE due to any 
cause, whether or not related to the study drug, 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 is: 
 
The events must be recorded on the standard AE eCRF. Preliminary reports of SAEs must be 
followed up by detailed descriptions later on, including clear and anonymized photocopies of 
hospital case reports, consultant reports, autopsy reports, and other documents when requested 
and applicable. SAE reports must be made whether or not the investigator considers the event to 
be related to the investigational drug. 
Appropriate remedial measures should be taken to treat the SAE, and the response should be 
recorded. The investigator must report all additional follow-up evaluations to the Catalyst 
Clinical Research Pharmacovigilance group within 24 hours of becoming aware of the additional 
information or as soon as is practicable. All SAEs will be followed up until the investigator and 
Sponsor agree the event is satisfactorily resolved. 
Any SAE that is not resolved by the end of the study or upon discontinuation of the subject’s 
participation in the study is to be followed up until it either resolves, stabilizes, returns to 
baseline values (if a baseline value is available), or is shown to not be attributable to the study 
drug or procedures. 
 Drug-Induced Liver Injury 
The sponsor has incorporated the following for monitoring of the drug induced liver injury: 
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 An increase of serum ALT or AST to >3 × upper limit of normal (ULN) should be 
followed by repeat testing within 48 to 72 hours of all 4 of the usual serum measures 
(ALT, AST, ALP, and total bilirubin) to confirm the abnormalities and to determine if 
they are increasing or decreasing. An inquiry should be made about the symptoms 
(fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, and rash). 
 Close observation should be initiated with ALT or AST >3 × ULN: 
o Repeat liver enzyme and serum bilirubin tests 2 or 3 times weekly. Frequency of 
retesting can decrease to once per week or less if abnormalities stabilize or the trial 
drug has been discontinued, and the subject is asymptomatic. 
o Obtain a more detailed history of symptoms and prior or concurrent diseases. 
o Obtain a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug 
use, and special diets. 
o Rule out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy; and biliary 
tract disease. 
o Obtain a history of exposure to environmental chemical agents. 
o Obtain additional tests to evaluate liver function, as appropriate (eg, international 
normalized ratio, direct bilirubin). 
o Consider gastroenterology or hepatology consultations. 
 Discontinuation of treatment should be considered if: 
o ALT or AST >8 × ULN 
o ALT or AST >5 × ULN for more than 2 weeks 
o ALT or AST >3 × ULN and (total bilirubin >2 × ULN or international normalized 
ratio >1.5) 
o ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or eosinophilia (>5%) 
 Hepatic adjudication of cases should include an evaluation for alternative causes such as 
viral, autoimmune, alcohol, hepatobiliary disorders, nonalcoholic steatohepatitis, 
concomitant medications, etc. 
 Follow up to resolution of elevated liver enzymes. 
 Gamma-glutamyl transpeptidase elevations alone should not prompt drug 
discontinuation. 
 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 
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The investigator will assess whether or not an event is causally related to study treatment. The 
Sponsor (or their designee Syneos Health) will consider the investigator’s assessment and 
determine whether the event meets the criteria for being reportable as a 7-day or 15-day safety 
report. SUSARs that are fatal or life-threatening must be reported to the regulatory authorities 
and the IEC/IRBs (where required) within 7 days after the Sponsor (or their designee) 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 their designee) first has knowledge of them. 
The Sponsor (or their designee) 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: 
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 
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after beginning treatment or increasing the dose. Advise subjects not to drive or operate heavy 
machinery until they know how trospium chloride affects them. If a subject experiences 
anticholinergic CNS effects, dose reduction or drug discontinuation should be considered. 
Anticholinergic Adverse Reactions in Subjects with Moderate Renal Impairment: 
Trospium is substantially excreted by the kidney. The effects of moderate renal impairment on 
systemic exposure are not known but systemic exposure is likely increased. Therefore, 
anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract 
infection, and urinary retention) are expected to be greater in subjects with moderate renal 
impairment. 
 
Pregnancy 
WOCBP must have a negative pregnancy test at screening. After administration of study drug, 
any known cases of pregnancy in female subjects will be reported until the subject completes or 
withdraws from the study. The pregnancy will be reported immediately by faxing/emailing a 
completed pregnancy report to the Sponsor (or designee) within 24 hours of knowledge of the 
event. The pregnancy will not be processed as an SAE; however, the investigator will follow up 
with the subject until completion of the pregnancy and must assess the outcome in the shortest 
possible time but not more than 30 days after completion of the pregnancy. 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 an SAE. 
Upon discontinuation from the study, only those procedures that would not expose the subject to 
undue risk will be performed. The investigator should also be notified of pregnancy occurring 
during the study but confirmed after completion of the study. In the event that a subject is 
subsequently found to be pregnant after inclusion in the study, any pregnancy will be followed to 
term, and the status of mother and child will be reported to the Sponsor after delivery. 
 
Overdose 
The investigator must immediately notify the Sponsor of any occurrence of overdose with study 
drug. Overdose should be managed with symptomatic and supportive care. 
12.8 Cambridge Neuropsychological Test Automated Battery 
The computerized CANTAB provides an objective measure of cognitive function correlated to 
neural networks. A short cognitive battery measuring core cognitive domains of impairment in 
schizophrenia (ie, as per Brief Assessment of Cognition Schizophrenia key cognitive domains) 
will be employed for this study, and it will take approximately 30 minutes to complete. These 
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CANTAB tests meet MATRICS workshop criteria[25]. Subjects will have 1 familiarization 
session with the CANTAB tests during the screening visit and will subsequently complete the 
same test battery on Visits 2a (baseline), Visit 7, and Visit 9. Subjects perform the test on a 
provisioned iPad with data immediately uploaded to the CANTAB Connect cloud-based 
platform (WiFi permitting). 
Cognition testing cannot be done within 8 hours of receiving benzodiazepine or sleep 
medications. 
Table 6 
Cognitive Tests and Cognitive Domains Assessed by the Cambridge 
Neuropsychological Test Automated Battery 
CANTAB Tests 
MATRICS Cognitive Domain 
Outcome Measures 
Rapid visual information 
processing 
Sustained attention/vigilance 
A’ Prime: Signal detection 
measure of how good the subject is 
at detecting the target sequence 
(string of three numbers); 
regardless of response tendency 
Verbal recognition memory 
Verbal memory and new learning 
Free Recall: The total number of 
words that are correctly recalled 
from the presentation phase by the 
subject during the immediate free 
recall stage 
Spatial Span 
Working memory 
Forward Span Length: The 
longest sequence of boxes 
successfully recalled by the subject 
One-touch stockings of Cambridge  
Executive Function 
Planning/Problem Solving 
Problems Solved on First Choice: 
The total number of assessed trials 
where the subject chose the correct 
answer on their first attempt 
Abbreviation: CANTAB = Cambridge Neuropsychological Test Automated Battery 
12.9 Simpson-Angus 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. 
12.10 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[26]. 
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12.11 Abnormal Involuntary Movement Scale 
The AIMS is a rating scale that is used to measure involuntary movements know as tardive 
dyskinesia, which can sometimes develop as a side effect of long-term treatment with 
antipsychotic medications. It is a 12-item scale to assess orofacial, extremity, and truncal 
movements as well as the overall severity, incapacitation, and the subject’s level of awareness of 
the movements. Items are scored from 0 (none) to 4 (severe). A higher score indicates more 
severe dyskinesia. 
12.12 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[27]. 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 “lifetime” version 
will be completed; for all subsequent visits the “Since Last Visit” version of the C-SSRS will be 
administered. 
12.13 Functional Constipation Inquiry 
Constipation refers to bowel movements that are infrequent or hard to pass[28]. The stool is 
often hard and dry[29]. Other symptoms may include abdominal pain, bloating, and feeling as if 
one has not completely passed the bowel movement[30]. The normal frequency of bowel 
movements in adults is between 3 per day and 3 per week[28]. Constipation will be defined per 
the Rome III criteria, as less than 3 bowel movements per week, APPENDIX 2 
(Longswreth,1486,C3)[31]. 
The Bristol Stool Form Scale has been correlated with a change in intestinal function, and had 
been shown to be a useful tool in clinical practice and research[32]. A sample Bristol Stool Form 
Scale is located in APPENDIX 2. 
As a measure of anticholinergic effects, at each visit, subjects will be asked whether they have 
experienced constipation per the ROME III criteria since the last visit, and if yes, whether the 
constipation required intervention. If the subject answers yes, sites are instructed to ask subjects 
to provide event date and ensure event is documented as an AE and treatment is documented as 
concomitant medication. Subjects will not be required to collect and present their stool sample 
nor will clinic staff be required to corroborate the subject assessment. 
Additional attention can be given to other complaints as well including: straining with bowel 
movements, excessive time needed to pass a bowel movement, hard stools and pain with bowel 
movements secondary to straining, abdominal pain, abdominal bloating, and the sensation of 
incomplete bowel evacuation[30, 33]. 
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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. 
12.14 Mini International Neuropsychiatric Interview Version 7.0.2 
The MINI is a short structured diagnostic interview developed for DSM-5 psychiatric disorders. 
With an administration time of approximately 15 minutes, it was designed to meet the need for a 
short but accurate structured psychiatric interview for multicenter clinical studies and 
epidemiology. 
12.15 Change in Prolactin 
Blood samples to assess the change in prolactin levels will be obtained on Visit 2a/Day -1, 
Visit 7/Day 21 ± 2 days, and Visit 10/Day 35 -2 days/Early Termination (ET). At each of these 
visits (except Visit 2a), blood sample must be collected before the morning dose of the study 
drug. 
 
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13 PHARMACOKINETICS 
13.1 Pharmacokinetic Sampling 
 
Blood Samples 
Blood samples for PK analysis of KarXT levels will be collected at the time points indicated in 
the Schedule of Assessments (Table 2). Approximately 6 mL of blood to be collected at each 
scheduled time point. The actual date and time of each blood sample collection will be recorded. 
 Serial blood samples to measure plasma concentrations of xanomeline and trospium will be 
obtained on Visit 5/Day 8 ± 2 days (first dose of fixed titration period) and Visit 8/Day 28 
± 2 days. Blood samples will be obtained at the following time points on these days:  
 Before the morning dose and at 0.5, 1, 2, 4, 8, and 12 hours after the morning dose (Note: 
The 12-hour sample must be collected before administration of the evening dose).  
 The 0.5 and 1 hour samples should be collected within ± 5 minutes of the scheduled time. 
The 2, 4, 8, and 12 hour samples should be collected within ± 10 minutes of their scheduled 
times and before the evening dose. It is very important that the exact time of each PK draw 
and dosing times are recorded in the eCRF and that PK samples are collected within the 
specified times of collection. 
 Should the use of visit windows be necessary, serial PK sampling must accompany the 
actual day of potential dose escalation for Visit 5. 
  For Visit 8, serial PK sampling is meant to capture the PK profile of the subject’s final 
KarXT dose level (125/30 or 100/20) after multiple doses. If visit windows are used for 
Visit 8, the PK sampling should occur at least 7 days after Visit 7 is completed, and there 
must be no changes in dose for at least 7 days leading up to Visit 8. PK sampling must 
accompany the actual day of Visit 8.  
Note: A single PK sample should be drawn before discharge (preferably in the morning) at 
Visit 10/Day 35 -2 days or ET. In addition, one PK sample may be drawn if a 
relevant/significant AE is reported during a scheduled visit or if there is a dose adjustment 
or relevant/significant AE reported during an unscheduled visit (no multiple draws). For an 
ET Visit that is related to an AE, the collection of a PK blood sample is not optional and 
should be drawn before discharge. 
Details of PK blood sample collection, processing, storage, and shipping procedures will be 
provided in a separate laboratory manual. 
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13.2 Pharmacokinetic Analytical Methodology 
Concentrations of trospium and xanomeline will be determined from plasma PK samples using a 
validated analytical method. Details of the method validation and sample analysis will be 
included with the final clinical study report. 
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14 STATISTICAL ANALYSIS 
A 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 compliment to the protocol and supersedes it in case of 
differences. 
The statistical evaluation will be performed using SAS® software version 9.4 or higher 
(SAS Institute, Cary, NC). All data will be listed, and summary tables will be provided. 
Summary statistics will be presented by dose group. For continuous variables, data will be 
summarized with the number of subjects (N), mean and standard deviation, median, minimum, 
and maximum by treatment group. For categorical variables, data will be tabulated with the 
number and proportion of subjects for each category by treatment group. 
14.1 Determination of Sample Size 
Assuming treatment difference of change from baseline in PANSS total score at Week 5 is 
8 points between drug and placebo (standard deviation 16), a sample size of approximately 
172 (86 evaluable subjects per arm) will result in a power of 90.3% for a 2-sided alpha of 0.05 
(P ≤ 0.05). With a dropout rate of 30%, a total of 246 subjects are estimated to be enrolled. 
14.2 Analysis Populations 
Intent-to-Treat Population 
All subjects who are randomized to the study will be included in the intent-to-treat (ITT) 
population. 
Modified ITT Population 
All subjects who are randomized, received at least 1 dose of study drug, have a baseline PANSS 
assessment, and at least 1 post-baseline PANSS assessment will be included in the mITT 
population and will be used in the efficacy analysis. 
Safety Population 
All subjects who received at least 1 dose of study drug will be included in the safety population 
and will be used in the safety analysis. 
PK Population 
All subjects who have an evaluable PK profile will be included in the PK population and will be 
used in the PK analysis. Subjects must have received at least 1 dose of active study drug and 
have at least 1 measurable plasma concentration of study drug.  
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14.3 General Statistical Considerations 
All efficacy analyses will be performed using the mITT population. The statistical analysis of the 
primary and key secondary efficacy variables will account for multiplicity by using a fixed 
sequence testing procedure. The primary endpoint of change from baseline to Week 5 in PANSS 
total score will be evaluated first. The endpoints are set up as a hierarchical list and step down 
through the statistical testing of each endpoint using an alpha of 0.05. Statistical testing of 
change from baseline to Week 5 in PANSS positive score, PANSS negative score, PANSS 
Negative Marder Factor score, CGI-S, and percentage of PANSS responders will be performed 
only if the primary endpoint is significant at the 0.05 alpha level (P ≤ 0.05), and testing would 
continue through a pre-ordered list of key secondary efficacy endpoints. If at any point P > 0.05, 
then formal statistical testing would stop. This will control the overall Type 1 error rate across all 
hypotheses/endpoints being tested. Table 7 outlines the testing procedure.  
Table 7 
Statistical Testing Procedure 
KarXT vs Placebo 
1. Change from baseline in PANSS total score at Week 5 
2. Change from baseline in PANSS positive score at Week 5 
3. Change from baseline in PANSS negative score at Week 5 
4. Change from baseline in PANSS Negative Marder Factor score at Week 5 
5. Change from baseline in CGI-S score at Week 5 
6. Percentage of PANSS responders (a 30% change in PANSS total score) at Week 5  
 
14.4 Efficacy Analysis 
 
Analysis of the Primary Efficacy Endpoint 
The primary efficacy endpoint of the study is the change from baseline in PANSS total score at 
Week 5. The difference between KarXT and placebo at Week 5 will be estimated using a mixed 
model for repeated measures (MMRM). The model will include the change from baseline 
PANSS total scores at Week 2, Week 3, Week 4, and Week 5 as the response. The treatment 
difference at Week 5 will be estimated using contrasts. The MMRM will include the treatment 
group (KarXT or placebo), visit, and the interaction between the treatment group and visit as 
fixed factors. Site, age, sex, and baseline PANSS total score will be used as covariates in the 
model. Low-enrolling sites will be pooled, if necessary, for modeling purposes. The algorithm 
for pooling sites will be specified in the SAP. 
Sensitivity analyses of the primary efficacy endpoint may be performed on an observed case 
basis, using multiple imputation techniques, and classifying treatment dropouts as treatment 
failures. The sensitivity analyses of the primary endpoint will be specified in the SAP. 
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Analysis of Secondary Efficacy Endpoints 
The continuous secondary endpoints (change from baseline to Week 5 in PANSS positive score, 
PANSS negative score, PANSS Negative Marder Factor score, and CGI-S) will be analyzed in 
the same manner as the primary efficacy analysis (ie, using MMRM).  
The categorical secondary endpoint (percentage of PANSS responders at Week 5) will be 
compared between the treatment groups (KarXT and placebo) using the Cochran-Mantel-
Haenszel test.  
The statistical analysis of the primary and key secondary efficacy variables will account for 
multiplicity by using a fixed sequence testing procedure. This testing procedure will control the 
overall Type 1 error rate across all hypotheses/endpoints being tested. 
14.5 Safety Analysis 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities version 
22.1 or higher. The incidence of TEAEs (events with onset dates on or after the start of the study 
drug) will be summarized for each treatment group separately by System Organ Class and 
Preferred Term. All AEs will be listed by subject, along with information regarding onset, 
duration, relationship and severity to study drug, action taken with study drug, treatment of 
event, and outcome. 
Orthostatic vital signs, clinical laboratory data, prolactin levels, ECG parameters, and physical 
examinations will be summarized using descriptive statistics, including observed and change 
from baseline values, as well as numbers of subjects with values outside limits of the normal 
range at each time point by treatment group. Similar descriptive summaries will be provided for 
C-SSRS, SAS, BARS, change in cognition (CANTAB), AIMS, body weight, BMI, and waist 
circumference. 
14.6 Pharmacokinetic Analysis 
 PK results will be listed for all subjects who received active treatment. The profiles or time 
points obtained with protocol deviations affecting PK results will be flagged and may be 
excluded from summaries and analyses. 
 The data will be presented graphically via individual plots and mean plots summarized by 
actual treatment, visit, and time point.  
 PK parameters for xanomeline and trospium will be derived from plasma concentration 
data using noncompartmental methods. Actual time elapsed from dosing will be used to 
estimate all individual PK parameters. The primary PK parameters of interest will include 
Cmax, Tmax, and AUC from 0 to 12 hours (or from 0 to the last measurable concentration). 
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Additional parameters (not limited to the following) such as the elimination half-life, 
clearance, and volume of distribution will be determined if the data permit. 
 The effect of dose on PK and other inferential analyses for exposure-response relationship 
may be performed. The details of the PK analysis will be described in the SAP. The 
noncompartmental analysis will be described as a part of final clinical study report. 
14.7 Interim Analysis  
No interim analysis is planned for this study. 
14.8 Handling of Missing Data 
Several different methods to handle the missing data in the primary efficacy endpoint analysis 
may be used. 
 For the primary efficacy analysis, likelihood-based modeling approach will be used to 
handle incomplete data. For this purpose, an MMRM will be applied. 
 Sensitivity analysis for the primary efficacy endpoint will be conducted using the last 
observation carried forward approach. In this analysis, the missing values will be 
replaced by the previous visit PANSS total score carried forward.  
 Sensitivity analysis for the primary efficacy endpoint will be conducted using the 
Multiple Imputation approach (ie, by replacing each missing value with a set of plausible 
values that represent the uncertainty about the right value to impute). 
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15 STUDY MANAGEMENT 
15.1 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. 
 
Independent Ethics Committee/Institutional Review Board 
Conduct of the study must be approved by an appropriately 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 principal investigator or designee must explain orally 
and in writing the nature of the study, its purpose, procedures, expected duration, alternative 
therapy available, and the benefits and risks involved in study participation. The subject should 
be informed that he/she may withdraw from the study at any time, and the subject will receive all 
information that is required by local regulations and guidelines for ICH. The principal 
investigator 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 caregiver informed consent (Ukraine only) should be obtained before any data pertaining to 
him or her and the subject is collected. 
Subject Registry (for the US only): 
Clinical trial registries, such as clinical trial subject database (CTSdatabase) and Verified 
Clinical Trials (VCT), seek to reduce duplicate enrollment by identifying potential protocol 
violations and duplicate subjects before randomization. At the time of providing the informed 
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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On Day -1 before any 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 reports will detail each protocol violation 
detected and specific washout period dates where applicable. Participants who are identified as 
verification failures by CTS or VCT should not be enrolled without documented approval from 
Karuna or Syneos Health.  
At the last subject contact, CTSdatabase and VCT staff will automatically close out the subject 
(safety follow-up, ET, or completer) based on interactive response system (IXRS). 
Verified Clinical Trials Registry (for Ukraine only): 
At participating sites in Ukraine, VCT will be used to verify participants’ current and past 
research study status in order to mitigate safety concerns associated with duplicate enrollment 
and protocol deviations associated with multiple trial enrollment. Following proper regionally 
compliant informed consent and after obtaining a subject number from IXRS, each participant 
will be checked in the VCT database. Partial identifiers will be utilized. Participants who are 
identified as verification failures by VCT should not be enrolled without documented approval 
from Karuna or Syneos Health. 
15.2 Data Handling 
Any data to be recorded directly on the eCRFs (to be considered as source data) will be 
identified at the start of the study. Data reported on the eCRF that are derived from source 
documents should be consistent with the source documents, or the discrepancies must be 
explained. See also Section 15.3.  
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Clinical data will be entered by site personnel on eCRFs for transmission to the Sponsor. Data on 
eCRFs transmitted via the web-based data system must correspond to and be supported by source 
documentation maintained at the study site, unless the study site makes direct data entry to the 
databases for which no other original or source documentation is maintained. In such cases, the 
study site should document which eCRFs are subject to direct data entry and should have in 
place procedures to obtain and retain copies of the information submitted by direct data entry. 
All study forms and records transmitted to the Sponsor must only include coded identifiers such 
that directly identifying personal information is not transmitted. The primary method of data 
transmittal is via the secure, internet-based electronic data capture (EDC) system maintained by 
Syneos Health. Access to the EDC system is available to only authorized users via the study’s 
secured internet web site, where a user unique assigned username and password are required for 
access. 
Any changes made to data after collection will be made through the use of the EDC system. 
Electronic CRFs will be considered complete when all missing and/or incorrect data have been 
resolved. 
15.3 Source Documents 
Source documents are considered to be all information in original records and certified copies of 
original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. The investigator will provide direct 
access to source documents and/or source data in the facilitation of trial-related monitoring, 
audits, review by IECs/IRBs, and regulatory inspections. 
The investigator/institution should maintain adequate and accurate source documents and trial 
records that include all pertinent observations on each of the site’s trial subjects. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, not obscure the original entry, and be explained if necessary. 
Data recorded on source documents will be transcribed onto eCRFs. Copies of completed eCRFs 
will be provided to the Sponsor and the sites at the end of the study. The completed eCRFs will 
be retained by the investigator. 
15.4 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 
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Health Insurance Portability Accountability Act of 1996 [HIPAA] 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. 
15.5 Monitoring 
The study will be monitored according to the KAR-009 monitoring plan to ensure that it is 
conducted and documented properly according to the protocol, GCP, and all applicable 
regulatory requirements. 
Monitoring visits, on-site and remote (telephone) or a combination and contacts will be made at 
appropriate times during the study. The Principal Investigator will assure him/her and adequate 
site personnel are available throughout the study to collaborate with clinical monitors. Clinical 
monitors must have direct access to source documentation in order to check the completeness, 
clarity, and consistency of the data recorded in the eCRFs for each subject. 
The investigator will make available to the clinical monitor all source documents and medical 
records necessary to review protocol adherence and eCRFs. In addition, the investigator will 
work closely with the clinical monitor and, as needed, provide them appropriate evidence that the 
study is being conducted in accordance with the protocol, applicable regulations, and GCP 
guidelines. 
15.6 Quality Control and Quality Assurance 
The Sponsor or its designee will perform the quality assurance and quality control activities of 
this study; however, responsibility for the accuracy, completeness, security, and reliability of the 
study data presented to the Sponsor lies with the investigator generating the data. 
The Sponsor will arrange audits as part of the implementation of quality assurance to ensure that 
the study is being conducted in compliance with the protocol, standard operating procedures, 
GCP, and all applicable regulatory requirements. Audits will be independent of and separate 
from the routine monitoring and quality control functions. Quality assurance procedures will be 
performed at study sites and during data management to assure that safety and efficacy data are 
adequate and well documented. 
15.7 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 
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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 eCRF/EDC system. Deviations considered 
major will be identified as such before study unblinding during medical monitor periodic 
review. 
Major protocol deviations will be tabulated including the frequency and percentage of subjects 
with each type of deviation by treatment group. 
15.8 Ethical Considerations 
This study will be conducted in accordance with this protocol, the accepted version of the 
Declaration of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, 
Subpart D, of Title 21 of the CFR; and in compliance with GCP guidelines. 
IECs/IRBs will review and approve this protocol and the ICF. All subjects and/or caregivers are 
required to give written informed consent before participation in the study. 
15.9 Financing and Insurance 
Before the study commences, the Sponsor (or its designee) and the investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study. This agreement will 
be documented in a financial agreement that will be signed by the investigator (or the institution 
signatory) and the Sponsor (or its designee). 
The investigator is required to have adequate current insurance to cover claims for negligence 
and/or malpractice (US only). The Sponsor will provide no-exclusion insurance coverage for the 
clinical study as required by national regulations. 
15.10 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 
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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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16 REFERENCES 
 
Patel KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: overview and treatment options. 
P T. 2014;Sep 39(9):638-645. 
 
van Os J, Kapur S. Schizophrenia. Lancet. 2009 Aug 22;374(9690):635-645. 
 
Wu EQ, Shi L, Birnbaum H, Hudson T, Kessler R. Annual prevalence of diagnosed 
schizophrenia in the USA: a claims data analysis approach. Psychol Med. 2006 
Nov;36(11):1535-1540. 
 
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. 
 
Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome 
in schizophrenia: implications for MATRICS. Schizophr Res. 2004;72(1):41-51. 
 
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. 
 
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. 
 
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. 
 
Emsley R, Chiliza B, Asmal L, Harvey BH. The nature of relapse in schizophrenia. BMC 
Psychiatry. 2013;13:50. 
 
Kahn RS, Sommer IE, Murray RM, et al. Schizophrenia. Nat Rev Dis Primers. 
2015;1:15067. 
 
Sellin AK, Shad M, Tamminga, C. Muscarinic agonists for the treatment of cognition in 
schizophrenia. CNS Spectr. 2008 Nov;13(11):985-996. 
 
Wess J, Eglen RM, Gautam D. Muscarinic acetylcholine receptors: mutant mice provide 
new insights for drug development. Nat Rev Drug Discov. 2007 Sep;6:(9):721-733. 
 
Mirza NR, Peters D, Sparks RG. Xanomeline and the antipsychotic potential of muscarinic 
receptor subtype selective agonists. CNS Drug Rev. 2003 Summer;9(2):159-186. 
 
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. 
 
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. 
 
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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Bodick NC, Offen WW, Shannon HE, et al. The selective muscarinic agonist xaqnomeline 
improves both the cognitive deficits and behavioral symptoms of Alzheimer’s disease. 
Alzheimer Dis Assoc Disord. 1997; 11 Suppl 4:S16-22. 
 
Shekhar A, Potter WZ, Lightfoot J, et al. Selective muscarinic receptor agonist xanomeline 
as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008 Aug;165(8):1033-
1039. 
 
Staskin D, Sand P, Zinner N, Dmochowski R, Trospium Study Group. Once daily trospium 
chloride is effective and well tolerated for the treatment of overactive bladder; results from 
a multicenter phase III trial. J Urol. 2007;178(3 Pt 1):978-983; discussion 983-984. 
 
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. 
 
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. 
 
[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. 
 
Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr Bull. 1987;13(2):261-276. 
 
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. 
 
Buchanan RW, Davis M, Goff D, et al. A summary of the FDA-NIMH-MATRICS 
workshop on clinical trial design for neurocognitive drugs for schizophrenia. 
Schizophrenia Bulletin. 2005 Jan;31(1):5-19. 
 
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989 
May;154 (5):672–676. 
 
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s 
pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007 
Jul;164(7):1035-1043. 
 
Chatoor D, Emmanuel A. Constipation and evacuation disorders. Best Pract Res Clin 
Gastroenterol. 2009;23(4):517–530. 
 
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. 
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American Gastroenterological Association, Bharucha AE, Dorn SD, Lembo A, Pressman 
A. American Gastroenterological Association medical position statement on constipation. 
Gastroenterology. 2013 Jan;144(1):211–217. 
 
Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. 
Functional bowel disorders. Gastroenterology. 2006 Apr;130(5):1480–1491. 
 
Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol. 1997 Sep;32(9):920–924. 
 
Locke GR III, Pemberton JH, Phillips SF. American Gastroenterological Association 
Medical Position Statement: guidelines on constipation. Gastroenterology. 2000 
Dec;119(6):1761–1766. 
 
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17 APPENDICES 
 
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APPENDIX 1. 
CONTRACEPTION GUIDELINES 
Women of childbearing potential (WOCBP) and men whose sexual partners are WOCBP must 
use at least 1 highly effective method of contraception during the study and for 7 days after the 
last dose of study treatment.  
A woman is considered to be a WOCBP (fertile) following menarche and until becoming 
postmenopausal, unless she is permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause. A high 
follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.  
A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
Highly effective methods of contraception are those which have a failure rate of <1% (when 
implemented consistently and correctly) and include: 
 combined (containing estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation (administration may be oral, intravaginal, or transdermal) 
 progestogen-only hormonal contraception associated with inhibition of ovulation 
(administration may be oral, injectable, or implantable) 
 intrauterine device 
 intrauterine hormone-releasing system 
 bilateral tubal ligation or occlusion 
 vasectomy (provided that the male has a medical assessment of surgical success) 
 sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of risk in relation to the duration of the clinical trial, in line with the preferred and 
usual lifestyle of the subject) 
All subjects will be strongly advised that they (or the female partners of male subjects) should 
not become pregnant while on study treatment or for 7 days after the last dose. A female subject 
will be advised that she must report immediately to the study site for pregnancy testing and 
appropriate management in the event that she may be pregnant. 
Reference: [HMA] Heads of Medicines Agencies. Clinical Trial Facilitation Group page. 
Recommendations related to contraception and pregnancy testing in clinical trials. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
September 15, 2014. Accessed April 01, 2020. 
 
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APPENDIX 2. 
FUNCTIONAL CONSTIPATION INQUIRY 
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Note to File 
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 1 of 1 
Filing requirement: ISF/TMF/PMF 
Project /Protocol No. 
 / KAR-009 
Date: 
11-Apr-2023 
CC: 
KAR-009 TMF 
 
RE:  KAR-009 Protocol V1.0 -  05-Aug-2020/27-Aug-2020 
 
KAR-009 Protocol V1.0 had two versions, one dated 05-Aug-2020 and one dated 27-Aug-2020. There 
were minor changes made to the 05-Aug-2020 Protocol v1.0 to match the KAR-007 protocol that resulted 
in the 27-Aug-2020 Protocol v1.0 and it was decided by Karuna to keep the same version number.  
 
 
 
 
 
Created by: 
 
 
 
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YYYY) 
 
 
Electronically signed by:
son: I am the author
Date: Apr 12, 2023 09:29 MDT
Apr 12, 2023
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Page 1 of 92 
1 
FINAL CLINICAL STUDY PROTOCOL 
 
Karuna Therapeutics 
Protocol Title: A Phase 3, Randomized, Double-blind, Parallel-group, Placebo-controlled, 
Multicenter Study to Evaluate the Efficacy and Safety of KarXT in Acutely Psychotic 
Hospitalized Adults with DSM-5 Schizophrenia 
Protocol Number: KAR-009 
 
IND Number: 
127471 
EudraCT Number: 
Not applicable 
Name of Investigational Product: 
KarXT 
Phase of Development: 
Phase 3 
Indication: 
Schizophrenia 
Sponsor: 
Karuna Therapeutics 
33 Arch Street 
Suite 3110 
Boston, MA 02110 
Tel: 
 
Email: 
 
Protocol Version:  
1.0 
Protocol Date: 
27 August 2020 
 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to Karuna Therapeutics (previously known 
as Karuna Pharmaceuticals). Any unauthorized copying or use of this document is prohibited. 
 
 
 
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Kar u na T her a p e utics 
K A R- 0 0 9 
Kar X T 
Fi nal 1. 0 
T his d o c u me nt is c o nfi de ntial. 
P a ge 2  of 9 2  
P R O T O C O L A P P R O V A L SI G N A T U R E S 
Pr ot oc ol Title: 
A P hase 3, Ra n d o mize d, D o u ble- bli n d, Parallel- gr o u p, 
Place b o- c o ntr olle d, M ultice nter St u d y t o E v al uate t h e Efficac y a n d 
Safet y of K ar X T i n Ac ut el y Ps yc h oti c H os pitalize d A d ults wit h 
D S M- 5 Sc hiz o p hre nia 
Pr ot oc ol N u m ber: 
K A R- 0 0 9 
T his st u d y will be c o n d u cte d i n c o m plia nce wit h t he cli nical st u d y pr ot oc ol (a n d 
a me n d me nts), I nter nati o n al C o u ncil f or H ar m o nisati o n (I C H) g ui deli nes f or c urre nt G o o d 
Cli nical Practi ce ( G C P) a n d a p plica ble r e g ulat or y r e q uire me nts . 
S p o ns or Si g n at or y 
 
 
Kar u na T h era pe utics 
 
Si g nat ure 
 
Date ( D D- M m m- Y Y Y Y) 
 
 
Kar u na T h era pe utics 
 
Si g nat ure 
 
Date ( D D- M m m- Y Y Y
C o ntr act R ese a rc h Or g a niz ati o n 
Si g n at or y 
 
 
 
S y ne os H ealt h 
 
 
Si g nat ure 
 
Date ( D D- M m m- Y Y Y Y) 
Bi ost atistici a n 
 
 
Ka va na g h Statistical C o ns ulti n g, L L C 
 
 
Si g nat ure 
 
Date ( D D- M m m- Y Y Y Y) 
A p p r o v e d
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Page 3 of 92 
INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
A Phase 3, Randomized, Double-blind, Parallel-group, Placebo-controlled, 
Multicenter Study to Evaluate the Efficacy and Safety of KarXT in Acutely 
Psychotic Hospitalized Adults with DSM-5 Schizophrenia 
Protocol Number: 
KAR-009 
• Confidentiality and Current Good Clinical Practice (GCP)/E6(R2) Compliance Statement 
• I, the undersigned, have reviewed this protocol (and amendments, including appendices, 
and I will conduct the study as described in compliance with this protocol (and 
amendments) and relevant International Council for Harmonisation (ICH) guidelines 
including GCP and applicable regulatory requirements. 
• I am thoroughly familiar with the appropriate use of the study drug, 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 
IEC/IRB, I will not modify this protocol without obtaining prior approval of Karuna 
Therapeutics and of the IEC/IRB. I will submit the protocol amendments and/or any 
informed consent form modifications to Karuna Therapeutics and the IEC/IRB, and 
approval will be obtained before any amendments are implemented. 
• I ensure that all persons or party assisting me with the study are adequately qualified and 
informed about the Karuna Therapeutics study drug 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. 
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<Name> 
 
<Title> 
Investigator Signature 
 
 
 
Date (DD-Mmm-YYYY) 
 
 
Institution 
 
 
 
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2 
SYNOPSIS 
Title of Study: 
A Phase 3, Randomized, Double-blind, Parallel-group, Placebo-controlled, 
Multicenter Study to Evaluate the Efficacy and Safety of KarXT in Acutely 
Psychotic Hospitalized Adults with DSM-5 Schizophrenia 
Protocol Number: 
KAR-009 
Study Sites: 
Approximately 10 sites in the United States and 10 sites in Ukraine 
Phase of Development: 
Phase 3 
Objectives: 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of KarXT (a 
fixed combination of xanomeline and trospium chloride [xanomeline 
125 mg/trospium 30 mg] twice daily [BID]) versus placebo in reducing 
Positive and Negative Syndrome Scale (PANSS) total scores in adult 
inpatients with a Diagnostic and Statistical Manual‒Fifth Edition (DSM-5) 
diagnosis of schizophrenia. 
Secondary Objectives: 
The secondary objectives of the study are: 
• 
To evaluate the reduction of PANSS positive score in subjects 
treated with KarXT versus placebo 
• 
To evaluate the improvement in Clinical Global Impression-Severity 
(CGI-S) results in subjects treated with KarXT versus placebo 
• 
To evaluate the reduction of PANSS negative score in subjects 
treated with KarXT versus placebo 
• 
To evaluate the reduction of PANSS Marder Factor negative 
symptoms score in subjects treated with KarXT versus placebo 
• 
To evaluate the safety and tolerability of KarXT 
• 
To assess the pharmacokinetics (PK) of xanomeline and trospium 
after administration of KarXT in adults who are acutely psychotic 
with a DSM-5 diagnosis of schizophrenia 
Exploratory Objective: 
The exploratory objective of the study is to evaluate the single nucleotide 
polymorphisms (SNPs) regarding schizophrenia subtypes and SNPs related to 
drug metabolism. 
Study Endpoints: 
Primary Endpoint:  
• 
Change from baseline in PANSS total score at Week 5 
Secondary Endpoints:  
Efficacy Endpoints 
• 
Change from baseline in PANSS positive score at Week 5 
• 
Change from baseline in PANSS negative score at Week 5 
• 
Change from baseline in PANSS Negative Marder Factor score at 
Week 5  
• 
Change from baseline in CGI-S score at Week 5 
• 
Percentage of PANSS responders (a 30% change in PANSS total 
score) at Week 5  
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Safety Endpoints 
• 
Spontaneously reported adverse events (AEs) 
• 
Spontaneously reported cholinergic symptoms 
• 
Simpson-Angus Scale (SAS) 
• 
Barnes Akathisia Rating Scale (BARS) 
• 
Abnormal Involuntary Movement Scale (AIMS) 
• 
Body weight, body mass index, waist circumference 
• 
Orthostatic vital signs (supine and standing after 2 minutes): blood 
pressure (systolic and diastolic) and heart rate 
• 
Clinical laboratory evaluations: hematology, clinical chemistry, 
coagulation, urinalysis, and drug screen 
• 
12-lead electrocardiogram (ECG) 
• 
Physical examination 
• 
Suicidal ideation scale with the use of Columbia Suicide Severity 
Rating Scale (C-SSRS) 
Pharmacokinetic Endpoints 
• 
Area under the plasma concentration-time curve (AUC) 
• 
Maximum observed plasma concentration (Cmax)  
• 
Time to maximum observed plasma concentration (Tmax) 
Exploratory Endpoint 
• 
Change in cognition measuring core domains of impairment in 
schizophrenia using the Cambridge Neuropsychological Test 
Automated Battery (CANTAB) 
• 
Change from baseline in prolactin levels at Week 5 
• 
Prediction of response based on SNP schizophrenia subtypes, and 
SNPs related to KarXT metabolism for both efficacy and tolerability 
 
Study Design: 
This is a Phase 3 randomized, double-blind, parallel-group, 
placebo-controlled, multicenter inpatient study in adults who are 
acutely psychotic with a DSM-5 diagnosis of schizophrenia. Subjects 
will be randomized (1:1 ratio) to receive either KarXT or placebo for a 
treatment period of 5 weeks. Subjects will start on a lead-in dose of 
KarXT 50/20 (xanomeline 50 mg/trospium 20 mg) BID for the first 
2 days (Days 1 and 2) followed by KarXT 100/20 (xanomeline 
100 mg/trospium 20 mg) BID for the remainder of Week 1 (Days 3 to 
7). On Day 8, dosing will be titrated upwards to KarXT 125/30 BID 
unless the subject is continuing to experience AEs from the previous 
dose increase of KarXT 100/20 BID. All subjects who were increased 
to KarXT 125/30 BID, depending on clinical response and tolerability, 
will have the option to return to KarXT 100/20 BID for the remainder 
of the treatment period. Dosing must not change after Visit 7 (Day 21) 
of the study and may be decreased for tolerability reasons no more than 
once during the study. In addition, dose escalation to KarXT 125/30 
BID may not occur outside of the permitted visit window for 
Visit 5/Day 8. 
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A safety follow-up visit (Visit 11/ Day 42 + 5 days) will be performed 
for all those subjects who do not rollover in to the long-term open-label 
study KAR-008.  
The study is designed to test the hypothesis that treatment with KarXT 
in adult schizophrenia subjects with acute psychosis will result in 
significantly greater reduction (ie, improvement) in the primary and 
secondary endpoints at Week 5 from baseline compared with placebo. 
The endpoints are set up as a hierarchical list and step down through 
the statistical testing of each endpoint using an alpha of 0.05. Statistical 
testing of change from baseline to Week 5 in PANSS positive score, 
PANSS negative score, PANSS Negative Marder Factor score, CGI-S, 
and percentage of PANSS responders will be performed only if the 
primary endpoint is significant at the 0.05 alpha level (P ≤ 0.05), and 
testing would continue through a preordered list of key secondary 
efficacy endpoints. If at any point P > 0.05, then formal statistical 
testing would stop. This will control the overall Type 1 error rate across 
all hypotheses/endpoints being tested. 
Selection of Subjects: 
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 must be provided before 
any study assessments are performed. 
b. Subject must be fluent (oral and written) in English (applicable to 
the US) or local language (Ukrainian or Russian applicable to 
Ukraine) 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 for 
Schizophrenia and Psychotic Disorder Studies (MINI) version 
7.0.2. 
4. Subject is experiencing an acute exacerbation or relapse of 
psychotic symptoms, with onset less than 2 months before 
screening. 
a. 
The subject requires hospitalization for this acute exacerbation or 
relapse of psychotic symptoms. 
b. If already an inpatient at screening, has been hospitalized 
for less than 2 weeks for the current exacerbation at the time 
of screening. 
5. Positive and Negative Syndrome Scale total score between 80 and 120, 
inclusive. 
a. 
Score of ≥4 (moderate or greater) for ≥2 of the following Positive 
Scale (P) items: 
i. Item 1 (P1; delusions) 
ii. Item 2 (P2; conceptual disorganization) 
iii. Item 3 (P3; hallucinatory behavior) 
iv. Item 6 (P6; suspiciousness/persecution) 
6. Subjects with no change (improvement) in PANSS total score between 
screening and baseline (Day -1) of more than 20%. 
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7. Subject has a CGI-S score of ≥4 at screening and baseline (Day -1) 
visits. 
8. Subject will have been off lithium therapy for at least 2 weeks 
before baseline and free of all oral antipsychotic medications for at 
least 5 half-lives or 1 week, whichever is longer, before baseline 
(Day -1). 
9. Subjects taking a long-acting injectable antipsychotic could not 
have received a dose of medication for at least 12 weeks (24 weeks 
for INVEGA TRINZA®) before baseline visit (Day -1). 
10. Subject is willing and able to be confined to an inpatient setting for 
the study duration, follow instructions, and comply with the 
protocol requirements. 
11. Body mass index must be ≥18 and ≤40 kg/m2. 
12. Subject resides in a stable living situation and is anticipated to 
return to that same stable living situation after discharge, in the 
opinion of the investigator. 
13. Subject has an identified reliable informant/caregiver. An 
informant/caregiver is needed at the screening and baseline 
visits as well as at the end of the study for relevant assessments 
(site staff may act as informant while the subject is an inpatient). 
An informant/caregiver may not be necessary if the subject has 
been the patient of the investigator for ≥1 year. 
14. Women of childbearing potential (WOCBP), or men whose 
sexual partners are WOCBP, must be able and willing to use at 
least 1 highly effective method of contraception during the study 
and for 7 days after the last dose of study drug. Sperm donation 
is not allowed for 90 days after the final dose of study drug. A 
female subject is considered to be a WOCBP after menarche and 
until she is in a postmenopausal state for 12 months or otherwise 
permanently sterile (for which acceptable methods include 
hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy). For the definition and list of highly effective 
methods of contraception, see APPENDIX 1. 
Exclusion Criteria: 
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, 
moderate to severe alcohol use disorder (within the past 
12 months), substance (other than nicotine or caffeine) use disorder 
within the past 12 months (use of cannabis at screening will result 
in screen failure with the allowance to rescreen at a later date if no 
moderate to severe substance use disorder is determined), major 
depressive disorder, bipolar I or II disorder, schizoaffective 
disorder, obsessive compulsive disorder, and post-traumatic stress 
disorder. Symptoms of mild mood dysphoria or anxiety are allowed 
as long as these symptoms are not the primary focus of treatment. 
a. 
A screening subject with mild substance abuse disorder within 
the 12 months before screening must be discussed and agreed 
upon with the medical monitor before he/she can be allowed 
into the study. 
2. History or presence of clinically significant cardiovascular, 
pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, 
immunologic, dermatologic, neurologic, or oncologic disease or 
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any other condition that, in the opinion of the investigator, would 
jeopardize the safety of the subject or the validity of the study 
results. 
3. Subjects with HIV, cirrhosis, biliary duct abnormalities, 
hepatobiliary carcinoma, and/or active hepatic viral infections 
based on either medical history or liver function test results. 
4. History or high risk of urinary retention, gastric retention, or 
narrow-angle glaucoma. 
5. History of irritable bowel syndrome (with or without 
constipation) or serious constipation requiring treatment 
within the last 6 months. 
6. 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. 
7. Clinically significant abnormal finding on the physical 
examination, medical history, ECG, or clinical laboratory 
results at screening. 
8. Subjects cannot currently (within 5 half-lives or 1 week, 
whichever is longer, before baseline [Day -1]) be receiving oral 
antipsychotic medications; monoamine oxidase inhibitors; 
anticonvulsants (eg, lamotrigine, Depakote); tricyclic 
antidepressants (eg, imipramine, desipramine); selective serotonin 
reuptake inhibitors; or any other psychoactive medications except 
for as needed anxiolytics (eg, lorazepam, chloral hydrate). 
9. Pregnant, lactating, or less than 3 months postpartum. 
10. If, in the opinion of the investigator (and/or Sponsor), subject is 
unsuitable for enrollment in the study or subject has any finding 
that, in the view of the investigator (and/or Sponsor), may 
compromise the safety of the subject or affect his/her ability to 
adhere to the protocol visit schedule or fulfill visit requirements. 
11. Positive test for coronavirus (COVID-19) within 2 weeks before 
screening.  
12. Subjects with extreme concerns relating to global pandemics, 
such as COVID-19, that preclude study participation. 
13. Subject has had psychiatric hospitalization(s) for more than 
30 days (cumulative) during the 90 days before screening. 
14. Subject has a history of treatment resistance to schizophrenia 
medications defined as failure to respond to 2 adequate courses 
of pharmacotherapy (a minimum of 4 weeks at an adequate dose 
per the label) or required clozapine within the last 12 months. 
15. Subjects with prior exposure to KarXT. 
16. Subjects who experienced any adverse effects due to xanomeline 
or trospium. 
17. Participation in another clinical study in which the subject 
received an experimental or investigational drug agent within 
3 months before screening. 
18. Risk of violent or destructive behavior. 
19. Current involuntary hospitalization or incarceration. 
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Planned Sample Size: 
A total of approximately 246 adult subjects (aged 18 to 65 years, inclusive) 
are planned to be randomized in a 1:1 ratio to 2 treatment groups, either 
KarXT or placebo. 
Investigational Therapy: 
1. Fixed dose KarXT 50/20 BID (50 mg xanomeline/20 mg trospium), 
oral (Days 1 to 2) 
2. Fixed dose KarXT 100/20 BID (100 mg xanomeline/20 mg 
trospium), oral (Days 3 to 7) 
3. Fixed dose KarXT 125/30 BID (125 mg xanomeline/30 mg 
trospium), oral (Days 8 to 35, if tolerated) 
Reference Therapy: 
Matching placebo BID oral 
Treatment Duration: 
Total study duration is up to 8 weeks, including a 7-day screening phase (up 
to a 7-day extension of the screening phase is allowed, if necessary), a 
5-week treatment period, and a 7-day follow-up period (only for subjects who 
do not rollover to KAR-008 study). Subjects completing this study will have 
the option of rolling over into a long-term open-label study (KAR-008) in 
which every subject will receive KarXT. 
Efficacy Assessments: 
PANSS total score, PANSS positive score, PANSS negative score, PANSS 
Negative Marder Factor score, and CGI-S score will be evaluated at 
scheduled visits. 
Safety Assessments: 
Spontaneous AEs, cholinergic symptoms, SAS, BARS, AIMS, body weight, 
body mass index, waist circumference, orthostatic vital signs, ECG, clinical 
laboratory assessments (hematology, clinical chemistry, coagulation, 
urinalysis, and drug screen), prolactin levels, physical examination, and 
C-SSRS will be evaluated throughout the study as scheduled. 
Pharmacokinetic Assessments: 
AUC, Cmax, and Tmax will be estimated at scheduled visits. 
Statistical Methods and 
Planned Analyses: 
Intent-to-treat (ITT) population: All subjects who are randomized to the study 
will be included in the ITT population. 
Modified ITT (mITT) population: All subjects who are randomized, received 
at least 1 dose of study drug, have a baseline PANSS assessment, and at least 
1 postbaseline PANSS assessment will be included in the mITT population 
and will be used in the efficacy analysis. 
Safety population: All subjects who received at least 1 dose of study drug 
will be included in the safety population and will be used in the safety 
analysis. 
PK population: All subjects who have an evaluable PK profile will be 
included in the PK population and will be used in the PK analysis. Subjects 
must have received at least 1 dose of active study drug and have at least 
1 measurable plasma concentration of study drug.  
The primary efficacy endpoint of the study is the change from baseline in 
PANSS total score at Week 5. The difference between KarXT and placebo 
will be estimated using a mixed model for repeated measures. The key 
secondary endpoints are the change from baseline to Week 5 in PANSS 
positive score, PANSS negative score, PANSS Negative Marder Factor 
score, CGI-S score, and percentage of PANSS responders at Week 5. The 
statistical analysis of the primary and key secondary efficacy variables will 
account for multiplicity by using a fixed sequence testing procedure. This 
testing procedure will control the overall Type 1 error rate across all 
hypotheses/endpoints being tested. 
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Assuming the treatment difference in the change from baseline in PANSS 
total score at Week 5 is 8 points between KarXT and placebo (standard 
deviation 16), a sample size of approximately 172 subjects (86 evaluable 
subjects per arm) will result in a power of 90.3% for a 2-sided alpha of 0.05 
(P ≤ 0.05). With an anticipated dropout rate of 30%, a total of 246 subjects 
are estimated to be enrolled.  
 
 
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3 
TABLE OF CONTENTS 
1 
FINAL CLINICAL STUDY PROTOCOL .......................................................................1 
2 
SYNOPSIS ........................................................................................................................5 
3 
TABLE OF CONTENTS ................................................................................................12 
3.1 
List of In-text Tables ..................................................................................................16 
3.2 
List of In-text Figures .................................................................................................17 
4 
LIST OF ABBREVIATIONS .........................................................................................18 
5 
INTRODUCTION ...........................................................................................................20 
5.1 
Background on Schizophrenia ....................................................................................20 
5.2 
Background on KarXT (Xanomeline Tartrate and Trospium Chloride) ....................20 
 
Nonclinical Studies ............................................................................................22 
 
Completed Clinical Studies ................................................................................25 
5.3 
Clinical Risks/Benefits of KarXT and Study Rationale .............................................33 
6 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................35 
6.1 
Study Objectives .........................................................................................................35 
 
Primary Objective ..............................................................................................35 
 
Secondary Objectives .........................................................................................35 
 
Exploratory Objective ........................................................................................35 
6.2 
Study Endpoints..........................................................................................................35 
 
Primary Endpoint ...............................................................................................35 
 
Secondary Endpoints ..........................................................................................35 
6.2.2.1 
Efficacy Endpoints .......................................................................................35 
6.2.2.2 
Safety Endpoints ..........................................................................................36 
 
Pharmacokinetic Endpoints ................................................................................36 
 
Exploratory Endpoints .......................................................................................36 
7 
INVESTIGATIONAL PLAN .........................................................................................37 
7.1 
Description of Overall Study Design and Plan ...........................................................37 
7.2 
Discussion of Study Design........................................................................................40 
7.3 
End of Study ...............................................................................................................40 
7.4 
Independent Safety Monitoring Committee ...............................................................40 
8 
SELECTION OF STUDY POPULATION .....................................................................41 
8.1 
Inclusion Criteria ........................................................................................................41 
8.2 
Exclusion Criteria .......................................................................................................42 
8.3 
Rescreening ................................................................................................................44 
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8.4 
Study Withdrawal, Removal, and Replacement of Subjects ......................................44 
 
Pregnancy ...........................................................................................................45 
8.5 
Completion of the Study or Lost to Follow-up ..........................................................46 
8.6 
Study Termination ......................................................................................................46 
9 
TREATMENTS ...............................................................................................................47 
9.1 
Details of Study Treatments .......................................................................................47 
 
Identity of Study Treatments ..............................................................................47 
 
Packaging and Labelling ....................................................................................47 
 
Study Drug Storage ............................................................................................48 
 
Study Drug Retention .........................................................................................48 
9.2 
Dose Schedule ............................................................................................................48 
 
Visit 2b/Day 1 Randomization and Dosing .......................................................48 
 
Visit 3/Day 3 and/or Visits Occurring on Weekends/Holidays .........................49 
 
Visit 5/Day 8 Dosing and PK Considerations and Visit 8/Day 28 PK 
Considerations ....................................................................................................49 
 
Visit 10/Day 35 Dosing ......................................................................................49 
9.3 
Measures to Minimize Bias: Study Treatment Assignment .......................................49 
 
Method of Study Treatment Assignment ...........................................................49 
 
Blinding ..............................................................................................................50 
9.4 
Dose Modification ......................................................................................................51 
9.5 
Treatment Accountability and Compliance ................................................................51 
9.6 
Prior and Concomitant Therapy .................................................................................51 
 
Prior and Concomitant Medications ..................................................................51 
 
Concomitant Medications for Anxiety and/or Sleep aid ....................................52 
10 
STUDY PROCEDURES .................................................................................................53 
10.1  Informed Consent .......................................................................................................59 
10.2  Study Procedures ........................................................................................................59 
11 
EFFICACY ASSESSMENTS .........................................................................................60 
11.1  Positive and Negative Syndrome Scale ......................................................................60 
11.2  Clinical Global Impression‒Severity .........................................................................60 
12 
SAFETY ASSESSMENTS .............................................................................................61 
12.1  Demographics, and Medical and Psychiatric History ................................................61 
12.2  Vital Signs ..................................................................................................................61 
12.3  Physical Examination .................................................................................................62 
12.4  Weight, Height, Body Mass Index, Waist Circumference .........................................62 
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12.5  Electrocardiograms .....................................................................................................62 
12.6  Laboratory Assessments .............................................................................................62 
 
Blood Sampling for Pharmacogenetics ..............................................................64 
12.7  Adverse Events ...........................................................................................................64 
 
Adverse Events ..................................................................................................64 
 
Adverse Events of Special Interest ....................................................................66 
 
Serious Adverse Events .....................................................................................66 
 
Serious Adverse Event Reporting ......................................................................67 
 
Drug-Induced Liver Injury .................................................................................67 
 
Suspected Unexpected Serious Adverse Reactions ...........................................68 
 
Pregnancy ...........................................................................................................70 
 
Overdose ............................................................................................................70 
12.8  Cambridge Neuropsychological Test Automated Battery ..........................................70 
12.9  Simpson-Angus Scale .................................................................................................71 
12.10  Barnes Akathisia Rating Scale ...................................................................................71 
12.11  Abnormal Involuntary Movement Scale ....................................................................72 
12.12  Columbia-Suicide Severity Rating Scale ...................................................................72 
12.13  Functional Constipation Inquiry .................................................................................72 
12.14  Mini International Neuropsychiatric Interview Version 7.0.2 ...................................73 
12.15  Change in Prolactin ....................................................................................................73 
13 
PHARMACOKINETICS ................................................................................................74 
13.1  Pharmacokinetic Sampling .........................................................................................74 
 
Blood Samples ...................................................................................................74 
13.2  Pharmacokinetic Analytical Methodology .................................................................75 
14 
STATISTICAL ANALYSIS ...........................................................................................76 
14.1  Determination of Sample Size ....................................................................................76 
14.2  Analysis Populations ..................................................................................................76 
14.3  General Statistical Considerations ..............................................................................77 
14.4  Efficacy Analysis........................................................................................................77 
 
Analysis of the Primary Efficacy Endpoint .......................................................77 
 
Analysis of Secondary Efficacy Endpoints ........................................................78 
14.5  Safety Analysis ...........................................................................................................78 
14.6  Pharmacokinetic Analysis ..........................................................................................78 
14.7  Interim Analysis .........................................................................................................79 
14.8  Handling of Missing Data ..........................................................................................79 
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15 
STUDY MANAGEMENT ..............................................................................................80 
15.1  Approval and Consent ................................................................................................80 
 
Regulatory Guidelines ........................................................................................80 
 
Independent Ethics Committee/Institutional Review Board ..............................80 
 
Informed Consent ...............................................................................................80 
15.2  Data Handling .............................................................................................................81 
15.3  Source Documents ......................................................................................................82 
15.4  Record Retention ........................................................................................................82 
15.5  Monitoring ..................................................................................................................83 
15.6  Quality Control and Quality Assurance .....................................................................83 
15.7  Protocol Amendment and Protocol Deviation ............................................................83 
 
Protocol Amendment .........................................................................................83 
 
Protocol Deviations ............................................................................................84 
15.8  Ethical Considerations ................................................................................................84 
15.9  Financing and Insurance .............................................................................................84 
15.10  Publication Policy/Disclosure of Data........................................................................84 
16 
REFERENCES ................................................................................................................86 
17 
APPENDICES .................................................................................................................89 
APPENDIX 1.  CONTRACEPTION GUIDELINES ............................................................90 
APPENDIX 2.  FUNCTIONAL CONSTIPATION INQUIRY ............................................91 
 
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3.1 
List of In-text Tables 
Table 1 
Study Design ...........................................................................................................39 
Table 2.  Schedule of Assessments ........................................................................................54 
Table 3.  Laboratory Assessments..........................................................................................63 
Table 4.  Classification of Adverse Events by Intensity ........................................................65 
Table 5.  Classification of Adverse Events by Relationship to Study Drug ..........................66 
Table 6 
Cognitive Tests and Cognitive Domains Assessed by the Cambridge 
Neuropsychological Test Automated Battery .........................................................71 
Table 7 
Statistical Testing Procedure ...................................................................................77 
 
 
 
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3.2 
List of In-text Figures 
Figure 1  Change from Baseline in PANSS Total Scores (KAR-004) ...................................29 
Figure 2  Change from Baseline in PANSS-Positive Scores (KAR-004) ..............................30 
Figure 3  Change from Baseline in CGI-S (KAR-004) ..........................................................31 
Figure 4  Change from Baseline in PANSS-Negative Scores (KAR-004) ............................32 
 
 
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4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AD 
Alzheimer’s disease 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
APD 
antipsychotic drug 
AUC 
area under the plasma concentration-time curve 
AUC0-12 
area under the plasma concentration-time curve from 0 to 12 hours 
AUC0-24 
area under the plasma concentration-time curve from 0 to 24 hours 
BARS 
Barnes Akathisia Rating Scale 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression‒Severity 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTS database 
Clinical Trial Subject database 
DSM-5 
Diagnostic and Statistical Manual‒Fifth Edition 
EDC 
electronic data capture 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EPS 
extrapyramidal symptoms 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability Accountability Act 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
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Abbreviation 
Definition 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
MCC 
microcrystalline cellulose 
MINI 
Mini International Neuropsychiatric Interview 
mITT 
modified intent-to-treat 
MMRM 
mixed model for repeated measures 
PANSS 
Positive and Negative Syndrome Scale 
PK 
Pharmacokinetic(s) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson Angus Scale 
SNP 
single nucleotide polymorphism 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TID 
thrice daily 
TK 
toxicokinetic 
Tmax 
Time to maximum observed plasma concentration 
ULN 
upper limit of normal  
US 
United States 
VAS 
visual analog scale 
VCT 
Verified Clinical Trials Registry 
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 US is 5.1 per 1000 lives[3]. It is found 
equally in males and females, with males usually having an earlier onset of symptoms[4].  
The mainstay for treating schizophrenia is antipsychotic drugs (APDs)[5]. All currently available 
antipsychotics act through blockage of all or subsets of dopamine receptors in the brain. First-
generation APDs include chlorpromazine and haloperidol; treatment with these agents is marked 
by high rates of parkinsonian extrapyramidal symptoms (EPS) and tardive dyskinesia, and they 
consequently have limited use today. The second-generation agents that include risperidone, 
olanzapine, quetiapine, lurasidone, aripiprazole, and lumateperone tend to have lower levels of 
EPS or tardive dyskinesia and are currently the most commonly prescribed APD class. However, 
the second-generation drugs also have problematic side effects that include significant weight 
gain, metabolic disturbances, sedation, and akathisia[6, 7, 8]. These side effects contribute to 
poor medication adherence resulting in frequent relapses and hospitalizations[9, 10]. Thus there 
is a need for medications for schizophrenia which act through alternative mechanisms. 
Central muscarinic receptors have been hypothesized to be therapeutic treatments for 
schizophrenia based on several converging lines of evidence including both animal and human 
studies[11,12]. There are 5 subtypes of muscarinic receptors (M1-M5). The therapeutic effect of 
central muscarinic receptor agonism is thought to be due to agonism of M1 and M4 receptors in 
the central nervous system (CNS)[13]. However, compounds that agonize M1 and M4 receptors 
are often not specific enough not to also agonize M2 and M3 receptors outside of the CNS due to 
the highly conserved allosteric binding sites that the receptors share, leading to adverse events 
(AEs) related to activation of these peripheral receptors. Thus, any potential benefit of 
muscarinic agonists in schizophrenia (or other indications such as Alzheimer’s disease [AD]) has 
been outweighed by the occurrence of AEs associated with peripheral cholinergic side effects 
(nausea, vomiting, diarrhea, sweating, and excess salivation).  
5.2 
Background on KarXT (Xanomeline Tartrate and Trospium Chloride) 
Xanomeline tartrate is a muscarinic-cholinergic receptor agonist. It has agonistic activity at all 
5 muscarinic receptors but preferentially stimulates M1 and M4 receptors and binding to M1 and 
M4 receptors in the CNS is thought to be responsible for the drug’s potential therapeutic effects 
(Roth, unpublished data). A recent study reports that xanomeline is a very potent M4 muscarinic 
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agonist in vivo, measured by various second messenger assays[14]. Xanomeline also enters the 
brain rapidly achieving a brain to plasma ratio of greater than 10 making it an attractive CNS 
drug candidate[15]. 
Xanomeline does not have any direct binding activity on dopaminergic receptors, suggesting that 
its mechanism of action is unrelated to direct dopamine involvement. 
Previous double-blind, placebo controlled clinical trials have provided strong evidence that 
xanomeline has clinically relevant antipsychotic efficacy. In a multicenter outpatient trial in AD 
(N = 343), 3 doses of xanomeline (up to 225 mg/day) and placebo were assessed for 
26 weeks[16, 17]. Significant dose-dependent improvements in psychotic symptoms relative to 
placebo were observed. Moreover, psychotic symptoms resolved quite rapidly in subjects who 
were symptomatic at baseline and a dose dependent reduction in the emergence of psychotic 
symptoms versus placebo was also observed. In a completer analysis, cognitive improvement 
was also found suggesting longer treatment intervals may be necessary for cognitive 
enhancement[16, 17]. In a subsequent small (N = 20) double-blind, placebo-controlled inpatient 
trial in treatment resistant subjects with schizophrenia, xanomeline (225 mg/day) demonstrated 
robust and relatively rapid improvement in psychosis compared to placebo. In addition, 
improvement in both negative symptoms and cognitive impairment was observed[18]. 
In both the AD and schizophrenia trials, as well as in previous healthy volunteer studies, dose 
dependent “cholinergic” AEs were also reported, namely vomiting, nausea, diarrhea, sweating 
and hypersalivation. These side effects were frequent and, at the higher doses of xanomeline led 
to significant rates of discontinuation in the AD studies. This “pro-cholinergic” AE profile 
curtailed further development of xanomeline as a single agent.  
It is believed that the procholinergic AEs associated with xanomeline are mediated by 
xanomeline’s stimulation of peripheral rather than central muscarinic receptors, which would 
make these AEs theoretically amenable to counteracting peripheral anticholinergic treatment. 
Trospium chloride is a peripherally acting muscarinic antagonist which binds to and antagonizes 
all five muscarinic receptor subtypes[19]. It is a commonly used generic drug approved for over 
10 years by the Food and Drug Administration (FDA) and by European authorities to treat 
overactive bladder and is generally well tolerated[19]. Several human subject studies have 
demonstrated that trospium does not appreciably cross the blood brain barrier, consistent with the 
drug’s quaternary ammonium structure[20].  
KarXT is a novel combination of xanomeline tartrate and trospium chloride. Karuna 
hypothesized that the addition of trospium would mitigate peripheral procholinergic side effects 
(vomiting, nausea, diarrhea, sweating and hyper-salivation) and thus provide a strategy to allow 
xanomeline to be administered and stimulate brain muscarinic receptors with a decreased side 
effect burden. Phase 1 studies in healthy volunteers of this combination demonstrated that 
KarXT reduced these side effects by 46% compared to xanomeline alone[21]. Moreover, the 
remaining cholinergic AEs were generally mild to moderate in severity and transient in nature, 
often lasting a few hours without recurrence and were generally single-episode. In general, 
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KarXT was well tolerated in healthy adult volunteers. These encouraging safety data prompted 
further work to assess KarXT for the treatment of schizophrenia and potentially other CNS 
disorders. 
Karuna has recently completed an adequate and well-controlled, randomized, multi-center 
Phase 2, placebo-controlled, inpatient clinical trial of acute psychosis with schizophrenia in 
182 adult subjects (KAR-004). KarXT demonstrated a statistically significant and clinically 
meaningful 11.6 point mean reduction in total Positive and Negative Syndrome Scale (PANSS) 
at 5 weeks compared to placebo (P < 0.0001), with statistical separation at each time point 
assessed (2, 4, and 5 weeks) and also demonstrated good overall safety and tolerability. 
The purpose of the current study is to evaluate the safety and efficacy of KarXT (xanomeline 
125 mg/trospium 30 mg) administered twice daily (BID) in adult inpatients with Diagnostic and 
Statistical Manual‒Fifth Edition (DSM-5) diagnosis of schizophrenia. A placebo arm is included 
to provide test sensitivity.  
Xanomeline is currently not approved or marketed in any country. Trospium is marketed in the 
US and other regions of the world for the treatment of overactive bladder. 
Nonclinical Studies 
The following is a summary of the important nonclinical safety and toxicology studies. More 
detailed information can be found in the KarXT Investigator’s Brochure (IB). 
The acute toxicity of xanomeline tartrate was evaluated in mice and rats. All animals were 
observed for 2 weeks for mortality and clinical signs of intolerance, and then necropsied for 
gross examinations. In-life findings attributed to the test article included excessive 
muscarinic-mediated pharmacology, such as excessive salivation, hypoactivity, ataxia, soft 
stools, exophthalmos, ocular discharge, tremors, and convulsions, with survivors typically 
appearing normal by Days 3 or 4. Gross findings at necropsy were generally unremarkable (eg, 
gas-distended or mucous-filled gastrointestinal [GI] tracts after oral dosing). 
KarXT-301 was a 14-day, repeat dose study of KarXT in rats where relatively high doses of 
xanomeline and trospium were given, with either xanomeline alone or in combination with 
trospium. Seven groups of 10 rats/sex/group were administered either vehicle (reverse osmosis 
water); xanomeline alone at 37, 75, 150, or 300 mg/kg/day (split into BID doses, every 
12 hours); or xanomeline/trospium combination dosages of 150/200 mg/kg/day or 
225/400 mg/kg/day, respectively (split into BID doses, every 12 hours).  
Satellite animals were included for the collection of plasma after the first and last doses for the 
determination of drug concentrations of each parent drug in support of toxicokinetic (TK) 
assessments.  
There was no target-organ toxicity revealed by clinical pathology or by gross or microscopic 
assessments. All intolerance could be attributed to recognized pharmacology of either test article. 
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No dose-related ophthalmic observations were noted. Findings were not indicative of specific 
target organ toxicity. In short, no new hazard was identified.  
Clinical observations noted in most animals administered 300 mg/kg/day xanomeline included 
hypoactivity, clear oral discharge, dilated pupils, irregular or labored respiration, and rough hair 
coat, among other observations. These findings are generally consistent with the anticipated 
pharmacology of xanomeline.  
Three TK animals in the low-dose combination group died or were euthanized in extremis. It is 
unclear to what extent the combination treatment effects versus the different handling of these 
animals (including 3 plasma samplings per animal) contributed to these deaths. If gavage 
accidents were involved (as happened with some TK animals), then they were not detected at 
gross necropsy. There was no microscopic evidence of toxicity was seen in any toxicity animals 
in this group or in the higher-dose combination group. 
Three toxicology and 3 TK animal deaths (total of 6) occurred in the high-dose combination 
group. Two toxicology animals had evidence of gavage accidents. For the third, the cause of 
death was undetermined, and a test article-related effect cannot be ruled out, but 
degeneration/regeneration of esophageal muscular is indicated some dosing-related trauma. If 
gavage accidents were involved, then they were not detected at gross necropsy. There was no 
evidence of target organ microscopic findings in GI tract or any other tissue of any animal, 
including the early death toxicity animals.  
A pharmacodynamics-mediated reduction in GI motility is consistent with the anti-muscarinic 
effects of trospium on intestinal musculature. Fecal retention, malabsorption, cessation of eating, 
dehydration, and rapid deterioration followed with continued dosing. Cessation of dosing in the 
high dose combination animals that survived led to rapid recovery, implying the deleterious 
effects had been pharmacodynamics-related. No effects on food consumption were seen in any 
xanomeline-alone group. The lack of microscopic findings in the GI tract of any early death or 
surviving animal implies that the adverse effects were pharmacologically mediated rather than 
direct target organ toxicity. 
Twenty-eight Day Repeat-Dose Studies with Xanomeline in Rats and Monkeys: Rats were fed 
xanomeline tartrate at 0%, 0.05%, 0.1%, or 0.2% daily and monkeys were fed xanomeline 
tartrate daily at 0, 5, 12.5, or 30 mg/kg. All animals survived until necropsy. Safety findings in 
rats included reduced body weight in the high dose group, increases in gamma-glutamyl-
transferase, cholesterol, and bilirubin, slight decreases in triglycerides, bile duct hyperplasia, 
higher serum potassium (males), and lower serum globulin (females). Findings in monkeys were 
dose related and included signs of intolerance such as emesis, salivation, diarrhea, hypoactivity, 
weight loss, and treatment-related tachycardia in the high-dose animals. 
Forty-Day Repeat Dose Study of KarXT in Rats (KarXT-302): Six groups of 15 rats/sex/group 
were given vehicle, xanomeline alone at 75 or 150 mg/kg/day, trospium alone at 100 mg/kg/day, 
or xanomeline/trospium combination at doses of 75/50 mg/kg/day or 150/100 mg/kg/day, with 
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all doses split into BID doses. Satellite rats (TK animals) were included for collection of plasma 
after the first and last doses to determine concentrations of each drug. Dosing was initially 
planned to be 90 days but was terminated after 40 days because of unexpected deaths in the TK 
animals. No target organ toxicity was seen. Safety findings included pharmacologically mediated 
constipation in the trospium alone and combination groups and mild biliary hyperplasia in the 
high-dose xanomeline alone and combination groups. There were 4 unscheduled deaths in TK 
animals; 2 in the high-dose xanomeline alone group (150 g/kg/day) and 2 in the high-dose 
combination group (150 mg/kg/day xanomeline plus 100 mg/kg/day trospium). Both 
xanomeline-only animals had necropsy gross findings of a gavage accident, and cause of death 
could not be determined. All toxicology animals survived to their scheduled sacrifice. Sponsor 
considers that the volume depletion and trauma of multiple bleeds (3 per animal), followed by 
reduced absorption of fluids and nutrients secondary to reduced GI motility with continued BID 
dosing explains the greater demise of TK animals relative to toxicity animals.  
Based on the results of the 90-day rat toxicology study, oral administration of trospium chloride 
and xanomeline tartrate alone or in combination to Crl:CD (SD) rats BID (12 hours ± 60 minutes 
apart) at dosage levels of 25 and 50 mg/kg/dose trospium chloride, 37 and 75 mg/kg/dose 
xanomeline tartrate, and a combination of 37/25, 75/25, and 75/50 mg/kg/dose xanomeline 
tartrate/trospium chloride for a minimum of 90 days resulted in minimal to moderate bile duct 
hyperplasia in the livers of the xanomeline tartrate and combination (xanomeline tartrate and 
trospium chloride) group males. Although there were no notable differences in the incidence of 
bile duct hyperplasia when comparing the single vs combination groups, there was an increased 
severity observed in the combination group males (specifically the 75/25 and 75/50 mg/kg/dose 
combination group males) when compared with the xanomeline tartrate group males at the 
terminal euthanasia. The bile duct hyperplasia was considered adverse in the high-dose 
xanomeline tartrate group males and in the 75/25 and 75/50 mg/kg/dose combination group 
males due to instances of moderate severity. Therefore, the no-observed-adverse-effect level was 
considered to be 50 mg/kg/dose for trospium chloride, 37 mg/kg/dose for xanomeline tartrate, 
and 37/25 mg/kg/dose for the combination of xanomeline tartrate/trospium chloride. At these 
doses for males, mean plasma AUC0-24 values were 27,700 pg•hr/mL for trospium, 146,000 
pg•hr/mL for xanomeline, and 4510 + 111,000 pg•hr/mL for trospium + xanomeline, 
respectively, on Day 91. At these dosages for females, mean plasma AUC0-24 values were 9230 
pg•hr/mL for trospium; 267,000 pg•hr/mL for xanomeline; and 16,700 + 171,000 pg•hr/mL for 
trospium + xanomeline, respectively, on Day 91. The absence of bile duct hyperplasia in females 
cannot be explained from differences in drug exposure. At the recovery euthanasia, bile duct 
hyperplasia was still present but was limited to minimal severity, and there was a decreased 
incidence in both the xanomeline tartrate and combination group males. There was also no 
notable difference in severity between the single vs combination groups at the recovery 
euthanasia. Given the decreased incidence/severity, in combination with the improved histologic 
appearance of bile ducts at the recovery euthanasia (i.e., smaller/flattened epithelium, 
noninflammatory, and an absence of portal bridging), changes at the recovery euthanasia were 
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consistent with a partial resolution of bile duct hyperplasia. With an absence of correlating serum 
liver enzyme elevations, bile acid alterations or hepatocellular degeneration, necrosis or 
regeneration, and with the apparent reversibility after cessation of treatment, these findings 
appear to have been tolerable by the affected animals. Therefore, the maximum tolerated dose 
was considered to be 50 mg/kg/dose for trospium chloride, 75 mg/kg/dose for xanomeline 
tartrate, and 75/50 mg/kg/dose for the combination of xanomeline tartrate/trospium chloride. For 
males, corresponding mean plasma AUC0-24 values were 27,700 pg•hr/mL for trospium; 
822,000 pg•hr/mL for xanomeline; and 133,000 + 276,000 pg•hr/mL for trospium + xanomeline, 
respectively, on Day 91. For females, corresponding mean plasma AUC0-24 values were 
9230 pg•hr/mL for trospium; 2,090,000 pg•hr/mL for xanomeline; and 17,600 + 
950,000 pg•hr/mL for trospium + xanomeline, respectively, on Day 91. 
In summary, no new findings on the “combination” of xanomeline and trospium (KarXT) were 
discovered; toxicology studies revealed the familiar exaggerations of systemic and CNS 
muscarinic effects that had previously been seen with xanomeline or trospium at high doses. 
Target organ findings with xanomeline alone were limited to biliary hyperplasia in the 28-day rat 
study but not the 28-day or 12-month monkey study, though similar findings were described in a 
6-month monkey study. With KarXT, biliary hyperplasia was not observed in the 14-day rat 
study but was reported in the 40-day rat study. Notably, these hyperplastic findings are not 
thought to represent pre-neoplastic lesions, because they were of low severity; no fibrosis or 
associated hepatocellular changes, and no significant effects were seen on hepatobiliary-related 
serum chemistry.  
Completed Clinical Studies 
Refer to the IB for complete information regarding previous clinical studies conducted with 
xanomeline by Eli Lilly, and studies KAR-001, KAR-002, KAR-003, and KAR-004 conducted 
by Karuna Therapeutics using xanomeline with trospium. 
To date, more than 750 subjects or volunteers have been exposed to xanomeline tartrate (oral 
formulation, either alone, in combination with trospium, or as the combination drug KarXT) in 
18 completed clinical studies conducted either by Eli Lilly or Karuna Therapeutics, some for as 
long as 3 years. In those studies, significant improvements in cognition and reduced psychotic 
symptoms were observed.  
A study of xanomeline monotherapy in subjects with schizophrenia was reported in 2008[18]. In 
this pilot study, the effects of xanomeline were examined in 20 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 
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. 
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These studies demonstrated the potential for xanomeline as a treatment for psychosis and 
cognition across multiple subject populations.  
Study H2Q-EW-E001, conducted by 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 mg, 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 in sitting and standing heart rate, slight increase in supine systolic 
BP, and postural hypotension. 
The clinical experience with KarXT initiated by Karuna Therapeutics to date includes 
3 completed Phase 1, clinical pharmacology studies in healthy volunteers (KAR-001, KAR-002, 
and KAR-003) and one completed Phase 2 study (KAR-004) in adult inpatients with DSM-5 
schizophrenia. 
The first study conducted by Karuna, KAR-001 was “A Phase 1, double-blind, randomized, 
multiple-dose, pilot study comparing xanomeline administered alone to xanomeline administered 
in combination with trospium chloride in normal healthy volunteers.” This study consisted of 
2 arms, in which xanomeline was administered TID, alone, at a total daily dose of 225 mg in one 
arm, and the second arm received the same dose of xanomeline in combination with trospium 
chloride 20 mg administered BID, a total daily dose of 40 mg. Subjects were treated for 7 days. 
The goal was to determine whether this dosing regimen would reduce the cholinergic side effects 
of xanomeline by co-administration of the muscarinic antagonist, trospium.  
Overall, treatment with xanomeline 225 mg daily + trospium 40 mg daily administered over 
7 days was considered safe and well tolerated. The results of key and supportive endpoints 
showed a numerical reduction (although not statistically significant) in visual analog scale (VAS) 
scores for cholinergic events for the xanomeline + trospium treatment arm compared to the 
xanomeline alone treatment arm. Specifically, consistent numerical reduction in VAS scores for 
the xanomeline + trospium treatment arm was observed for the supportive endpoints of 
maximum weekly individual VAS scores and mean daily maximum composite VAS scores.  
Results of the clinician-administered scales were supportive of a reduction in vomiting, feelings 
of nausea, excess salivation, and sweating that interfered with daily activities in the 
xanomeline + trospium treatment arm compared to the xanomeline alone treatment arm. 
There were no meaningful differences between treatment groups in heart rate, resting BP, 
orthostatic BP or any electrocardiogram (ECG) parameters including QT. A small subset of 
subjects in both treatment arms had transient increases in heart rate and orthostatic BP changes 
which may have contributed to syncope and postural dizziness in those subjects. Two subjects 
(both in the xanomeline alone arm) experienced syncope. The incidence of orthostatic AEs in the 
KarXT group was approximately one-half that of subjects in the xanomeline alone group. 
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The most commonly reported treatment-emergent AEs (TEAEs) in KAR-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. 
Study KAR-002 was a Phase 1, double-blind, randomized, multiple-dose adaptive design pilot 
study to evaluate the safety and tolerability of KarXT in normal healthy volunteers. Subjects 
received either 100 mg xanomeline + 20 mg trospium BID or placebo. The first cohort of this 
study was stopped after 1.5 days when the US FDA put the program on hold due to a preliminary 
rat finding in the 14-day study. This study used a new formulation of KarXT in which 
xanomeline and trospium were combined into a single dose form and given BID. Safety findings 
included an increase in orthostatic complaints. Caution should be used in drawing conclusions 
from this study, as subjects did not have time to reach steady state plasma levels from dosing, as 
only 3 doses were given. 
Study KAR-003 was a Phase 1, double-blind, randomized, multiple-dose, adaptive design, 
inpatient pilot study to evaluate the safety and tolerability of KarXT in normal healthy 
volunteers. The primary objective of this study was to assess the safety and tolerability of 7 days 
of daily administration of KarXT at various dose combinations, administered BID. Subjects 
received either KarXT or placebo (3:1 ratio). All subjects on KarXT received 2 days of 50 mg 
xanomeline + 20 mg trospium BID, and then increased to different doses for Days 3 to 7. This 
study also used the new formulation of KarXT in which xanomeline and trospium were 
combined into a single dosage form and given BID.  
There was a relatively high degree of variability in xanomeline and trospium exposures between 
individuals in all cohorts, which is consistent with previous results with KarXT, 
xanomeline-alone, and trospium-alone. Peak plasma concentrations were observed at a median 
time of 2.0 hours for xanomeline and 1.0 hour for trospium across all treatment groups and study 
days.  
Although there was insufficient data to draw a definitive conclusion regarding the impact of 
trospium on the pharmacokinetics (PK) and bioavailability of xanomeline, or the impact of 
xanomeline on the PK and bioavailability of trospium, the PK results suggest that neither drug 
had a meaningful impact on the PK behavior of the other drug. 
During the 2-day lead-in phase, the most common AEs (≥20% of subjects) when all the subjects 
completed dosing were dry mouth, nausea, and constipation. For the treatment groups that 
completed dosing, although the incidence of TEAEs was lower in the KarXT 100/20 BID 
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(66.7%) group compared to KarXT 125/40 group (88.9%), the incidence of cholinergic TEAEs 
(nausea, vomiting, diarrhea, sweating, and excess salivation) was similar between the 2 groups. 
The most commonly reported TEAEs (20% of subjects in either treatment group) in these 
groups were dizziness, nausea, dry mouth, headache, vomiting, dyspepsia, somnolence, vision 
blurred, and dysuria. For the treatment groups that did not complete dosing (KarXT 150/20 BID 
group and KarXT 150/40 BID group), the cholinergic TEAEs were generally higher compared to 
the treatment groups that completed dosing.  
Overall, anticholinergic TEAEs appeared to occur primarily in the treatment groups that were 
dosed with 40 mg trospium BID (KarXT 150/40 BID and KarXT 125/40 BID groups), 
particularly when paired with 125 mg xanomeline BID, suggesting to consider slightly lowering 
the trospium dose from 40 mg BID in future studies. All TEAEs were mild or moderate in 
severity, and there were no SAEs or deaths. Treatment-emergent AEs were primarily cholinergic 
or orthostatic (and a few anticholinergic). Doses of 100 mg and 125 mg BID of xanomeline were 
well tolerated when paired with 20 mg and 40 mg BID of trospium, respectively. The safety and 
tolerability profile of KarXT 100/20 BID and KarXT 125/40 BID was acceptable and supports 
further evaluation at similar doses in future studies. Doses of KarXT 150/20 BID and 
150/40 BID were not well tolerated in this study. A pairing of 150 mg xanomeline with 40 mg 
trospium appeared to be better tolerated than 150/20, but some subjects still experienced 
tolerability issues. 
Study KAR-004 was a Phase 2 randomized, double-blinded study to assess the safety 
tolerability, and efficacy of KarXT in adults with DSM-5 schizophrenia, hospitalized with acute 
psychosis. The primary objective of the study was to assess the efficacy of KarXT 125/30 BID 
versus placebo in reducing PANSS total scores in adult inpatients with a DSM-5 diagnosis of 
schizophrenia. Subjects received either KarXT or placebo (1:1 ratio) for a treatment period of 
5 weeks. All subjects on KarXT received a lead-in dose of KarXT 50/20 BID for the first 2 days 
followed by KarXT 100/20 BID on Days 3 to 7. On Day 8, dosing was titrated upwards to 
KarXT 125/30 BID unless the subject was continuing to experience AEs from previous dose 
increase of 100/20 BID. The clinical portion of this study was completed and clinical study 
report is in progress. No new safety concerns have arisen during this study. 
The KAR-004 trial results are unambiguous regarding efficacy, where not only the primary 
outcome measure showed a robust separation from placebo, but the additional sensitivity and 
secondary outcome measures were consistently robust as well.  
KarXT demonstrated statistically significant and clinically meaningful mean reductions in total 
PANSS scores at 5 weeks compared to placebo (P < 0.0001) in the modified intent-to-treat 
(mITT) population. The KarXT group showed an adjusted mean improvement of 17.40 points at 
Week 5 compared to an adjusted mean 5.85 point improvement in the placebo group for a 
difference of 11.56 points in the total PANSS score (Figure 1). Substantial significant differences 
were also seen between KarXT and placebo at Weeks 2 and 4; moreover, the difference appears 
to be widening with each successive timepoint. In addition, sensitivity analyses of the primary 
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outcome measure all showed the same strong differences from placebo attesting to the robustness 
of the finding in Completer, last observation carried forward, and Per Protocol populations (all 
with p < 0.0001). Also, analyses exploring missingness via imputation for missing data at 
random or not missing at random also showed strong separation (both with p < 0.0001). The 
Cohen’s d effect size observed in this trial was 0.75. 
Figure 1 
Change from Baseline in PANSS Total Scores (KAR-004) 
 
Abbreviations: LS = least squares; mITT = modified intent-to-treat; PANSS = Positive and Negative Syndrome 
Scale; SEM = standard error of the mean. 
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 timepoints (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. 
In regards to the Clinical Global Impression – Severity of Illness (CGI-S), subjects in the KarXT 
group overall significantly improved in ratings compared with placebo, with a P value of <0.001 
at Week 5. At Week 5, 8% of subjects on placebo improved (decreased) their CGI-S ratings by 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 with 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 
• Most common TEAEs were constipation, nausea, dry mouth, dyspepsia, and vomiting. 
None of these TEAEs were rated as severe, and none led to discontinuations 
• 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.  
• No syncope or mean changes in BP were seen 
• A 5.5 bpm peak mean placebo adjusted resting heart rate increase with a downward trend 
after week 2 was seen 
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• One subject (on KarXT) was discontinued due to an elevated gamma-glutamyl 
transpeptidase 
• There were no new safety findings associated with KarXT that have not been observed 
with either xanomeline-alone or trospium-alone in previous trials 
• KarXT did not show evidence of many of the kinds of AEs that often occur in currently 
available antipsychotics for the treatment of schizophrenia.  
• The rates of the following AEs were similar for KarXT and placebo: somnolence, weight 
gain, and extrapyramidal symptoms. 
Another Phase 3 study (KAR-007) is planned at approximately 20 study sites in the US. 
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 with all available 
APDs. 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 with placebo, demonstrated highly significant reduction in PANSS total scores 
(P < 0.0001) at all post randomization time points (Weeks 2, 4, and, 5) with a calculated effects 
size (Cohen’s d) of 0.75. KarXT, as compared to placebo, demonstrated significant improvement 
at all post randomization time points for PANSS positive symptom subscores, PANSS negative 
symptom subscores, PANSS Marder Factor negative symptom subscores, and CGI-S scores. 
More than 750 subjects or volunteers have been exposed to xanomeline tartrate (oral 
formulation, either alone, in combination with trospium, or as the fixed dose combination drug 
KarXT) in clinical studies. These early clinical studies, as well as nonclinical pharmacology and 
toxicology studies, have not revealed any specific contraindications to the use of xanomeline. 
The most common side effects/symptoms are the cholinergic related effects: nausea, vomiting, 
excess salivation, excess sweating, and diarrhea. In addition, subjects treated with xanomeline 
alone have reported both syncope and orthostatic dizziness. The addition of trospium decreases 
the peripheral cholinergic effect of xanomeline creating a better tolerated therapy. In addition, a 
titration phase also increases the tolerability of KarXT. 
Trospium chloride has been marketed in the US for 12 years. The most frequently reported AEs 
reported in pivotal trials were dry mouth, constipation, abdominal pain, headache, urinary 
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retention, and abnormal vision and accommodation. For additional information, the package 
insert for trospium chloride tablets for oral use can be found in the IB. 
In a Phase 2 (KAR-004) clinical study, KarXT (100/20 and 125/30) significantly reduced the 
symptoms of schizophrenia in subjects with acute psychosis after treatment for 28 days. KarXT 
also showed an acceptable safety profile with the most common TEAEs being constipation, 
nausea, dry mouth, dyspepsia, and vomiting. All the reported TEAEs were mild or moderate in 
intensity. One SAE (psychotic disorder) was reported by a single subject and no deaths were 
reported in the study. KarXT was generally well-tolerated and found to be safe in this patient 
population. 
KarXT represents a novel approach to the treatment of patients with schizophrenia that will 
provide an important and meaningful alternative to current therapies. The current tolerability and 
AE profile and the efficacy of KarXT justify further development of KarXT in this patient 
population by advancing to Phase 3 trials. 
Subjects assigned to active study drug may benefit by improvement in schizophrenia symptoms. 
Since subjects will be having an acute psychotic event, subjects will be hospitalized where the 
clinical staff is available to help them 24 hours a day. In addition, the inpatient setting represents 
an important venue for research, examining the effects of KarXT and helps to eliminate or 
reduce to the extent possible, subjectivity and bias. Furthermore, this inpatient setting will also 
enhance measurable quality standards as well as increased adherence. 
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6 
STUDY OBJECTIVES AND ENDPOINTS 
6.1 
Study Objectives 
 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of KarXT 125/30 BID versus 
placebo in reducing PANSS total scores in adult inpatients with a DSM-5 diagnosis of 
schizophrenia. 
 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the reduction of PANSS positive score in subjects treated with KarXT versus 
placebo 
• To evaluate the improvement in CGI-S results in subjects treated with KarXT versus 
placebo 
• To evaluate the reduction of PANSS negative score in subjects treated with KarXT 
versus placebo 
• To evaluate the reduction of PANSS Marder Factor negative symptoms score in subjects 
treated with KarXT versus placebo 
• To evaluate the safety and tolerability of KarXT 
• To assess the PK of xanomeline and trospium after administration of KarXT in adults 
who are acutely psychotic with a DSM-5 diagnosis of schizophrenia 
 
Exploratory Objective 
The exploratory objective of the study is to evaluate the single nucleotide polymorphisms (SNPs) 
regarding schizophrenia subtypes and SNPs related to drug metabolism. 
6.2 
Study Endpoints 
 
Primary Endpoint 
The primary endpoint of this study is change from baseline in PANSS total score at Week 5 
 
Secondary Endpoints 
6.2.2.1 
Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
• Change from baseline in PANSS positive score at Week 5 
• Change from baseline in PANSS negative score at Week 5 
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• Change from baseline in PANSS Negative Marder Factor score at Week 5 
• Change from baseline in CGI-S score at Week 5 
• Percentage of PANSS responders (a 30% change in PANSS total score) at Week 5  
6.2.2.2 
Safety Endpoints 
The safety endpoints of this study are as follows: 
• Spontaneously reported AEs 
• Spontaneously reported cholinergic symptoms 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
• Body weight, body mass index (BMI), waist circumference 
• Orthostatic vital signs (supine and standing after 2 minutes): BP (systolic and diastolic) 
and heart rate 
• Clinical laboratory evaluations: hematology, clinical chemistry, coagulation, urinalysis, 
and drug screen 
• 12-lead ECG 
• Physical examination 
• Suicidal ideation scale with the use of Columbia Suicide Severity Rating Scale (C-SSRS) 
 
Pharmacokinetic Endpoints 
The PK endpoints of this study are as follows: 
• Area under the plasma concentration-time curve (AUC) 
• Maximum observed plasma concentration (Cmax) 
• Time to maximum observed plasma concentration (Tmax) 
 
Exploratory Endpoints 
• Change in cognition measuring core domains of cognitive impairment in schizophrenia 
using the Cambridge Neuropsychological Test Automated Battery (CANTAB) 
• Change from baseline in prolactin levels at Week 5 
• Prediction of response based on SNP schizophrenia subtypes, and SNPs related to KarXT 
metabolism for both efficacy and tolerability 
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7 
INVESTIGATIONAL PLAN 
7.1 
Description of Overall Study Design and Plan 
This Phase 3, randomized, double-blind, parallel-group, placebo-controlled, multicenter, 
inpatient clinical study in adults who are acutely psychotic with a DSM-5 diagnosis of 
schizophrenia is designed to test the hypothesis that treatment with KarXT will result in 
significantly greater reduction (ie, improvement) in the primary and secondary endpoints at 
Week 5 from baseline compared with placebo. Total study duration is up to 8 weeks, including a 
7-day screening phase (up to a 7-day extension of the screening phase is allowed, if necessary), a 
5 week treatment period, and a 7-day follow-up period (only for subjects who do not rollover to 
KAR-008 study). Subjects completing this study will have the option of rolling over into a 
long-term open-label study (KAR-008) in which every subject will receive KarXT. 
Screening Period:  
Screening of subjects will take place in 7 days or less before Day -1 (Days -8 to -2). Up to a 
7-day extension of the screening time is allowed, if necessary. 
A suitable number of subjects will be screened to randomize approximately 246 subjects across 
approximately 10 sites in the US and 10 sites in Ukraine. Subjects will be randomized through 
the IWRS in a 1:1 ratio to receive either KarXT or placebo for a treatment duration of 5 weeks. 
Treatment Period:  
In the treatment period, all subjects assigned to KarXT will start on a lead-in dose of 
KarXT 50/20 (xanomeline 50 mg/trospium 20 mg) BID for the first 2 days (Days 1 and 2) 
followed by KarXT 100/20 (xanomeline 100 mg/trospium 20 mg) BID for the remainder of 
Week 1 (Days 3 to 7). On Day 8, dosing will be titrated upwards to KarXT 125/30 BID unless 
the subject is continuing to experience AEs from the previous dose of KarXT 100/20 BID. All 
subjects who are increased to KarXT 125/30 BID, depending on clinical response and 
tolerability, will have the option to return to KarXT 100/20 BID for the remainder of the 
treatment period. Dosing must not change after Visit 7 (Day 21) of the study and may be 
decreased for tolerability reasons no more than once during the study. In addition, dose 
escalation to KarXT 125/30 BID may not occur outside of the permitted visit window for 
Visit 5/Day 8.  
All randomized 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. 
Efficacy assessments (PANSS scores and CGI-S score) will be assessed at scheduled visits. 
Refer to Section 11 for more details. 
Safety will be assessed through spontaneous AEs, cholinergic symptoms, cognition testing, SAS, 
BARS, AIMS, body weight, BMI, waist circumference, orthostatic vital signs, ECG, clinical 
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laboratory assessments (hematology, clinical chemistry, coagulation, urinalysis, and drug 
screen), prolactin levels, physical examination, and C-SSRS will be evaluated throughout the 
study as scheduled. Section 12 provides complete details on these safety assessments. 
Details on PK assessments are provided in Section 13. 
Safety Follow-up Period: 
A safety follow-up visit (Visit 11/ Day 42 + 5 days) will be performed for all those subjects who 
do not rollover into the long-term open-label study KAR-008. 
An Independent Safety Monitoring Committee (ISMC) will be responsible for reviewing on a 
periodic basis the safety data from this study and confirming that the study may continue. 
Table 1 presents the study design.
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Table 1 
Study Design 
 
Phase: 
Screening 
Inpatient Treatment 
End of 
Treatment 
Safety 
Follow-up 
Day: 
Days -8 
to -2 
Day -1 
Day 1 
Day 3 + 
1 day 
Day 7 ± 
2 days 
Day 8 ± 
2 days 
Day 14 ± 2 
days 
Day 21 ± 2 
days 
Day 28 
± 2 days 
Day 32 
+ 1 
day 
Day 35  
- 2 daysc 
Day 42 + 
5 days 
Visit: 
Visit 1 
Visit 2a 
Visit 
2b 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Xanomeline
/ trospium 
(KarXT)*: 
N/A 
 
50/20 
BID 
100/20 
BID 
100/20 
BID 
125/30 
BID 
(Option: 
100 /20 
BID)a 
125/30 BID 
(Option: 
100 /20 
BID)a 
125/30 BID 
(Option: 
100/20 
BID)a 
125/30 
BIDb 
125/30 
BIDb 
N/A 
 
Comment: 
Up to a 
7-day 
extension 
to the 
screening 
phase is 
allowed. 
Baseline 
2-day 
lead-in 
dose 
Upward 
titration 
of dose 
 
Upward 
titration 
of dose 
Downward dose 
adjustment allowed 
according to clinical 
response/tolerability 
No dose 
adjustment 
allowed (after 
Day 21) 
 
For 
subjects 
who do 
not enter 
in to 
rollover 
Study 
(KAR-
008) 
Abbreviation: BID = twice daily. 
* All the KarXT doses are in mg. 
a. 
All subjects who are increased to KarXT 125/30, depending on clinical response and tolerability, will have the option to return to KarXT 100/20 BID for 
the remainder of the treatment period. 
b. No dose adjustment will be allowed after Visit 7. All subjects will continue taking the doses chosen for KarXT at Visit 7. 
c. 
For subjects rolling over in to KAR-008 study, the last dose of study drug will be administered the evening of Visit 10. For the subjects who do not rollover 
in to KAR-008 study, the last dose will be administered the evening before Visit 10. 
 
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7.2 
Discussion of Study Design 
A randomized, double-blind, parallel-group, placebo-controlled study design is suitable for 
conducting any interventional studies. This design will minimize bias and provide reference data 
for comparison of efficacy and safety parameters of the investigational drug. 
Schizophrenia is a long-term mental disorder which requires a chronic therapy. A 5-week 
treatment duration is considered an acceptable treatment duration to observe clinically significant 
response (ie. primary endpoint can be achieved). The 5-week treatment duration is substantiated 
by the statistically significant outcome of the KAR-004 study of the same duration.  
7.3 
End of Study 
A subject will have fulfilled the requirements for study completion when the subject has 
completed all study periods, including the End of Study visit (Visit 10/Day 35 (End of 
Treatment) for subjects who roll over into KAR-008 or Visit 11/Day 42 (Follow-up) for subjects 
who do not roll over into the KAR-008 study) as indicated in the Schedule of Assessments 
(Table 2) in accordance with the protocol. 
Subjects completing this study will have the option of rolling over into a long-term open-label 
study (KAR-008) in which every subject will receive KarXT. 
Note: A safety follow-up visit will be performed 1 week after the End of Study visit for subjects 
who do not rollover in to the long-term open-label study. 
7.4 
Independent Safety Monitoring Committee 
For the purpose of this study, the ISMC is an independent group of individuals with pertinent 
expertise that reviews on a regular basis accumulating safety data from the clinical study. This 
committee will be responsible, on a periodic basis, for confirming the safety of KarXT 
throughout the study, with particular focus on assessing for any new toxicities that might be 
involved with KarXT. 
The reviews will be of unblinded data to allow a comparison of event rates and detection of 
safety signals across treatment groups to identify important safety information. The ISMC 
charter will contain the details of the types of data to be reviewed, the defined triggers for 
review, the minimum frequency of meetings (timed, if no triggers), and the communication plan 
for disseminating review recommendations. 
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8 
SELECTION OF STUDY POPULATION 
Section 7.1 provides information regarding number of subjects planned to be randomized. 
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 must be provided before any study assessments are 
performed. 
b. Subject must be fluent (oral and written) in English (applicable to the US) or local 
language (Ukrainian or Russian applicable to Ukraine) 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 for 
Schizophrenia and Psychotic Disorder Studies (MINI) version 7.0.2. 
4. Subject is experiencing an acute exacerbation or relapse of psychotic symptoms, 
with onset less than 2 months before screening. 
a. The subject requires hospitalization for this acute exacerbation or relapse of psychotic 
symptoms. 
b. If already an inpatient at screening, has been hospitalized for less than 2 weeks for 
the current exacerbation at the time of screening. 
5. Positive and Negative Syndrome Scale total score between 80 and 120, inclusive. 
a. Score of ≥4 (moderate or greater) for ≥2 of the following Positive Scale (P) items: 
i. Item 1 (P1; delusions) 
ii. Item 2 (P2; conceptual disorganization) 
iii. Item 3 (P3; hallucinatory behavior) 
iv. Item 6 (P6; suspiciousness/persecution) 
6. Subjects with no change (improvement) in PANSS total score between screening and 
baseline (Day -1) of more than 20%. 
7. Subject has a CGI-S score of ≥4 at screening and baseline (Day -1) visits. 
8. Subject will have been off lithium therapy for at least 2 weeks before baseline and free 
of all oral antipsychotic medications for at least 5 half-lives or 1 week, whichever is 
longer, before baseline (Day -1). 
9. Subjects taking a long-acting injectable antipsychotic could not have received a dose of 
medication for at least 12 weeks (24 weeks for INVEGA TRINZA®) before baseline 
visit (Day -1). 
10. Subject is willing and able to be confined to an inpatient setting for the study duration, 
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follow instructions, and comply with the protocol requirements. 
11. BMI must be ≥18 and ≤40 kg/m2. 
12. Subject resides in a stable living situation and is anticipated to return to that same stable 
living situation after discharge, in the opinion of the investigator. 
13. Subject has an identified reliable informant/caregiver. An informant/caregiver is 
needed at the screening and baseline visits as well as at the end of the study for 
relevant assessments (site staff may act as informant while the subject is an inpatient). 
An informant/caregiver may not be necessary if the subject has been the patient of the 
investigator for ≥1 year. 
14. Women of childbearing potential (WOCBP), or men whose sexual partners are 
WOCBP, must be able and willing to use at least 1 highly effective method of 
contraception during the study and for 7 days after the last dose of study drug. Sperm 
donation is not allowed for 90 days after the final dose of study drug. A female 
subject is considered to be a WOCBP after menarche and until she is in a 
postmenopausal state for 12 months or otherwise permanently sterile (for which 
acceptable methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy)[22]. For the definition and list of highly effective methods of 
contraception, see APPENDIX 1.  
8.2 
Exclusion Criteria 
Individuals meeting any of the following criteria at screening or baseline are ineligible to 
participate in this study: 
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, moderate to severe alcohol use disorder (within the past 
12 months), substance (other than nicotine or caffeine) use disorder within the past 
12 months (use of cannabis at screening will result in screen failure with the allowance 
to rescreen at a later date if no moderate to severe substance use disorder is determined), 
major depressive disorder, bipolar I or II disorder, schizoaffective disorder, obsessive 
compulsive disorder, and post-traumatic stress disorder. Symptoms of mild mood 
dysphoria or anxiety are allowed as long as these symptoms are not the primary focus of 
treatment. 
a. A screening subject with mild substance abuse disorder within the 12 months before 
screening must be discussed and agreed upon with the medical monitor before he/she 
can be allowed into the study. 
2. 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. 
3. Subjects with HIV, cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma, and/or 
active hepatic viral infections based on either medical history or liver function test 
results. 
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4. History or high risk of urinary retention, gastric retention, or narrow-angle glaucoma. 
5. History of irritable bowel syndrome (with or without constipation) or serious 
constipation requiring treatment within the last 6 months. 
6. 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. 
7. Clinically significant abnormal finding on the physical examination, medical history, 
ECG, or clinical laboratory results at screening. 
8. Subjects cannot currently (within 5 half-lives or 1 week, whichever is longer, before 
baseline [Day -1]) be receiving oral antipsychotic medications; monoamine oxidase 
inhibitors; anticonvulsants (eg, lamotrigine, Depakote); tricyclic antidepressants (eg, 
imipramine, desipramine); selective serotonin reuptake inhibitors; or any other 
psychoactive medications except for as needed anxiolytics (eg, lorazepam, chloral 
hydrate). 
9. Pregnant, lactating, or less than 3 months postpartum. 
10. If, in the opinion of the investigator (and/or Sponsor), subject is unsuitable for 
enrollment in the study or subject has any finding that, in the view of the investigator 
(and/or Sponsor), may compromise the safety of the subject or affect his/her ability to 
adhere to the protocol visit schedule or fulfill visit requirements. 
11. Positive test for coronavirus (COVID-19) within 2 weeks before screening. 
12. Subjects with extreme concerns relating to global pandemics, such as COVID-19, that 
preclude study participation. 
13. Subject has had psychiatric hospitalization(s) for more than 30 days (cumulative) 
during the 90 days before screening. 
14. Subject has a history of treatment resistance to schizophrenia medications defined as 
failure to respond to 2 adequate courses of pharmacotherapy (a minimum of 4 weeks 
at an adequate dose per the label) or required clozapine within the last 12 months. 
15. Subjects with prior exposure to KarXT. 
16. Subjects who experienced any adverse effects due to xanomeline or trospium. 
17. Participation in another clinical study in which the subject received an experimental or 
investigational drug agent within 3 months before screening. 
18. Risk of violent or destructive behavior. 
19. Current involuntary hospitalization or incarceration. 
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8.3 
Rescreening 
Individuals who sign the informed consent form (ICF) to participate in the study but who do not 
subsequently meet all the requirements for safety laboratory assessments and therefore do not 
enroll (screen failures) may be rescreened, upon approval of the medical monitor on a case by 
case basis. Such individuals may be allowed to rescreen up to 1 time. When re-testing within the 
same screening procedure, only the exclusionary laboratory tests will be repeated once in case 
the exclusionary laboratory result was not due to a pathological condition and was occasional 
(except for individuals who have positive serology results).  
8.4 
Study Withdrawal, Removal, and Replacement of Subjects 
If a subject discontinues study treatment and is withdrawn from the study for any reason, the 
study site must immediately notify the medical monitor. The date and the reason for study 
discontinuation must be recorded on the electronic case report form (eCRF). Subjects who 
complete or discontinue early from the study will be discharged from the study site, if clinically 
warranted after completing all the Visit 10/early termination assessments as indicated in the 
Schedule of Assessments (Table 2). 
Note: A safety follow-up visit will be performed 1 week after the End of Study visit for those 
subjects who do not roll over into the long-term open-label study KAR-008. 
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 will 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 the investigator’s clinical judgment. The 
reason for subject withdrawal will be noted on the eCRF. 
• intercurrent illness: a condition, injury, or disease unrelated to the primary diagnosis that 
became apparent during treatment and necessitated the subject’s termination from the 
study 
• general or specific changes in the subject’s condition that renders him/her ineligible for 
further treatment according to the inclusion/exclusion criteria (eg, subject has need for a 
medication prohibited by the protocol) 
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• subject fails to adhere to the protocol requirements (eg, drug noncompliance [if a study 
subject is off study drug for >5 days in a row])  
• violation of entry criteria; ie, subjects who are enrolled but are later discovered not to 
meet entry criteria 
• development of suicidal or assaultive behavior 
• alcohol or illegal drug use 
• pregnancy, as indicated in Section 12.7.7. Any study subject who becomes pregnant 
while participating in the study will be unblinded to study treatment randomization. If she 
is found to be on active treatment assignment, she will be followed until her pregnancy 
reaches term. 
• Sponsor’s decision to discontinue study. 
Subjects withdrawing 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 leave the unit or are lost to follow-up. 
These efforts must be documented in the subject’s file. Subjects with AEs ongoing at end of 
study will be followed until the AE is resolved (regardless of whether they enroll in the 
long-term open-label study KAR-008) or the subject is considered to be in stable condition. 
The Sponsor has the right to terminate the study at any time in case of SAEs or if special 
circumstances concerning the study drug 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, women of childbearing potential in this study must be willing to use a highly effective 
method of birth control (see APPENDIX 1 for a list of acceptable highly effective methods of 
contraception) during the study and for 7 days after the last dose of study drug. Females of 
childbearing potential will have a serum pregnancy test at screening and a urine pregnancy test 
on Day 1 (before receiving KarXT) and Day 35.  
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. 
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Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment 
of the mother with KarXT, women who are breastfeeding must not be enrolled in the study. 
The effects of study drug on sperm are unknown. Men who are willing to participate in the study 
must agree to use a highly effective method of birth control (see APPENDIX 1 for a list of 
acceptable highly effective methods of contraception) and must not impregnate a sexual partner 
during or for 90 days after the last dose of study drug. They must also agree to refrain from 
sperm donation for 90 days after the last dose of study drug. 
Female subjects of child-bearing potential will be instructed that known or suspected pregnancy 
occurring during the study should be confirmed and reported to the investigator. If a female 
subject becomes pregnant, the investigator must withdraw her from the study without delay. The 
subject must not receive any further doses of the study drug. Upon discontinuation from the 
study, only those procedures that would not expose the pregnant female subject to undue risk 
will be performed. See Section 12.7.7 for further reporting and monitoring details. 
Full details of the pregnancy will be recorded on the withdrawal page (exit form) of the eCRF, or 
a pregnancy report will be completed if the subject has completed the study. Notification of the 
pregnancy should be submitted on 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 SAE (Section 12.7.4). 
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 leave the facility and are lost to 
follow-up to obtain end of study 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 Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB) may take such actions. If the study is terminated for safety reasons, subjects 
will be notified immediately and assured that appropriate treatment and follow-up will be 
available. If an investigator terminates the study, the Sponsor, subjects, and IEC/IRB will be 
informed about the reason for such action. Similarly, if the Sponsor terminates the study, it will 
inform the investigators, the IEC/IRB, and the subjects of the reason for such an action. Similar 
notifications will be sent by the IEC/IRB if it takes such an action. 
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9 
TREATMENTS 
9.1 
Details of Study Treatments 
KarXT is formulated as hard hydroxypropyl methylcellulose oral capsules containing 2 distinct 
populations of drug beads, one of which is loaded with xanomeline tartrate and the other of 
which is loaded with trospium chloride. Each capsule contains the freebase equivalent of 
xanomeline and trospium according to the desired dose strength. In addition to the active 
ingredients, the drug beads contain microcrystalline cellulose (MCC). The beads are not coated 
and are formulated for immediate release of the active ingredients. 
 
Identity of Study Treatments 
Active study agents for treatment group will be size 0, Swedish orange-white, opaque, and 
hydroxypropyl methylcellulose hard capsules. Placebo will be prepared in matching capsules; 
therefore, an unblinded pharmacist will be required to dispense study agent at each day of 
dosing. For the 2-day lead-in period (Days 1 and 2), subjects randomized to active drug will 
receive capsule strength KarXT 50/20 BID, followed by 2 capsules of KarXT 50/10 mg BID or a 
dosage of 100/20 BID for a total daily dosage of 200/40 mg xanomeline/trospium chloride for 
the remainder of Week 1 (Days 3 to 7). At the beginning of Week 2, dosing may be increased to 
2 capsules of KarXT 62.5/15 mg or a dosage of 125/30 BID for a total daily dosage of 
250/60 mg xanomeline/trospium chloride, depending on clinical response and tolerability. 
Investigators have the option to return a subject to KarXT 100/20 BID for the remainder of the 
treatment period, but dosing must not change after Visit 7 of the study.  
KarXT 50/10 mg is composed of 44.4% xanomeline tartrate, 5.8% trospium chloride, excipients 
37.59% MCC, 11.5% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a size 0, 
Swedish orange, hydroxypropyl methylcellulose hard capsule. 
KarXT 50/20 mg is composed of 33.4% xanomeline tartrate, 8.7% trospium chloride, excipients 
39.8% MCC, 17.3% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a size 0, Swedish 
orange, hydroxypropyl methylcellulose hard capsule. 
KarXT 62.5/15 mg is composed of 41.7% xanomeline tartrate, 6.5% trospium chloride, 
excipients 38.1% MCC, 12.9% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a 
size 0, Swedish orange, hydroxypropyl methylcellulose hard capsule. 
Placebo is composed of sugar spheres pf011, 850/1000 suglets, 99.05% colorcon, and 10.05% 
talc in a size 0, Swedish orange, an opaque white hydroxypropyl methylcellulose hard capsule. 
All investigational agents are to be stored according to requirements. 
 
Packaging and Labelling 
The study packaging and labelling will be performed by Corealis Pharma, located in Laval, 
Quebec, Canada, Catalent Pharma Solutions, located in Winchester, Kentucky (labelling for the 
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US sites), and Catalent Pharma Solutions, located in Philadelphia, Pennsylvania (labelling for 
Ukrainian sites). All packaging and labelling operations will be performed according to Good 
Manufacturing Practice for Medicinal Products and the relevant regulatory requirements. 
Bulk supply bottles are labeled with the name of the drug, recommended storage conditions, the 
name and address of the manufacturer, and the Investigational Use Statement (“Caution: New 
Drug – Limited by Federal [US] Law to Investigational Use”). 
Further details on labelling of investigational products will be provided in the Pharmacy Manual.  
 
Study Drug Storage 
KarXT and placebo must be stored at controlled room temperature 15°C-25°C in a secured 
location with no access to unauthorized personnel. 
 
Study Drug Retention 
Study drug not used in KAR-009 may be used for the long-term extension study (KAR-008). 
Therefore, unused study drug for this particular study must be retained until completion or 
termination of the KarXT program, and written authorization from the Sponsor has been 
received. All unused and used study drug must be destroyed at the site or returned, as specified 
by Sponsor. It is the investigator’s responsibility to ensure that the Sponsor has provided written 
authorization prior to return or destruction, and that appropriate records of the disposal are 
documented and maintained. No used or unused study drug may be disposed until fully 
accounted for by the study monitor. 
9.2 
Dose Schedule 
The first dose of the study drug will be administered in the morning of Day 1. For subjects who 
roll over to Study KAR-008, the last dose will be administered in the evening of Visit 10 
(Day 35 -2 days). Subjects who do not rollover to Study KAR-008 study will have the last dose 
of the study drug administered in the evening before Visit 10 (Day 35 -2 days). The study drug 
should be administered daily BID on an empty stomach (ie, at least 1 hour before a meal) or 2 to 
3 hours after a meal. Some considerations for dosing and PK blood withdrawals are provided in 
the subsections below. 
 
Visit 2b/Day 1 Randomization and Dosing 
• 
The first dose will be administered in the morning, and the evening dose will be 
administered 12 ± 0.5 hours after the morning dose.  
• 
All subjects must be administered 4 dosages of the KarXT 50/20 or placebo before dose 
escalation to KarXT 100/20 BID. 
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Visit 3/Day 3 and/or Visits Occurring on Weekends/Holidays 
• 
When Day 3 occurs on a weekend, it is expected that the complete Visit 3 will be 
performed, and the subject’s dose will be escalated on Day 3. 
• 
If completion of the visit is not possible on Day 3, the +1-day visit window may be used. 
In this instance, the dose will not be escalated until the study visit occurs. In all cases, 
the subject must have had at least 4 doses of KarXT 50/20 or placebo before escalating 
to KarXT 100/20 or placebo. 
• 
This may result in only 4 days of the KarXT 100/20 or placebo dose at Visit 5/Day 8, 
which is acceptable. 
• 
All subjects must be administered 8 doses of the KarXT 100/20 or placebo before dose 
escalation to KarXT 125/30 BID. 
 
Visit 5/Day 8 Dosing and PK Considerations and Visit 8/Day 28 PK 
Considerations 
• 
If dose escalation to the KarXT 125/30 or placebo level is confirmed by investigator 
order on Visit 5/Day 8, that dose is to be administered in the morning (after the predose 
PK blood draw) to allow for serial postdose PK blood draws per protocol (Table 2, 
Footnote p). 
• 
Should the use of visit windows be necessary, serial PK sampling must accompany the 
actual day of dose escalation for Visit 5.  
• 
For Visit 8, serial PK sampling is meant to capture the PK profile of the subject’s final 
KarXT dose level (125/30 or 100/20) after multiple doses; therefore, Visit 8 should 
occur at least 7 days after Visit 7 is completed, and there must be no changes in dose for 
at least 7 days leading up to Visit 8. PK sampling must accompany the actual day of 
Visit 8 if a window is used. 
 
Visit 10/Day 35 Dosing 
• Subjects willing to rollover in to Study KAR-008 will continued to be dosed at 
Visit 10/Day 35, and their last dose will be the evening of Visit 10. These subjects will 
start their at-home dosing on Day 1 of Study KAR-008. 
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 
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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 t3-digit study code and a 3-digit site identification followed by a 3-digit 
number assigned sequentially within each site, starting at 
. 
On Day -1, all eligible subjects will be randomly assigned in a 1:1 ratio to either KarXT or 
placebo groups. Subjects will be assigned a randomization number through the IWRS, in 
accordance with the randomization code generated by the authorized personnel at VERISTAT. 
At the study site, the randomization schedule will only be accessible to authorized unblinded 
pharmacy personnel or designee. Once a randomization number is allocated to one subject, it 
may not be assigned to another subject even if the former discontinued the study. 
 
Blinding 
An IWRS will allocate treatment based on a prespecified randomization list generated by 
VERISTAT. Active and placebo study drug will be provided in bulk to each site participating in 
the study. For each dose, study drug and packaging will be identical in size, shape, color, and 
appearance (see Section 9.1.2). No other study site personnel (except the pharmacist or other 
designated unblinded individual), subjects, informants/caregivers, Sponsor personnel, or Sponsor 
designees (eg, Sponsor’s Medical Monitor) will be unblinded to treatment assignment throughout 
the duration of the study unless unblinding is required. Both active study drug and placebo will 
be supplied as identical matching capsules. This prevents bias on the part of the study staff and 
the subject to influence the results of the study.  
If an investigator becomes unblinded to a given subject’s study treatment, that subject will be 
discontinued from the study unless there are ethical reasons for that subject not to be 
discontinued; approval from the Sponsor/medical monitor must be obtained in such instances. 
VERISTAT will generate and maintain the security of the randomization code. In the event that 
emergency unblinding is required for a given subject because of AEs or concerns for the 
subject’s safety or wellbeing, the investigator may break the randomization code for just that 
subject via the IWRS, by which system the unblinding will be captured after consultation and 
agreement with the medical monitor/Sponsor. The unblinding and its cause will also be 
documented in the eCRF. Unblinding according to the protocol will occur only after completion 
of the study. 
If an AE is thought to be related to the study drug and poses a safety risk, the investigator must 
decide whether to stop investigational treatment and/or treat the subject. Subject withdrawal 
should be avoided, if possible. If discontinuation of treatment occurs, every attempt should be 
made to restart study drug if medically appropriate, whatever the duration of discontinuation. 
When a subject has an AE that requires that the investigator be unblinded, the investigator can 
obtain the treatment assignment from the IWRS system. The site is expected to notify the study 
medical monitor before breaking the study blind unless it is in the subject’s best interest if the 
blind is broken immediately. Note: In most circumstances, it is not necessary to unblind a 
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subject, even if an SAE has occurred. For many drugs there is no specific therapy for AEs. The 
appropriate course of action is to stop the investigational drug and treat the signs and symptoms 
resulting from the AE. 
The members of the ISMC will be unblinded as they review the safety data from the study. 
9.4 
Dose Modification 
Subjects will be dosed as described in Section 7.1 and in accordance with the Schedule of 
Assessments (Table 2). The study drug 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 at Visits 5, 6, and 7 and at unscheduled visits. No dose adjustments are allowed after 
Visit 7. No other dose modifications are permissible in this study except those specified in this 
protocol. 
9.5 
Treatment Accountability and Compliance 
The pharmacist or other designated unblinded 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 study drug will be supervised by study site personnel to ensure compliance. 
Investigators will maintain records that adequately document that the subjects were provided 
with the correct study treatment bulk supply and reconcile the products received from the drug 
dispensing center. Investigational product will not be returned to the Sponsor or designee until 
accountability has been fully monitored through the end of the study. Study drug accountability 
will be assessed periodically by the assigned unblinded study monitor. 
9.6 
Prior and Concomitant Therapy 
 
Prior and Concomitant Medications 
Subjects will be asked for all prior medications he/she were taking up to 6 months before the 
study, up to the time of the first dose of study medication on Day 1. All prior medications will be 
recorded on the eCRF. 
Restricted prior therapies are provided in Section 8.2.  
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 (ie, from the time of enrollment at the screening visit until study completion), 
subjects will refrain from the use of any new concomitant medications without the specific prior 
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approval of the investigator. The administration of any other concomitant medications during the 
study period is prohibited without the prior approval of the investigator unless its use is deemed 
necessary in a medical emergency. Any medication or therapy that is taken by or administered to 
the subject during the course of the study must be recorded in the eCRF. The entry must include 
the dose, regimen, route, indication, and dates of use. 
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. 
• Within 5 half-lives or 1 week, whichever is longer, before baseline (Day -1), subjects 
could not have taken oral antipsychotic medications, MAO inhibitors, mood stabilizers 
(ie, lithium), anticonvulsants (eg, lamotrigine, Depakote), tricyclic antidepressants (eg, 
imipramine, desipramine), selective serotonin reuptake inhibitors, or any other 
psychoactive medications except for anxiolytics that were taken on an as needed basis 
(eg, lorazepam, chloral hydrate).  
• Subjects taking a long acting injectable antipsychotic could not have received a dose of 
medication for at least 12 weeks (24 weeks for INVEGA TRINZA®).  
Note: Please direct questions relating to prohibited medications to the Medical Monitor. 
 
Concomitant Medications for Anxiety and/or Sleep aid 
Subjects are allowed to take benzodiazepines (up to 6 mg lorazepam/day or equivalent) for 
anxiety, agitation, and insomnia. Subjects may also use non-benzodiazepine medications 
(eg, zolpidem, zaleplon) as a sleep aid. Study sites must record the use of rescue medications in 
the eCRF and subject’s source document. Note: Cognition testing should not be done within 
8 hours of receiving a benzodiazepine or sleep medication. 
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10 STUDY PROCEDURES 
Table 2 outlines the timing of procedures and assessments to be performed throughout the study. 
Section 12.6 specifies laboratory assessment samples to be obtained. See Sections 11, 12, and 13 
for additional details regarding efficacy, safety, and PK assessments, respectively. 
  
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Table 2. 
Schedule of Assessments 
PROCEDURE 
SCREENING 
PHASE 
TREATMENT PHASE 
SAFETY 
FOLLOW
-UPv 
Unscheduled 
Visit(s)b 
VISIT 
1 
(Day -8 
to -2)a 
2a 
(Day 
-1) 
2b 
(Day 
1) 
3 
(Day
3 +1 
day)
4 
(Day 
7 ±2 
days) 
5 
(Day 
8 ±2 
days) 
6 
(Day 
14 ±2 
days) 
7 
(Day 
21 ±2 
days) 
8 
(Day 
28 ±2 
days)u 
9 
(Day 
32 +1 
day) 
10/ET 
(Day 35 
-2 days)
11 
(Day 42 
+5 days) 
WEEKS PAST 
RANDOMIZATION 
NA 
0 
 
 
1 
 
2 
3 
4 
 
5 
6 
 
Written informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Collect 
demographic 
information (date of 
birth, sex, race) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(females of 
childbearing 
potential only)c 
X
c 
X
c 
 
 
 
 
 
 
 
 
X
c 
X
c 
 
Urine test for 
drugs of abuse 
and alcohol 
testingd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Review of 
inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Subject eligibility 
verification process 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, 
psychiatric, and 
medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examinatione 
X
e 
 
 
 
 
 
 
 
 
 
X
e 
X 
 
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PROCEDURE 
SCREENING 
PHASE 
TREATMENT PHASE 
SAFETY 
FOLLOW
-UPv 
Unscheduled 
Visit(s)b 
VISIT 
1 
(Day -8 
to -2)a 
2a 
(Day 
-1) 
2b 
(Day 
1) 
3 
(Day
3 +1 
day)
4 
(Day 
7 ±2 
days) 
5 
(Day 
8 ±2 
days) 
6 
(Day 
14 ±2 
days) 
7 
(Day 
21 ±2 
days) 
8 
(Day 
28 ±2 
days)u 
9 
(Day 
32 +1 
day) 
10/ET 
(Day 35 
-2 days)
11 
(Day 42 
+5 days) 
WEEKS PAST 
RANDOMIZATION 
NA 
0 
 
 
1 
 
2 
3 
4 
 
5 
6 
 
Spontaneous AEsf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of 
concomitant 
medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height (Screening 
only) and body 
weight, BMI, waist 
circumference 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Orthostatic vital 
signs: BP and heart 
rateg 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Resting 12-lead ECGh 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
Blood samples for 
hematology, 
coagulation, and 
serum chemistry and 
urine sample for 
urinalysisi 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
COVID-19 
testing 
X 
X 
 
 
 
 
 
 
 
 
 
 
Xj 
Blood sample 
for prolactink 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Blood sample 
for viral 
serologyl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
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PROCEDURE 
SCREENING 
PHASE 
TREATMENT PHASE 
SAFETY 
FOLLOW
-UPv 
Unscheduled 
Visit(s)b 
VISIT 
1 
(Day -8 
to -2)a 
2a 
(Day 
-1) 
2b 
(Day 
1) 
3 
(Day
3 +1 
day)
4 
(Day 
7 ±2 
days) 
5 
(Day 
8 ±2 
days) 
6 
(Day 
14 ±2 
days) 
7 
(Day 
21 ±2 
days) 
8 
(Day 
28 ±2 
days)u 
9 
(Day 
32 +1 
day) 
10/ET 
(Day 35 
-2 days)
11 
(Day 42 
+5 days) 
WEEKS PAST 
RANDOMIZATION 
NA 
0 
 
 
1 
 
2 
3 
4 
 
5 
6 
 
Blood sample 
for DNA testing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Functional 
constipation inquirym 
 
X 
 
X
X 
X 
X 
X 
X 
 
X 
X 
X 
Admission of subject 
to inpatient unitn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization/
assignment of 
subject 
randomization 
number 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Determination of dose 
adjustment 
 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
Study drug provided 
(randomized, double- 
blind) and 
administered daily 
BIDo 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Blood samples for PK 
analysisp 
 
 
 
 
 
X
p 
 
 
X
p 
 
X
p 
 
X
p 
MINI version 7.0.2q 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Positive and Negative 
Syndrome Scale 
(PANSS) for 
schizophreniar 
X 
X 
 
 
 
 
X 
X 
X 
 
X 
 
 
C-SSRSs 
X 
X 
 
 
X 
 
X 
X 
X 
 
X 
X 
X
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PROCEDURE 
SCREENING 
PHASE 
TREATMENT PHASE 
SAFETY 
FOLLOW
-UPv 
Unscheduled 
Visit(s)b 
VISIT 
1 
(Day -8 
to -2)a 
2a 
(Day 
-1) 
2b 
(Day 
1) 
3 
(Day
3 +1 
day)
4 
(Day 
7 ±2 
days) 
5 
(Day 
8 ±2 
days) 
6 
(Day 
14 ±2 
days) 
7 
(Day 
21 ±2 
days) 
8 
(Day 
28 ±2 
days)u 
9 
(Day 
32 +1 
day) 
10/ET 
(Day 35 
-2 days)
11 
(Day 42 
+5 days) 
WEEKS PAST 
RANDOMIZATION 
NA 
0 
 
 
1 
 
2 
3 
4 
 
5 
6 
 
CGI-S Scale 
X 
X 
 
 
X 
 
X 
X 
X 
 
X 
 
 
Cognition testingt 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
Simpson-Angus 
Rating Scale 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Barnes Rating Scale 
for Akathisia 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Abnormal 
Involuntary 
Movement Scale 
(AIMS) 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Abbreviations: AE = adverse event; BID = twice daily; BMI = body mass index; BP = blood pressure; CGI-S = Clinical Global Impression‒Severity scale; 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ET = early termination; ID = identification; MINI = Mini International 
Neuropsychiatric Interview; PK = pharmacokinetic; QTcF = QT interval corrected by Fridericia. 
a. 
Up to a 7-day extension of the screening phase is allowed, if needed. 
b. 
Other assessments as needed. 
c. 
A serum pregnancy test for females of childbearing potential should be done at screening, and urine pregnancy tests should be done at other visits. 
d. 
A National Institute on Drug Abuse-5 urine drug screen (cannabinoids or marijuana, phencyclidine, amphetamines, opiates, and cocaine) will be 
performed at screening and at Visit 2a (baseline). If a subject leaves the study site, he/she should have a urine drug screen and test for alcohol 
(breathalyzer or blood alcohol level) upon returning to the study site.  
e. 
A complete physical examination includes body temperature (°C), general appearance, head/eyes/ears/nose/throat, examination of thorax and 
abdomen, assessment of cardiac, musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited neurological 
examination. 
f. 
AEs as reported by subjects or observed by clinical staff and occurs from Day -1. One PK blood sample may be drawn if a relevant/significant AE 
(based on medical judgement) is reported during a scheduled visit or if there is a dose adjustment or a relevant/significant AE reported during an 
unscheduled visit (no multiple draws). 
g. 
Vital signs taken supine and standing after 2 minutes. BP includes systolic and diastolic BP and is to be taken in the same arm for the duration of the 
study. Heart rate is measured in beats/minute. During treatment, beginning with Day 1, orthostatic vital signs should occur 2 (±1) hours after morning 
dosing. Orthostatic vital signs are only required after the morning dose of the specified visit days, but additional orthostatic vital sign monitoring is 
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allowed at the investigator’s discretion. It would be acceptable, for example, to do orthostatic vital signs BID after dosing increases for a day or 2 for 
subjects where it seems warranted, but this should not be done automatically. 
h. 
ECG on Day 1 will be done at 2 hours + 15 minutes post morning dose. ECGs at all other scheduled visits will be performed before blood withdrawal for 
any safety laboratory tests and/or PK analysis. During the ECG, ventricular rate (bpm), PR (msec), QRS (msec), QT (msec), and QTcF (msec) 
measurements should be obtained.  
i. 
Refer to Table 3 for individual laboratory tests. 
j. 
Optional COVID-19 test may be performed at unscheduled visits based on the Investigator’s discretion. 
k. 
Blood sample for prolactin must be obtained before the morning dose of the study drug at scheduled visits (except at Visit 2a). 
l. 
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. 
m. Functional constipation inquiry: At specified visits, subjects will be asked whether they have experienced constipation (per the ROME III criteria and 
Bristol Stool Form scale; see APPENDIX 2) since the last visit and if yes, whether the constipation required intervention. If the subject answers yes, 
sites are instructed to ask subjects to provide event date and ensure the event is documented as an AE and treatment is documented as concomitant 
medication.  
n. 
If an eligible subject is not already an inpatient, the subject should be admitted to the inpatient unit. 
o. 
Starting on Day 1, study drug is administered daily BID (first dose of study will be administered in the morning of Day 1, and evening dose will be 
administered 12 ± 0.5 hours after the morning dose and after last PK sampling [for Visits 5 and 8] is completed), on an empty stomach (ie, at least 
1 hour before a meal) or 2 to 3 hours after a meal by the study staff, with the last dose administered on the evening before Visit 10 for subjects who do 
not enter Study KAR-008. For subjects rolling over to Study KAR-008, the last dose will be administered on the evening of Visit 10. All subjects must 
receive at least 4 dosages of the 50/20 BID before dose escalation to KarXT 100/20 BID. 
p. 
For Visit 5/Day 8 and Visit 8/Day 28, 7 PK blood draws are required: before the morning dose, and at 0.5 hour ± 5 minutes, 1 hour ± 5 minutes, 
2 hours ± 10 minutes, 4 hours ± 10 minutes, 8 hours ± 10 minutes, and 12 hours ± 10 minutes after the morning dose (Note: The 12-hour samples must 
be collected before administration of the evening dose). PK blood draws at Visit 5 must be drawn in relation to the first dose of KarXT 125/30 for 
subjects who are escalated in the morning of Visit 5/Day 8 ± 2 days. PK blood must also be drawn in relation to the morning dose for subjects who are 
not escalated at Visit 5/Day 8 ± 2 days. For Visit 10/ET, a single PK blood sample should be drawn before discharge (preferably in the morning) for 
completed (and early termination) subjects. One PK blood sample may also be drawn if a relevant/ significant AE is reported during a scheduled visit 
or if there is a dose adjustment or a relevant/significant AE reported during an unscheduled visit (no multiple draws). For an ET Visit that is related to 
an AE, the collection of a PK blood sample is not optional and should be drawn before discharge. 
q. 
It should be performed before PANSS assessment. 
r. 
It is recommended, if at all possible, that the PANSS assessment should be performed before all the other scale assessments for all visits at 
which it is performed. The PANSS assessment includes the Marder Factor. 
s. 
C-SSRS first time use lifetime, other times use “Since Last Visit” version. At the Unscheduled visit, the C-SSRS should be performed to monitor subjects 
for suicidality. 
t. 
During screening, subjects will complete each of the CANTAB tests for familiarization purposes. These same tests will then be administered on Visits 
2a, 7, and 9. Note: Cognition testing cannot be done within 8 hours of receiving benzodiazepine or sleep medications. 
u. 
Visit 8 must occur at least after 7 days after completion of Visit 7, and there must be no changes in dose for at least 7 days leading up to Visit 8. 
v. 
Safety follow-up visit will be performed 1 week (Day 42 +5 days) after the end of study visit for subjects who did not rollover in to the long-term 
open-label study KAR-008. 
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10.1 Informed Consent 
Informed consent forms must be approved for use by the reviewing IEC/IRB. Before performing 
any study-related procedures, the investigator (or designee) will obtain written informed consent 
from the subject.  
10.2 Study Procedures 
Assessments and their timings are to be performed as outlined in the Schedule of Assessments 
(Table 2). Section 12.6 specifies laboratory assessment samples to be obtained.  
Assessments and procedures scheduled at a visit where study drug is administered should be 
performed before administration of treatment unless otherwise indicated in the Schedule of 
Assessments (Table 2). 
Efficacy assessments are described in Section 11 and include PANSS and CGI-S scores. 
Safety assessments are described in Section 12 and include spontaneous AEs; cholinergic 
symptoms; cognition testing (CANTAB); SAS; BARS; AIMS; body weight; BMI; waist 
circumference; orthostatic vital signs; ECG; clinical laboratory assessments (hematology, clinical 
chemistry, coagulation, urinalysis, and drug screen); prolactin levels; physical examination; and 
C-SSRS. 
PK assessments are described in Section 13 and include estimation of AUC, Cmax, and Tmax. 
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 study drug. 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 after discussion with the 
medical monitor. 
Study discontinuation procedures are described in Section 8.4 and 8.6. 
 
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11 EFFICACY ASSESSMENTS 
The Schedule of Assessments (Table 2) outlines the efficacy assessments to be performed 
throughout the study and their timing. 
11.1 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[23]. 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. The PANSS assessment includes the Marder Factor. 
It is recommended, if at all possible, that the PANSS assessment should be performed before all 
the other scale assessments for all visits at which it is performed.  
11.2 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 modified CGI-S 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[24]. 
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 previous 7 days. 
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12 SAFETY ASSESSMENTS 
Safety assessments (spontaneous AEs; cholinergic symptoms; cognition testing [CANTAB]; 
SAS; BARS; AIMS; body weight; BMI; waist circumference; orthostatic vital signs; ECG; 
clinical laboratory assessments [hematology, clinical chemistry, coagulation, urinalysis, 
prolactin, and drug screen]; physical examination; and C-SSRS) are to be performed at 
protocol-specified visits, as specified in the Schedule of Assessments (Table 2).  
12.1 Demographics, and Medical 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 and psychiatric 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 12.7. All 
changes not present at baseline or described in the past medical history and identified as 
clinically noteworthy must be recorded as AEs. 
12.2 Vital Signs 
Orthostatic vital signs (systolic and diastolic BP and heart rate measurements) will be evaluated 
at the 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, beginning with Day 1, orthostatic vital signs should 
occur 2 (±1) hours after morning dosing. Orthostatic vital signs are only required after the 
morning dose of the specified visit days, but additional orthostatic vital sign monitoring is 
allowed at the investigator’s discretion. 
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. 
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12.3 Physical Examination 
A complete physical examination (body temperature, general appearance, 
head/eyes/ears/nose/throat, examination of thorax and abdomen, assessment of cardiac, 
musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited 
neurological examination) will be performed at visits as specified in Table 2. Physical 
examinations will be performed by a physician. 
12.4 Weight, Height, Body Mass Index, 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. 
12.5 Electrocardiograms 
A 12-lead, resting ECG will be obtained at the visits indicated in the Schedule of Assessments 
(Table 2). During the ECG, ventricular rate (bpm), PR (msec), QRS (msec), QT (msec), and 
QTcF (msec) measurements will be obtained. ECG at Day 1 will be performed 2 hours (+ 
15 minutes) post morning dose. ECGs at all other scheduled visits will be performed before 
blood withdrawal for any safety laboratory tests and/or PK analysis. 
All the ECGs obtained will be interpreted by experienced independent blinded reader(s) at the 
central laboratory. 
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 on the eCRF. ECGs will be 
repeated if clinically significant abnormalities are observed or artifacts are present. 
12.6 Laboratory Assessments 
Laboratory assessment samples (Table 3) are to be obtained at designated visits as detailed in the 
Schedule of Assessments (Table 2). 
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Table 3. 
Laboratory Assessments 
Hematology 
Serum Chemistry 
Urine Analysis (Dipstick) 
Full and differential blood count 
Hct 
Hb 
MCH 
MCHC 
MCV 
Platelet count 
RBC count 
WBC count with differential 
 
Albumin 
ALT 
ALP 
AST 
Albumin 
Uric acid 
BUN or urea 
Carbon dioxide 
Creatinine 
Creatine kinase and subtypes 
Electrolytes (sodium, 
potassium, chloride, calcium, 
phosphorus) 
GGT 
Glucose 
LDH 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Triglycerides 
Total protein 
Appearance 
pH 
Protein 
Glucose 
Ketone bodies 
Indicators of blood and WBCs 
Specific gravity 
Urobilinogen 
Occult blood 
WBCs 
 
Prolactin 
Coagulation 
Serologya 
COVID-19 
PT 
Activated PTT 
Fibrinogen 
HBV 
HCV 
HIV 
 
Pregnancy test: A serum pregnancy test will be performed on all women of childbearing potential at 
screening and a urine pregnancy test (urine HCG) will be performed at other scheduled visits.  
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; GGT = gamma-glutamyl transpeptidase; Hb = hemoglobin; HBV = Hepatitis B; 
HCG = human chorionic gonadotropin; Hct = hematocrit; HCV = Hepatitis C; HIV = Human Immunodeficiency 
virus; LDH = lactate dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular 
hemoglobin concentration; MCV = mean corpuscular volume; PT = prothrombin time; PTT = partial 
thromboplastin time; RBC = red blood cell; WBC = white blood cell. 
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. 
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 urine volume of 10 mL will be obtained to perform urinalysis and urine drug screen 
at scheduled time points as per Table 2.  
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Blood and urine samples will be analyzed at a central laboratory facility. Urine samples will be 
analyzed by dipstick, and a microscopic analysis will be performed if the results of dipstick 
indicate abnormalities to be further investigated. All laboratory reports must be reviewed, signed, 
and dated by the investigator. A legible copy of all reports must be filed with both the subject’s 
eCRF and medical record (source document) for that visit. Any laboratory test result considered 
by the investigator to be clinically significant should be considered an AE (clinically significant 
AEs include those that require an intervention). Clinically significant abnormal values occurring 
during the study will be followed up with until repeat test results return to normal, stabilize, or 
are no longer clinically significant.  
All the study subjects will be closely monitored for drug-induced liver toxicity, detailed in 
Section 12.7.5, during the study. 
Other Laboratory Assessments: 
• A National Institute on Drug Abuse-5 urine drug screen (cannabinoids or marijuana, 
phencyclidine, amphetamines, opiates, and cocaine) will be performed at screening and at 
Visit 2a (baseline).  
• Alcohol testing is performed using a breathalyzer or blood alcohol test.  
• If a subject leaves the study site, he/she should have a urine drug screen test and test for 
alcohol (breathalyzer or blood alcohol test) upon returning to the study site. 
 
Blood Sampling for Pharmacogenetics 
A blood sample may be collected at baseline (Day -1) for exploratory pharmacogenetic analysis. 
Approximately 9 mL of blood may be collected for subsequent DNA extraction. The samples 
will be stored at a central laboratory facility, where DNA will be extracted and retained. The 
collection, storage, shipping, processing of the blood samples, and the analytical methods to be 
used will be detailed in the laboratory manual.  
The genetic variants to be analyzed may include SNPs and any other variants as deemed 
necessary by the Sponsor.  
The details on the statistical analysis will be provided either in the statistical analysis plan (SAP) 
or the clinical study report. 
12.7 Adverse Events 
 
Adverse Events 
An AE is any symptom, physical sign, syndrome, or disease that either emerges during the study 
or, if present at screening, 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) 
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present at screening will be documented in the medical history eCRF. Changes in these 
conditions and new symptoms, physical signs, syndromes, or diseases should be noted on the AE 
eCRF during the rest of the study. Clinically significant laboratory abnormalities should also be 
recorded as AEs. Surgical procedures that were planned before the subject enrolled in the study 
are not considered AEs if the conditions were known before study inclusion; the medical 
condition should be reported in the subject’s medical history. 
In accordance with the protocol, the investigator and/or study staff will elicit AEs and 
intercurrent illness during and at the end of the study period, and these will be recorded on the 
appropriate page of the eCRF. 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 laboratory tests 
are available. 
Each AE is to be documented on the eCRF with reference to date of onset, duration, frequency, 
severity, relationship to study drug, action taken with study drug, treatment of event, and 
outcome. Furthermore, each AE is to be classified as being serious or nonserious. Changes in 
AEs and resolution dates are to be documented on the eCRF. 
For the purposes of this study, the period of observation for collection of AEs extends from the 
time immediately after the administration of study drug on Day 1 until the End of Study (Visit 10 
for subjects who roll over and Visit 11 for subjects who do not roll over to Study KAR-008 
study) or early termination. Follow up of the AE, even after the date of therapy discontinuation, 
is required if the AE persists until the event resolves or stabilizes at a level acceptable to the 
investigator. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the event should be noted. If the intensity category changes over a number of days, 
then those changes should be recorded separately (with distinct onset dates). 
The severity of AEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events, version 5.0 (Grades 1 through 5). 
Specific guidelines for classifying AEs by intensity and relationship to study drug are given in 
Table 4 and Table 5. 
Table 4. 
Classification of Adverse Events by Intensity 
MILD: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with 
everyday activities. 
MODERATE: An event that is sufficiently discomforting to interfere with normal everyday activities. 
SEVERE: An event that prevents normal everyday activities. 
 
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Table 5. 
Classification of Adverse Events by Relationship to Study Drug 
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 study drug 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 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 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 reexposure to drug (if rechallenge occurs); and (4) it follows a known pattern 
of response to the test drug. 
Abbreviation: AE, adverse event. 
 
 
Adverse Events of Special Interest 
The AEs of special interest will be monitored. AE of special interest is orthostasis. 
AEs of special interest should be recorded as AEs and reported as SAEs when appropriate. 
 
Serious Adverse Events 
A, 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 
(hospitalization for elective treatment of a pre-existing, nonworsening condition is not, 
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however, considered an SAE; the details of such hospitalizations must be recorded on the 
medical history or physical examination page of the eCRF), 
• results in persistent or significant disability/incapacity, and/or 
• is a congenital anomaly/birth defect. 
Other important medical events that may not be immediately life-threatening or result in death or 
hospitalization, based upon appropriate medical judgment, are considered SAEs if they are 
thought to jeopardize the subject and/or require medical or surgical intervention to prevent one 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 first dose of the study drug is administered, during the study, or 
within 1 week of stopping the treatment must be reported to the Catalyst Clinical Research 
Pharmacovigilance group and will be communicated to the Sponsor. Any such SAE due to any 
cause, whether or not related to the study drug, 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 is: 
 
The events must be recorded on the standard AE eCRF. Preliminary reports of SAEs must be 
followed up by detailed descriptions later on, including clear and anonymized photocopies of 
hospital case reports, consultant reports, autopsy reports, and other documents when requested 
and applicable. SAE reports must be made whether or not the investigator considers the event to 
be related to the investigational drug. 
Appropriate remedial measures should be taken to treat the SAE, and the response should be 
recorded. The investigator must report all additional follow-up evaluations to the Catalyst 
Clinical Research Pharmacovigilance group within 24 hours of becoming aware of the additional 
information or as soon as is practicable. All SAEs will be followed up until the investigator and 
Sponsor agree the event is satisfactorily resolved. 
Any SAE that is not resolved by the end of the study or upon discontinuation of the subject’s 
participation in the study is to be followed up until it either resolves, stabilizes, returns to 
baseline values (if a baseline value is available), or is shown to not be attributable to the study 
drug or procedures. 
 Drug-Induced Liver Injury 
The sponsor has incorporated the following for monitoring of the drug induced liver injury: 
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• An increase of serum ALT or AST to >3 × upper limit of normal (ULN) should be 
followed by repeat testing within 48 to 72 hours of all 4 of the usual serum measures 
(ALT, AST, ALP, and total bilirubin) to confirm the abnormalities and to determine if 
they are increasing or decreasing. An inquiry should be made about the symptoms 
(fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, and rash). 
• Close observation should be initiated with ALT or AST >3 × ULN: 
o Repeat liver enzyme and serum bilirubin tests 2 or 3 times weekly. Frequency of 
retesting can decrease to once per week or less if abnormalities stabilize or the trial 
drug has been discontinued, and the subject is asymptomatic. 
o Obtain a more detailed history of symptoms and prior or concurrent diseases. 
o Obtain a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug 
use, and special diets. 
o Rule out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy; and biliary 
tract disease. 
o Obtain a history of exposure to environmental chemical agents. 
o Obtain additional tests to evaluate liver function, as appropriate (eg, international 
normalized ratio, direct bilirubin). 
o Consider gastroenterology or hepatology consultations. 
• Discontinuation of treatment should be considered if: 
o ALT or AST >8 × ULN 
o ALT or AST >5 × ULN for more than 2 weeks 
o ALT or AST >3 × ULN and (total bilirubin >2 × ULN or international normalized 
ratio >1.5) 
o ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or eosinophilia (>5%) 
• Hepatic adjudication of cases should include an evaluation for alternative causes such as 
viral, autoimmune, alcohol, hepatobiliary disorders, nonalcoholic steatohepatitis, 
concomitant medications, etc. 
• Follow up to resolution of elevated liver enzymes. 
• Gamma-glutamyl transpeptidase elevations alone should not prompt drug 
discontinuation. 
 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 
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The investigator will assess whether or not an event is causally related to study treatment. The 
Sponsor (or their designee Syneos Health) will consider the investigator’s assessment and 
determine whether the event meets the criteria for being reportable as a 7-day or 15-day safety 
report. SUSARs that are fatal or life-threatening must be reported to the regulatory authorities 
and the IEC/IRBs (where required) within 7 days after the Sponsor (or their designee) 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 their designee) first has knowledge of them. 
The Sponsor (or their designee) 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: 
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 
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after beginning treatment or increasing the dose. Advise subjects not to drive or operate heavy 
machinery until they know how trospium chloride affects them. If a subject experiences 
anticholinergic CNS effects, dose reduction or drug discontinuation should be considered. 
Anticholinergic Adverse Reactions in Subjects with Moderate Renal Impairment: 
Trospium is substantially excreted by the kidney. The effects of moderate renal impairment on 
systemic exposure are not known but systemic exposure is likely increased. Therefore, 
anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract 
infection, and urinary retention) are expected to be greater in subjects with moderate renal 
impairment. 
 
Pregnancy 
WOCBP must have a negative pregnancy test at screening. After administration of study drug, 
any known cases of pregnancy in female subjects will be reported until the subject completes or 
withdraws from the study. The pregnancy will be reported immediately by faxing/emailing a 
completed pregnancy report to the Sponsor (or designee) within 24 hours of knowledge of the 
event. The pregnancy will not be processed as an SAE; however, the investigator will follow up 
with the subject until completion of the pregnancy and must assess the outcome in the shortest 
possible time but not more than 30 days after completion of the pregnancy. 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 an SAE. 
Upon discontinuation from the study, only those procedures that would not expose the subject to 
undue risk will be performed. The investigator should also be notified of pregnancy occurring 
during the study but confirmed after completion of the study. In the event that a subject is 
subsequently found to be pregnant after inclusion in the study, any pregnancy will be followed to 
term, and the status of mother and child will be reported to the Sponsor after delivery. 
 
Overdose 
The investigator must immediately notify the Sponsor of any occurrence of overdose with study 
drug. Overdose should be managed with symptomatic and supportive care. 
12.8 Cambridge Neuropsychological Test Automated Battery 
The computerized CANTAB provides an objective measure of cognitive function correlated to 
neural networks. A short cognitive battery measuring core cognitive domains of impairment in 
schizophrenia (ie, as per Brief Assessment of Cognition Schizophrenia key cognitive domains) 
will be employed for this study, and it will take approximately 30 minutes to complete. These 
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CANTAB tests meet MATRICS workshop criteria[25]. Subjects will have 1 familiarization 
session with the CANTAB tests during the screening visit and will subsequently complete the 
same test battery on Visits 2a (baseline), Visit 7, and Visit 9. Subjects perform the test on a 
provisioned iPad with data immediately uploaded to the CANTAB Connect cloud-based 
platform (WiFi permitting). 
Cognition testing cannot be done within 8 hours of receiving benzodiazepine or sleep 
medications. 
Table 6 
Cognitive Tests and Cognitive Domains Assessed by the Cambridge 
Neuropsychological Test Automated Battery 
CANTAB Tests 
MATRICS Cognitive Domain 
Outcome Measures 
Rapid visual information 
processing 
Sustained attention/vigilance 
A’ Prime: Signal detection 
measure of how good the subject is 
at detecting the target sequence 
(string of three numbers); 
regardless of response tendency 
Verbal recognition memory 
Verbal memory and new learning 
Free Recall: The total number of 
words that are correctly recalled 
from the presentation phase by the 
subject during the immediate free 
recall stage 
Spatial Span 
Working memory 
Forward Span Length: The 
longest sequence of boxes 
successfully recalled by the subject 
One-touch stockings of Cambridge  
Executive Function 
Planning/Problem Solving 
Problems Solved on First Choice: 
The total number of assessed trials 
where the subject chose the correct 
answer on their first attempt 
Abbreviation: CANTAB = Cambridge Neuropsychological Test Automated Battery 
12.9 Simpson-Angus 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. 
12.10 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[26]. 
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12.11 Abnormal Involuntary Movement Scale 
The AIMS is a rating scale that is used to measure involuntary movements know as tardive 
dyskinesia, which can sometimes develop as a side effect of long-term treatment with 
antipsychotic medications. It is a 12-item scale to assess orofacial, extremity, and truncal 
movements as well as the overall severity, incapacitation, and the subject’s level of awareness of 
the movements. Items are scored from 0 (none) to 4 (severe). A higher score indicates more 
severe dyskinesia. 
12.12 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[27]. 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 “lifetime” version 
will be completed; for all subsequent visits the “Since Last Visit” version of the C-SSRS will be 
administered. 
12.13 Functional Constipation Inquiry 
Constipation refers to bowel movements that are infrequent or hard to pass[28]. The stool is 
often hard and dry[29]. Other symptoms may include abdominal pain, bloating, and feeling as if 
one has not completely passed the bowel movement[30]. The normal frequency of bowel 
movements in adults is between 3 per day and 3 per week[28]. Constipation will be defined per 
the Rome III criteria, as less than 3 bowel movements per week, APPENDIX 2 
(Longswreth,1486,C3)[31]. 
The Bristol Stool Form Scale has been correlated with a change in intestinal function, and had 
been shown to be a useful tool in clinical practice and research[32]. A sample Bristol Stool Form 
Scale is located in APPENDIX 2. 
As a measure of anticholinergic effects, at each visit, subjects will be asked whether they have 
experienced constipation per the ROME III criteria since the last visit, and if yes, whether the 
constipation required intervention. If the subject answers yes, sites are instructed to ask subjects 
to provide event date and ensure event is documented as an AE and treatment is documented as 
concomitant medication. Subjects will not be required to collect and present their stool sample 
nor will clinic staff be required to corroborate the subject assessment. 
Additional attention can be given to other complaints as well including: straining with bowel 
movements, excessive time needed to pass a bowel movement, hard stools and pain with bowel 
movements secondary to straining, abdominal pain, abdominal bloating, and the sensation of 
incomplete bowel evacuation[30, 33]. 
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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. 
12.14 Mini International Neuropsychiatric Interview Version 7.0.2 
The MINI is a short structured diagnostic interview developed for DSM-5 psychiatric disorders. 
With an administration time of approximately 15 minutes, it was designed to meet the need for a 
short but accurate structured psychiatric interview for multicenter clinical studies and 
epidemiology. 
12.15 Change in Prolactin 
Blood samples to assess the change in prolactin levels will be obtained on Visit 2a/Day -1, 
Visit 7/Day 21 ± 2 days, and Visit 10/Day 35 -2 days/Early Termination (ET). At each of these 
visits (except Visit 2a), blood sample must be collected before the morning dose of the study 
drug. 
 
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13 PHARMACOKINETICS 
13.1 Pharmacokinetic Sampling 
 
Blood Samples 
Blood samples for PK analysis of KarXT levels will be collected at the time points indicated in 
the Schedule of Assessments (Table 2). Approximately 6 mL of blood to be collected at each 
scheduled time point. The actual date and time of each blood sample collection will be recorded. 
• Serial blood samples to measure plasma concentrations of xanomeline and trospium will be 
obtained on Visit 5/Day 8 ± 2 days (first dose of fixed titration period) and Visit 8/Day 28 
± 2 days. Blood samples will be obtained at the following time points on these days:  
• Before the morning dose and at 0.5, 1, 2, 4, 8, and 12 hours after the morning dose (Note: 
The 12-hour sample must be collected before administration of the evening dose).  
• The 0.5 and 1 hour samples should be collected within ± 5 minutes of the scheduled time. 
The 2, 4, 8, and 12 hour samples should be collected within ± 10 minutes of their scheduled 
times and before the evening dose. It is very important that the exact time of each PK draw 
and dosing times are recorded in the eCRF and that PK samples are collected within the 
specified times of collection. 
• Should the use of visit windows be necessary, serial PK sampling must accompany the 
actual day of potential dose escalation for Visit 5. 
•  For Visit 8, serial PK sampling is meant to capture the PK profile of the subject’s final 
KarXT dose level (125/30 or 100/20) after multiple doses. If visit windows are used for 
Visit 8, the PK sampling should occur at least 7 days after Visit 7 is completed, and there 
must be no changes in dose for at least 7 days leading up to Visit 8. PK sampling must 
accompany the actual day of Visit 8.  
Note: A single PK sample should be drawn before discharge (preferably in the morning) at 
Visit 10/Day 35 -2 days or ET. In addition, one PK sample may be drawn if a 
relevant/significant AE is reported during a scheduled visit or if there is a dose adjustment 
or relevant/significant AE reported during an unscheduled visit (no multiple draws). For an 
ET Visit that is related to an AE, the collection of a PK blood sample is not optional and 
should be drawn before discharge. 
Details of PK blood sample collection, processing, storage, and shipping procedures will be 
provided in a separate laboratory manual. 
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13.2 Pharmacokinetic Analytical Methodology 
Concentrations of trospium and xanomeline will be determined from plasma PK samples using a 
validated analytical method. Details of the method validation and sample analysis will be 
included with the final clinical study report. 
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14 STATISTICAL ANALYSIS 
A 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 compliment to the protocol and supersedes it in case of 
differences. 
The statistical evaluation will be performed using SAS® software version 9.4 or higher 
(SAS Institute, Cary, NC). All data will be listed, and summary tables will be provided. 
Summary statistics will be presented by dose group. For continuous variables, data will be 
summarized with the number of subjects (N), mean and standard deviation, median, minimum, 
and maximum by treatment group. For categorical variables, data will be tabulated with the 
number and proportion of subjects for each category by treatment group. 
14.1 Determination of Sample Size 
Assuming treatment difference of change from baseline in PANSS total score at Week 5 is 
8 points between drug and placebo (standard deviation 16), a sample size of approximately 
172 (86 evaluable subjects per arm) will result in a power of 90.3% for a 2-sided alpha of 0.05 
(P ≤ 0.05). With a dropout rate of 30%, a total of 246 subjects are estimated to be enrolled. 
14.2 Analysis Populations 
Intent-to-Treat Population 
All subjects who are randomized to the study will be included in the intent-to-treat (ITT) 
population. 
Modified ITT Population 
All subjects who are randomized, received at least 1 dose of study drug, have a baseline PANSS 
assessment, and at least 1 post-baseline PANSS assessment will be included in the mITT 
population and will be used in the efficacy analysis. 
Safety Population 
All subjects who received at least 1 dose of study drug will be included in the safety population 
and will be used in the safety analysis. 
PK Population 
All subjects who have an evaluable PK profile will be included in the PK population and will be 
used in the PK analysis. Subjects must have received at least 1 dose of active study drug and 
have at least 1 measurable plasma concentration of study drug.  
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14.3 General Statistical Considerations 
All efficacy analyses will be performed using the mITT population. The statistical analysis of the 
primary and key secondary efficacy variables will account for multiplicity by using a fixed 
sequence testing procedure. The primary endpoint of change from baseline to Week 5 in PANSS 
total score will be evaluated first. The endpoints are set up as a hierarchical list and step down 
through the statistical testing of each endpoint using an alpha of 0.05. Statistical testing of 
change from baseline to Week 5 in PANSS positive score, PANSS negative score, PANSS 
Negative Marder Factor score, CGI-S, and percentage of PANSS responders will be performed 
only if the primary endpoint is significant at the 0.05 alpha level (P ≤ 0.05), and testing would 
continue through a pre-ordered list of key secondary efficacy endpoints. If at any point P > 0.05, 
then formal statistical testing would stop. This will control the overall Type 1 error rate across all 
hypotheses/endpoints being tested. Table 7 outlines the testing procedure.  
Table 7 
Statistical Testing Procedure 
KarXT vs Placebo 
1. Change from baseline in PANSS total score at Week 5 
2. Change from baseline in PANSS positive score at Week 5 
3. Change from baseline in PANSS negative score at Week 5 
4. Change from baseline in PANSS Negative Marder Factor score at Week 5 
5. Change from baseline in CGI-S score at Week 5 
6. Percentage of PANSS responders (a 30% change in PANSS total score) at Week 5  
 
14.4 Efficacy Analysis 
 
Analysis of the Primary Efficacy Endpoint 
The primary efficacy endpoint of the study is the change from baseline in PANSS total score at 
Week 5. The difference between KarXT and placebo at Week 5 will be estimated using a mixed 
model for repeated measures (MMRM). The model will include the change from baseline 
PANSS total scores at Week 2, Week 3, Week 4, and Week 5 as the response. The treatment 
difference at Week 5 will be estimated using contrasts. The MMRM will include the treatment 
group (KarXT or placebo), visit, and the interaction between the treatment group and visit as 
fixed factors. Site, age, sex, and baseline PANSS total score will be used as covariates in the 
model. Low-enrolling sites will be pooled, if necessary, for modeling purposes. The algorithm 
for pooling sites will be specified in the SAP. 
Sensitivity analyses of the primary efficacy endpoint may be performed on an observed case 
basis, using multiple imputation techniques, and classifying treatment dropouts as treatment 
failures. The sensitivity analyses of the primary endpoint will be specified in the SAP. 
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Analysis of Secondary Efficacy Endpoints 
The continuous secondary endpoints (change from baseline to Week 5 in PANSS positive score, 
PANSS negative score, PANSS Negative Marder Factor score, and CGI-S) will be analyzed in 
the same manner as the primary efficacy analysis (ie, using MMRM).  
The categorical secondary endpoint (percentage of PANSS responders at Week 5) will be 
compared between the treatment groups (KarXT and placebo) using the Cochran-Mantel-
Haenszel test.  
The statistical analysis of the primary and key secondary efficacy variables will account for 
multiplicity by using a fixed sequence testing procedure. This testing procedure will control the 
overall Type 1 error rate across all hypotheses/endpoints being tested. 
14.5 Safety Analysis 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities version 
22.1 or higher. The incidence of TEAEs (events with onset dates on or after the start of the study 
drug) will be summarized for each treatment group separately by System Organ Class and 
Preferred Term. All AEs will be listed by subject, along with information regarding onset, 
duration, relationship and severity to study drug, action taken with study drug, treatment of 
event, and outcome. 
Orthostatic vital signs, clinical laboratory data, prolactin levels, ECG parameters, and physical 
examinations will be summarized using descriptive statistics, including observed and change 
from baseline values, as well as numbers of subjects with values outside limits of the normal 
range at each time point by treatment group. Similar descriptive summaries will be provided for 
C-SSRS, SAS, BARS, change in cognition (CANTAB), AIMS, body weight, BMI, and waist 
circumference. 
14.6 Pharmacokinetic Analysis 
• PK results will be listed for all subjects who received active treatment. The profiles or time 
points obtained with protocol deviations affecting PK results will be flagged and may be 
excluded from summaries and analyses. 
• The data will be presented graphically via individual plots and mean plots summarized by 
actual treatment, visit, and time point.  
• PK parameters for xanomeline and trospium will be derived from plasma concentration 
data using noncompartmental methods. Actual time elapsed from dosing will be used to 
estimate all individual PK parameters. The primary PK parameters of interest will include 
Cmax, Tmax, and AUC from 0 to 12 hours (or from 0 to the last measurable concentration). 
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Additional parameters (not limited to the following) such as the elimination half-life, 
clearance, and volume of distribution will be determined if the data permit. 
• The effect of dose on PK and other inferential analyses for exposure-response relationship 
may be performed. The details of the PK analysis will be described in the SAP. The 
noncompartmental analysis will be described as a part of final clinical study report. 
14.7 Interim Analysis  
No interim analysis is planned for this study. 
14.8 Handling of Missing Data 
Several different methods to handle the missing data in the primary efficacy endpoint analysis 
may be used. 
• For the primary efficacy analysis, likelihood-based modeling approach will be used to 
handle incomplete data. For this purpose, an MMRM will be applied. 
• Sensitivity analysis for the primary efficacy endpoint will be conducted using the last 
observation carried forward approach. In this analysis, the missing values will be 
replaced by the previous visit PANSS total score carried forward.  
• Sensitivity analysis for the primary efficacy endpoint will be conducted using the 
Multiple Imputation approach (ie, by replacing each missing value with a set of plausible 
values that represent the uncertainty about the right value to impute). 
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15 STUDY MANAGEMENT 
15.1 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. 
 
Independent Ethics Committee/Institutional Review Board 
Conduct of the study must be approved by an appropriately 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 principal investigator or designee must explain orally 
and in writing the nature of the study, its purpose, procedures, expected duration, alternative 
therapy available, and the benefits and risks involved in study participation. The subject should 
be informed that he/she may withdraw from the study at any time, and the subject will receive all 
information that is required by local regulations and guidelines for ICH. The principal 
investigator 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 caregiver informed consent (Ukraine only) should be obtained before any data pertaining to 
him or her and the subject is collected. 
Subject Registry (for the US only): 
Clinical trial registries, such as clinical trial subject database (CTSdatabase) and Verified 
Clinical Trials (VCT), seek to reduce duplicate enrollment by identifying potential protocol 
violations and duplicate subjects before randomization. At the time of providing the informed 
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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On Day -1 before any 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 reports will detail each protocol violation 
detected and specific washout period dates where applicable. Participants who are identified as 
verification failures by CTS or VCT should not be enrolled without documented approval from 
Karuna or Syneos Health.  
At the last subject contact, CTSdatabase and VCT staff will automatically close out the subject 
(safety follow-up, ET, or completer) based on interactive response system (IXRS). 
Verified Clinical Trials Registry (for Ukraine only): 
At participating sites in Ukraine, VCT will be used to verify participants’ current and past 
research study status in order to mitigate safety concerns associated with duplicate enrollment 
and protocol deviations associated with multiple trial enrollment. Following proper regionally 
compliant informed consent and after obtaining a subject number from IXRS, each participant 
will be checked in the VCT database. Partial identifiers will be utilized. Participants who are 
identified as verification failures by VCT should not be enrolled without documented approval 
from Karuna or Syneos Health. 
15.2 Data Handling 
Any data to be recorded directly on the eCRFs (to be considered as source data) will be 
identified at the start of the study. Data reported on the eCRF that are derived from source 
documents should be consistent with the source documents, or the discrepancies must be 
explained. See also Section 15.3.  
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Clinical data will be entered by site personnel on eCRFs for transmission to the Sponsor. Data on 
eCRFs transmitted via the web-based data system must correspond to and be supported by source 
documentation maintained at the study site, unless the study site makes direct data entry to the 
databases for which no other original or source documentation is maintained. In such cases, the 
study site should document which eCRFs are subject to direct data entry and should have in 
place procedures to obtain and retain copies of the information submitted by direct data entry. 
All study forms and records transmitted to the Sponsor must only include coded identifiers such 
that directly identifying personal information is not transmitted. The primary method of data 
transmittal is via the secure, internet-based electronic data capture (EDC) system maintained by 
Syneos Health. Access to the EDC system is available to only authorized users via the study’s 
secured internet web site, where a user unique assigned username and password are required for 
access. 
Any changes made to data after collection will be made through the use of the EDC system. 
Electronic CRFs will be considered complete when all missing and/or incorrect data have been 
resolved. 
15.3 Source Documents 
Source documents are considered to be all information in original records and certified copies of 
original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. The investigator will provide direct 
access to source documents and/or source data in the facilitation of trial-related monitoring, 
audits, review by IECs/IRBs, and regulatory inspections. 
The investigator/institution should maintain adequate and accurate source documents and trial 
records that include all pertinent observations on each of the site’s trial subjects. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, not obscure the original entry, and be explained if necessary. 
Data recorded on source documents will be transcribed onto eCRFs. Copies of completed eCRFs 
will be provided to the Sponsor and the sites at the end of the study. The completed eCRFs will 
be retained by the investigator. 
15.4 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 
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Health Insurance Portability Accountability Act of 1996 [HIPAA] 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. 
15.5 Monitoring 
The study will be monitored according to the KAR-009 monitoring plan to ensure that it is 
conducted and documented properly according to the protocol, GCP, and all applicable 
regulatory requirements. 
Monitoring visits, on-site and remote (telephone) or a combination and contacts will be made at 
appropriate times during the study. The Principal Investigator will assure him/her and adequate 
site personnel are available throughout the study to collaborate with clinical monitors. Clinical 
monitors must have direct access to source documentation in order to check the completeness, 
clarity, and consistency of the data recorded in the eCRFs for each subject. 
The investigator will make available to the clinical monitor all source documents and medical 
records necessary to review protocol adherence and eCRFs. In addition, the investigator will 
work closely with the clinical monitor and, as needed, provide them appropriate evidence that the 
study is being conducted in accordance with the protocol, applicable regulations, and GCP 
guidelines. 
15.6 Quality Control and Quality Assurance 
The Sponsor or its designee will perform the quality assurance and quality control activities of 
this study; however, responsibility for the accuracy, completeness, security, and reliability of the 
study data presented to the Sponsor lies with the investigator generating the data. 
The Sponsor will arrange audits as part of the implementation of quality assurance to ensure that 
the study is being conducted in compliance with the protocol, standard operating procedures, 
GCP, and all applicable regulatory requirements. Audits will be independent of and separate 
from the routine monitoring and quality control functions. Quality assurance procedures will be 
performed at study sites and during data management to assure that safety and efficacy data are 
adequate and well documented. 
15.7 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 
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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 eCRF/EDC system. Deviations considered 
major will be identified as such before study unblinding during medical monitor periodic 
review. 
Major protocol deviations will be tabulated including the frequency and percentage of subjects 
with each type of deviation by treatment group. 
15.8 Ethical Considerations 
This study will be conducted in accordance with this protocol, the accepted version of the 
Declaration of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, 
Subpart D, of Title 21 of the CFR; and in compliance with GCP guidelines. 
IECs/IRBs will review and approve this protocol and the ICF. All subjects and/or caregivers are 
required to give written informed consent before participation in the study. 
15.9 Financing and Insurance 
Before the study commences, the Sponsor (or its designee) and the investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study. This agreement will 
be documented in a financial agreement that will be signed by the investigator (or the institution 
signatory) and the Sponsor (or its designee). 
The investigator is required to have adequate current insurance to cover claims for negligence 
and/or malpractice (US only). The Sponsor will provide no-exclusion insurance coverage for the 
clinical study as required by national regulations. 
15.10 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 
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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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16 REFERENCES 
 
Patel KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: overview and treatment options. 
P T. 2014;Sep 39(9):638-645. 
 
van Os J, Kapur S. Schizophrenia. Lancet. 2009 Aug 22;374(9690):635-645. 
 
Wu EQ, Shi L, Birnbaum H, Hudson T, Kessler R. Annual prevalence of diagnosed 
schizophrenia in the USA: a claims data analysis approach. Psychol Med. 2006 
Nov;36(11):1535-1540. 
 
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. 
 
Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome 
in schizophrenia: implications for MATRICS. Schizophr Res. 2004;72(1):41-51. 
 
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. 
 
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. 
 
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. 
 
Emsley R, Chiliza B, Asmal L, Harvey BH. The nature of relapse in schizophrenia. BMC 
Psychiatry. 2013;13:50. 
 
Kahn RS, Sommer IE, Murray RM, et al. Schizophrenia. Nat Rev Dis Primers. 
2015;1:15067. 
 
Sellin AK, Shad M, Tamminga, C. Muscarinic agonists for the treatment of cognition in 
schizophrenia. CNS Spectr. 2008 Nov;13(11):985-996. 
 
Wess J, Eglen RM, Gautam D. Muscarinic acetylcholine receptors: mutant mice provide 
new insights for drug development. Nat Rev Drug Discov. 2007 Sep;6:(9):721-733. 
 
Mirza NR, Peters D, Sparks RG. Xanomeline and the antipsychotic potential of muscarinic 
receptor subtype selective agonists. CNS Drug Rev. 2003 Summer;9(2):159-186. 
 
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. 
 
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. 
 
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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Bodick NC, Offen WW, Shannon HE, et al. The selective muscarinic agonist xaqnomeline 
improves both the cognitive deficits and behavioral symptoms of Alzheimer’s disease. 
Alzheimer Dis Assoc Disord. 1997; 11 Suppl 4:S16-22. 
 
Shekhar A, Potter WZ, Lightfoot J, et al. Selective muscarinic receptor agonist xanomeline 
as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008 Aug;165(8):1033-
1039. 
 
Staskin D, Sand P, Zinner N, Dmochowski R, Trospium Study Group. Once daily trospium 
chloride is effective and well tolerated for the treatment of overactive bladder; results from 
a multicenter phase III trial. J Urol. 2007;178(3 Pt 1):978-983; discussion 983-984. 
 
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. 
 
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. 
 
[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. 
 
Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr Bull. 1987;13(2):261-276. 
 
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. 
 
Buchanan RW, Davis M, Goff D, et al. A summary of the FDA-NIMH-MATRICS 
workshop on clinical trial design for neurocognitive drugs for schizophrenia. 
Schizophrenia Bulletin. 2005 Jan;31(1):5-19. 
 
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989 
May;154 (5):672–676. 
 
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s 
pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007 
Jul;164(7):1035-1043. 
 
Chatoor D, Emmanuel A. Constipation and evacuation disorders. Best Pract Res Clin 
Gastroenterol. 2009;23(4):517–530. 
 
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. 
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American Gastroenterological Association, Bharucha AE, Dorn SD, Lembo A, Pressman 
A. American Gastroenterological Association medical position statement on constipation. 
Gastroenterology. 2013 Jan;144(1):211–217. 
 
Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. 
Functional bowel disorders. Gastroenterology. 2006 Apr;130(5):1480–1491. 
 
Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol. 1997 Sep;32(9):920–924. 
 
Locke GR III, Pemberton JH, Phillips SF. American Gastroenterological Association 
Medical Position Statement: guidelines on constipation. Gastroenterology. 2000 
Dec;119(6):1761–1766. 
 
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17 APPENDICES 
 
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APPENDIX 1. 
CONTRACEPTION GUIDELINES 
Women of childbearing potential (WOCBP) and men whose sexual partners are WOCBP must 
use at least 1 highly effective method of contraception during the study and for 7 days after the 
last dose of study treatment.  
A woman is considered to be a WOCBP (fertile) following menarche and until becoming 
postmenopausal, unless she is permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause. A high 
follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.  
A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
Highly effective methods of contraception are those which have a failure rate of <1% (when 
implemented consistently and correctly) and include: 
• combined (containing estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation (administration may be oral, intravaginal, or transdermal) 
• progestogen-only hormonal contraception associated with inhibition of ovulation 
(administration may be oral, injectable, or implantable) 
• intrauterine device 
• intrauterine hormone-releasing system 
• bilateral tubal ligation or occlusion 
• vasectomy (provided that the male has a medical assessment of surgical success) 
• sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of risk in relation to the duration of the clinical trial, in line with the preferred and 
usual lifestyle of the subject) 
All subjects will be strongly advised that they (or the female partners of male subjects) should 
not become pregnant while on study treatment or for 7 days after the last dose. A female subject 
will be advised that she must report immediately to the study site for pregnancy testing and 
appropriate management in the event that she may be pregnant. 
Reference: [HMA] Heads of Medicines Agencies. Clinical Trial Facilitation Group page. 
Recommendations related to contraception and pregnancy testing in clinical trials. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
September 15, 2014. Accessed April 01, 2020. 
 
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APPENDIX 2. 
FUNCTIONAL CONSTIPATION INQUIRY 
 
 
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1 
FINAL CLINICAL STUDY PROTOCOL 
 
Karuna Therapeutics 
Protocol Title: A Phase 3, Randomized, Double-blind, Parallel-group, Placebo-controlled, 
Multicenter Study to Evaluate the Efficacy and Safety of KarXT in Acutely Psychotic 
Hospitalized Adults with DSM-5 Schizophrenia 
Protocol Number: KAR-009 
 
IND Number: 
127471 
EudraCT Number: 
Not applicable 
Name of Investigational Product: 
KarXT 
Phase of Development: 
Phase 3 
Indication: 
Schizophrenia 
Sponsor: 
Karuna Therapeutics 
33 Arch Street 
Suite 3110 
Boston, MA 02110 
Tel: 
Email: 
Protocol Version:  
1.1 
Protocol Date: 
23 November 2020 
 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to Karuna Therapeutics (previously known 
as Karuna Pharmaceuticals). Any unauthorized copying or use of this document is prohibited. 
 
 
 
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Kar u na T her a p e utics 
K A R- 0 0 9 
Kar X T 
Fi nal 1. 1 
T his d o c u me nt is c o nfi de ntial. 
P a ge 2  of 9 6  
P R O T O C O L A P P R O V A L SI G N A T U R E S 
Pr ot oc ol Title: 
A P hase 3, Ra n d o mize d, D o u ble- bli n d, Parallel- gr o u p, 
Place b o- c o ntr olle d, M ultice nter St u d y t o E v al uate t h e Efficac y a n d 
Safet y of K ar X T i n A c utel y Ps yc h otic H os pitalize d A d ults wit h 
D S M- 5 Sc hiz o p hre nia 
Pr ot oc ol N u m ber: 
K A R- 0 0 9 
T his st u d y will be c o n d u cte d i n c o m plia nce wit h t he cli nical st u d y pr ot oc ol (a n d 
a me n d me nts), I nter nati o n al C o u ncil f or H ar m o nisati o n (I C H) g ui d eli nes f or c urre nt G o o d 
Cli nical Practi ce ( G C P) a n d a p plica ble r e g ulat or y r e q uire me nts . 
S p o ns or Si g n at or y 
 
 
Kar u na T h era pe utics 
 
Si g nat ure 
 
Date ( D D- M m m- Y Y Y Y) 
 
 
Kar u na T h era pe utics 
 
Si g nat ure 
 
Date ( D D- M m m- Y Y
C o ntr act R ese a rc h Or g a niz ati o n 
Si g n at or y 
 
 
 
S y ne os H ealt h 
 
 
Si g nat ure 
 
Date ( D D- M m m- Y Y Y Y) 
Bi ost atistici a n 
 
 
Veristat 
 
 
Si g nat ure 
 
Date ( D D- M m m- Y Y Y Y) 
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INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
A Phase 3, Randomized, Double-blind, Parallel-group, Placebo-controlled, 
Multicenter Study to Evaluate the Efficacy and Safety of KarXT in Acutely 
Psychotic Hospitalized Adults with DSM-5 Schizophrenia 
Protocol Number: 
KAR-009 
• Confidentiality and Current Good Clinical Practice (GCP)/E6(R2) Compliance Statement 
• I, the undersigned, have reviewed this protocol (and amendments, including appendices, 
and I will conduct the study as described in compliance with this protocol (and 
amendments) and relevant International Council for Harmonisation (ICH) guidelines 
including GCP and applicable regulatory requirements. 
• I am thoroughly familiar with the appropriate use of the study drug, 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 
IEC/IRB, I will not modify this protocol without obtaining prior approval of Karuna 
Therapeutics and of the IEC/IRB. I will submit the protocol amendments and/or any 
informed consent form modifications to Karuna Therapeutics and the IEC/IRB, and 
approval will be obtained before any amendments are implemented. 
• I ensure that all persons or party assisting me with the study are adequately qualified and 
informed about the Karuna Therapeutics study drug 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. 
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<Name> 
 
<Title> 
Investigator Signature 
 
 
 
Date (DD-Mmm-YYYY) 
 
 
Institution 
 
 
 
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2 
SYNOPSIS 
Title of Study: 
A Phase 3, Randomized, Double-blind, Parallel-group, Placebo-controlled, 
Multicenter Study to Evaluate the Efficacy and Safety of KarXT in Acutely 
Psychotic Hospitalized Adults with DSM-5 Schizophrenia 
Protocol Number: 
KAR-009 
Study Sites: 
Approximately 10 sites in the United States and 10 sites in Ukraine 
Phase of Development: 
Phase 3 
Objectives: 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of KarXT (a 
fixed combination of xanomeline and trospium chloride [xanomeline 
125 mg/trospium 30 mg] twice daily [BID]) versus placebo in reducing 
Positive and Negative Syndrome Scale (PANSS) total scores in adult 
inpatients with a Diagnostic and Statistical Manual‒Fifth Edition (DSM-5) 
diagnosis of schizophrenia. 
Secondary Objectives: 
The secondary objectives of the study are: 
• 
To evaluate the reduction of PANSS positive score in subjects 
treated with KarXT versus placebo 
• 
To evaluate the improvement in Clinical Global Impression-Severity 
(CGI-S) results in subjects treated with KarXT versus placebo 
• 
To evaluate the reduction of PANSS negative score in subjects 
treated with KarXT versus placebo 
• 
To evaluate the reduction of PANSS Marder Factor negative 
symptoms score in subjects treated with KarXT versus placebo 
• 
To evaluate the safety and tolerability of KarXT 
• 
To assess the pharmacokinetics (PK) of xanomeline and trospium 
after administration of KarXT in adults who are acutely psychotic 
with a DSM-5 diagnosis of schizophrenia 
Exploratory Objectives: 
The exploratory objectives of this study are:  
• 
To evaluate the change in cognition measuring core domains of 
impairment in schizophrenia using Cambridge Neuropsychological 
Test Automated Battery (CANTAB) 
• 
To evaluate the change in prolactin levels after administration of 
KarXT 
• 
To evaluate the single nucleotide polymorphisms (SNPs) regarding 
schizophrenia subtypes and SNPs related to drug metabolism. 
Study Endpoints: 
Primary Endpoint:  
• 
Change from baseline in PANSS total score at Week 5 
Secondary Endpoints:  
Efficacy Endpoints: 
• 
Change from baseline in PANSS positive score at Week 5 
• 
Change from baseline in PANSS negative score at Week 5 
• 
Change from baseline in PANSS Negative Marder Factor score at 
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Week 5  
• 
Change from baseline in CGI-S score at Week 5 
• 
Percentage of PANSS responders (a 30% change in PANSS total 
score) at Week 5  
Safety Endpoints: 
• 
Spontaneously reported adverse events (AEs) including AEs of 
special interest (AESIs) 
• 
Spontaneously reported procholinergic and anticholinergic 
symptoms 
• 
Simpson-Angus Scale (SAS) 
• 
Barnes Akathisia Rating Scale (BARS) 
• 
Abnormal Involuntary Movement Scale (AIMS) 
• 
Body weight, body mass index, waist circumference 
• 
Orthostatic vital signs (supine and standing after 2 minutes): blood 
pressure (systolic and diastolic) and heart rate 
• 
Clinical laboratory evaluations: hematology, clinical chemistry, 
coagulation, urinalysis, and drug screen 
• 
12-lead electrocardiogram (ECG) 
• 
Physical examination 
• 
Suicidal ideation scale with the use of Columbia Suicide Severity 
Rating Scale (C-SSRS) 
Pharmacokinetic Endpoints: 
• 
Area under the plasma concentration-time curve (AUC) 
• 
Maximum observed plasma concentration (Cmax)  
• 
Time to maximum observed plasma concentration (Tmax) 
Exploratory Endpoints: 
• 
Change in cognition measuring core domains of impairment in 
schizophrenia using CANTAB 
• 
Change from baseline in prolactin levels at Week 5 
• 
Prediction of response based on SNP schizophrenia subtypes, and 
SNPs related to KarXT metabolism for both efficacy and tolerability 
 
Study Design: 
This is a Phase 3 randomized, double-blind, parallel-group, 
placebo-controlled, multicenter inpatient study in adults who are 
acutely psychotic with a DSM-5 diagnosis of schizophrenia. Subjects 
will be randomized (1:1 ratio) to receive either KarXT or placebo for a 
treatment period of 5 weeks. Subjects will start on a lead-in dose of 
KarXT 50/20 (xanomeline 50 mg/trospium 20 mg) BID for the first 
2 days (Days 1 and 2) followed by KarXT 100/20 (xanomeline 
100 mg/trospium 20 mg) BID for the remainder of Week 1 (Days 3 to 
7). On Day 8, dosing will be titrated upwards to KarXT 125/30 BID 
unless the subject is continuing to experience AEs from the previous 
dose increase of KarXT 100/20 BID. All subjects who were increased 
to KarXT 125/30 BID, depending on clinical response and tolerability, 
will have the option to return to KarXT 100/20 BID for the remainder 
of the treatment period. Dosing must not change after Visit 7 (Day 21) 
of the study and may be decreased for tolerability reasons no more than 
once during the study. In addition, dose escalation to KarXT 125/30 
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BID may not occur outside of the permitted visit window for 
Visit 5/Day 8. 
A safety follow-up visit (Visit 11/ Day 42 + 5 days) will be performed 
for all those subjects who do not rollover in to the long-term open-label 
study KAR-008.  
The study is designed to test the hypothesis that treatment with KarXT 
in adult schizophrenia subjects with acute psychosis will result in 
significantly greater reduction (ie, improvement) in the primary and 
secondary endpoints at Week 5 from baseline compared with placebo. 
The endpoints are set up as a hierarchical list and step down through 
the statistical testing of each endpoint using an alpha of 0.05. Statistical 
testing of change from baseline to Week 5 in PANSS positive score, 
PANSS negative score, PANSS Negative Marder Factor score, CGI-S, 
and percentage of PANSS responders will be performed only if the 
primary endpoint is significant at the 0.05 alpha level (P ≤ 0.05), and 
testing would continue through a preordered list of key secondary 
efficacy endpoints. If at any point P > 0.05, then formal statistical 
testing would stop. This will control the overall Type 1 error rate across 
all hypotheses/endpoints being tested. 
Selection of Subjects: 
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 must be provided before 
any study assessments are performed. 
b. Subject must be fluent (oral and written) in English (applicable to 
the Unites States) or local language (Ukrainian or Russian 
applicable to Ukraine) 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 for 
Schizophrenia and Psychotic Disorder Studies (MINI) version 
7.0.2. 
4. Subject is experiencing an acute exacerbation or relapse of 
psychotic symptoms, with onset less than 2 months before 
screening. 
a. 
The subject requires hospitalization for this acute exacerbation or 
relapse of psychotic symptoms. 
b. If already an inpatient at screening, has been hospitalized 
for less than 2 weeks for the current exacerbation at the time 
of screening. 
5. Positive and Negative Syndrome Scale total score between 80 and 120, 
inclusive. 
a. 
Score of ≥4 (moderate or greater) for ≥2 of the following Positive 
Scale (P) items: 
i. Item 1 (P1; delusions) 
ii. Item 2 (P2; conceptual disorganization) 
iii. Item 3 (P3; hallucinatory behavior) 
iv. Item 6 (P6; suspiciousness/persecution) 
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6. Subjects with no change (improvement) in PANSS total score between 
screening and baseline (Day -1) of more than 20%. 
7. Subject has a CGI-S score of ≥4 at screening and baseline (Day -1) 
visits. 
8. Subject will have been off lithium therapy for at least 2 weeks 
before baseline and free of all oral antipsychotic medications for at 
least 5 half-lives or 1 week, whichever is longer, before baseline 
(Day -1). 
9. Subjects taking a long-acting injectable antipsychotic could not 
have received a dose of medication for at least 12 weeks (24 weeks 
for INVEGA TRINZA®) before baseline visit (Day -1). 
10. Subject is willing and able to be confined to an inpatient setting for 
the study duration, follow instructions, and comply with the 
protocol requirements. 
11. Body mass index must be ≥18 and ≤40 kg/m2. 
12. Subject resides in a stable living situation and is anticipated to 
return to that same stable living situation after discharge, in the 
opinion of the investigator. 
13. Subject has an identified reliable informant/caregiver. An 
informant/caregiver is needed at the screening and baseline 
visits as well as at the end of the study for relevant assessments 
(site staff may act as informant while the subject is an inpatient). 
An informant/caregiver may not be necessary if the subject has 
been the patient of the investigator for ≥1 year. 
14. Women of childbearing potential (WOCBP), or men whose 
sexual partners are WOCBP, must be able and willing to use at 
least 1 highly effective method of contraception during the study 
and for 7 days after the last dose of study drug. Sperm donation 
is not allowed for 7 days after the final dose of study drug. A 
female subject is considered to be a WOCBP after menarche and 
until she is in a postmenopausal state for 12 months or otherwise 
permanently sterile (for which acceptable methods include 
hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy). For the definition and list of highly effective 
methods of contraception, see APPENDIX 1. 
Exclusion Criteria: 
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, 
moderate to severe alcohol use disorder (within the past 
12 months), substance (other than nicotine or caffeine) use disorder 
within the past 12 months (use of cannabis at screening will result 
in screen failure with the allowance to rescreen at a later date if no 
moderate to severe substance use disorder is determined), major 
depressive disorder, bipolar I or II disorder, schizoaffective 
disorder, obsessive compulsive disorder, and post-traumatic stress 
disorder. Symptoms of mild mood dysphoria or anxiety are allowed 
as long as these symptoms are not the primary focus of treatment. 
a. 
A screening subject with mild substance abuse disorder within 
the 12 months before screening must be discussed and agreed 
upon with the medical monitor before they can be allowed into 
the study. 
2. Subjects who are newly diagnosed or are experiencing their first 
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treated episode of schizophrenia. 
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 
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. 
9. Subjects cannot currently (within 5 half-lives or 1 week, 
whichever is longer, before baseline [Day -1]) be receiving oral 
antipsychotic medications; monoamine oxidase inhibitors; 
anticonvulsants (eg, lamotrigine, Depakote); tricyclic 
antidepressants (eg, imipramine, desipramine); selective serotonin 
reuptake inhibitors; or any other psychoactive medications except 
for as needed anxiolytics (eg, lorazepam, chloral hydrate). 
10. Pregnant, lactating, or less than 3 months postpartum. 
11. If, in the opinion of the investigator (and/or Sponsor), subject is 
unsuitable for enrollment in the study or subject has any finding 
that, in the view of the investigator (and/or Sponsor), may 
compromise the safety of the subject or affect his/her ability to 
adhere to the protocol visit schedule or fulfill visit requirements. 
12. Positive test for coronavirus (COVID-19) within 2 weeks before 
screening and at screening.  
13. Subjects with extreme concerns relating to global pandemics, 
such as COVID-19, that preclude study participation. 
14. Subject has had psychiatric hospitalization(s) for more than 
30 days (cumulative) during the 90 days before screening. 
15. Subject has a history of treatment resistance to schizophrenia 
medications defined as failure to respond to 2 adequate courses 
of pharmacotherapy (a minimum of 4 weeks at an adequate dose 
per the label) or required clozapine within the last 12 months. 
16. Subjects with prior exposure to KarXT. 
17. Subjects who experienced any adverse effects due to xanomeline 
or trospium. 
18. Participation in another clinical study in which the subject 
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received an experimental or investigational drug agent within 
3 months before screening. 
19. Risk of violent or destructive behavior. 
20. Current involuntary hospitalization or incarceration. 
Planned Sample Size: 
A total of approximately 246 adult subjects (aged 18 to 65 years, inclusive) 
are planned to be randomized in a 1:1 ratio to 2 treatment groups, either 
KarXT or placebo. 
Investigational Therapy: 
1. Fixed dose KarXT 50/20 BID (50 mg xanomeline/20 mg trospium), 
oral (Days 1 to 2) 
2. Fixed dose KarXT 100/20 BID (100 mg xanomeline/20 mg 
trospium), oral (Days 3 to 7) 
3. Fixed dose KarXT 125/30 BID (125 mg xanomeline/30 mg 
trospium), oral (Days 8 to 35, if tolerated) 
Reference Therapy: 
Matching placebo BID oral 
Treatment Duration: 
Total study duration is up to 8 weeks, including a 7-day screening phase (up 
to a 7-day extension of the screening phase is allowed, if necessary), a 
5-week treatment period, and a 7-day follow-up period (only for subjects who 
do not rollover to KAR-008 study). Subjects completing this study will have 
the option of rolling over into a long-term open-label study (KAR-008) in 
which every subject will receive KarXT. 
Efficacy Assessments: 
PANSS total score, PANSS positive score, PANSS negative score, PANSS 
Negative Marder Factor score, and CGI-S score will be evaluated at 
scheduled visits. 
Safety Assessments: 
Spontaneous AEs including AESIs, procholinergic and anticholinergic 
symptoms, SAS, BARS, AIMS, body weight, body mass index, waist 
circumference, orthostatic vital signs, ECG, clinical laboratory assessments 
(hematology, clinical chemistry, coagulation, urinalysis, and drug screen), 
prolactin levels, physical examination, and C-SSRS will be evaluated 
throughout the study as scheduled. 
Pharmacokinetic Assessments: 
AUC, Cmax, and Tmax will be estimated at scheduled visits. 
Statistical Methods and 
Planned Analyses: 
Intent-to-treat (ITT) population: All subjects who are randomized to the study 
will be included in the ITT population. 
Modified ITT (mITT) population: All subjects who are randomized, received 
at least 1 dose of study drug, have a baseline PANSS assessment, and at least 
1 postbaseline PANSS assessment will be included in the mITT population 
and will be used in the efficacy analysis. 
Safety population: All subjects who received at least 1 dose of study drug 
will be included in the safety population and will be used in the safety 
analysis. 
PK population: All subjects who have an evaluable PK profile will be 
included in the PK population and will be used in the PK analysis. Subjects 
must have received at least 1 dose of active study drug and have at least 
1 measurable plasma concentration of study drug.  
The primary efficacy endpoint of the study is the change from baseline in 
PANSS total score at Week 5. The difference between KarXT and placebo 
will be estimated using a mixed model for repeated measures. The key 
secondary endpoints are the change from baseline to Week 5 in PANSS 
positive score, PANSS negative score, PANSS Negative Marder Factor 
score, CGI-S score, and percentage of PANSS responders at Week 5. The 
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statistical analysis of the primary and key secondary efficacy variables will 
account for multiplicity by using a fixed sequence testing procedure. This 
testing procedure will control the overall Type 1 error rate across all 
hypotheses/endpoints being tested. 
Assuming the treatment difference in the change from baseline in PANSS 
total score at Week 5 is 8 points between KarXT and placebo (standard 
deviation 16), a sample size of approximately 172 subjects (86 evaluable 
subjects per arm) will result in a power of 90.3% for a 2-sided alpha of 0.05 
(P ≤ 0.05). With an anticipated dropout rate of 30%, a total of 246 subjects 
are estimated to be enrolled.  
 
 
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3 
TABLE OF CONTENTS 
1 
FINAL CLINICAL STUDY PROTOCOL .......................................................................1 
2 
SYNOPSIS ........................................................................................................................5 
3 
TABLE OF CONTENTS ................................................................................................12 
3.1 
List of In-text Tables ..................................................................................................16 
3.2 
List of In-text Figures .................................................................................................17 
4 
LIST OF ABBREVIATIONS .........................................................................................18 
5 
INTRODUCTION ...........................................................................................................20 
5.1 
Background on Schizophrenia ....................................................................................20 
5.2 
Background on KarXT (Xanomeline Tartrate and Trospium Chloride) ....................20 
 
Nonclinical Studies ............................................................................................22 
 
Completed Clinical Studies ................................................................................25 
5.3 
Clinical Risks/Benefits of KarXT and Study Rationale .............................................33 
6 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................35 
6.1 
Study Objectives .........................................................................................................35 
 
Primary Objective ..............................................................................................35 
 
Secondary Objectives .........................................................................................35 
 
Exploratory Objectives ......................................................................................35 
6.2 
Study Endpoints..........................................................................................................36 
 
Primary Endpoint ...............................................................................................36 
 
Secondary Endpoints ..........................................................................................36 
6.2.2.1 
Efficacy Endpoints .......................................................................................36 
6.2.2.2 
Safety Endpoints ..........................................................................................36 
 
Pharmacokinetic Endpoints ................................................................................36 
 
Exploratory Endpoints .......................................................................................37 
7 
INVESTIGATIONAL PLAN .........................................................................................38 
7.1 
Description of Overall Study Design and Plan ...........................................................38 
7.2 
Discussion of Study Design........................................................................................41 
7.3 
End of Study ...............................................................................................................41 
7.4 
Independent Safety Monitoring Committee ...............................................................41 
8 
SELECTION OF STUDY POPULATION .....................................................................42 
8.1 
Inclusion Criteria ........................................................................................................42 
8.2 
Exclusion Criteria .......................................................................................................43 
8.3 
Rescreening ................................................................................................................45 
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8.4 
Study Withdrawal, Removal, and Replacement of Subjects ......................................45 
 
Pregnancy ...........................................................................................................46 
8.5 
Completion of the Study or Lost to Follow-up ..........................................................47 
8.6 
Study Termination ......................................................................................................47 
9 
TREATMENTS ...............................................................................................................49 
9.1 
Details of Study Treatments .......................................................................................49 
 
Identity of Study Treatments ..............................................................................49 
 
Packaging and Labelling ....................................................................................49 
 
Study Drug Storage ............................................................................................50 
 
Study Drug Retention .........................................................................................50 
9.2 
Dose Schedule ............................................................................................................50 
 
Visit 2b/Day 1 Randomization and Dosing .......................................................50 
 
Visit 3/Day 3 and/or Visits Occurring on Weekends/Holidays .........................51 
 
Visit 5/Day 8 Dosing and PK Considerations and Visit 8/Day 28 PK 
Considerations ....................................................................................................51 
 
Visit 10/Day 35 Dosing ......................................................................................51 
9.3 
Measures to Minimize Bias: Study Treatment Assignment .......................................52 
 
Method of Study Treatment Assignment ...........................................................52 
 
Blinding ..............................................................................................................52 
9.4 
Dose Modification ......................................................................................................53 
9.5 
Treatment Accountability and Compliance ................................................................53 
9.6 
Prior and Concomitant Therapy .................................................................................53 
 
Prior and Concomitant Medications ..................................................................53 
 
Concomitant Medications for Anxiety and/or Sleep aid ....................................54 
10 
STUDY PROCEDURES .................................................................................................55 
10.1  Informed Consent .......................................................................................................61 
10.2  Study Procedures ........................................................................................................61 
11 
EFFICACY ASSESSMENTS .........................................................................................62 
11.1  Positive and Negative Syndrome Scale ......................................................................62 
11.2  Clinical Global Impression‒Severity .........................................................................62 
12 
SAFETY ASSESSMENTS .............................................................................................63 
12.1  Demographics, and Medical and Psychiatric History ................................................63 
12.2  Vital Signs ..................................................................................................................63 
12.3  Physical Examination .................................................................................................64 
12.4  Weight, Height, Body Mass Index, Waist Circumference .........................................64 
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12.5  Electrocardiograms .....................................................................................................64 
12.6  Laboratory Assessments .............................................................................................64 
 
Blood Sampling for Pharmacogenetics ..............................................................66 
12.7  Adverse Events ...........................................................................................................66 
 
Adverse Events ..................................................................................................66 
 
Adverse Events of Special Interest ....................................................................68 
 
Serious Adverse Events .....................................................................................68 
 
Serious Adverse Event Reporting ......................................................................69 
 
Drug-Induced Liver Injury .................................................................................69 
 
Trial Discontinuation Criteria Other than DILI and Pregnancy ........................70 
12.7.6.1 
Individual Stopping Criteria .........................................................................70 
12.7.6.2 
Trial Stopping Rules .....................................................................................70 
 
Suspected Unexpected Serious Adverse Reactions ...........................................71 
 
Pregnancy ...........................................................................................................72 
 
Overdose ............................................................................................................73 
12.8  Cambridge Neuropsychological Test Automated Battery ..........................................73 
12.9  Simpson-Angus Scale .................................................................................................74 
12.10  Barnes Akathisia Rating Scale ...................................................................................74 
12.11  Abnormal Involuntary Movement Scale ....................................................................74 
12.12  Columbia-Suicide Severity Rating Scale ...................................................................74 
12.13  Functional Constipation Inquiry .................................................................................75 
12.14  Mini International Neuropsychiatric Interview Version 7.0.2 ...................................75 
12.15  Change in Prolactin ....................................................................................................76 
13 
PHARMACOKINETICS ................................................................................................77 
13.1  Pharmacokinetic Sampling .........................................................................................77 
 
Blood Samples ...................................................................................................77 
13.2  Pharmacokinetic Analytical Methodology .................................................................78 
14 
STATISTICAL ANALYSIS ...........................................................................................79 
14.1  Determination of Sample Size ....................................................................................79 
14.2  Analysis Populations ..................................................................................................79 
14.3  General Statistical Considerations ..............................................................................80 
14.4  Efficacy Analysis........................................................................................................80 
 
Primary Estimand ...............................................................................................80 
 
Analysis of the Primary Efficacy Endpoint .......................................................81 
 
Analysis of Secondary Efficacy Endpoints ........................................................81 
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14.5  Safety Analysis ...........................................................................................................82 
14.6  Pharmacokinetic Analysis ..........................................................................................82 
14.7  Interim Analysis .........................................................................................................82 
14.8  Handling of Missing Data ..........................................................................................83 
15 
STUDY MANAGEMENT ..............................................................................................84 
15.1  Approval and Consent ................................................................................................84 
 
Regulatory Guidelines ........................................................................................84 
 
Independent Ethics Committee/Institutional Review Board ..............................84 
 
Informed Consent ...............................................................................................84 
15.2  Data Handling .............................................................................................................85 
15.3  Source Documents ......................................................................................................86 
15.4  Record Retention ........................................................................................................86 
15.5  Monitoring ..................................................................................................................87 
15.6  Quality Control and Quality Assurance .....................................................................87 
15.7  Protocol Amendment and Protocol Deviation ............................................................87 
 
Protocol Amendment .........................................................................................87 
 
Protocol Deviations ............................................................................................88 
15.8  Ethical Considerations ................................................................................................88 
15.9  Financing and Insurance .............................................................................................88 
15.10  Publication Policy/Disclosure of Data........................................................................88 
16 
REFERENCES ................................................................................................................90 
17 
APPENDICES .................................................................................................................93 
APPENDIX 1.  CONTRACEPTION GUIDELINES ............................................................94 
APPENDIX 2.  FUNCTIONAL CONSTIPATION INQUIRY ............................................95 
 
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3.1 
List of In-text Tables 
Table 1 
Study Design ...........................................................................................................40 
Table 2.  Schedule of Assessments ........................................................................................56 
Table 3.  Laboratory Assessments..........................................................................................65 
Table 4.  Classification of Adverse Events by Intensity ........................................................67 
Table 5.  Classification of Adverse Events by Relationship to Study Drug ..........................68 
Table 6 
Cognitive Tests and Cognitive Domains Assessed by the Cambridge 
Neuropsychological Test Automated Battery .........................................................73 
Table 7 
Statistical Testing Procedure ...................................................................................80 
 
 
 
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3.2 
List of In-text Figures 
Figure 1  Change from Baseline in PANSS Total Scores (KAR-004) ...................................29 
Figure 2  Change from Baseline in PANSS-Positive Scores (KAR-004) ..............................30 
Figure 3  Change from Baseline in CGI-S (KAR-004) ..........................................................31 
Figure 4  Change from Baseline in PANSS-Negative Scores (KAR-004) ............................32 
 
 
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4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AD 
Alzheimer’s disease 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
APD 
antipsychotic drug 
AUC 
area under the plasma concentration-time curve 
AUC0-12 
area under the plasma concentration-time curve from 0 to 12 hours 
AUC0-24 
area under the plasma concentration-time curve from 0 to 24 hours 
BARS 
Barnes Akathisia Rating Scale 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression‒Severity 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTS 
Clinical Trial Subject 
CTCAE 
Common Terminology Criteria for Adverse Events 
DILI 
drug-induced liver injury 
DSM-5 
Diagnostic and Statistical Manual‒Fifth Edition 
EDC 
electronic data capture 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EPS 
extrapyramidal symptoms 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability Accountability Act 
IB 
Investigator’s Brochure 
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Abbreviation 
Definition 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
MCC 
microcrystalline cellulose 
MINI 
Mini International Neuropsychiatric Interview 
mITT 
modified intent-to-treat 
MMRM 
mixed model repeated measures 
NCI 
National Cancer Institute 
PANSS 
Positive and Negative Syndrome Scale 
PK 
Pharmacokinetic(s) 
PRN 
as needed 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson Angus Scale 
SNP 
single nucleotide polymorphism 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TID 
thrice daily 
TK 
toxicokinetic 
Tmax 
Time to maximum observed plasma concentration 
ULN 
upper limit of normal  
US 
United States 
VAS 
visual analog scale 
VCT 
Verified Clinical Trials Registry 
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 US is 5.1 per 1000 lives[3]. It is found 
equally in males and females, with males usually having an earlier onset of symptoms[4].  
The mainstay for treating schizophrenia is antipsychotic drugs (APDs)[5]. All currently available 
antipsychotics act through blockage of all or subsets of dopamine receptors in the brain. 
First-generation APDs include chlorpromazine and haloperidol; treatment with these agents is 
marked by high rates of parkinsonian extrapyramidal symptoms (EPS) and tardive dyskinesia, 
and they consequently have limited use today. The second-generation agents that include 
risperidone, olanzapine, quetiapine, lurasidone, aripiprazole, and lumateperone tend to have 
lower levels of EPS or tardive dyskinesia and are currently the most commonly prescribed APD 
class. However, the second-generation drugs also have problematic side effects that include 
significant weight gain, metabolic disturbances, sedation, and akathisia[6,7,8]. These side effects 
contribute to poor medication adherence resulting in frequent relapses and hospitalizations[9,10]. 
Thus there is a need for medications for schizophrenia which act through alternative 
mechanisms. 
Central muscarinic receptors have been hypothesized to be therapeutic treatments for 
schizophrenia based on several converging lines of evidence including both animal and human 
studies[11,12]. There are 5 subtypes of muscarinic receptors (M1-M5). The therapeutic effect of 
central muscarinic receptor agonism is thought to be due to agonism of M1 and M4 receptors in 
the central nervous system (CNS)[13]. However, compounds that agonize M1 and M4 receptors 
are often not specific enough not to also agonize M2 and M3 receptors outside of the CNS due to 
the highly conserved allosteric binding sites that the receptors share, leading to adverse events 
(AEs) related to activation of these peripheral receptors. Thus, any potential benefit of 
muscarinic agonists in schizophrenia (or other indications such as Alzheimer’s disease [AD]) has 
been outweighed by the occurrence of AEs associated with peripheral cholinergic side effects 
(nausea, vomiting, diarrhea, sweating, and excess salivation).  
5.2 
Background on KarXT (Xanomeline Tartrate and Trospium Chloride) 
Xanomeline tartrate is a muscarinic-cholinergic receptor agonist. It has agonistic activity at all 
5 muscarinic receptors but preferentially stimulates M1 and M4 receptors and binding to M1 and 
M4 receptors in the CNS is thought to be responsible for the drug’s potential therapeutic effects 
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(Roth, unpublished data). A recent study reports that xanomeline is a very potent M4 muscarinic 
agonist in vivo, measured by various second messenger assays[14]. Xanomeline also enters the 
brain rapidly achieving a brain to plasma ratio of greater than 10 making it an attractive CNS 
drug candidate[15]. 
Xanomeline does not have any direct binding activity on dopaminergic receptors, suggesting that 
its mechanism of action is unrelated to direct dopamine involvement. 
Previous double-blind, placebo controlled clinical trials have provided strong evidence that 
xanomeline has clinically relevant antipsychotic efficacy. In a multicenter outpatient trial in AD 
(N = 343), 3 doses of xanomeline (up to 225 mg/day) and placebo were assessed for 
26 weeks[16,17]. Significant dose-dependent improvements in psychotic symptoms relative to 
placebo were observed. Moreover, psychotic symptoms resolved quite rapidly in subjects who 
were symptomatic at baseline and a dose dependent reduction in the emergence of psychotic 
symptoms versus placebo was also observed. In a completer analysis, cognitive improvement 
was also found suggesting longer treatment intervals may be necessary for cognitive 
enhancement[16,17]. In a subsequent small (N = 20) double-blind, placebo-controlled inpatient 
trial in treatment resistant subjects with schizophrenia, xanomeline (225 mg/day) demonstrated 
robust and relatively rapid improvement in psychosis compared to placebo. In addition, 
improvement in both negative symptoms and cognitive impairment was observed[18]. 
In both the AD and schizophrenia trials, as well as in previous healthy volunteer studies, dose 
dependent “cholinergic” AEs were also reported, namely vomiting, nausea, diarrhea, sweating 
and hypersalivation. These side effects were frequent and, at the higher doses of xanomeline led 
to significant rates of discontinuation in the AD studies. This “procholinergic” AE profile 
curtailed further development of xanomeline as a single agent.  
It is believed that the procholinergic AEs associated with xanomeline are mediated by 
xanomeline’s stimulation of peripheral rather than central muscarinic receptors, which would 
make these AEs theoretically amenable to counteracting peripheral anticholinergic treatment. 
Trospium chloride is a peripherally acting muscarinic antagonist which binds to and antagonizes 
all five muscarinic receptor subtypes[19]. It is a commonly used generic drug approved for over 
10 years by the Food and Drug Administration (FDA) and by European authorities to treat 
overactive bladder and is generally well tolerated[19]. Several human subject studies have 
demonstrated that trospium does not appreciably cross the blood brain barrier, consistent with the 
drug’s quaternary ammonium structure[20].  
KarXT is a novel combination of xanomeline tartrate and trospium chloride. Karuna 
hypothesized that the addition of trospium would mitigate peripheral procholinergic side effects 
(vomiting, nausea, diarrhea, sweating and hyper-salivation) and thus provide a strategy to allow 
xanomeline to be administered and stimulate brain muscarinic receptors with a decreased side 
effect burden. Phase 1 studies in healthy volunteers of this combination demonstrated that 
KarXT reduced these side effects by 46% compared to xanomeline alone[21]. Moreover, the 
remaining cholinergic AEs were generally mild to moderate in severity and transient in nature, 
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often lasting a few hours without recurrence and were generally single-episode. In general, 
KarXT was well tolerated in healthy adult volunteers. These encouraging safety data prompted 
further work to assess KarXT for the treatment of schizophrenia and potentially other CNS 
disorders. 
Karuna has recently completed an adequate and well-controlled, randomized, multi-center 
Phase 2, placebo-controlled, inpatient clinical trial of acute psychosis with schizophrenia in 
182 adult subjects (KAR-004). KarXT demonstrated a statistically significant and clinically 
meaningful 11.6 point mean reduction in total Positive and Negative Syndrome Scale (PANSS) 
at 5 weeks compared to placebo (P < 0.0001), with statistical separation at each time point 
assessed (2, 4, and 5 weeks) and also demonstrated good overall safety and tolerability. 
The purpose of the current study is to evaluate the safety and efficacy of KarXT (xanomeline 
125 mg/trospium 30 mg) administered twice daily (BID) in adult inpatients with Diagnostic and 
Statistical Manual‒Fifth Edition (DSM-5) diagnosis of schizophrenia. A placebo arm is included 
to provide test sensitivity.  
Xanomeline is currently not approved or marketed in any country. Trospium is marketed in the 
US and other regions of the world for the treatment of overactive bladder. 
Nonclinical Studies 
The following is a summary of the important nonclinical safety and toxicology studies. 
More detailed information can be found in the KarXT Investigator’s Brochure (IB). 
The acute toxicity of xanomeline tartrate was evaluated in mice and rats. All animals were 
observed for 2 weeks for mortality and clinical signs of intolerance, and then necropsied for 
gross examinations. In-life findings attributed to the test article included excessive 
muscarinic-mediated pharmacology, such as excessive salivation, hypoactivity, ataxia, soft 
stools, exophthalmos, ocular discharge, tremors, and convulsions, with survivors typically 
appearing normal by Days 3 or 4. Gross findings at necropsy were generally unremarkable (eg, 
gas-distended or mucous-filled gastrointestinal [GI] tracts after oral dosing). 
KarXT-301 was a 14-day, repeat dose study of KarXT in rats where relatively high doses of 
xanomeline and trospium were given, with either xanomeline alone or in combination with 
trospium. Seven groups of 10 rats/sex/group were administered either vehicle (reverse osmosis 
water); xanomeline alone at 37, 75, 150, or 300 mg/kg/day (split into BID doses, every 
12 hours); or xanomeline/trospium combination dosages of 150/200 mg/kg/day or 
225/400 mg/kg/day, respectively (split into BID doses, every 12 hours).  
Satellite animals were included for the collection of plasma after the first and last doses for the 
determination of drug concentrations of each parent drug in support of toxicokinetic (TK) 
assessments.  
There was no target-organ toxicity revealed by clinical pathology or by gross or microscopic 
assessments. All intolerance could be attributed to recognized pharmacology of either test article. 
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No dose-related ophthalmic observations were noted. Findings were not indicative of specific 
target organ toxicity. In short, no new hazard was identified.  
Clinical observations noted in most animals administered 300 mg/kg/day xanomeline included 
hypoactivity, clear oral discharge, dilated pupils, irregular or labored respiration, and rough hair 
coat, among other observations. These findings are generally consistent with the anticipated 
pharmacology of xanomeline.  
Three TK animals in the low-dose combination group died or were euthanized in extremis. It is 
unclear to what extent the combination treatment effects versus the different handling of these 
animals (including 3 plasma samplings per animal) contributed to these deaths. If gavage 
accidents were involved (as happened with some TK animals), then they were not detected at 
gross necropsy. There was no microscopic evidence of toxicity was seen in any toxicity animals 
in this group or in the higher-dose combination group. 
Three toxicology and 3 TK animal deaths (total of 6) occurred in the high-dose combination 
group. Two toxicology animals had evidence of gavage accidents. For the third, the cause of 
death was undetermined, and a test article-related effect cannot be ruled out, but 
degeneration/regeneration of esophageal muscular is indicated some dosing-related trauma. If 
gavage accidents were involved, then they were not detected at gross necropsy. There was no 
evidence of target organ microscopic findings in GI tract or any other tissue of any animal, 
including the early death toxicity animals.  
A pharmacodynamics-mediated reduction in GI motility is consistent with the anti-muscarinic 
effects of trospium on intestinal musculature. Fecal retention, malabsorption, cessation of eating, 
dehydration, and rapid deterioration followed with continued dosing. Cessation of dosing in the 
high dose combination animals that survived led to rapid recovery, implying the deleterious 
effects had been pharmacodynamics-related. No effects on food consumption were seen in any 
xanomeline-alone group. The lack of microscopic findings in the GI tract of any early death or 
surviving animal implies that the adverse effects were pharmacologically mediated rather than 
direct target organ toxicity. 
Twenty-eight Day Repeat-Dose Studies with Xanomeline in Rats and Monkeys: Rats were fed 
xanomeline tartrate at 0%, 0.05%, 0.1%, or 0.2% daily and monkeys were fed xanomeline 
tartrate daily at 0, 5, 12.5, or 30 mg/kg. All animals survived until necropsy. Safety findings in 
rats included reduced body weight in the high dose group, increases in gamma-glutamyl-
transferase, cholesterol, and bilirubin, slight decreases in triglycerides, bile duct hyperplasia, 
higher serum potassium (males), and lower serum globulin (females). Findings in monkeys were 
dose related and included signs of intolerance such as emesis, salivation, diarrhea, hypoactivity, 
weight loss, and treatment-related tachycardia in the high-dose animals. 
Forty-Day Repeat Dose Study of KarXT in Rats (KarXT-302): Six groups of 15 rats/sex/group 
were given vehicle, xanomeline alone at 75 or 150 mg/kg/day, trospium alone at 100 mg/kg/day, 
or xanomeline/trospium combination at doses of 75/50 mg/kg/day or 150/100 mg/kg/day, with 
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all doses split into BID doses. Satellite rats (TK animals) were included for collection of plasma 
after the first and last doses to determine concentrations of each drug. Dosing was initially 
planned to be 90 days but was terminated after 40 days because of unexpected deaths in the TK 
animals. No target organ toxicity was seen. Safety findings included pharmacologically mediated 
constipation in the trospium alone and combination groups and mild biliary hyperplasia in the 
high-dose xanomeline alone and combination groups. There were 4 unscheduled deaths in TK 
animals; 2 in the high-dose xanomeline alone group (150 g/kg/day) and 2 in the high-dose 
combination group (150 mg/kg/day xanomeline plus 100 mg/kg/day trospium). Both 
xanomeline-only animals had necropsy gross findings of a gavage accident, and cause of death 
could not be determined. All toxicology animals survived to their scheduled sacrifice. Sponsor 
considers that the volume depletion and trauma of multiple bleeds (3 per animal), followed by 
reduced absorption of fluids and nutrients secondary to reduced GI motility with continued BID 
dosing explains the greater demise of TK animals relative to toxicity animals.  
Based on the results of the 90-day rat toxicology study, oral administration of trospium chloride 
and xanomeline tartrate alone or in combination to Crl:CD (SD) rats BID (12 hours ± 60 minutes 
apart) at dosage levels of 25 and 50 mg/kg/dose trospium chloride, 37 and 75 mg/kg/dose 
xanomeline tartrate, and a combination of 37/25, 75/25, and 75/50 mg/kg/dose xanomeline 
tartrate/trospium chloride for a minimum of 90 days resulted in minimal to moderate bile duct 
hyperplasia in the livers of the xanomeline tartrate and combination (xanomeline tartrate and 
trospium chloride) group males. Although there were no notable differences in the incidence of 
bile duct hyperplasia when comparing the single vs combination groups, there was an increased 
severity observed in the combination group males (specifically the 75/25 and 75/50 mg/kg/dose 
combination group males) when compared with the xanomeline tartrate group males at the 
terminal euthanasia. The bile duct hyperplasia was considered adverse in the high-dose 
xanomeline tartrate group males and in the 75/25 and 75/50 mg/kg/dose combination group 
males due to instances of moderate severity. Therefore, the no-observed-adverse-effect level was 
considered to be 50 mg/kg/dose for trospium chloride, 37 mg/kg/dose for xanomeline tartrate, 
and 37/25 mg/kg/dose for the combination of xanomeline tartrate/trospium chloride. At these 
doses for males, mean plasma AUC0-24 values were 27,700 pg•hr/mL for trospium, 
146,000 pg•hr/mL for xanomeline, and 4510 + 111,000 pg•hr/mL for trospium + xanomeline, 
respectively, on Day 91. At these dosages for females, mean plasma AUC0-24 values were 
9230 pg•hr/mL for trospium; 267,000 pg•hr/mL for xanomeline; and 16,700 + 171,000 pg•hr/mL 
for trospium + xanomeline, respectively, on Day 91. The absence of bile duct hyperplasia in 
females cannot be explained from differences in drug exposure. At the recovery euthanasia, bile 
duct hyperplasia was still present but was limited to minimal severity, and there was a decreased 
incidence in both the xanomeline tartrate and combination group males. There was also no 
notable difference in severity between the single vs combination groups at the recovery 
euthanasia. Given the decreased incidence/severity, in combination with the improved histologic 
appearance of bile ducts at the recovery euthanasia (i.e., smaller/flattened epithelium, 
noninflammatory, and an absence of portal bridging), changes at the recovery euthanasia were 
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consistent with a partial resolution of bile duct hyperplasia. With an absence of correlating serum 
liver enzyme elevations, bile acid alterations or hepatocellular degeneration, necrosis or 
regeneration, and with the apparent reversibility after cessation of treatment, these findings 
appear to have been tolerable by the affected animals. Therefore, the maximum tolerated dose 
was considered to be 50 mg/kg/dose for trospium chloride, 75 mg/kg/dose for xanomeline 
tartrate, and 75/50 mg/kg/dose for the combination of xanomeline tartrate/trospium chloride. For 
males, corresponding mean plasma AUC0-24 values were 27,700 pg•hr/mL for trospium; 
822,000 pg•hr/mL for xanomeline; and 133,000 + 276,000 pg•hr/mL for trospium + xanomeline, 
respectively, on Day 91. For females, corresponding mean plasma AUC0-24 values were 
9230 pg•hr/mL for trospium; 2,090,000 pg•hr/mL for xanomeline; and 17,600 + 
950,000 pg•hr/mL for trospium + xanomeline, respectively, on Day 91. 
In summary, no new findings on the “combination” of xanomeline and trospium (KarXT) were 
discovered; toxicology studies revealed the familiar exaggerations of systemic and CNS 
muscarinic effects that had previously been seen with xanomeline or trospium at high doses. 
Target organ findings with xanomeline alone were limited to biliary hyperplasia in the 28-day rat 
study but not the 28-day or 12-month monkey study, though similar findings were described in a 
6-month monkey study. With KarXT, biliary hyperplasia was not observed in the 14-day rat 
study but was reported in the 40-day rat study. Notably, these hyperplastic findings are not 
thought to represent pre-neoplastic lesions, because they were of low severity; no fibrosis or 
associated hepatocellular changes, and no significant effects were seen on hepatobiliary-related 
serum chemistry.  
Completed Clinical Studies 
Refer to the IB for complete information regarding previous clinical studies conducted with 
xanomeline by Eli Lilly, and studies KAR-001, KAR-002, KAR-003, and KAR-004 conducted 
by Karuna Therapeutics using xanomeline with trospium. 
To date, more than 840 subjects or volunteers have been exposed to xanomeline tartrate (oral 
formulation, either alone, in combination with trospium, or as the combination drug KarXT) in 
19 completed clinical studies conducted either by Eli Lilly or Karuna Therapeutics, some for as 
long as 3 years. In those studies, significant improvements in cognition and reduced psychotic 
symptoms were observed.  
A study of xanomeline monotherapy in subjects with schizophrenia was reported in 2008[18]. In 
this pilot study, the effects of xanomeline were examined in 20 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 
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. 
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These studies demonstrated the potential for xanomeline as a treatment for psychosis and 
cognition across multiple subject populations.  
Study H2Q-EW-E001, conducted by 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 mg, 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 in sitting and standing heart rate, slight increase in supine systolic 
BP, and postural hypotension. 
The clinical experience with KarXT initiated by Karuna Therapeutics to date includes 
3 completed Phase 1, clinical pharmacology studies in healthy volunteers (KAR-001, KAR-002, 
and KAR-003) and one completed Phase 2 study (KAR-004) in adult inpatients with DSM-5 
schizophrenia. 
The first study conducted by Karuna, KAR-001 was “A Phase 1, double-blind, randomized, 
multiple-dose, pilot study comparing xanomeline administered alone to xanomeline administered 
in combination with trospium chloride in normal healthy volunteers.” This study consisted of 
2 arms, in which xanomeline was administered TID, alone, at a total daily dose of 225 mg in one 
arm, and the second arm received the same dose of xanomeline in combination with trospium 
chloride 20 mg administered BID, a total daily dose of 40 mg. Subjects were treated for 7 days. 
The goal was to determine whether this dosing regimen would reduce the cholinergic side effects 
of xanomeline by co-administration of the muscarinic antagonist, trospium.  
Overall, treatment with xanomeline 225 mg daily + trospium 40 mg daily administered over 
7 days was considered safe and well tolerated. The results of key and supportive endpoints 
showed a numerical reduction (although not statistically significant) in visual analog scale (VAS) 
scores for cholinergic events for the xanomeline + trospium treatment arm compared to the 
xanomeline alone treatment arm. Specifically, consistent numerical reduction in VAS scores for 
the xanomeline + trospium treatment arm was observed for the supportive endpoints of 
maximum weekly individual VAS scores and mean daily maximum composite VAS scores.  
Results of the clinician-administered scales were supportive of a reduction in vomiting, feelings 
of nausea, excess salivation, and sweating that interfered with daily activities in the 
xanomeline + trospium treatment arm compared to the xanomeline alone treatment arm. 
There were no meaningful differences between treatment groups in heart rate, resting BP, 
orthostatic BP or any electrocardiogram (ECG) parameters including QT. A small subset of 
subjects in both treatment arms had transient increases in heart rate and orthostatic BP changes 
which may have contributed to syncope and postural dizziness in those subjects. Two subjects 
(both in the xanomeline alone arm) experienced syncope. The incidence of orthostatic AEs in the 
KarXT group was approximately one-half that of subjects in the xanomeline alone group. 
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The most commonly reported treatment-emergent AEs (TEAEs) in KAR-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. 
Study KAR-002 was a Phase 1, double-blind, randomized, multiple-dose adaptive design pilot 
study to evaluate the safety and tolerability of KarXT in normal healthy volunteers. Subjects 
received either 100 mg xanomeline + 20 mg trospium BID or placebo. The first cohort of this 
study was stopped after 1.5 days when the US FDA put the program on hold due to a preliminary 
rat finding in the 14-day study. This study used a new formulation of KarXT in which 
xanomeline and trospium were combined into a single dose form and given BID. Safety findings 
included an increase in orthostatic complaints. Caution should be used in drawing conclusions 
from this study, as subjects did not have time to reach steady state plasma levels from dosing, as 
only 3 doses were given. 
Study KAR-003 was a Phase 1, double-blind, randomized, multiple-dose, adaptive design, 
inpatient pilot study to evaluate the safety and tolerability of KarXT in normal healthy 
volunteers. The primary objective of this study was to assess the safety and tolerability of 7 days 
of daily administration of KarXT at various dose combinations, administered BID. Subjects 
received either KarXT or placebo (3:1 ratio). All subjects on KarXT received 2 days of 50 mg 
xanomeline + 20 mg trospium BID, and then increased to different doses for Days 3 to 7. This 
study also used the new formulation of KarXT in which xanomeline and trospium were 
combined into a single dosage form and given BID.  
There was a relatively high degree of variability in xanomeline and trospium exposures between 
individuals in all cohorts, which is consistent with previous results with KarXT, 
xanomeline-alone, and trospium-alone. Peak plasma concentrations were observed at a median 
time of 2.0 hours for xanomeline and 1.0 hour for trospium across all treatment groups and study 
days.  
Although there was insufficient data to draw a definitive conclusion regarding the impact of 
trospium on the pharmacokinetics (PK) and bioavailability of xanomeline, or the impact of 
xanomeline on the PK and bioavailability of trospium, the PK results suggest that neither drug 
had a meaningful impact on the PK behavior of the other drug. 
During the 2-day lead-in phase, the most common AEs (≥20% of subjects) when all the subjects 
completed dosing were dry mouth, nausea, and constipation. For the treatment groups that 
completed dosing, although the incidence of TEAEs was lower in the KarXT 100/20 BID 
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(66.7%) group compared to KarXT 125/40 group (88.9%), the incidence of cholinergic TEAEs 
(nausea, vomiting, diarrhea, sweating, and excess salivation) was similar between the 2 groups. 
The most commonly reported TEAEs (20% of subjects in either treatment group) in these 
groups were dizziness, nausea, dry mouth, headache, vomiting, dyspepsia, somnolence, vision 
blurred, and dysuria. For the treatment groups that did not complete dosing (KarXT 150/20 BID 
group and KarXT 150/40 BID group), the cholinergic TEAEs were generally higher compared to 
the treatment groups that completed dosing.  
Overall, anticholinergic TEAEs appeared to occur primarily in the treatment groups that were 
dosed with 40 mg trospium BID (KarXT 150/40 BID and KarXT 125/40 BID groups), 
particularly when paired with 125 mg xanomeline BID, suggesting to consider slightly lowering 
the trospium dose from 40 mg BID in future studies. All TEAEs were mild or moderate in 
severity, and there were no SAEs or deaths. Treatment-emergent AEs were primarily cholinergic 
or orthostatic (and a few anticholinergic). Doses of 100 mg and 125 mg BID of xanomeline were 
well tolerated when paired with 20 mg and 40 mg BID of trospium, respectively. The safety and 
tolerability profile of KarXT 100/20 BID and KarXT 125/40 BID was acceptable and supports 
further evaluation at similar doses in future studies. Doses of KarXT 150/20 BID and 
150/40 BID were not well tolerated in this study. A pairing of 150 mg xanomeline with 40 mg 
trospium appeared to be better tolerated than 150/20, but some subjects still experienced 
tolerability issues. 
Study KAR-004 was a Phase 2 randomized, double-blinded study to assess the safety 
tolerability, and efficacy of KarXT in adults with DSM-5 schizophrenia, hospitalized with acute 
psychosis. The primary objective of the study was to assess the efficacy of KarXT 125/30 BID 
versus placebo in reducing PANSS total scores in adult inpatients with a DSM-5 diagnosis of 
schizophrenia. Subjects received either KarXT or placebo (1:1 ratio) for a treatment period of 
5 weeks. All subjects on KarXT received a lead-in dose of KarXT 50/20 BID for the first 2 days 
followed by KarXT 100/20 BID on Days 3 to 7. On Day 8, dosing was titrated upwards to 
KarXT 125/30 BID unless the subject was continuing to experience AEs from previous dose 
increase of 100/20 BID. The clinical portion of this study was completed and clinical study 
report is in progress. No new safety concerns have arisen during this study. 
The KAR-004 trial results are unambiguous regarding efficacy, where not only the primary 
outcome measure showed a robust separation from placebo, but the additional sensitivity and 
secondary outcome measures were consistently robust as well.  
KarXT demonstrated statistically significant and clinically meaningful mean reductions in total 
PANSS scores at 5 weeks compared to placebo (P < 0.0001) in the modified intent-to-treat 
(mITT) population. The KarXT group showed an adjusted mean improvement of 17.40 points at 
Week 5 compared to an adjusted mean 5.85 point improvement in the placebo group for a 
difference of 11.56 points in the total PANSS score (Figure 1). Substantial significant differences 
were also seen between KarXT and placebo at Weeks 2 and 4; moreover, the difference appears 
to be widening with each successive timepoint. In addition, sensitivity analyses of the primary 
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outcome measure all showed the same strong differences from placebo attesting to the robustness 
of the finding in Completer, last observation carried forward, and Per Protocol populations (all 
with p < 0.0001). Also, analyses exploring missingness via imputation for missing data at 
random or not missing at random also showed strong separation (both with p < 0.0001). The 
Cohen’s d effect size observed in this trial was 0.75. 
Figure 1 
Change from Baseline in PANSS Total Scores (KAR-004) 
• 
 
Abbreviations: LS = least squares; mITT = modified intent-to-treat; PANSS = Positive and Negative Syndrome 
Scale; SEM = standard error of the mean. 
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 timepoints (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. 
In regards to the Clinical Global Impression – Severity of Illness (CGI-S), subjects in the KarXT 
group overall significantly improved in ratings compared with placebo, with a P value of <0.001 
at Week 5. At Week 5, 8% of subjects on placebo improved (decreased) their CGI-S ratings by 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 with 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 
• Most common TEAEs were constipation, nausea, dry mouth, dyspepsia, and vomiting. 
None of these TEAEs were rated as severe, and none led to discontinuations 
• 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.  
• No syncope or mean changes in BP were seen 
• A 5.5 bpm peak mean placebo adjusted resting heart rate increase with a downward trend 
after week 2 was seen 
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• One subject (on KarXT) was discontinued due to an elevated gamma-glutamyl 
transpeptidase 
• There were no new safety findings associated with KarXT that have not been observed 
with either xanomeline-alone or trospium-alone in previous trials 
• KarXT did not show evidence of many of the kinds of AEs that often occur in currently 
available antipsychotics for the treatment of schizophrenia.  
• The rates of the following AEs were similar for KarXT and placebo: somnolence, weight 
gain, and extrapyramidal symptoms. 
• Another Phase 3 study (KAR-007) is planned at approximately 20 study sites in the US. 
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 with all available 
APDs. 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 with placebo, demonstrated highly significant reduction in PANSS total scores 
(P < 0.0001) at all post randomization time points (Weeks 2, 4, and, 5) with a calculated effects 
size (Cohen’s d) of 0.75. KarXT, as compared to placebo, demonstrated significant improvement 
at all post randomization time points for PANSS positive symptom subscores, PANSS negative 
symptom subscores, PANSS Marder Factor negative symptom subscores, and CGI-S scores. 
More than 840 subjects or volunteers have been exposed to xanomeline tartrate (oral 
formulation, either alone, in combination with trospium, or as the fixed dose combination drug 
KarXT) in clinical studies. These early clinical studies, as well as nonclinical pharmacology and 
toxicology studies, have not revealed any specific contraindications to the use of xanomeline. 
The most common side effects/symptoms are the cholinergic related effects: nausea, vomiting, 
excess salivation, excess sweating, and diarrhea. In addition, subjects treated with xanomeline 
alone have reported both syncope and orthostatic dizziness. The addition of trospium decreases 
the peripheral cholinergic effect of xanomeline creating a better tolerated therapy. In addition, a 
titration phase also increases the tolerability of KarXT. 
Trospium chloride has been marketed in the US for 12 years. The most frequently reported AEs 
reported in pivotal trials were dry mouth, constipation, abdominal pain, headache, urinary 
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retention, and abnormal vision and accommodation. For additional information, the 
package insert for trospium chloride tablets for oral use can be found in the IB. 
In a Phase 2 (KAR-004) clinical study, KarXT (100/20 and 125/30) significantly reduced the 
symptoms of schizophrenia in subjects with acute psychosis after treatment for 28 days. KarXT 
also showed an acceptable safety profile with the most common TEAEs being constipation, 
nausea, dry mouth, dyspepsia, and vomiting. All the reported TEAEs were mild or moderate in 
intensity. One SAE (psychotic disorder) was reported by a single subject and no deaths were 
reported in the study. KarXT was generally well-tolerated and found to be safe in this patient 
population. 
KarXT represents a novel approach to the treatment of patients with schizophrenia that will 
provide an important and meaningful alternative to current therapies. The current tolerability and 
AE profile and the efficacy of KarXT justify further development of KarXT in this patient 
population by advancing to Phase 3 trials. 
Subjects assigned to active study drug may benefit by improvement in schizophrenia symptoms. 
Since subjects will be having an acute psychotic event, subjects will be hospitalized where the 
clinical staff is available to help them 24 hours a day. In addition, the inpatient setting represents 
an important venue for research, examining the effects of KarXT and helps to eliminate or 
reduce to the extent possible, subjectivity and bias. Furthermore, this inpatient setting will also 
enhance measurable quality standards as well as increased adherence. 
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6 
STUDY OBJECTIVES AND ENDPOINTS 
6.1 
Study Objectives 
 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of KarXT 125/30 BID versus 
placebo in reducing PANSS total scores in adult inpatients with a DSM-5 diagnosis of 
schizophrenia. 
 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the reduction of PANSS positive score in subjects treated with KarXT versus 
placebo 
• To evaluate the improvement in CGI-S results in subjects treated with KarXT versus 
placebo 
• To evaluate the reduction of PANSS negative score in subjects treated with KarXT 
versus placebo 
• To evaluate the reduction of PANSS Marder Factor negative symptoms score in subjects 
treated with KarXT versus placebo 
• To evaluate the safety and tolerability of KarXT 
• To assess the PK of xanomeline and trospium after administration of KarXT in adults 
who are acutely psychotic with a DSM-5 diagnosis of schizophrenia 
 
Exploratory Objectives 
The exploratory objectives of this study are: 
• To evaluate change in cognition measuring core domains of cognitive impairment in 
schizophrenia using the Cambridge Neuropsychological Test Automated Battery 
(CANTAB) 
• To evaluate the change in prolactin levels after administration of KarXT 
• To evaluate the single nucleotide polymorphisms (SNPs) regarding schizophrenia 
subtypes and SNPs related to drug metabolism 
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6.2 
Study Endpoints 
 
Primary Endpoint 
The primary endpoint of this study is change from baseline in PANSS total score at Week 5 
 
Secondary Endpoints 
6.2.2.1 
Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
• Change from baseline in PANSS positive score at Week 5 
• Change from baseline in PANSS negative score at Week 5 
• Change from baseline in PANSS Negative Marder Factor score at Week 5 
• Change from baseline in CGI-S score at Week 5 
• Percentage of PANSS responders (a 30% change in PANSS total score) at Week 5  
6.2.2.2 
Safety Endpoints 
The safety endpoints of this study are as follows: 
• Spontaneously reported AEs including AEs of special interest (AESI) 
• Spontaneously reported procholinergic and anticholinergic symptoms 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
• Body weight, body mass index (BMI), waist circumference 
• Orthostatic vital signs (supine and standing after 2 minutes): BP (systolic and diastolic) 
and heart rate 
• Clinical laboratory evaluations: hematology, clinical chemistry, coagulation, urinalysis, 
and drug screen 
• 12-lead ECG 
• Physical examination 
• Suicidal ideation scale with the use of Columbia Suicide Severity Rating Scale (C-SSRS) 
 
Pharmacokinetic Endpoints 
The PK endpoints of this study are as follows: 
• Area under the plasma concentration-time curve (AUC) 
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• Maximum observed plasma concentration (Cmax) 
• Time to maximum observed plasma concentration (Tmax) 
 
Exploratory Endpoints 
• Change in cognition measuring core domains of cognitive impairment in schizophrenia 
using CANTAB 
• Change from baseline in prolactin levels at Week 5 
• Prediction of response based on SNP schizophrenia subtypes, and SNPs related to KarXT 
metabolism for both efficacy and tolerability 
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7 
INVESTIGATIONAL PLAN 
7.1 
Description of Overall Study Design and Plan 
This Phase 3, randomized, double-blind, parallel-group, placebo-controlled, multicenter, 
inpatient clinical study in adults who are acutely psychotic with a DSM-5 diagnosis of 
schizophrenia is designed to test the hypothesis that treatment with KarXT will result in 
significantly greater reduction (ie, improvement) in the primary and secondary endpoints at 
Week 5 from baseline compared with placebo. Total study duration is up to 8 weeks, including a 
7-day screening phase (up to a 7-day extension of the screening phase is allowed, if necessary), a 
5 week treatment period, and a 7-day follow-up period (only for subjects who do not rollover to 
KAR-008 study). Subjects completing this study will have the option of rolling over into a 
long-term open-label study (KAR-008) in which every subject will receive KarXT. 
Screening Period:  
Screening of subjects will take place in 7 days or less before Day -1 (Days -8 to -2). Up to a 
7-day extension of the screening time is allowed, if necessary. 
A suitable number of subjects will be screened to randomize approximately 246 subjects across 
approximately 10 sites in the US and 10 sites in Ukraine. Subjects will be randomized through 
the IWRS in a 1:1 ratio to receive either KarXT or placebo for a treatment duration of 5 weeks. 
Treatment Period:  
In the treatment period, all subjects assigned to KarXT will start on a lead-in dose of 
KarXT 50/20 (xanomeline 50 mg/trospium 20 mg) BID for the first 2 days (Days 1 and 2) 
followed by KarXT 100/20 (xanomeline 100 mg/trospium 20 mg) BID for the remainder of 
Week 1 (Days 3 to 7). On Day 8, dosing will be titrated upwards to KarXT 125/30 BID unless 
the subject is continuing to experience AEs from the previous dose of KarXT 100/20 BID. All 
subjects who are increased to KarXT 125/30 BID, depending on clinical response and 
tolerability, will have the option to return to KarXT 100/20 BID for the remainder of the 
treatment period. Dosing must not change after Visit 7 (Day 21) of the study and may be 
decreased for tolerability reasons no more than once during the study. In addition, dose 
escalation to KarXT 125/30 BID may not occur outside of the permitted visit window for 
Visit 5/Day 8.  
All randomized 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. 
Efficacy assessments (PANSS scores and CGI-S score) will be assessed at scheduled visits. 
Refer to Section 11 for more details. 
Safety will be assessed through spontaneous AEs including AESIs, procholinergic and 
anticholinergic symptoms, cognition testing, SAS, BARS, AIMS, body weight, BMI, waist 
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circumference, orthostatic vital signs, ECG, clinical laboratory assessments (hematology, clinical 
chemistry, coagulation, urinalysis, and drug screen), prolactin levels, physical examination, and 
C-SSRS will be evaluated throughout the study as scheduled. Section 12 provides complete 
details on these safety assessments. 
Details on PK assessments are provided in Section 13. 
Safety Follow-up Period: 
A safety follow-up visit (Visit 11/ Day 42 + 5 days) will be performed for all those subjects who 
do not rollover into the long-term open-label study KAR-008. 
An Independent Safety Monitoring Committee (ISMC) will be responsible for reviewing on a 
periodic basis the safety data from this study and confirming that the study may continue. 
Table 1 presents the study design.
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Table 1 
Study Design 
 
Phase: 
Screening 
Inpatient Treatment 
End of 
Treatment 
Safety 
Follow-up 
Day: 
Days -8 
to -2 
Day -1 
Day 1 
Day 3 + 
1 day 
Day 7 ± 
2 days 
Day 8 ± 
2 days 
Day 14 ± 
2 days 
Day 21 ± 2 
days 
Day 28 
± 2 
days 
Day 32 + 
1 day 
Day 35  
- 2 daysc 
Day 42 + 
5 days 
Visit: 
Visit 1 
Visit 2a 
Visit 
2b 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Xanomeline
/ trospium 
(KarXT)*: 
N/A 
 
50/20 
BID 
100/20 
BID 
100/20 
BID 
125/30 
BID 
(Option: 
100 /20 
BID)a 
125/30 
BID 
(Option: 
100 /20 
BID)a 
125/30 BID 
(Option: 
100/20 
BID)a 
125/30 
BIDb 
125/30 
BIDb 
125/30 
BIDb 
 
Comment: 
Up to a 
7-day 
extension 
to the 
screening 
phase is 
allowed. 
Baseline 
2-day 
lead-in 
dose 
Upward 
titration 
of dose 
 
Upward 
titration 
of dose 
Downward dose 
adjustment allowed 
according to clinical 
response/tolerability 
No dose 
adjustment allowed 
(after Day 21) 
 
For 
subjects 
who do 
not enter 
in to 
rollover 
Study 
(KAR-
008) 
Abbreviation: BID = twice daily. 
* All the KarXT doses are in mg. 
a. 
All subjects who are increased to KarXT 125/30, depending on clinical response and tolerability, will have the option to return to KarXT 100/20 BID for 
the remainder of the treatment period. 
b. No dose adjustment will be allowed after Visit 7. All subjects will continue taking the doses chosen for KarXT at Visit 7. 
c. 
The last dose of study drug will be administered the morning of Visit 10.  
 
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7.2 
Discussion of Study Design 
A randomized, double-blind, parallel-group, placebo-controlled study design is suitable for 
conducting any interventional studies. This design will minimize bias and provide reference data 
for comparison of efficacy and safety parameters of the investigational drug. 
Schizophrenia is a long-term mental disorder which requires a chronic therapy. A 5-week 
treatment duration is considered an acceptable treatment duration to observe clinically significant 
response (ie. primary endpoint can be achieved). The 5-week treatment duration is substantiated 
by the statistically significant outcome of the KAR-004 study of the same duration.  
7.3 
End of Study 
A subject will have fulfilled the requirements for study completion when the subject has 
completed all study periods, including the End of Study visit (Visit 10/Day 35 [End of 
Treatment] for subjects who roll over into KAR-008 or Visit 11/Day 42 [Follow-up] for subjects 
who do not roll over into the KAR-008 study) as indicated in the Schedule of Assessments 
(Table 2) in accordance with the protocol. 
Subjects completing this study will have the option of rolling over into a long-term open-label 
study (KAR-008) in which every subject will receive KarXT, following completion of 
Visit 10/Day 35 of the current study (KAR-009). 
Note: A safety follow-up visit will be performed 1 week after the End of Study visit for subjects 
who have completed Visit 10/Day 35 but do not rollover in to the long-term open-label study. 
7.4 
Independent Safety Monitoring Committee 
For the purpose of this study, the ISMC is an independent group of individuals with pertinent 
expertise that reviews on a regular basis accumulating safety and tolerability data from the 
clinical study. The ISMC will include 3 clinicians and a reporting statistician. This committee 
will be responsible, on a periodic basis, for confirming the safety and tolerability of KarXT 
throughout the study, with particular focus on assessing for any new toxicities that might be 
involved with KarXT. 
The reviews will be of unblinded data to allow a comparison of event rates and detection of 
safety signals across treatment groups to identify important safety information. The ISMC 
charter will contain the details of the types of data to be reviewed, the defined triggers for 
review, the minimum frequency of meetings (timed, if no triggers), and the communication plan 
for disseminating review recommendations. 
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8 
SELECTION OF STUDY POPULATION 
Section 7.1 provides information regarding number of subjects planned to be randomized. 
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 must be provided before any study assessments are 
performed. 
b. Subject must be fluent (oral and written) in English (applicable to the US) or local 
language (Ukrainian or Russian applicable to Ukraine) 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 for 
Schizophrenia and Psychotic Disorder Studies (MINI) version 7.0.2. 
4. Subject is experiencing an acute exacerbation or relapse of psychotic symptoms, 
with onset less than 2 months before screening. 
a. The subject requires hospitalization for this acute exacerbation or relapse of psychotic 
symptoms. 
b. If already an inpatient at screening, has been hospitalized for less than 2 weeks for 
the current exacerbation at the time of screening. 
5. Positive and Negative Syndrome Scale total score between 80 and 120, inclusive. 
a. Score of ≥4 (moderate or greater) for ≥2 of the following Positive Scale (P) items: 
i. Item 1 (P1; delusions) 
ii. Item 2 (P2; conceptual disorganization) 
iii. Item 3 (P3; hallucinatory behavior) 
iv. Item 6 (P6; suspiciousness/persecution) 
6. Subjects with no change (improvement) in PANSS total score between screening and 
baseline (Day -1) of more than 20%. 
7. Subject has a CGI-S score of ≥4 at screening and baseline (Day -1) visits. 
8. Subject will have been off lithium therapy for at least 2 weeks before baseline and free 
of all oral antipsychotic medications for at least 5 half-lives or 1 week, whichever is 
longer, before baseline (Day -1). 
9. Subjects taking a long-acting injectable antipsychotic could not have received a dose of 
medication for at least 12 weeks (24 weeks for INVEGA TRINZA®) before baseline 
visit (Day -1). 
10. Subject is willing and able to be confined to an inpatient setting for the study duration, 
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follow instructions, and comply with the protocol requirements. 
11. BMI must be ≥18 and ≤40 kg/m2. 
12. Subject resides in a stable living situation and is anticipated to return to that same stable 
living situation after discharge, in the opinion of the investigator. 
13. Subject has an identified reliable informant/caregiver. An informant/caregiver is 
needed at the screening and baseline visits as well as at the end of the study for 
relevant assessments (site staff may act as informant while the subject is an inpatient). 
An informant/caregiver may not be necessary if the subject has been the patient of the 
investigator for ≥1 year. 
14. Women of childbearing potential (WOCBP), or men whose sexual partners are 
WOCBP, must be able and willing to use at least 1 highly effective method of 
contraception during the study and for 7 days after the last dose of study drug. Sperm 
donation is not allowed for 7 days after the final dose of study drug. A female subject 
is considered to be a WOCBP after menarche and until she is in a postmenopausal 
state for 12 months or otherwise permanently sterile (for which acceptable methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy)[22]. For 
the definition and list of highly effective methods of contraception, see APPENDIX 1.  
8.2 
Exclusion Criteria 
Individuals meeting any of the following criteria at screening or baseline are ineligible to 
participate in this study: 
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, moderate to severe alcohol use disorder (within the past 
12 months), substance (other than nicotine or caffeine) use disorder within the past 
12 months (use of cannabis at screening will result in screen failure with the allowance 
to rescreen at a later date if no moderate to severe substance use disorder is determined), 
major depressive disorder, bipolar I or II disorder, schizoaffective disorder, obsessive 
compulsive disorder, and post-traumatic stress disorder. Symptoms of mild mood 
dysphoria or anxiety are allowed as long as these symptoms are not the primary focus of 
treatment. 
a. A screening subject with mild substance abuse disorder within the 12 months before 
screening must be discussed and agreed upon with the medical monitor before they 
can be allowed into the study 
2. Subjects who are newly diagnosed or are experiencing their first treated episode of 
schizophrenia. 
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 
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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. 
9. Subjects cannot currently (within 5 half-lives or 1 week, whichever is longer, before 
baseline [Day -1]) be receiving oral antipsychotic medications; monoamine oxidase 
inhibitors; anticonvulsants (eg, lamotrigine, Depakote); tricyclic antidepressants (eg, 
imipramine, desipramine); selective serotonin reuptake inhibitors; or any other 
psychoactive medications except for as needed anxiolytics (eg, lorazepam, chloral 
hydrate). 
10. Pregnant, lactating, or less than 3 months postpartum. 
11. If, in the opinion of the investigator (and/or Sponsor), subject is unsuitable for 
enrollment in the study or subject has any finding that, in the view of the investigator 
(and/or Sponsor), may compromise the safety of the subject or affect his/her ability to 
adhere to the protocol visit schedule or fulfill visit requirements. 
12. Positive test for coronavirus (COVID-19) within 2 weeks before screening and at 
screening. 
13. Subjects with extreme concerns relating to global pandemics, such as COVID-19, that 
preclude study participation. 
14. Subject has had psychiatric hospitalization(s) for more than 30 days (cumulative) 
during the 90 days before screening. 
15. Subject has a history of treatment resistance to schizophrenia medications defined as 
failure to respond to 2 adequate courses of pharmacotherapy (a minimum of 4 weeks 
at an adequate dose per the label) or required clozapine within the last 12 months. 
16. Subjects with prior exposure to KarXT. 
17. Subjects who experienced any adverse effects due to xanomeline or trospium. 
18. Participation in another clinical study in which the subject received an experimental or 
investigational drug agent within 3 months before screening. 
19. Risk of violent or destructive behavior. 
20. Current involuntary hospitalization or incarceration. 
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8.3 
Rescreening 
Individuals who sign the informed consent form (ICF) to participate in the study but who do not 
subsequently meet all the requirements for safety laboratory assessments and therefore do not 
enroll (screen failures) may be rescreened, upon approval of the medical monitor on a case by 
case basis. Such individuals may be allowed to rescreen up to 1 time. When re-testing within the 
same screening procedure, only the exclusionary laboratory tests will be repeated once in case 
the exclusionary laboratory result was not due to a pathological condition and was occasional 
(except for individuals who have positive serology results).  
8.4 
Study Withdrawal, Removal, and Replacement of Subjects 
If a subject discontinues study treatment and is withdrawn from the study for any reason, the 
study site must immediately notify the medical monitor. The date and the reason for study 
discontinuation must be recorded on the electronic case report form (eCRF). Subjects who 
complete or discontinue early from the study will be discharged from the study site, if clinically 
warranted after completing all the Visit 10/early termination assessments as indicated in the 
Schedule of Assessments (Table 2). 
Note: A safety follow-up visit will be performed 1 week after the End of Study visit for those 
subjects who do not roll over into the long-term open-label study KAR-008. 
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 will 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. The reason for subject withdrawal will be noted on the 
eCRF 
• on the basis of the investigator’s clinical judgement 
• 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 
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• general or specific changes in the subject’s condition that renders him/her ineligible for 
further treatment according to the inclusion/exclusion criteria (eg, subject has need for a 
medication prohibited by the protocol) 
• subject fails to adhere to the protocol requirements (eg, drug noncompliance [if a study 
subject is off study drug for >5 days in a row])  
• violation of entry criteria; ie, subjects who are enrolled but are later discovered not to 
meet entry criteria 
• development of suicidal or assaultive behavior 
• alcohol or illegal drug use 
• pregnancy, as indicated in Section 12.7.8. Any study subject who becomes pregnant 
while participating in the study will be unblinded to study treatment randomization. If she 
is found to be on active treatment assignment, she will be followed until her pregnancy 
reaches term 
• Sponsor’s decision to discontinue study 
Subjects withdrawing 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 leave the unit or are lost to follow-up. 
These efforts must be documented in the subject’s file. Subjects with AEs ongoing at end of 
study will be followed until the AE is resolved (regardless of whether they enroll in the 
long-term open-label study KAR-008) or the subject is considered to be in stable condition. 
The Sponsor has the right to terminate the study at any time in case of SAEs or if special 
circumstances concerning the study drug 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, women of childbearing potential in this study must be willing to use a highly effective 
method of birth control (see APPENDIX 1 for a list of acceptable highly effective methods of 
contraception) during the study and for 7 days after the last dose of study drug. Females of 
childbearing potential will have a serum pregnancy test at screening and a urine pregnancy test 
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on Day 1 (before receiving KarXT), Day 35, and Day 42 (only for females of childbearing 
potential who do not roll over to KAR-008).  
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 are breastfeeding must not be enrolled in the study. 
The effects of study drug on sperm are unknown. Men who are willing to participate in the study 
must agree to use a highly effective method of birth control (see APPENDIX 1 for a list of 
acceptable highly effective methods of contraception) and must not impregnate a sexual partner 
during or for 7 days after the last dose of study drug. They must also agree to refrain from sperm 
donation for 7 days after the last dose of study drug. 
Female subjects of child-bearing potential will be instructed that known or suspected pregnancy 
occurring during the study should be confirmed and reported to the investigator. If a female 
subject becomes pregnant, the investigator must withdraw her from the study without delay. The 
subject must not receive any further doses of the study drug. Upon discontinuation from the 
study, only those procedures that would not expose the pregnant female subject to undue risk 
will be performed. See Section 12.7.8 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 report will be completed if the subject has completed the study. Notification of the 
pregnancy should be submitted on 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 SAE (Section 12.7.4). 
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 leave the facility and are lost to 
follow-up to obtain end of study 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 Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB) may take such actions. If the study is terminated for safety reasons, subjects 
will be notified immediately and assured that appropriate treatment and follow-up will be 
available. If an investigator terminates the study, the Sponsor, subjects, and IEC/IRB will be 
informed about the reason for such action. Similarly, if the Sponsor terminates the study, it will 
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inform the investigators, the IEC/IRB, and the subjects of the reason for such an action. Similar 
notifications will be sent by the IEC/IRB if it takes such an action. 
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9 
TREATMENTS 
9.1 
Details of Study Treatments 
KarXT is formulated as hard hydroxypropyl methylcellulose oral capsules containing 2 distinct 
populations of drug beads, one of which is loaded with xanomeline tartrate and the other of 
which is loaded with trospium chloride. Each capsule contains the freebase equivalent of 
xanomeline and trospium according to the desired dose strength. In addition to the active 
ingredients, the drug beads contain microcrystalline cellulose (MCC). The beads are not coated 
and are formulated for immediate release of the active ingredients. 
 
Identity of Study Treatments 
Active study agents for treatment group will be size 0, Swedish orange-white, opaque, and 
hydroxypropyl methylcellulose hard capsules. Placebo will be prepared in matching capsules; 
therefore, an unblinded pharmacist will be required to dispense study agent at each day of 
dosing. For the 2-day lead-in period (Days 1 and 2), subjects randomized to active drug will 
receive capsule strength KarXT 50/20 BID, followed by 2 capsules of KarXT 50/10 mg BID or a 
dosage of 100/20 BID for a total daily dosage of 200/40 mg xanomeline/trospium chloride for 
the remainder of Week 1 (Days 3 to 7). At the beginning of Week 2, dosing may be increased to 
2 capsules of KarXT 62.5/15 mg or a dosage of 125/30 BID for a total daily dosage of 
250/60 mg xanomeline/trospium chloride, depending on clinical response and tolerability. 
Investigators have the option to return a subject to KarXT 100/20 BID for the remainder of the 
treatment period, but dosing must not change after Visit 7 of the study.  
KarXT 50/10 mg is composed of 44.4% xanomeline tartrate, 5.8% trospium chloride, excipients 
37.59% MCC, 11.5% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a size 0, 
Swedish orange, hydroxypropyl methylcellulose hard capsule. 
KarXT 50/20 mg is composed of 33.4% xanomeline tartrate, 8.7% trospium chloride, excipients 
39.8% MCC, 17.3% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a size 0, Swedish 
orange, hydroxypropyl methylcellulose hard capsule. 
KarXT 62.5/15 mg is composed of 41.7% xanomeline tartrate, 6.5% trospium chloride, 
excipients 38.1% MCC, 12.9% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a 
size 0, Swedish orange, hydroxypropyl methylcellulose hard capsule. 
Placebo is composed of sugar spheres pf011, 850/1000 suglets, 99.05% colorcon, and 10.05% 
talc in a size 0, Swedish orange, an opaque white hydroxypropyl methylcellulose hard capsule. 
All investigational agents are to be stored according to requirements. 
 
Packaging and Labelling 
The study packaging and labelling will be performed by Corealis Pharma, located in Laval, 
Quebec, Canada, Catalent Pharma Solutions, located in Winchester, Kentucky (labelling for the 
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US sites), and Catalent Pharma Solutions, located in Philadelphia, Pennsylvania (labelling for 
Ukrainian sites). All packaging and labelling operations will be performed according to Good 
Manufacturing Practice for Medicinal Products and the relevant regulatory requirements. 
Bulk supply bottles are labeled with the name of the drug, recommended storage conditions, the 
name and address of the manufacturer, and the Investigational Use Statement (“Caution: New 
Drug – Limited by Federal [US] Law to Investigational Use”). 
Further details on labelling of investigational products will be provided in the Pharmacy Manual.  
 
Study Drug Storage 
KarXT and placebo must be stored at controlled room temperature 15°C-25°C in a secured 
location with no access to unauthorized personnel. 
 
Study Drug Retention 
Study drug not used in KAR-009 may be used for the long-term extension study (KAR-008). 
Therefore, unused study drug for this particular study must be retained until completion or 
termination of the KarXT program, and written authorization from the Sponsor has been 
received. The unused study drug can be reassigned in the IWRS to subjects in the KAR-008 
study. All unused and used study drug must be destroyed at the site or returned, as specified by 
Sponsor. It is the investigator’s responsibility to ensure that the Sponsor has provided written 
authorization prior to return or destruction, and that appropriate records of the disposal are 
documented and maintained. No used or unused study drug may be disposed until fully 
accounted for by the study monitor. 
9.2 
Dose Schedule 
The first dose of the study drug will be administered in the morning of Day 1. The last dose will 
be administered in the morning of Visit 10 (Day 35 -2 days). The study drug should be 
administered daily BID on an empty stomach ie, at least 1 hour before a meal or 2 to 3 hours 
after a meal. Some considerations for dosing and PK blood withdrawals are provided in the 
subsections below. 
 
Visit 2b/Day 1 Randomization and Dosing 
• 
The first dose will be administered in the morning, and the evening dose will be 
administered 12 ± 0.5 hours after the morning dose.  
• 
All subjects must be administered 4 dosages of the KarXT 50/20 or placebo before dose 
escalation to KarXT 100/20 or placebo BID. 
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Visit 3/Day 3 and/or Visits Occurring on Weekends/Holidays 
• 
If dose escalation to the KarXT 100/20 or placebo level is confirmed by investigator 
order on Visit 3/Day 3, that dose is to be administered in the morning. 
• 
When Day 3 occurs on a weekend, it is expected that the complete Visit 3 will be 
performed, and the subject’s dose will be escalated on Day 3. 
• 
If completion of the visit is not possible on Day 3, the +1-day visit window may be used. 
In this instance, the dose will not be escalated until the study visit occurs. In all cases, 
the subject must have had at least 4 doses of KarXT 50/20 or placebo before escalating 
to KarXT 100/20 or placebo. 
• 
This may result in only 4 days of the KarXT 100/20 or placebo dose at Visit 5/Day 8, 
which is acceptable. 
• 
All subjects must be administered 8 doses of the KarXT 100/20 or placebo before dose 
escalation to KarXT 125/30 or placebo BID. 
 
Visit 5/Day 8 Dosing and PK Considerations and Visit 8/Day 28 PK 
Considerations 
• 
If dose escalation to the KarXT 125/30 or placebo level is confirmed by investigator 
order on Visit 5/Day 8, that dose is to be administered in the morning (after the predose 
PK blood draw) to allow for serial postdose PK blood draws per protocol (Table 2, 
Footnote p). 
• 
Should the use of visit windows be necessary, serial PK sampling must accompany the 
actual day of dose escalation for Visit 5.  
• 
For Visit 8, serial PK sampling is meant to capture the PK profile of the subject’s final 
KarXT dose level (125/30 or 100/20) after multiple doses; therefore, there must be no 
changes in dose for at least 7 days prior to Visit 8. PK sampling must accompany the 
actual day of Visit 8 if a window is used. 
 
Visit 10/Day 35 Dosing 
• All subjects will receive their final dose of KarXT or placebo on the morning of 
Visit 10/Day 35. It is intended that subjects rolling over to KAR-008 will begin 
open-label treatment the next day in the morning. 
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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 t3-digit study code and a 3-digit site identification followed by a 3-digit 
subject number assigned sequentially within each site, starting at 
. 
On Day -1, all eligible subjects will be randomly assigned in a 1:1 ratio to either KarXT or 
placebo groups. Subjects will be assigned a randomization number through the IWRS, in 
accordance with the randomization code generated by the authorized personnel at VERISTAT. 
At the study site, the randomization schedule will only be accessible to authorized unblinded 
pharmacy personnel or designee. Once a randomization number is allocated to one subject, it 
may not be assigned to another subject even if the former discontinued the study. 
 
Blinding 
An IWRS will allocate treatment based on a prespecified randomization list generated by 
VERISTAT. Active and placebo study drug will be provided in bulk to each site participating in 
the study. For each dose, study drug and packaging will be identical in size, shape, color, and 
appearance (see Section 9.1.2). No other study site personnel (except the pharmacist or other 
designated unblinded individual), subjects, informants/caregivers, Sponsor personnel, or Sponsor 
designees (eg, Sponsor’s Medical Monitor) will be unblinded to treatment assignment throughout 
the duration of the study unless unblinding is required. Both active study drug and placebo will 
be supplied as identical matching capsules. This prevents bias on the part of the study staff and 
the subject to influence the results of the study.  
If an investigator becomes unblinded to a given subject’s study treatment, that subject will be 
discontinued from the study unless there are ethical reasons for that subject not to be 
discontinued; approval from the Sponsor/medical monitor must be obtained in such instances. 
VERISTAT will generate and maintain the security of the randomization code. In the event that 
emergency unblinding is required for a given subject because of AEs or concerns for the 
subject’s safety or wellbeing, the investigator may break the randomization code for just that 
subject via the IWRS, by which system the unblinding will be captured after consultation and 
agreement with the medical monitor/Sponsor. The unblinding and its cause will also be 
documented in the eCRF. Unblinding according to the protocol will occur only after completion 
of the study. 
If an AE is thought to be related to the study drug and poses a safety risk, the investigator must 
decide whether to stop investigational treatment and/or treat the subject. Subject withdrawal 
should be avoided, if possible. If discontinuation of treatment occurs, every attempt should be 
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made to restart study drug if medically appropriate, whatever the duration of discontinuation. 
When a subject has an AE that requires that the investigator be unblinded, the investigator can 
obtain the treatment assignment from the IWRS system. The site is expected to notify the study 
medical monitor before breaking the study blind unless it is in the subject’s best interest if the 
blind is broken immediately. Note: In most circumstances, it is not necessary to unblind a 
subject, even if an SAE has occurred. For many drugs there is no specific therapy for AEs. The 
appropriate course of action is to stop the investigational drug and treat the signs and symptoms 
resulting from the AE. 
The members of the ISMC will be unblinded as they review the safety data from the study. 
9.4 
Dose Modification 
Subjects will be dosed as described in Section 7.1 and in accordance with the Schedule of 
Assessments (Table 2). The study drug 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 at Visits 5, 6, and 7 and at unscheduled visits. No dose adjustments are allowed after 
Visit 7. No other dose modifications are permissible in this study except those specified in this 
protocol. 
9.5 
Treatment Accountability and Compliance 
The pharmacist or other designated unblinded 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 study drug will be supervised by study site personnel to ensure compliance. 
Investigators will maintain records that adequately document that the subjects were provided 
with the correct study treatment bulk supply and reconcile the products received from the drug 
dispensing center. Investigational product will not be returned to the Sponsor or designee until 
accountability has been fully monitored through the end of the study. Study drug accountability 
will be assessed periodically by the assigned unblinded study monitor. 
9.6 
Prior and Concomitant Therapy 
 
Prior and Concomitant Medications 
Subjects will be asked for all prior medications they were taking up to 6 months before the study, 
up to the time of the first dose of study medication on Day 1. All prior medications will be 
recorded on the eCRF. 
Restricted prior therapies are provided in Section 8.2.  
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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 (ie, from the time of screening visit until study completion), subjects will 
refrain from the use of any new concomitant medications without the specific prior approval of 
the investigator. The administration of any other concomitant medications during the study 
period is prohibited without the prior approval of the investigator unless its use is deemed 
necessary in a medical emergency. Any medication or therapy that is taken by or administered to 
the subject during the course of the study must be recorded in the eCRF. The entry must include 
the dose, regimen, route, indication, dates of use, and time of use (only for concomitant 
medications used on an as-needed [PRN] basis). 
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. 
• Within 5 half-lives or 1 week, whichever is longer, before baseline (Day -1), subjects 
could not have taken oral antipsychotic medications, MAO inhibitors, mood stabilizers 
(ie, lithium), anticonvulsants (eg, lamotrigine, Depakote), tricyclic antidepressants (eg, 
imipramine, desipramine), selective serotonin reuptake inhibitors, or any other 
psychoactive medications except for anxiolytics that were taken on an as needed basis 
(eg, lorazepam, chloral hydrate).  
• Subjects taking a long acting injectable antipsychotic could not have received a dose of 
medication for at least 12 weeks (24 weeks for INVEGA TRINZA®).  
Note: Please direct questions relating to prohibited medications to the Medical Monitor. 
 
Concomitant Medications for Anxiety and/or Sleep aid 
Subjects are allowed to take benzodiazepines (up to 6 mg lorazepam/day or equivalent) for 
anxiety, agitation, and insomnia on a PRN basis. Subjects may also use non-benzodiazepine 
medications (eg, zolpidem, zaleplon) as a sleep aid also on a PRN basis. Study sites must record 
the use of such medications in the eCRF on a per-administration basis and subject’s source 
document. Note: Cognition testing should not be done within 8 hours of receiving a 
benzodiazepine or sleep medication. 
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10 STUDY PROCEDURES 
Table 2 outlines the timing of procedures and assessments to be performed throughout the study. 
Section 12.6 specifies laboratory assessment samples to be obtained. See Sections 11, 12, and 13 
for additional details regarding efficacy, safety, and PK assessments, respectively. 
  
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Table 2. 
Schedule of Assessments 
PROCEDURE 
SCREENING 
PHASE 
TREATMENT PHASE 
SAFETY 
FOLLOW
-UPv 
Unscheduled 
Visit(s)b 
VISIT 
1 
(Day -8 
to -2)a 
2a 
(Day 
-1) 
2b 
(Day 
1) 
3 
(Day
3 +1 
day)
4 
(Day 
7 ±2 
days) 
5 
(Day 
8 ±2 
days) 
6 
(Day 
14 ±2 
days) 
7 
(Day 
21 ±2 
days) 
8 
(Day 
28 ±2 
days)u 
9 
(Day 
32 +1 
day) 
10/ET 
(Day 35 
-2 days)
11 
(Day 42 
+5 days) 
WEEKS PAST 
RANDOMIZATION 
NA 
0 
 
 
1 
 
2 
3 
4 
 
5 
6 
 
Written informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Collect 
demographic 
information (date of 
birth, sex, race) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(females of 
childbearing 
potential only)c 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Urine test for 
drugs of abuse 
and alcohol 
testingd 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Review of 
inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Subject eligibility 
verification process 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, 
psychiatric, and 
medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examinatione 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
Spontaneous AEsf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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PROCEDURE 
SCREENING 
PHASE 
TREATMENT PHASE 
SAFETY 
FOLLOW
-UPv 
Unscheduled 
Visit(s)b 
VISIT 
1 
(Day -8 
to -2)a 
2a 
(Day 
-1) 
2b 
(Day 
1) 
3 
(Day
3 +1 
day)
4 
(Day 
7 ±2 
days) 
5 
(Day 
8 ±2 
days) 
6 
(Day 
14 ±2 
days) 
7 
(Day 
21 ±2 
days) 
8 
(Day 
28 ±2 
days)u 
9 
(Day 
32 +1 
day) 
10/ET 
(Day 35 
-2 days)
11 
(Day 42 
+5 days) 
WEEKS PAST 
RANDOMIZATION 
NA 
0 
 
 
1 
 
2 
3 
4 
 
5 
6 
 
Review of 
concomitant 
medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height (Screening 
only) and body 
weight, BMI, waist 
circumference 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Orthostatic vital 
signs: BP and heart 
rateg 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Resting 12-lead ECGh 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
Blood samples for 
hematology, 
coagulation, and 
serum chemistry and 
urine sample for 
urinalysisi 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
COVID-19 
testingj 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Blood sample 
for prolactink 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Blood sample 
for viral 
serologyl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample 
for DNA testing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
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PROCEDURE 
SCREENING 
PHASE 
TREATMENT PHASE 
SAFETY 
FOLLOW
-UPv 
Unscheduled 
Visit(s)b 
VISIT 
1 
(Day -8 
to -2)a 
2a 
(Day 
-1) 
2b 
(Day 
1) 
3 
(Day
3 +1 
day)
4 
(Day 
7 ±2 
days) 
5 
(Day 
8 ±2 
days) 
6 
(Day 
14 ±2 
days) 
7 
(Day 
21 ±2 
days) 
8 
(Day 
28 ±2 
days)u 
9 
(Day 
32 +1 
day) 
10/ET 
(Day 35 
-2 days)
11 
(Day 42 
+5 days) 
WEEKS PAST 
RANDOMIZATION 
NA 
0 
 
 
1 
 
2 
3 
4 
 
5 
6 
 
Functional 
constipation inquirym 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Admission of subject 
to inpatient unitn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization/
assignment of 
subject 
randomization 
number 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Determination of dose 
adjustment 
 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
Study drug provided 
(randomized, double- 
blind) and 
administered daily 
BIDo 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Blood samples for PK 
analysisp 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
MINI version 7.0.2q 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Positive and Negative 
Syndrome Scale 
(PANSS) for 
schizophreniar 
X 
X 
 
 
 
 
X 
X 
X 
 
X 
X 
 
C-SSRSs 
X 
X 
 
 
X 
 
X 
X 
X 
 
X 
X 
X
CGI-S Scale 
X 
X 
 
 
X 
 
X 
X 
X 
 
X 
 
 
Cognition testingt 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
Simpson-Angus 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
X 
 
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PROCEDURE 
SCREENING 
PHASE 
TREATMENT PHASE 
SAFETY 
FOLLOW
-UPv 
Unscheduled 
Visit(s)b 
VISIT 
1 
(Day -8 
to -2)a 
2a 
(Day 
-1) 
2b 
(Day 
1) 
3 
(Day
3 +1 
day)
4 
(Day 
7 ±2 
days) 
5 
(Day 
8 ±2 
days) 
6 
(Day 
14 ±2 
days) 
7 
(Day 
21 ±2 
days) 
8 
(Day 
28 ±2 
days)u 
9 
(Day 
32 +1 
day) 
10/ET 
(Day 35 
-2 days)
11 
(Day 42 
+5 days) 
WEEKS PAST 
RANDOMIZATION 
NA 
0 
 
 
1 
 
2 
3 
4 
 
5 
6 
 
Rating Scale 
Barnes Rating Scale 
for Akathisia 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
X 
 
Abnormal 
Involuntary 
Movement Scale 
(AIMS) 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
X 
 
Abbreviations: AE = adverse event; BID = twice daily; BMI = body mass index; BP = blood pressure; CGI-S = Clinical Global Impression‒Severity scale; 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ET = early termination; ID = identification; MINI = Mini International 
Neuropsychiatric Interview; PK = pharmacokinetic; QTcF = QT interval corrected by Fridericia. 
a. 
Up to a 7-day extension of the screening phase is allowed, if needed. 
b. 
Other assessments as needed. 
c. 
A serum pregnancy test for females of childbearing potential should be done at screening, and urine pregnancy tests should be done at other visits. 
d. 
A National Institute on Drug Abuse-5 urine drug screen (cannabinoids or marijuana, phencyclidine, amphetamines, opiates, and cocaine) will be 
performed at screening and at Visit 2a (baseline). If a subject leaves the study site, they should have a urine drug screen and test for alcohol (breathalyzer 
or blood alcohol level) upon returning to the study site.  
e. 
A complete physical examination includes body temperature (°C), general appearance, head/eyes/ears/nose/throat, examination of thorax and 
abdomen, assessment of cardiac, musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited neurological 
examination. 
f. 
AEs as reported by subjects or observed by clinical staff and occurs from Day -1. One PK blood sample may be drawn if a relevant/significant AE 
(based on medical judgement) is reported during a scheduled visit or if there is a dose adjustment or a relevant/significant AE reported during an 
unscheduled visit (no multiple draws). 
g. 
Vital signs taken supine and standing after 2 minutes. BP includes systolic and diastolic BP and is to be taken in the same arm for the duration of the 
study. Heart rate is measured in beats/minute. During treatment, beginning with Day 1, orthostatic vital signs should occur 2 (±1) hours after morning 
dosing. Orthostatic vital signs are only required after the morning dose of the specified visit days, but additional orthostatic vital sign monitoring is 
allowed at the investigator’s discretion. It would be acceptable, for example, to do orthostatic vital signs BID after dosing increases for a day or 2 for 
subjects where it seems warranted, but this should not be done automatically. 
h. 
ECG on Day 1 will be done at 2 hours + 15 minutes post morning dose. ECGs at all other scheduled visits will be performed before blood withdrawal for 
any safety laboratory tests and/or PK analysis. During the ECG, ventricular rate (bpm), PR (msec), QRS (msec), QT (msec), and QTcF (msec) 
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measurements should be obtained.  
i. 
Refer to Table 3 for individual laboratory tests. For urinalysis, a urine dipstick will be performed at the site, and the sample will be sent to the central 
laboratory in case of abnormalities. 
j. 
Optional COVID-19 test may be performed at unscheduled visits based on the Investigator’s discretion. 
k. 
Blood sample for prolactin must be obtained before the morning dose of the study drug at scheduled visits (except at Visit 2a). 
l. 
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. 
m. Functional constipation inquiry: At specified visits, subjects will be asked whether they have experienced constipation (per the ROME III criteria and 
Bristol Stool Form scale; see APPENDIX 2) since the last visit and if yes, whether the constipation required intervention. If the subject answers yes, 
sites are instructed to ask subjects to provide event date and ensure the event is documented as an AE and treatment is documented as concomitant 
medication.  
n. 
If an eligible subject is not already an inpatient, the subject should be admitted to the inpatient unit. 
o. 
Starting on Day 1, study drug is administered daily BID (first dose of study will be administered in the morning of Day 1, and evening dose will be 
administered 12 ± 0.5 hours after the morning dose and after last PK sampling [for Visits 5 and 8] is completed), on an empty stomach ie, at least 1 hour 
before a meal or 2 to 3 hours after a meal by the study staff, with the last dose administered on the morning of Visit 10. All subjects must receive at 
least 4 dosages of the 50/20 BID before dose escalation to KarXT 100/20 BID. 
p. 
For Visit 5/Day 8 and Visit 8/Day 28, 7 PK blood draws are required: before the morning dose, and at 0.5 hour ± 5 minutes, 1 hour ± 5 minutes, 
2 hours ± 10 minutes, 4 hours ± 10 minutes, 8 hours ± 10 minutes, and 12 hours ± 10 minutes after the morning dose (Note: The 12-hour samples must 
be collected before administration of the evening dose). PK blood draws at Visit 5 must be drawn in relation to the first dose of KarXT 125/30 for 
subjects who are escalated in the morning of Visit 5/Day 8 ± 2 days. PK blood must also be drawn in relation to the morning dose for subjects who are 
not escalated at Visit 5/Day 8 ± 2 days. For Visit 10/ET, a single PK blood sample should be withdrawn before discharge (preferably in the morning 
after the last dose of the study drug). One PK blood sample may also be drawn if a relevant/ significant AE is reported during a scheduled visit or if 
there is a dose adjustment or a relevant/significant AE reported during an unscheduled visit (no multiple draws). For an ET Visit that is related to an 
AE, the collection of a PK blood sample is not optional and should be drawn before discharge. 
q. 
It should be performed before PANSS assessment. 
r. 
It is recommended, if at all possible, that the PANSS assessment should be performed before all the other scale assessments (except MINI) for 
all visits at which it is performed. The PANSS assessment includes the Marder Factor. 
s. 
C-SSRS first time use lifetime, other times use “Since Last Visit” version. At the Unscheduled visit, the C-SSRS should be performed to monitor subjects 
for suicidality. 
t. 
During screening, subjects will complete each of the CANTAB tests for familiarization purposes. These same tests will then be administered on Visits 
2a, 7, and 9. Note: Cognition testing cannot be done within 8 hours of receiving benzodiazepine or sleep medications. 
u. 
There must be no changes in dose for at least 7 days leading up to Visit 8. 
v. 
Safety follow-up visit will be performed 1 week (Day 42 +5 days) after the end of study visit (Visit 10) for subjects who do not rollover in to the 
long-term open-label study KAR-008. 
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10.1 Informed Consent 
Informed consent forms must be approved for use by the reviewing IEC/IRB. Before performing 
any study-related procedures, the investigator (or designee) will obtain written informed consent 
from the subject.  
10.2 Study Procedures 
Assessments and their timings are to be performed as outlined in the Schedule of Assessments 
(Table 2). Section 12.6 specifies laboratory assessment samples to be obtained.  
Assessments and procedures scheduled at a visit where study drug is administered should be 
performed before administration of treatment unless otherwise indicated in the Schedule of 
Assessments (Table 2). 
Efficacy assessments are described in Section 11 and include PANSS and CGI-S scores. 
Safety assessments are described in Section 12 and include spontaneous AEs; AESIs, 
procholinergic and anticholinergic symptoms; cognition testing (CANTAB); SAS; BARS; 
AIMS; body weight; BMI; waist circumference; orthostatic vital signs; ECG; clinical laboratory 
assessments (hematology, clinical chemistry, coagulation, urinalysis, and drug screen); prolactin 
levels; physical examination; and C-SSRS. 
PK assessments are described in Section 13 and include estimation of AUC, Cmax, and Tmax. 
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 study drug. 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 after discussion with the 
medical monitor. 
Study discontinuation procedures are described in Section 8.4 and 8.6. 
 
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11 EFFICACY ASSESSMENTS 
The Schedule of Assessments (Table 2) outlines the efficacy assessments to be performed 
throughout the study and their timing. 
11.1 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[23]. 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. The PANSS assessment includes the Marder Factor. 
It is recommended, if at all possible, that the PANSS assessment should be performed before all 
the other scale assessments (except MINI at screening) for all visits at which it is performed.  
11.2 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 modified CGI-S 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[24]. 
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 previous 7 days. 
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12 SAFETY ASSESSMENTS 
Safety assessments (spontaneous AEs; AESIs; procholinergic and anticholinergic symptoms; 
cognition testing [CANTAB]; SAS; BARS; AIMS; body weight; BMI; waist circumference; 
orthostatic vital signs; ECG; clinical laboratory assessments [hematology, clinical chemistry, 
coagulation, urinalysis, prolactin, and drug screen]; physical examination; and C-SSRS) are to be 
performed at protocol-specified visits, as specified in the Schedule of Assessments (Table 2).  
12.1 Demographics, and Medical 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 and psychiatric 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 12.7. All 
changes not present at baseline or described in the past medical history and identified as 
clinically noteworthy must be recorded as AEs. 
12.2 Vital Signs 
Orthostatic vital signs (systolic and diastolic BP and heart rate measurements) will be evaluated 
at the 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, beginning with Day 1, orthostatic vital signs should 
occur 2 (±1) hours after morning dosing. Orthostatic vital signs are only required after the 
morning dose of the specified visit days, but additional orthostatic vital sign monitoring is 
allowed at the investigator’s discretion. 
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. 
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12.3 Physical Examination 
A complete physical examination (body temperature, general appearance, 
head/eyes/ears/nose/throat, examination of thorax and abdomen, assessment of cardiac, 
musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited 
neurological examination) will be performed at visits as specified in Table 2. Physical 
examinations will be performed by a physician. 
12.4 Weight, Height, Body Mass Index, 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. 
12.5 Electrocardiograms 
A 12-lead, resting ECG will be obtained at the visits indicated in the Schedule of Assessments 
(Table 2). During the ECG, ventricular rate (bpm), PR (msec), QRS (msec), QT (msec), and 
QTcF (msec) measurements will be obtained. ECG at Day 1 will be performed 2 hours 
(+ 15 minutes) post morning dose. ECGs at all other scheduled visits will be performed before 
blood withdrawal for any safety laboratory tests and/or PK analysis. 
All the ECGs obtained will be interpreted by experienced independent blinded reader(s) at the 
central reading facility. 
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 on the eCRF. ECGs will be 
repeated if clinically significant abnormalities are observed or artifacts are present. 
12.6 Laboratory Assessments 
Laboratory assessment samples (Table 3) are to be obtained at designated visits as detailed in the 
Schedule of Assessments (Table 2). 
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Table 3. 
Laboratory Assessments 
Hematology 
Serum Chemistry 
Urine Analysis (Dipstick) 
Full and differential blood count 
Hct 
Hb 
MCH 
MCHC 
MCV 
Platelet count 
RBC count 
WBC count with differential 
 
Albumin 
ALT 
ALP 
AST 
Albumin 
Uric acid 
BUN or urea 
Carbon dioxide 
Creatinine 
Creatine kinase and subtypes 
Electrolytes (sodium, 
potassium, chloride, calcium, 
phosphorus) 
GGT 
Glucose 
LDH 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Triglycerides 
Total protein 
Appearance 
pH 
Protein 
Glucose 
Ketone bodies 
Indicators of blood and WBCs 
Specific gravity 
Urobilinogen 
Occult blood 
WBCs 
 
Prolactin 
Coagulation 
Serologya 
COVID-19 
PT 
Activated PTT 
Fibrinogen 
HBV 
HCV 
HIV 
 
Pregnancy test: A serum pregnancy test will be performed on all women of childbearing potential at 
screening and a urine pregnancy test (urine HCG) will be performed at other scheduled visits at the site. If a 
urine pregnancy test is positive, a serum sample should be sent to central laboratory for confirmation of the 
result. 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; GGT = gamma-glutamyl transpeptidase; Hb = hemoglobin; HBV = Hepatitis B; 
HCG = human chorionic gonadotropin; Hct = hematocrit; HCV = Hepatitis C; HIV = Human Immunodeficiency 
virus; LDH = lactate dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular 
hemoglobin concentration; MCV = mean corpuscular volume; PT = prothrombin time; PTT = partial 
thromboplastin time; RBC = red blood cell; WBC = white blood cell. 
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. 
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 urine volume of 10 mL will be obtained to perform urinalysis (if abnormalities 
observed on dipstick) and urine drug screen at scheduled time points as per Table 2.  
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Blood and abnormal urine (microscopic analysis) samples will be analyzed at a central 
laboratory facility. Urine samples will first be analyzed by dipstick at the site. If the results of the 
dipstick indicate abnormalities to be further investigated, the sample will be sent the central 
laboratory, and a microscopic analysis will be performed. All laboratory reports must be 
reviewed, signed, and dated by the investigator. A legible copy of all reports must be filed with 
both the subject’s eCRF and medical record (source document) for that visit. Any laboratory test 
result considered by the investigator to be clinically significant should be considered an AE 
(clinically significant AEs include those that require an intervention). Clinically significant 
abnormal values occurring during the study will be followed up with until repeat test results 
return to normal, stabilize, or are no longer clinically significant.  
All the study subjects will be closely monitored for drug-induced liver toxicity, detailed in 
Section 12.7.5, during the study. 
Other Laboratory Assessments: 
• A National Institute on Drug Abuse-5 urine drug screen (cannabinoids or marijuana, 
phencyclidine, amphetamines, opiates, and cocaine) will be performed using a dipstick at 
screening, Visit 2a (baseline), and at unscheduled visits.  
• Alcohol testing is performed using a breathalyzer or blood alcohol test.  
• If a subject leaves the study site, they should have a urine drug screen test and test for 
alcohol (breathalyzer or blood alcohol test) upon returning to the study site. 
 
Blood Sampling for Pharmacogenetics 
A blood sample may be collected at baseline (Day -1) for exploratory pharmacogenetic analysis. 
Approximately 9 mL of blood may be collected for subsequent DNA extraction. The samples 
will be stored at a central laboratory facility, where DNA will be extracted and retained. The 
collection, storage, shipping, processing of the blood samples, and the analytical methods to be 
used will be detailed in the laboratory manual.  
The genetic variants to be analyzed may include SNPs and any other variants as deemed 
necessary by the Sponsor.  
The details on the statistical analysis will be provided either in the statistical analysis plan (SAP) 
or the clinical study report. 
12.7 Adverse Events 
 
Adverse Events 
An AE is any symptom, physical sign, syndrome, or disease that either emerges during the study 
or, if present at screening, worsens during the study, regardless of the suspected cause of the 
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event. All medical and psychiatric conditions (except those related to the indication under study) 
present at screening will be documented in the medical history eCRF. Changes in these 
conditions and new symptoms, physical signs, syndromes, or diseases should be noted on the AE 
eCRF during the rest of the study. Clinically significant 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 on 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 laboratory tests 
are available. 
Each AE is to be documented on the eCRF with reference to date of onset, duration, frequency, 
severity, relationship to study drug, action taken with study drug, treatment of event, and 
outcome. Furthermore, each AE is to be classified as being serious or nonserious. Changes in 
AEs and resolution dates are to be documented on the eCRF. 
For the purposes of this study, the period of observation for collection of TEAEs extends from 
the time immediately after the administration of study drug on Day 1 until the End of Study 
(Visit 10 for subjects who roll over and Visit 11 for subjects who do not roll over to Study KAR-
008 study) or early termination. 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 study drug are given in 
Table 4 and Table 5. 
Table 4. 
Classification of Adverse Events by Intensity 
MILD: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with 
everyday activities. 
MODERATE: An event that is sufficiently discomforting to interfere with normal everyday activities. 
SEVERE: An event that prevents normal everyday activities. 
 
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Table 5. 
Classification of Adverse Events by Relationship to Study Drug 
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 study drug 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 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 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 reexposure to drug (if rechallenge occurs); and (4) it follows a known pattern 
of response to the test drug. 
Abbreviation: AE, adverse event. 
 
 
Adverse Events of Special Interest 
The AESIs will be monitored and include orthostasis and liver function test elevations inclusive 
of DILI. 
AEs of special interest should be recorded as AEs and reported as SAEs when appropriate. 
 
Serious Adverse Events 
A, 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 
(hospitalization for elective treatment of a pre-existing, nonworsening condition is not, 
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however, considered an SAE; the details of such hospitalizations must be recorded on the 
medical history or physical examination page of the eCRF), 
• results in persistent or significant disability/incapacity, and/or 
• is a congenital anomaly/birth defect. 
Other important medical events that may not be immediately life-threatening or result in death or 
hospitalization, based upon appropriate medical judgment, are considered SAEs if they are 
thought to jeopardize the subject and/or require medical or surgical intervention to prevent one 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 first dose of the study drug is administered, during the study, or 
within 1 week of stopping the treatment must be reported to the Catalyst Clinical Research 
Pharmacovigilance group and will be communicated to the Sponsor. Any such SAE due to any 
cause, whether or not related to the study drug, 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 is: 
 
The events must be recorded on the standard AE eCRF. Preliminary reports of SAEs must be 
followed up by detailed descriptions later on, including clear and anonymized photocopies of 
hospital case reports, consultant reports, autopsy reports, and other documents when requested 
and applicable. SAE reports must be made whether or not the investigator considers the event to 
be related to the investigational drug. 
Appropriate remedial measures should be taken to treat the SAE, and the response should be 
recorded. The investigator must report all additional follow-up evaluations to the Catalyst 
Clinical Research Pharmacovigilance group within 24 hours of becoming aware of the additional 
information or as soon as is practicable. All SAEs will be followed up until the investigator and 
Sponsor agree the event is satisfactorily resolved. 
Any SAE that is not resolved by the end of the study or upon discontinuation of the subject’s 
participation in the study is to be followed up until it either resolves, stabilizes, returns to 
baseline values (if a baseline value is available), or is shown to not be attributable to the study 
drug or procedures. 
 Drug-Induced Liver Injury 
The sponsor has incorporated the following for monitoring of the drug induced liver injury: 
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• An increase of serum ALT or AST to >3 × upper limit of normal (ULN) should be 
followed by repeat testing within 48 to 72 hours of all 4 of the usual serum measures 
(ALT, AST, ALP, and total bilirubin) to confirm the abnormalities and to determine if 
they are increasing or decreasing. An inquiry should be made about the symptoms 
(fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, and rash). 
• Close observation should be initiated with ALT or AST >3 × ULN: 
o Repeat liver enzyme and serum bilirubin tests 2 or 3 times weekly. Frequency of 
retesting can decrease to once per week or less if abnormalities stabilize or the trial 
drug has been discontinued, and the subject is asymptomatic. 
o Obtain a more detailed history of symptoms and prior or concurrent diseases. 
o Obtain a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug 
use, and special diets. 
o Rule out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy; and biliary 
tract disease. 
o Obtain a history of exposure to environmental chemical agents. 
o Obtain additional tests to evaluate liver function, as appropriate (eg, international 
normalized ratio, direct bilirubin). 
o Consider gastroenterology or hepatology consultations. 
• Discontinuation of treatment should be considered if: 
o ALT or AST >8 × ULN 
o ALT or AST >5 × ULN for more than 2 weeks 
o ALT or AST >3 × ULN and (total bilirubin >2 × ULN or international normalized 
ratio >1.5) 
o ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or eosinophilia (>5%) 
• Hepatic adjudication of cases should include an evaluation for alternative causes such as 
viral, autoimmune, alcohol, hepatobiliary disorders, nonalcoholic steatohepatitis, 
concomitant medications, etc. 
• Follow up to resolution of elevated liver enzymes. 
• Gamma-glutamyl transpeptidase elevations alone should not prompt drug 
discontinuation. 
 Trial Discontinuation Criteria Other than DILI and Pregnancy 
12.7.6.1 
Individual Stopping Criteria 
Based on NCI CTCAE v5.0, the 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 12.7.5) will be at the discretion of the investigator. 
12.7.6.2 
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: 
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a. continue the clinical study without modification; or 
b. continue the clinical study with modification (listing the specific modifications 
recommended); or 
c. terminate the study. 
 Suspected Unexpected Serious Adverse Reactions 
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 or not an event is causally related to study treatment. The 
Sponsor (or their designee Syneos Health) will consider the investigator’s assessment and 
determine whether the event meets the criteria for being reportable as a 7-day or 15-day safety 
report. SUSARs that are fatal or life-threatening must be reported to the regulatory authorities 
and the IEC/IRBs (where required) within 7 days after the Sponsor (or their designee) 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 their designee) first has knowledge of them. 
The Sponsor (or their designee) is responsible for reporting SUSARs and any other events 
required to be reported in an expedited manner to the regulatory authorities and for informing 
investigators of reportable events, in compliance with applicable regulatory requirements within 
specific timeframes. Investigators will notify the relevant IEC/IRBs of reportable events within 
the applicable timeframes. 
Warnings and Precautions 
Risk of Urinary Retention: 
Trospium chloride tablets should be administered with caution to subjects with clinically 
significant bladder outflow obstruction because of the risk of urinary retention. 
Angioedema: 
Angioedema of the face, lips, tongue, and/or larynx has been reported with trospium chloride, the 
active ingredient in trospium chloride tablets. In one case, angioedema occurred after the first 
dose of trospium chloride. Angioedema associated with upper airway swelling may be life 
threatening. If involvement of the tongue, hypopharynx, or larynx occurs, trospium chloride 
should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a 
patent airway should be promptly provided. 
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Decreased Gastrointestinal Motility: 
Trospium should be administered with caution to subjects with GI obstructive disorders because 
of the risk of gastric retention. Trospium chloride, like other antimuscarinic agents, may decrease 
GI motility and should be used with caution in subjects with conditions such as ulcerative colitis, 
intestinal atony, and myasthenia gravis. 
Controlled Narrow-angle Glaucoma: 
In subjects being treated for narrow-angle glaucoma, trospium chloride should only be used if 
the potential benefits outweigh the risks and in that circumstance only with careful monitoring. 
Central Nervous System Effects: 
Trospium chloride is associated with anticholinergic CNS effects. A variety of CNS 
anticholinergic effects have been reported, including dizziness, confusion, hallucinations, and 
somnolence. Subjects should be monitored for signs of anticholinergic CNS effects, particularly 
after beginning treatment or increasing the dose. Advise subjects not to drive or operate heavy 
machinery until they know how trospium chloride affects them. If a subject experiences 
anticholinergic CNS effects, dose reduction or drug discontinuation should be considered. 
Anticholinergic Adverse Reactions in Subjects with Moderate Renal Impairment: 
Trospium is substantially excreted by the kidney. The effects of moderate renal impairment on 
systemic exposure are not known but systemic exposure is likely increased. Therefore, 
anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract 
infection, and urinary retention) are expected to be greater in subjects with moderate renal 
impairment. 
Elevation of liver enzymes: 
Elevated liver enzymes have been reported in previous studies of xanomeline alone in patients 
with Alzheimer’s disease. It is notable, however, that hepatic enzyme elevations were not 
observed in the Phase 1 studies in healthy volunteers, and that the liver function test elevations 
observed in the Phase 2 schizophrenia study (KAR-004) with KarXT (a combination of 
xanomeline and trospium) were quite limited in contrast to the effects observed with xanomeline 
in the elderly Alzheimer’s population. Moreover, even in patients with Alzheimer disease who 
experienced more hepatic enzyme elevations, the data demonstrate reversibility even with 
continued xanomeline treatment in those patients for whom 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. After administration of study drug, 
any known cases of pregnancy in female subjects will be reported until the subject completes or 
withdraws from the study. The pregnancy will be reported immediately by faxing/emailing a 
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completed pregnancy report to the Sponsor (or designee) within 24 hours of knowledge of the 
event. The pregnancy will not be processed as an SAE; however, the investigator will follow up 
with the subject until completion of the pregnancy and must assess the outcome in the shortest 
possible time but not more than 30 days after completion of the pregnancy. The investigator 
should notify the Sponsor (or designee) of the pregnancy outcome by submitting a follow-up 
pregnancy report. If the outcome of the pregnancy involved spontaneous or therapeutic abortion 
(any congenital anomaly detected in an aborted fetus is to be documented), stillbirth, neonatal 
death, or congenital anomaly, the investigator will report the event by faxing/emailing a 
completed pregnancy report form to the Sponsor (or designee) within 24 hours of knowledge of 
the event. This event is considered an SAE. 
Upon discontinuation from the study, only those procedures that would not expose the subject to 
undue risk will be performed. The investigator should also be notified of pregnancy occurring 
during the study but confirmed after completion of the study. In the event that a subject is 
subsequently found to be pregnant after inclusion in the study, any pregnancy will be followed to 
term, and the status of mother and child will be reported to the Sponsor after delivery. 
 
Overdose 
The investigator must immediately notify the Sponsor of any occurrence of overdose with study 
drug. Overdose should be managed with symptomatic and supportive care. 
12.8 Cambridge Neuropsychological Test Automated Battery 
The computerized CANTAB provides an objective measure of cognitive function correlated to 
neural networks. A short cognitive battery measuring core cognitive domains of impairment in 
schizophrenia (ie, as per Brief Assessment of Cognition Schizophrenia key cognitive domains) 
will be employed for this study, and it will take approximately 30 minutes to complete. These 
CANTAB tests meet MATRICS workshop criteria [25]. Subjects will have 1 familiarization 
session with the CANTAB tests during the screening visit and will subsequently complete the 
same test battery on Visits 2a (baseline), Visit 7, and Visit 9. Subjects perform the test on a 
provisioned iPad with data immediately uploaded to the CANTAB Connect cloud-based 
platform (WiFi permitting). 
Cognition testing cannot be done within 8 hours of receiving benzodiazepine or sleep 
medications. 
Table 6 
Cognitive Tests and Cognitive Domains Assessed by the Cambridge 
Neuropsychological Test Automated Battery 
CANTAB Tests 
MATRICS Cognitive Domain 
Outcome Measures 
Rapid visual information 
processing 
Sustained attention/vigilance 
A’ Prime: Signal detection 
measure of how good the subject is 
at detecting the target sequence 
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CANTAB Tests 
MATRICS Cognitive Domain 
Outcome Measures 
(string of three numbers); 
regardless of response tendency 
Verbal recognition memory 
Verbal memory and new learning 
Free Recall: The total number of 
words that are correctly recalled 
from the presentation phase by the 
subject during the immediate free 
recall stage 
Spatial Span 
Working memory 
Forward Span Length: The 
longest sequence of boxes 
successfully recalled by the subject 
One-touch stockings of Cambridge  
Executive Function 
Planning/Problem Solving 
Problems Solved on First Choice: 
The total number of assessed trials 
where the subject chose the correct 
answer on their first attempt 
Abbreviation: CANTAB = Cambridge Neuropsychological Test Automated Battery 
12.9 Simpson-Angus 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. 
12.10 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[26]. 
12.11 Abnormal Involuntary Movement Scale 
The AIMS is a rating scale that is used to measure involuntary movements know as tardive 
dyskinesia, which can sometimes develop as a side effect of long-term treatment with 
antipsychotic medications. It is a 12-item scale to assess orofacial, extremity, and truncal 
movements as well as the overall severity, incapacitation, and the subject’s level of awareness of 
the movements. Items are scored from 0 (none) to 4 (severe). A higher score indicates more 
severe dyskinesia. 
12.12 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[27]. 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. 
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This study will utilize 2 versions of the C-SSRS. At the screening visit, the “lifetime” version 
will be completed; for all subsequent visits the “Since Last Visit” version of the C-SSRS will be 
administered. 
12.13 Functional Constipation Inquiry 
Constipation refers to bowel movements that are infrequent or hard to pass[28]. The stool is 
often hard and dry[29]. Other symptoms may include abdominal pain, bloating, and feeling as if 
one has not completely passed the bowel movement[30]. The normal frequency of bowel 
movements in adults is between 3 per day and 3 per week[28]. Constipation will be defined per 
the Rome III criteria, as less than 3 bowel movements per week, APPENDIX 2 
(Longswreth,1486,C3)[31]. 
The Bristol Stool Form Scale has been correlated with a change in intestinal function, and had 
been shown to be a useful tool in clinical practice and research[32]. A sample Bristol Stool Form 
Scale is located in APPENDIX 2. 
As a measure of anticholinergic effects, at each visit (except at Visit 2a), 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 and pain with bowel 
movements secondary to straining, abdominal pain, abdominal bloating, and the sensation of 
incomplete bowel evacuation[30,33]. 
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. 
12.14 Mini International Neuropsychiatric Interview Version 7.0.2 
The MINI is a short structured diagnostic interview developed for DSM-5 psychiatric disorders. 
With an administration time of approximately 15 minutes, it was designed to meet the need for a 
short but accurate structured psychiatric interview for multicenter clinical studies and 
epidemiology. 
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12.15 Change in Prolactin 
Blood samples to assess the change in prolactin levels will be obtained on Visit 2a/Day -1, 
Visit 7/Day 21 ± 2 days, and Visit 10/Day 35 -2 days/Early Termination (ET). At each of these 
visits (except Visit 2a), blood sample must be collected before the morning dose of the study 
drug. 
 
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13 PHARMACOKINETICS 
13.1 Pharmacokinetic Sampling 
 
Blood Samples 
Blood samples for PK analysis of KarXT levels will be collected at the time points indicated in 
the Schedule of Assessments (Table 2). Approximately 6 mL of blood to be collected at each 
scheduled time point. The actual date and time of each blood sample collection will be recorded. 
• Serial blood samples to measure plasma concentrations of xanomeline and trospium will be 
obtained on Visit 5/Day 8 ± 2 days (first dose of fixed titration period) and Visit 8/Day 28 
± 2 days. Blood samples will be obtained at the following time points on these days:  
PK Sample 
Timing of Collection 
Collection Window 
1 
Before morning dose 
 
 
After morning dose 
 
2 
   0.5 hours 
± 0.5 min 
3 
   1 hour 
± 0.5 min 
4 
   2 hours 
± 10 min 
5 
   4 hours 
± 10 min 
6 
   8 hours 
± 10 min 
7 
    12 hours after (but before the 
evening dose) 
± 10 min 
• It is very important that the exact time of each PK draw and dosing times are recorded in 
the eCRF and that PK samples are collected within the specified times of collection. 
• Should the use of visit windows be necessary, serial PK sampling must accompany the 
actual day of potential dose escalation for Visit 5. 
•  For Visit 8, serial PK sampling is meant to capture the PK profile of the subject’s final 
KarXT dose level (125/30 or 100/20) after multiple doses. If visit windows are used for 
Visit 8, the PK sampling should occur at least 7 days after Visit 7 is completed, and there 
must be no changes in dose for at least 7 days leading up to Visit 8. PK sampling must 
accompany the actual day of Visit 8.  
• Note: A single PK sample should be drawn before discharge (preferably in the morning 
after the last dose of the study drug) at Visit 10/Day 35 -2 days or ET. In addition, one PK 
sample may be drawn if a relevant/significant AE is reported during a scheduled visit or if 
there is a dose adjustment or relevant/significant AE reported during an unscheduled visit 
(no multiple draws). For an ET Visit that is related to an AE, the collection of a PK blood 
sample is not optional and should be drawn before discharge. 
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Details of PK blood sample collection, processing, storage, and shipping procedures will be 
provided in a separate laboratory manual. 
13.2 Pharmacokinetic Analytical Methodology 
Concentrations of trospium and xanomeline will be determined from plasma PK samples using a 
validated analytical method. Details of the method validation and sample analysis will be 
included with the final clinical study report. 
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14 STATISTICAL ANALYSIS 
A 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 compliment to the protocol and supersedes it in case of 
differences. 
The statistical evaluation will be performed using SAS® software version 9.4 or higher 
(SAS Institute, Cary, NC). All data will be listed, and summary tables will be provided. 
Summary statistics will be presented by dose group. For continuous variables, data will be 
summarized with the number of subjects (N), mean and standard deviation, median, minimum, 
and maximum by treatment group. For categorical variables, data will be tabulated with the 
number and proportion of subjects for each category by treatment group. 
14.1 Determination of Sample Size 
Assuming treatment difference of change from baseline in PANSS total score at Week 5 is 
8 points between drug and placebo (standard deviation 16), a sample size of approximately 
172 (86 evaluable subjects per arm) will result in a power of 90.3% for a 2-sided alpha of 0.05 
(P ≤ 0.05). With a dropout rate of 30%, a total of 246 subjects are estimated to be enrolled. 
14.2 Analysis Populations 
Intent-to-Treat Population 
All subjects who are randomized to the study will be included in the intent-to-treat (ITT) 
population. 
Modified ITT Population 
All subjects who are randomized, received at least 1 dose of study drug, have a baseline PANSS 
assessment, and at least 1 post-baseline PANSS assessment will be included in the mITT 
population and will be used in the efficacy analysis. 
Safety Population 
All subjects who received at least 1 dose of study drug will be included in the safety population 
and will be used in the safety analysis. 
PK Population 
All subjects who have an evaluable PK profile will be included in the PK population and will be 
used in the PK analysis. Subjects must have received at least 1 dose of active study drug and 
have at least 1 measurable plasma concentration of study drug.  
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14.3 General Statistical Considerations 
All efficacy analyses will be performed using the mITT population. The statistical analysis of the 
primary and key secondary efficacy variables will account for multiplicity by using a fixed 
sequence testing procedure. The primary endpoint of change from baseline to Week 5 in PANSS 
total score will be evaluated first. The endpoints are set up as a hierarchical list and step down 
through the statistical testing of each endpoint using an alpha of 0.05. Statistical testing of 
change from baseline to Week 5 in PANSS positive score, PANSS negative score, PANSS 
Negative Marder Factor score, CGI-S, and percentage of PANSS responders will be performed 
only if the primary endpoint is significant at the 0.05 alpha level (P ≤ 0.05), and testing would 
continue through a pre-ordered list of key secondary efficacy endpoints. If at any point P > 0.05, 
then formal statistical testing would stop. This will control the overall Type 1 error rate across all 
hypotheses/endpoints being tested. Table 7 outlines the testing procedure.  
Table 7 
Statistical Testing Procedure 
KarXT vs Placebo 
1. Change from baseline in PANSS total score at Week 5 
2. Change from baseline in PANSS positive score at Week 5 
3. Change from baseline in PANSS negative score at Week 5 
4. Change from baseline in PANSS Negative Marder Factor score at Week 5 
5. Change from baseline in CGI-S score at Week 5 
6. Percentage of PANSS responders (a 30% change in PANSS total score) at Week 5  
 
14.4 Efficacy Analysis 
 
Primary Estimand 
The population of the primary estimand is among adult inpatients (aged 18-65 years) with a 
DSM-5 diagnosis of schizophrenia, confirmed by MINI for schizophrenia, who are acutely 
psychotic and hospitalized with PANSS score of 80-120 at time of enrollment, defined according 
to the inclusion/exclusion criteria. The primary analysis will be executed on the mITT 
population, including all subjects with a baseline and at least 1 post-baseline PANSS 
measurement, grouped as randomized.  
The variable is the change from baseline in PANSS total score at Week 5.   
Intercurrent events: 
• Modification to dose level: Treatment policy strategy where results will be used 
regardless of dose modifications 
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• Withdrawal from study before the completion of the 5 weeks of efficacy assessments: 
While on treatment strategy where efficacy results recorded before subject 
discontinuation from the study will be included in the analysis 
• Use of concomitant medication for anxiety and/or sleep aid: Treatment policy strategy 
where results will be used regardless of concomitant medications for anxiety and/or sleep 
aid 
The population level summary is the difference between treatment groups (KarXT vs placebo) in 
mean change from baseline in PANSS at Week 5, obtained from a mixed modelrepeated 
measures (MMRM). 
Robustness of the estimand will be assessed through sensitivity analyses using alternative 
methods for handling of missing data (eg, multiple imputation); accounting for changes in dosing 
(eg, including actual dose as a time varying covariate in the MMRM), and accounting for use of 
concomitant medications for anxiety and/or sleep aid (eg, subgroup by use of concomitant 
medication or including use of such concomitant medications as time-varying covariate in the 
MMRM). 
 
Analysis of the Primary Efficacy Endpoint 
The primary efficacy endpoint of the study is the change from baseline in PANSS total score at 
Week 5. The difference between KarXT and placebo at Week 5 will be estimated using an 
MMRM. The model will include the change from baseline PANSS total scores at Week 2, Week 
3, Week 4, and Week 5 as the response. Within-subject correlation will be accounted for using 
an unstructured covariance matrix. Fixed effects will include the treatment group (KarXT or 
placebo), visit, and the interaction between the treatment group and visit, site, age, sex, and 
baseline PANSS total score. Low-enrolling sites may be pooled, if necessary, for modeling 
purposes. The algorithm for pooling sites will be specified in the SAP. 
Sensitivity analyses of the primary efficacy endpoint may be performed on an observed case 
basis, using multiple imputation techniques, and classifying treatment dropouts as treatment 
failures. Alternative time-varying parameterizations of dose level and use of concomitant 
medication for anxiety and/or sleep aid may also be included in sensitivity analyses. In addition, 
alternative covariance matrices for the MMRM may be investigated. The sensitivity analyses of 
the primary endpoint will be specified in the SAP. 
 
Analysis of Secondary Efficacy Endpoints 
The continuous secondary endpoints (change from baseline to Week 5 in PANSS positive score, 
PANSS negative score, PANSS Negative Marder Factor score, and CGI-S) will be analyzed in 
the same manner as the primary efficacy analysis (ie, using MMRM).  
The categorical secondary endpoint (percentage of PANSS responders at Week 5) will be 
compared between the treatment groups (KarXT and placebo) using the Cochran-Mantel-
Haenszel test.  
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The statistical analysis of the primary and key secondary efficacy variables will account for 
multiplicity by using a fixed sequence testing procedure. This testing procedure will control the 
overall Type 1 error rate across all hypotheses/endpoints being tested. 
14.5 Safety Analysis 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities version 
22.1 or higher. The incidence of TEAEs (events with onset dates on or after the start of the study 
drug) will be summarized for each treatment group separately by System Organ Class and 
Preferred Term. All AEs will be listed by subject, along with information regarding onset, 
duration, relationship and severity to study drug, action taken with study drug, treatment of 
event, and outcome. 
Orthostatic vital signs, clinical laboratory data, prolactin levels, ECG parameters, and physical 
examinations will be summarized using descriptive statistics, including observed and change 
from baseline values, as well as numbers of subjects with values outside limits of the normal 
range at each time point by treatment group. Similar descriptive summaries will be provided for 
SAS, BARS, change in cognition (CANTAB), AIMS, body weight, BMI, and waist 
circumference. 
14.6 Pharmacokinetic Analysis 
• PK results will be listed for all subjects who received active treatment. The profiles or time 
points obtained with protocol deviations affecting PK results will be flagged and may be 
excluded from summaries and analyses. 
• The data will be presented graphically via individual plots and mean plots summarized by 
actual treatment, visit, and time point.  
• PK parameters for xanomeline and trospium will be derived from plasma concentration 
data using noncompartmental methods. Actual time elapsed from dosing will be used to 
estimate all individual PK parameters. The primary PK parameters of interest will include 
Cmax, Tmax, and AUC from 0 to 12 hours (or from 0 to the last measurable concentration). 
Additional parameters (not limited to the following) such as the elimination half-life, 
clearance, and volume of distribution will be determined if the data permit. 
• The effect of dose on PK and other inferential analyses for exposure-response relationship 
may be performed. The details of the PK analysis will be described in the SAP. The 
noncompartmental analysis will be described as a part of final clinical study report. 
14.7 Interim Analysis  
No interim analysis is planned for this study. 
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14.8 Handling of Missing Data 
Several different methods to handle the missing data in the primary efficacy endpoint analysis 
may be used. 
• For the primary efficacy analysis, likelihood-based modeling approach will be used to 
handle incomplete data. For this purpose, an MMRM will be applied. 
• Sensitivity analysis for the primary efficacy endpoint will be conducted using the last 
observation carried forward approach. In this analysis, the missing values will be 
replaced by the previous visit PANSS total score carried forward.  
• Sensitivity analysis for the primary efficacy endpoint will be conducted using the 
Multiple Imputation approach (ie, by replacing each missing value with a set of plausible 
values that represent the uncertainty about the right value to impute). 
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15 STUDY MANAGEMENT 
15.1 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. 
 
Independent Ethics Committee/Institutional Review Board 
Conduct of the study must be approved by an appropriately 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 principal investigator 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 principal 
investigator 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 caregiver informed consent (Ukraine only) should be obtained before any data pertaining to 
him or her and the subject is collected. 
Subject Registry (for the US only): 
Clinical trial registries, such as clinical trial subject database (CTSdatabase) and Verified 
Clinical Trials (VCT), seek to reduce duplicate enrollment by identifying potential protocol 
violations and duplicate subjects before randomization. At the time of providing the informed 
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 screening visit, following informed consent and before any 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 reports will 
detail each protocol violation detected and specific washout period dates where applicable. 
Participants who are identified as verification failures by CTS or VCT should not be enrolled 
without documented approval from Karuna or Syneos Health.  
At the last subject contact, CTSdatabase and VCT staff will automatically close out the subject 
(safety follow-up, ET, or completer) based on interactive response system (IXRS). 
Verified Clinical Trials Registry (for Ukraine only): 
At participating sites in Ukraine, VCT will be used to verify participants’ current and past 
research study status in order to mitigate safety concerns associated with duplicate enrollment 
and protocol deviations associated with multiple trial enrollment. Following proper regionally 
compliant informed consent and after obtaining a subject number from IXRS, each participant 
will be checked in the VCT database. Partial identifiers will be utilized. Participants who are 
identified as verification failures by VCT should not be enrolled without documented approval 
from Karuna or Syneos Health. 
15.2 Data Handling 
Any data to be recorded directly on the eCRFs (to be considered as source data) will be 
identified at the start of the study. Data reported on the eCRF that are derived from source 
documents should be consistent with the source documents, or the discrepancies must be 
explained. See also Section 15.3.  
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Clinical data will be entered by site personnel on eCRFs for transmission to the Sponsor. Data on 
eCRFs transmitted via the web-based data system must correspond to and be supported by source 
documentation maintained at the study site, unless the study site makes direct data entry to the 
databases for which no other original or source documentation is maintained. In such cases, the 
study site should document which eCRFs are subject to direct data entry and should have in 
place procedures to obtain and retain copies of the information submitted by direct data entry. 
All study forms and records transmitted to the Sponsor must only include coded identifiers such 
that directly identifying personal information is not transmitted. The primary method of data 
transmittal is via the secure, internet-based electronic data capture (EDC) system maintained by 
Syneos Health. Access to the EDC system is available to only authorized users via the study’s 
secured internet web site, where a user unique assigned username and password are required for 
access. 
Any changes made to data after collection will be made through the use of the EDC system. 
Electronic CRFs will be considered complete when all missing and/or incorrect data have been 
resolved. 
15.3 Source Documents 
Source documents are considered to be all information in original records and certified copies of 
original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. The investigator will provide direct 
access to source documents and/or source data in the facilitation of trial-related monitoring, 
audits, review by IECs/IRBs, and regulatory inspections. 
The investigator/institution should maintain adequate and accurate source documents and trial 
records that include all pertinent observations on each of the site’s trial subjects. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, not obscure the original entry, and be explained if necessary. 
Data recorded on source documents will be transcribed onto eCRFs. Copies of completed eCRFs 
will be provided to the Sponsor and the sites at the end of the study. The completed eCRFs will 
be retained by the investigator. 
15.4 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 
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Health Insurance Portability Accountability Act of 1996 [HIPAA] 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. 
15.5 Monitoring 
The study will be monitored according to the KAR-009 monitoring plan to ensure that it is 
conducted and documented properly according to the protocol, GCP, and all applicable 
regulatory requirements. 
Monitoring visits, on-site and remote (telephone) or a combination and contacts will be made at 
appropriate times during the study. The Principal Investigator will assure him/her and adequate 
site personnel are available throughout the study to collaborate with clinical monitors. Clinical 
monitors must have direct access to source documentation in order to check the completeness, 
clarity, and consistency of the data recorded in the eCRFs for each subject. 
The investigator will make available to the clinical monitor all source documents and medical 
records necessary to review protocol adherence and eCRFs. In addition, the investigator will 
work closely with the clinical monitor and, as needed, provide them appropriate evidence that the 
study is being conducted in accordance with the protocol, applicable regulations, and GCP 
guidelines. 
15.6 Quality Control and Quality Assurance 
The Sponsor or its designee will perform the quality assurance and quality control activities of 
this study; however, responsibility for the accuracy, completeness, security, and reliability of the 
study data presented to the Sponsor lies with the investigator generating the data. 
The Sponsor will arrange audits as part of the implementation of quality assurance to ensure that 
the study is being conducted in compliance with the protocol, standard operating procedures, 
GCP, and all applicable regulatory requirements. Audits will be independent of and separate 
from the routine monitoring and quality control functions. Quality assurance procedures will be 
performed at study sites and during data management to assure that safety and efficacy data are 
adequate and well documented. 
15.7 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 
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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. 
15.8 Ethical Considerations 
This study will be conducted in accordance with this protocol, the accepted version of the 
Declaration of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, 
Subpart D, of Title 21 of the CFR; and in compliance with GCP guidelines. 
IECs/IRBs will review and approve this protocol and the ICF. All subjects and/or caregivers are 
required to give written informed consent before participation in the study. 
15.9 Financing and Insurance 
Before the study commences, the Sponsor (or its designee) and the investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study. This agreement will 
be documented in a financial agreement that will be signed by the investigator (or the institution 
signatory) and the Sponsor (or its designee). 
The investigator is required to have adequate current insurance to cover claims for negligence 
and/or malpractice (US only). The Sponsor will provide no-exclusion insurance coverage for the 
clinical study as required by national regulations. 
15.10 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 
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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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16 REFERENCES 
 
Patel KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: overview and treatment options. 
P T. 2014;Sep 39(9):638-645. 
 
van Os J, Kapur S. Schizophrenia. Lancet. 2009 Aug 22;374(9690):635-645. 
 
Wu EQ, Shi L, Birnbaum H, Hudson T, Kessler R. Annual prevalence of diagnosed 
schizophrenia in the USA: a claims data analysis approach. Psychol Med. 2006 
Nov;36(11):1535-1540. 
 
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. 
 
Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome 
in schizophrenia: implications for MATRICS. Schizophr Res. 2004;72(1):41-51. 
 
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. 
 
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. 
 
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. 
 
Emsley R, Chiliza B, Asmal L, Harvey BH. The nature of relapse in schizophrenia. BMC 
Psychiatry. 2013;13:50. 
 
Kahn RS, Sommer IE, Murray RM, et al. Schizophrenia. Nat Rev Dis Primers. 
2015;1:15067. 
 
Sellin AK, Shad M, Tamminga, C. Muscarinic agonists for the treatment of cognition in 
schizophrenia. CNS Spectr. 2008 Nov;13(11):985-996. 
 
Wess J, Eglen RM, Gautam D. Muscarinic acetylcholine receptors: mutant mice provide 
new insights for drug development. Nat Rev Drug Discov. 2007 Sep;6:(9):721-733. 
 
Mirza NR, Peters D, Sparks RG. Xanomeline and the antipsychotic potential of muscarinic 
receptor subtype selective agonists. CNS Drug Rev. 2003 Summer;9(2):159-186. 
 
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. 
 
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. 
 
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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Bodick NC, Offen WW, Shannon HE, et al. The selective muscarinic agonist xaqnomeline 
improves both the cognitive deficits and behavioral symptoms of Alzheimer’s disease. 
Alzheimer Dis Assoc Disord. 1997; 11 Suppl 4:S16-22. 
 
Shekhar A, Potter WZ, Lightfoot J, et al. Selective muscarinic receptor agonist xanomeline 
as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008 Aug;165(8):1033-
1039. 
 
Staskin D, Sand P, Zinner N, Dmochowski R, Trospium Study Group. Once daily trospium 
chloride is effective and well tolerated for the treatment of overactive bladder; results from 
a multicenter phase III trial. J Urol. 2007;178(3 Pt 1):978-983; discussion 983-984. 
 
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. 
 
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. 
 
[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. 
 
Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr Bull. 1987;13(2):261-276. 
 
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. 
 
Buchanan RW, Davis M, Goff D, et al. A summary of the FDA-NIMH-MATRICS 
workshop on clinical trial design for neurocognitive drugs for schizophrenia. 
Schizophrenia Bulletin. 2005 Jan;31(1):5-19. 
 
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989 
May;154 (5):672–676. 
 
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s 
pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007 
Jul;164(7):1035-1043. 
 
Chatoor D, Emmanuel A. Constipation and evacuation disorders. Best Pract Res Clin 
Gastroenterol. 2009;23(4):517–530. 
 
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. 
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American Gastroenterological Association, Bharucha AE, Dorn SD, Lembo A, Pressman 
A. American Gastroenterological Association medical position statement on constipation. 
Gastroenterology. 2013 Jan;144(1):211–217. 
 
Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. 
Functional bowel disorders. Gastroenterology. 2006 Apr;130(5):1480–1491. 
 
Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol. 1997 Sep;32(9):920–924. 
 
Locke GR III, Pemberton JH, Phillips SF. American Gastroenterological Association 
Medical Position Statement: guidelines on constipation. Gastroenterology. 2000 
Dec;119(6):1761–1766. 
 
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17 APPENDICES 
 
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APPENDIX 1. 
CONTRACEPTION GUIDELINES 
Women of childbearing potential (WOCBP) and men whose sexual partners are WOCBP must 
use at least 1 highly effective method of contraception during the study and for 7 days after the 
last dose of study treatment.  
A woman is considered to be a WOCBP (fertile) following menarche and until becoming 
postmenopausal, unless she is permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause. A high 
follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.  
A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
Highly effective methods of contraception are those which have a failure rate of <1% (when 
implemented consistently and correctly) and include: 
• combined (containing estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation (administration may be oral, intravaginal, or transdermal) 
• progestogen-only hormonal contraception associated with inhibition of ovulation 
(administration may be oral, injectable, or implantable) 
• intrauterine device 
• intrauterine hormone-releasing system 
• bilateral tubal ligation or occlusion 
• vasectomy (provided that the male has a medical assessment of surgical success) 
• sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of risk in relation to the duration of the clinical trial, in line with the preferred and 
usual lifestyle of the subject) 
All subjects will be strongly advised that they (or the female partners of male subjects) should 
not become pregnant while on study treatment or for 7 days after the last dose. A female subject 
will be advised that she must report immediately to the study site for pregnancy testing and 
appropriate management in the event that she may be pregnant. 
Reference: [HMA] Heads of Medicines Agencies. Clinical Trial Facilitation Group page. 
Recommendations related to contraception and pregnancy testing in clinical trials. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
September 15, 2014. Accessed April 01, 2020. 
 
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APPENDIX 2. 
FUNCTIONAL CONSTIPATION INQUIRY 
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1 
FINAL CLINICAL STUDY PROTOCOL 
Karuna Therapeutics 
Protocol Title: A Phase 3, Randomized, Double-blind, Parallel-group, Placebo-controlled, 
Multicenter Study to Evaluate the Efficacy and Safety of KarXT in Acutely Psychotic 
Hospitalized Adults with DSM-5 Schizophrenia 
Protocol Number: KAR-009 
IND Number: 
127471 
EudraCT Number: 
Not applicable 
Name of Investigational Product: 
KarXT 
Phase of Development: 
Phase 3 
Indication: 
Schizophrenia 
Sponsor: 
Karuna Therapeutics 
33 Arch Street 
Suite 3110 
Boston, MA 02110 
Tel: 
Email: 
Protocol Version: 
1.2 
Protocol Date: 
09 August 2021 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to Karuna Therapeutics (previously known 
as Karuna Pharmaceuticals). Any unauthorized copying or use of this document is prohibited. 
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Kar u na T hera pe utics 
K A R- 0 0 9 
Kar X T 
Fi nal v 1. 2 
T his d oc u me nt is c o nfi de ntial. 
Pa ge 2  of 9 4
P R O T O C O L A P P R O V A L SI G N A T U R E S
Pr ot oc ol Title: 
A P hase 3, Ra n d o mize d, D o u ble- bli n d, Parallel- gr o u p, 
Pla ce b o- c o ntr olle d, M ultice nter St u d y t o E val uate t he Effic ac y a n d 
Safet y of Kar X T i n Ac utel y Ps yc h otic H os pitalize d A d ults wit h 
D S M- 5 S c hiz o p hre nia 
Pr ot oc ol N u m ber: 
K A R- 0 0 9
T his st u d y will be c o n d ucte d i n c o m plia nce wit h t he cli nical st u d y pr ot oc ol (a n d 
a me n d me nts), I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) g ui deli nes f or c urre nt G o o d 
Cli nical Practi ce ( G C P) a n d a p plica ble re g ulat or y re q uire me nts . 
S p o ns or Si g n at o r y
 
 
Kar u na T hera pe utics 
Si g nat ure
Date ( D D- M m m- Y Y Y Y) 
 
 
Ka r u na T hera pe utics 
Si g nat ure
Date
C o ntr act Rese arc h Or g a niz ati o n 
Si g n at or y 
 
 
S y ne os Healt h 
Si g nat ure
Date ( D D- M m m- Y Y Y Y) 
Bi ost atistici a n 
Veristat 
Si g nat ure
Date ( D D- M m m- Y Y Y Y) 
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INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
A Phase 3, Randomized, Double-blind, Parallel-group, 
Placebo-controlled, Multicenter Study to Evaluate the Efficacy and 
Safety of KarXT in Acutely Psychotic Hospitalized Adults with 
DSM-5 Schizophrenia 
Protocol Number: 
KAR-009 
Confidentiality and Current Good Clinical Practice (GCP)/E6(R2) Compliance Statement 
•
I, the undersigned, have reviewed this protocol (and amendments, including appendices,
and I will conduct the study as described in compliance with this protocol (and
amendments) and relevant International Council for Harmonisation (ICH) guidelines
including GCP and applicable regulatory requirements.
•
I am thoroughly familiar with the appropriate use of the study drug, 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
IEC/IRB, I will not modify this protocol without obtaining prior approval of Karuna
Therapeutics and of the IEC/IRB. I will submit the protocol amendments and/or any
informed consent form modifications to Karuna Therapeutics and the IEC/IRB, and
approval will be obtained before any amendments are implemented.
•
I ensure that all persons or party assisting me with the study are adequately qualified and
informed about the Karuna Therapeutics study drug 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.
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<Name> 
<Title> 
Investigator Signature 
Date (DD-Mmm-YYYY) 
Institution 
 
 
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2 
SYNOPSIS 
Title of Study: 
A Phase 3, Randomized, Double-blind, Parallel-group, Placebo-controlled, 
Multicenter Study to Evaluate the Efficacy and Safety of KarXT in Acutely 
Psychotic Hospitalized Adults with DSM-5 Schizophrenia 
Protocol Number: 
KAR-009 
Study Sites: 
Approximately 10 sites in the United States and 10 sites in Ukraine 
Phase of Development: 
Phase 3 
Objectives: 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of KarXT (a 
fixed combination of xanomeline and trospium chloride [xanomeline 
125 mg/trospium 30 mg] twice daily [BID]) versus placebo in reducing 
Positive and Negative Syndrome Scale (PANSS) total scores in adult 
inpatients with a Diagnostic and Statistical Manual‒Fifth Edition (DSM-5) 
diagnosis of schizophrenia. 
Secondary Objectives: 
The secondary objectives of the study are: 
• 
To evaluate the reduction of PANSS positive score in subjects 
treated with KarXT versus placebo 
• 
To evaluate the improvement in Clinical Global Impression-Severity 
(CGI-S) results in subjects treated with KarXT versus placebo 
• 
To evaluate the reduction of PANSS negative score in subjects 
treated with KarXT versus placebo 
• 
To evaluate the reduction of PANSS Marder Factor negative 
symptoms score in subjects treated with KarXT versus placebo 
• 
To evaluate the safety and tolerability of KarXT 
• 
To assess the pharmacokinetics (PK) of xanomeline and trospium 
after administration of KarXT in adults who are acutely psychotic 
with a DSM-5 diagnosis of schizophrenia 
Exploratory Objectives: 
The exploratory objectives of this study are:  
• 
To evaluate the change in cognition measuring core domains of 
impairment in schizophrenia using Cambridge Neuropsychological 
Test Automated Battery (CANTAB) 
• 
To evaluate the change in prolactin levels after administration of 
KarXT 
• 
To evaluate the single nucleotide polymorphisms (SNPs) regarding 
schizophrenia subtypes and SNPs related to drug metabolism. 
Study Endpoints: 
Primary Endpoint:  
• 
Change from baseline in PANSS total score at Week 5 
Secondary Endpoints: 
Efficacy Endpoints: 
• 
Change from baseline in PANSS positive score at Week 5 
• 
Change from baseline in PANSS negative score at Week 5 
• 
Change from baseline in PANSS Negative Marder Factor score at 
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Week 5 
• 
CGI-S score at Week 5 
• 
Percentage of PANSS responders (a 30% change in PANSS total 
score) at Week 5 
Safety Endpoints: 
• 
Spontaneously reported adverse events (AEs) including AEs of 
special interest (AESIs) 
• 
Spontaneously reported procholinergic and anticholinergic 
symptoms 
• 
Simpson-Angus Scale (SAS) 
• 
Barnes Akathisia Rating Scale (BARS) 
• 
Abnormal Involuntary Movement Scale (AIMS) 
• 
Body weight, body mass index, waist circumference 
• 
Orthostatic vital signs (supine and standing after 2 minutes): blood 
pressure (systolic and diastolic) and heart rate 
• 
Clinical laboratory evaluations: hematology, clinical chemistry, 
coagulation, urinalysis, and drug screen 
• 
12-lead electrocardiogram (ECG) 
• 
Physical examination 
• 
Suicidal ideation scale with the use of Columbia Suicide Severity 
Rating Scale (C-SSRS) 
Pharmacokinetic Endpoints: 
• 
Area under the plasma concentration-time curve (AUC) 
• 
Maximum observed plasma concentration (Cmax)  
• 
Time to maximum observed plasma concentration (Tmax) 
Exploratory Endpoints: 
• 
Change in cognition measuring core domains of impairment in 
schizophrenia using CANTAB 
• 
Change from baseline in prolactin levels at Week 5 
• 
Prediction of response based on SNP schizophrenia subtypes, and 
SNPs related to KarXT metabolism for both efficacy and tolerability 
Study Design: 
This is a Phase 3 randomized, double-blind, parallel-group, 
placebo-controlled, multicenter inpatient study in adults who are 
acutely psychotic with a DSM-5 diagnosis of schizophrenia. Subjects 
will be randomized (1:1 ratio) to receive either KarXT or placebo for a 
treatment period of 5 weeks. Subjects will start on a lead-in dose of 
KarXT 50/20 (xanomeline 50 mg/trospium 20 mg) BID for the first 
2 days (Days 1 and 2) followed by KarXT 100/20 (xanomeline 
100 mg/trospium 20 mg) BID for the remainder of Week 1 (Days 3 to 
7). On Day 8, dosing will be titrated upwards to KarXT 125/30 BID 
unless the subject is continuing to experience AEs from the previous 
dose increase of KarXT 100/20 BID. All subjects who were increased 
to KarXT 125/30 BID, depending on clinical response and tolerability, 
will have the option to return to KarXT 100/20 BID for the remainder 
of the treatment period. Dosing must not change after Visit 7 (Day 21) 
of the study and may be decreased for tolerability reasons no more than 
once during the study. In addition, dose escalation to KarXT 125/30 
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BID may not occur outside of the permitted visit window for 
Visit 5/Day 8. 
A safety follow-up visit (Visit 11/ Day 42 + 5 days) will be performed 
for all those subjects who do not rollover in to the long-term open-label 
study KAR-008. 
The study is designed to test the hypothesis that treatment with KarXT 
in adult schizophrenia subjects with acute psychosis will result in 
significantly greater reduction (ie, improvement) in the primary and 
secondary endpoints at Week 5 from baseline compared with placebo. 
The endpoints are set up as a hierarchical list and step down through 
the statistical testing of each endpoint using an alpha of 0.05. Statistical 
testing of change from baseline to Week 5 in PANSS positive score, 
PANSS negative score, and PANSS Negative Marder Factor score, 
CGI-S score at Week 5, and percentage of PANSS responders will be 
performed only if the primary endpoint is significant at the 0.05 alpha 
level (P ≤ 0.05), and testing would continue through a preordered list of 
key secondary efficacy endpoints. If at any point P > 0.05, then formal 
statistical testing would stop. This will control the overall Type 1 error 
rate across all hypotheses/endpoints being tested. 
Selection of Subjects: 
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 must be provided before 
any study assessments are performed. 
b. Subject must be fluent (oral and written) in English (applicable to 
the Unites States) or local language (Ukrainian or Russian 
applicable to Ukraine) 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 for 
Schizophrenia and Psychotic Disorder Studies (MINI) version 
7.0.2. 
4. Subject is experiencing an acute exacerbation or relapse of 
psychotic symptoms, with onset less than 2 months before 
screening. 
a. 
The subject requires hospitalization for this acute exacerbation or 
relapse of psychotic symptoms. 
b. If already an inpatient at screening, has been hospitalized 
for less than 2 weeks for the current exacerbation at the time 
of screening. 
5. Positive and Negative Syndrome Scale total score between 80 and 120, 
inclusive. 
a. 
Score of ≥4 (moderate or greater) for ≥2 of the following Positive 
Scale (P) items: 
i. Item 1 (P1; delusions) 
ii. Item 2 (P2; conceptual disorganization) 
iii. Item 3 (P3; hallucinatory behavior) 
iv. Item 6 (P6; suspiciousness/persecution) 
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6. Subjects with no change (improvement) in PANSS total score between 
screening and baseline (Day -1) of more than 20%. 
7. Subject has a CGI-S score of ≥4 at screening and baseline (Day -1) 
visits. 
8. Subject will have been off lithium therapy for at least 2 weeks 
before baseline and free of all oral antipsychotic medications for at 
least 5 half-lives or 1 week, whichever is longer, before baseline 
(Day -1). 
9. Subjects taking a long-acting injectable antipsychotic could not 
have received a dose of medication for at least 12 weeks (24 weeks 
for INVEGA TRINZA®) before baseline visit (Day -1). 
10. Subject is willing and able to be confined to an inpatient setting for 
the study duration, follow instructions, and comply with the 
protocol requirements. 
11. Body mass index must be ≥18 and ≤40 kg/m2. 
12. Subject resides in a stable living situation and is anticipated to 
return to that same stable living situation after discharge, in the 
opinion of the investigator. 
13. Subject has an identified reliable informant/caregiver. An 
informant/caregiver is needed at the screening and baseline 
visits as well as at the end of the study for relevant assessments 
(site staff may act as informant while the subject is an inpatient). 
An informant/caregiver may not be necessary if the subject has 
been the patient of the investigator for ≥1 year. 
14. 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, 
moderate to severe alcohol use disorder (within the past 
12 months), substance (other than nicotine or caffeine) use disorder 
within the past 12 months (use of cannabis at screening will result 
in screen failure with the allowance to rescreen at a later date if no 
moderate to severe substance use disorder is determined), major 
depressive disorder, bipolar I or II disorder, schizoaffective 
disorder, obsessive compulsive disorder, and post-traumatic stress 
disorder. Symptoms of mild mood dysphoria or anxiety are allowed 
as long as these symptoms are not the primary focus of treatment. 
a. 
A screening subject with mild substance abuse disorder within 
the 12 months before screening must be discussed and agreed 
upon with the medical monitor before they can be allowed into 
the study. 
2. Subjects who are newly diagnosed or are experiencing their first 
treated episode of schizophrenia. 
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, 
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hepatobiliary carcinoma, and/or active hepatic viral infections 
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. 
9. Subjects cannot currently (within 5 half-lives or 1 week, 
whichever is longer, before baseline [Day -1]) be receiving oral 
antipsychotic medications; monoamine oxidase inhibitors; 
anticonvulsants (eg, lamotrigine, Depakote); tricyclic 
antidepressants (eg, imipramine, desipramine); selective serotonin 
reuptake inhibitors; or any other psychoactive medications except 
for as needed anxiolytics (eg, lorazepam, chloral hydrate). 
10. Pregnant, lactating, or less than 3 months postpartum. 
11. If, in the opinion of the investigator (and/or Sponsor), subject is 
unsuitable for enrollment in the study or subject has any finding 
that, in the view of the investigator (and/or Sponsor), may 
compromise the safety of the subject or affect his/her ability to 
adhere to the protocol visit schedule or fulfill visit requirements. 
12. Positive test for coronavirus (COVID-19) within 2 weeks before 
screening and at screening.  
13. Subjects with extreme concerns relating to global pandemics, 
such as COVID-19, that preclude study participation. 
14. Subject has had psychiatric hospitalization(s) for more than 
30 days (cumulative) during the 90 days before screening. 
15. Subject has a history of treatment resistance to schizophrenia 
medications defined as failure to respond to 2 adequate courses 
of pharmacotherapy (a minimum of 4 weeks at an adequate dose 
per the label) or required clozapine within the last 12 months. 
16. Subjects with prior exposure to KarXT. 
17. Subjects who experienced any adverse effects due to xanomeline 
or trospium. 
18. Participation in another clinical study in which the subject 
received an experimental or investigational drug agent within 
3 months before screening. 
19. Risk of violent or destructive behavior. 
20. Current involuntary hospitalization or incarceration. 
Planned Sample Size: 
A total of approximately 246 adult subjects (aged 18 to 65 years, inclusive) 
are planned to be randomized in a 1:1 ratio to 2 treatment groups, either 
KarXT or placebo. 
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Investigational Therapy: 
1. Fixed dose KarXT 50/20 BID (50 mg xanomeline/20 mg trospium), 
oral (Days 1 to 2) 
2. Fixed dose KarXT 100/20 BID (100 mg xanomeline/20 mg 
trospium), oral (Days 3 to 7) 
3. Fixed dose KarXT 125/30 BID (125 mg xanomeline/30 mg 
trospium), oral (Days 8 to 35, if tolerated) 
Reference Therapy: 
Matching placebo BID oral 
Treatment Duration: 
Total study duration is up to 8 weeks, including a 7-day screening phase (up 
to a 7-day extension of the screening phase is allowed, if necessary), a 
5-week treatment period, and a 7-day follow-up period (only for subjects who 
do not rollover to KAR-008 study). Subjects completing this study will have 
the option of rolling over into a long-term open-label study (KAR-008) in 
which every subject will receive KarXT. 
Efficacy Assessments: 
PANSS total score, PANSS positive score, PANSS negative score, PANSS 
Negative Marder Factor score, and CGI-S score will be evaluated at 
scheduled visits. 
Safety Assessments: 
Spontaneous AEs including AESIs, procholinergic and anticholinergic 
symptoms, SAS, BARS, AIMS, body weight, body mass index, waist 
circumference, orthostatic vital signs, ECG, clinical laboratory assessments 
(hematology, clinical chemistry, coagulation, urinalysis, and drug screen), 
prolactin levels, physical examination, and C-SSRS will be evaluated 
throughout the study as scheduled. 
Pharmacokinetic Assessments: 
AUC, Cmax, and Tmax will be estimated at scheduled visits. 
Statistical Methods and 
Planned Analyses: 
Intent-to-treat (ITT) population: All subjects who are randomized to the study 
will be included in the ITT population. 
Modified ITT (mITT) population: All subjects who are randomized, received 
at least 1 dose of study drug, have a baseline PANSS assessment, and at least 
1 postbaseline PANSS assessment will be included in the mITT population 
and will be used in the efficacy analysis. 
Safety population: All subjects who received at least 1 dose of study drug 
will be included in the safety population and will be used in the safety 
analysis. 
PK population: All subjects who have an evaluable PK profile will be 
included in the PK population and will be used in the PK analysis. Subjects 
must have received at least 1 dose of active study drug and have at least 
1 measurable plasma concentration of study drug.  
The primary efficacy endpoint of the study is the change from baseline in 
PANSS total score at Week 5. The difference between KarXT and placebo 
will be estimated using a mixed model for repeated measures. The key 
secondary endpoints are the change from baseline to Week 5 in PANSS 
positive score, PANSS negative score, and PANSS Negative Marder Factor 
score, CGI-S score at Week 5, and percentage of PANSS responders at 
Week 5. The statistical analysis of the primary and key secondary efficacy 
variables will account for multiplicity by using a fixed sequence testing 
procedure. This testing procedure will control the overall Type 1 error rate 
across all hypotheses/endpoints being tested. 
Assuming the treatment difference in the change from baseline in PANSS 
total score at Week 5 is 8 points between KarXT and placebo (standard 
deviation 16), a sample size of approximately 172 subjects (86 evaluable 
subjects per arm) will result in a power of 90.3% for a 2-sided alpha of 0.05 
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(P ≤ 0.05). With an anticipated dropout rate of 30%, a total of 246 subjects 
are estimated to be enrolled. 
 
 
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3 
TABLE OF CONTENTS 
1 
FINAL CLINICAL STUDY PROTOCOL .......................................................................1 
2 
SYNOPSIS ........................................................................................................................5 
3 
TABLE OF CONTENTS ................................................................................................12 
3.1 
List of In-text Tables ..................................................................................................15 
3.2 
List of In-text Figures .................................................................................................16 
4 
LIST OF ABBREVIATIONS .........................................................................................17 
5 
INTRODUCTION ...........................................................................................................19 
5.1 
Background on Schizophrenia ....................................................................................19 
5.2 
Background on KarXT (Xanomeline Tartrate and Trospium Chloride) ....................19 
 
Nonclinical Studies ............................................................................................21 
 
Completed Clinical Studies ................................................................................24 
5.3 
Clinical Risks/Benefits of KarXT and Study Rationale .............................................32 
6 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................34 
6.1 
Study Objectives .........................................................................................................34 
 
Primary Objective ..............................................................................................34 
 
Secondary Objectives .........................................................................................34 
 
Exploratory Objectives ......................................................................................34 
6.2 
Study Endpoints..........................................................................................................35 
 
Primary Endpoint ...............................................................................................35 
 
Secondary Endpoints ..........................................................................................35 
6.2.2.1 
Efficacy Endpoints .......................................................................................35 
6.2.2.2 
Safety Endpoints ..........................................................................................35 
 
Pharmacokinetic Endpoints ................................................................................35 
 
Exploratory Endpoints .......................................................................................36 
7 
INVESTIGATIONAL PLAN .........................................................................................37 
7.1 
Description of Overall Study Design and Plan...........................................................37 
7.2 
Discussion of Study Design........................................................................................40 
7.3 
End of Study ...............................................................................................................40 
7.4 
Independent Safety Monitoring Committee ...............................................................40 
8 
SELECTION OF STUDY POPULATION .....................................................................41 
8.1 
Inclusion Criteria ........................................................................................................41 
8.2 
Exclusion Criteria .......................................................................................................42 
8.3 
Rescreening ................................................................................................................43 
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8.4 
Study Withdrawal, Removal, and Replacement of Subjects ......................................44 
 
Pregnancy ...........................................................................................................45 
8.5 
Completion of the Study or Lost to Follow-up ..........................................................46 
8.6 
Study Termination ......................................................................................................46 
9 
TREATMENTS ...............................................................................................................47 
9.1 
Details of Study Treatments .......................................................................................47 
 
Identity of Study Treatments ..............................................................................47 
 
Packaging and Labelling ....................................................................................48 
 
Study Drug Storage ............................................................................................48 
 
Study Drug Retention .........................................................................................48 
9.2 
Dose Schedule ............................................................................................................48 
 
Visit 2b/Day 1 Randomization and Dosing .......................................................48 
 
Visit 3/Day 3 and/or Visits Occurring on Weekends/Holidays .........................49 
 
Visit 5/Day 8 Dosing and PK Considerations and Visit 8/Day 28 PK 
Considerations ....................................................................................................49 
 
Visit 10/Day 35 Dosing ......................................................................................49 
9.3 
Measures to Minimize Bias: Study Treatment Assignment .......................................49 
 
Method of Study Treatment Assignment ...........................................................49 
 
Blinding 50 
9.4 
Dose Modification ......................................................................................................51 
9.5 
Treatment Accountability and Compliance ................................................................51 
9.6 
Prior and Concomitant Therapy .................................................................................51 
 
Prior and Concomitant Medications ..................................................................51 
 
Concomitant Medications for Anxiety and/or Sleep aid ....................................52 
10 
STUDY PROCEDURES .................................................................................................53 
10.1 Informed Consent .......................................................................................................60 
10.2 Study Procedures ........................................................................................................60 
11 
EFFICACY ASSESSMENTS .........................................................................................61 
11.1 Positive and Negative Syndrome Scale ......................................................................61 
11.2 Clinical Global Impression‒Severity .........................................................................61 
12 
SAFETY ASSESSMENTS .............................................................................................62 
12.1 Demographics, and Medical and Psychiatric History ................................................62 
12.2 Vital Signs ..................................................................................................................62 
12.3 Physical Examination .................................................................................................63 
12.4 Weight, Height, Body Mass Index, Waist Circumference .........................................63 
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12.5 Electrocardiograms .....................................................................................................63 
12.6 Laboratory Assessments .............................................................................................63 
 
Blood Sampling for Pharmacogenetics ..............................................................65 
12.7 Adverse Events ...........................................................................................................65 
 
Adverse Events ..................................................................................................65 
 
Adverse Events of Special Interest ....................................................................67 
 
Serious Adverse Events .....................................................................................67 
 
Serious Adverse Event Reporting ......................................................................68 
 
Drug-Induced Liver Injury .................................................................................68 
 
Trial Discontinuation Criteria Other than DILI and Pregnancy ........................69 
12.7.6.1 
Individual Stopping Criteria .........................................................................69 
12.7.6.2 
Trial Stopping Rules .....................................................................................69 
 
Suspected Unexpected Serious Adverse Reactions ...........................................70 
 
Pregnancy ...........................................................................................................72 
 
Overdose ............................................................................................................72 
12.8 Cambridge Neuropsychological Test Automated Battery ..........................................72 
12.9 Simpson-Angus Scale .................................................................................................73 
12.10 Barnes Akathisia Rating Scale ...................................................................................73 
12.11 Abnormal Involuntary Movement Scale ....................................................................74 
12.12 Columbia-Suicide Severity Rating Scale ...................................................................74 
12.13 Functional Constipation Inquiry .................................................................................74 
12.14 Mini International Neuropsychiatric Interview Version 7.0.2 ...................................75 
12.15 Change in Prolactin ....................................................................................................75 
13 
PHARMACOKINETICS ................................................................................................76 
13.1 Pharmacokinetic Sampling .........................................................................................76 
 
Blood Samples ...................................................................................................76 
13.2 Pharmacokinetic Analytical Methodology .................................................................77 
14 
STATISTICAL ANALYSIS ...........................................................................................78 
14.1 Determination of Sample Size ....................................................................................78 
14.2 Analysis Populations ..................................................................................................78 
14.3 General Statistical Considerations ..............................................................................78 
14.4 Efficacy Analysis........................................................................................................79 
 
Primary Estimand ...............................................................................................79 
 
Analysis of the Primary Efficacy Endpoint .......................................................80 
 
Analysis of Secondary Efficacy Endpoints ........................................................80 
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14.5 Safety Analysis ...........................................................................................................81 
14.6 Pharmacokinetic Analysis ..........................................................................................81 
14.7 Interim Analysis .........................................................................................................81 
14.8 Handling of Missing Data ..........................................................................................81 
15 
STUDY MANAGEMENT ..............................................................................................83 
15.1 Approval and Consent ................................................................................................83 
 
Regulatory Guidelines ........................................................................................83 
 
Independent Ethics Committee/Institutional Review Board ..............................83 
 
Informed Consent ...............................................................................................83 
15.2 Data Handling .............................................................................................................84 
15.3 Source Documents ......................................................................................................84 
15.4 Record Retention ........................................................................................................85 
15.5 Monitoring ..................................................................................................................85 
15.6 Quality Control and Quality Assurance .....................................................................86 
15.7 Protocol Amendment and Protocol Deviation ............................................................86 
 
Protocol Amendment .........................................................................................86 
 
Protocol Deviations ............................................................................................86 
15.8 Ethical Considerations ................................................................................................86 
15.9 Financing and Insurance .............................................................................................87 
15.10 Publication Policy/Disclosure of Data........................................................................87 
16 
REFERENCES ................................................................................................................88 
17 
APPENDICES .................................................................................................................91 
APPENDIX 1. CONTRACEPTION GUIDELINES ............................................................92 
APPENDIX 2. FUNCTIONAL CONSTIPATION INQUIRY ............................................93 
3.1 
List of In-text Tables 
Table 1 
Study Design ...........................................................................................................39 
Table 2. Schedule of Assessments ........................................................................................54 
Table 3. Laboratory Assessments..........................................................................................64 
Table 4. Classification of Adverse Events by Intensity ........................................................66 
Table 5. Classification of Adverse Events by Relationship to Study Drug ..........................67 
Table 6 
Cognitive Tests and Cognitive Domains Assessed by the Cambridge 
Neuropsychological Test Automated Battery .........................................................73 
Table 7 
Statistical Testing Procedure ...................................................................................79 
 
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3.2 
List of In-text Figures 
Figure 1 Change from Baseline in PANSS Total Scores (KAR-004) ...................................28 
Figure 2 Change from Baseline in PANSS-Positive Scores (KAR-004) ..............................29 
Figure 3 Change from Baseline in CGI-S (KAR-004) ..........................................................30 
Figure 4 Change from Baseline in PANSS-Negative Scores (KAR-004).............................31 
 
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4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AD 
Alzheimer’s disease 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
APD 
antipsychotic drug 
AUC 
area under the plasma concentration-time curve 
AUC0-12 
area under the plasma concentration-time curve from 0 to 12 hours 
AUC0-24 
area under the plasma concentration-time curve from 0 to 24 hours 
BARS 
Barnes Akathisia Rating Scale 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression‒Severity 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTS 
Clinical Trial Subject 
CTCAE 
Common Terminology Criteria for Adverse Events 
DILI 
drug-induced liver injury 
DSM-5 
Diagnostic and Statistical Manual‒Fifth Edition 
EDC 
electronic data capture 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EPS 
extrapyramidal symptoms 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability Accountability Act 
IB 
Investigator’s Brochure 
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Abbreviation 
Definition 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
MCC 
microcrystalline cellulose 
MINI 
Mini International Neuropsychiatric Interview 
mITT 
modified intent-to-treat 
MMRM 
mixed model repeated measures 
NCI 
National Cancer Institute 
PANSS 
Positive and Negative Syndrome Scale 
PK 
Pharmacokinetic(s) 
PRN 
as needed 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson Angus Scale 
SNP 
single nucleotide polymorphism 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TID 
thrice daily 
TK 
toxicokinetic 
Tmax 
Time to maximum observed plasma concentration 
ULN 
upper limit of normal  
US 
United States 
VAS 
visual analog scale 
VCT 
Verified Clinical Trials Registry 
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 US is 5.1 per 1000 lives[3]. It is found 
equally in males and females, with males usually having an earlier onset of symptoms[4].  
The mainstay for treating schizophrenia is antipsychotic drugs (APDs)[5]. All currently available 
antipsychotics act through blockage of all or subsets of dopamine receptors in the brain. 
First-generation APDs include chlorpromazine and haloperidol; treatment with these agents is 
marked by high rates of parkinsonian extrapyramidal symptoms (EPS) and tardive dyskinesia, 
and they consequently have limited use today. The second-generation agents that include 
risperidone, olanzapine, quetiapine, lurasidone, aripiprazole, and lumateperone tend to have 
lower levels of EPS or tardive dyskinesia and are currently the most commonly prescribed APD 
class. However, the second-generation drugs also have problematic side effects that include 
significant weight gain, metabolic disturbances, sedation, and akathisia[6,7,8]. These side effects 
contribute to poor medication adherence resulting in frequent relapses and hospitalizations[9,10]. 
Thus there is a need for medications for schizophrenia which act through alternative 
mechanisms. 
Central muscarinic receptors have been hypothesized to be therapeutic treatments for 
schizophrenia based on several converging lines of evidence including both animal and human 
studies[11,12]. There are 5 subtypes of muscarinic receptors (M1-M5). The therapeutic effect of 
central muscarinic receptor agonism is thought to be due to agonism of M1 and M4 receptors in 
the central nervous system (CNS)[13]. However, compounds that agonize M1 and M4 receptors 
are often not specific enough not to also agonize M2 and M3 receptors outside of the CNS due to 
the highly conserved allosteric binding sites that the receptors share, leading to adverse events 
(AEs) related to activation of these peripheral receptors. Thus, any potential benefit of 
muscarinic agonists in schizophrenia (or other indications such as Alzheimer’s disease [AD]) has 
been outweighed by the occurrence of AEs associated with peripheral cholinergic side effects 
(nausea, vomiting, diarrhea, sweating, and excess salivation).  
5.2 
Background on KarXT (Xanomeline Tartrate and Trospium Chloride) 
Xanomeline tartrate is a muscarinic-cholinergic receptor agonist. It has agonistic activity at all 
5 muscarinic receptors but preferentially stimulates M1 and M4 receptors and binding to M1 and 
M4 receptors in the CNS is thought to be responsible for the drug’s potential therapeutic effects 
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(Roth, unpublished data). A recent study reports that xanomeline is a very potent M4 muscarinic 
agonist in vivo, measured by various second messenger assays[14]. Xanomeline also enters the 
brain rapidly achieving a brain to plasma ratio of greater than 10 making it an attractive CNS 
drug candidate[15]. 
Xanomeline does not have any direct binding activity on dopaminergic receptors, suggesting that 
its mechanism of action is unrelated to direct dopamine involvement. 
Previous double-blind, placebo controlled clinical trials have provided strong evidence that 
xanomeline has clinically relevant antipsychotic efficacy. In a multicenter outpatient trial in AD 
(N = 343), 3 doses of xanomeline (up to 225 mg/day) and placebo were assessed for 
26 weeks[16,17]. Significant dose-dependent improvements in psychotic symptoms relative to 
placebo were observed. Moreover, psychotic symptoms resolved quite rapidly in subjects who 
were symptomatic at baseline and a dose dependent reduction in the emergence of psychotic 
symptoms versus placebo was also observed. In a completer analysis, cognitive improvement 
was also found suggesting longer treatment intervals may be necessary for cognitive 
enhancement[16,17]. In a subsequent small (N = 20) double-blind, placebo-controlled inpatient 
trial in treatment resistant subjects with schizophrenia, xanomeline (225 mg/day) demonstrated 
robust and relatively rapid improvement in psychosis compared to placebo. In addition, 
improvement in both negative symptoms and cognitive impairment was observed[18]. 
In both the AD and schizophrenia trials, as well as in previous healthy volunteer studies, dose 
dependent “cholinergic” AEs were also reported, namely vomiting, nausea, diarrhea, sweating 
and hypersalivation. These side effects were frequent and, at the higher doses of xanomeline led 
to significant rates of discontinuation in the AD studies. This “procholinergic” AE profile 
curtailed further development of xanomeline as a single agent.  
It is believed that the procholinergic AEs associated with xanomeline are mediated by 
xanomeline’s stimulation of peripheral rather than central muscarinic receptors, which would 
make these AEs theoretically amenable to counteracting peripheral anticholinergic treatment. 
Trospium chloride is a peripherally acting muscarinic antagonist which binds to and antagonizes 
all five muscarinic receptor subtypes[19]. It is a commonly used generic drug approved for over 
10 years by the Food and Drug Administration (FDA) and by European authorities to treat 
overactive bladder and is generally well tolerated[19]. Several human subject studies have 
demonstrated that trospium does not appreciably cross the blood brain barrier, consistent with the 
drug’s quaternary ammonium structure[20].  
KarXT is a novel combination of xanomeline tartrate and trospium chloride. Karuna 
hypothesized that the addition of trospium would mitigate peripheral procholinergic side effects 
(vomiting, nausea, diarrhea, sweating and hyper-salivation) and thus provide a strategy to allow 
xanomeline to be administered and stimulate brain muscarinic receptors with a decreased side 
effect burden. Phase 1 studies in healthy volunteers of this combination demonstrated that 
KarXT reduced these side effects by 46% compared to xanomeline alone[21]. Moreover, the 
remaining cholinergic AEs were generally mild to moderate in severity and transient in nature, 
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often lasting a few hours without recurrence and were generally single-episode. In general, 
KarXT was well tolerated in healthy adult volunteers. These encouraging safety data prompted 
further work to assess KarXT for the treatment of schizophrenia and potentially other CNS 
disorders. 
Karuna has recently completed an adequate and well-controlled, randomized, multi-center 
Phase 2, placebo-controlled, inpatient clinical trial of acute psychosis with schizophrenia in 
182 adult subjects (KAR-004). KarXT demonstrated a statistically significant and clinically 
meaningful 11.6 point mean reduction in total Positive and Negative Syndrome Scale (PANSS) 
at 5 weeks compared to placebo (P < 0.0001), with statistical separation at each time point 
assessed (2, 4, and 5 weeks) and also demonstrated good overall safety and tolerability. 
The purpose of the current study is to evaluate the safety and efficacy of KarXT (xanomeline 
125 mg/trospium 30 mg) administered twice daily (BID) in adult inpatients with Diagnostic and 
Statistical Manual‒Fifth Edition (DSM-5) diagnosis of schizophrenia. A placebo arm is included 
to provide test sensitivity. 
Xanomeline is currently not approved or marketed in any country. Trospium is marketed in the 
US and other regions of the world for the treatment of overactive bladder. 
Nonclinical Studies 
The following is a summary of the important nonclinical safety and toxicology studies. More 
detailed information can be found in the KarXT Investigator’s Brochure (IB). 
The acute toxicity of xanomeline tartrate was evaluated in mice and rats. All animals were 
observed for 2 weeks for mortality and clinical signs of intolerance, and then necropsied for 
gross examinations. In-life findings attributed to the test article included excessive 
muscarinic-mediated pharmacology, such as excessive salivation, hypoactivity, ataxia, soft 
stools, exophthalmos, ocular discharge, tremors, and convulsions, with survivors typically 
appearing normal by Days 3 or 4. Gross findings at necropsy were generally unremarkable (eg, 
gas-distended or mucous-filled gastrointestinal [GI] tracts after oral dosing). 
KarXT-301 was a 14-day, repeat dose study of KarXT in rats where relatively high doses of 
xanomeline and trospium were given, with either xanomeline alone or in combination with 
trospium. Seven groups of 10 rats/sex/group were administered either vehicle (reverse osmosis 
water); xanomeline alone at 37, 75, 150, or 300 mg/kg/day (split into BID doses, every 
12 hours); or xanomeline/trospium combination dosages of 150/200 mg/kg/day or 
225/400 mg/kg/day, respectively (split into BID doses, every 12 hours). 
Satellite animals were included for the collection of plasma after the first and last doses for the 
determination of drug concentrations of each parent drug in support of toxicokinetic (TK) 
assessments. 
There was no target-organ toxicity revealed by clinical pathology or by gross or microscopic 
assessments. All intolerance could be attributed to recognized pharmacology of either test article. 
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No dose-related ophthalmic observations were noted. Findings were not indicative of specific 
target organ toxicity. In short, no new hazard was identified. 
Clinical observations noted in most animals administered 300 mg/kg/day xanomeline included 
hypoactivity, clear oral discharge, dilated pupils, irregular or labored respiration, and rough 
haircoat, among other observations. These findings are generally consistent with the anticipated 
pharmacology of xanomeline. 
Three TK animals in the low-dose combination group died or were euthanized in extremis. It is 
unclear to what extent the combination treatment effects versus the different handling of these 
animals (including 3 plasma samplings per animal) contributed to these deaths. If gavage 
accidents were involved (as happened with some TK animals), then they were not detected at 
gross necropsy. There was no microscopic evidence of toxicity was seen in any toxicity animals 
in this group or in the higher-dose combination group. 
Three toxicology and 3 TK animal deaths (total of 6) occurred in the high-dose combination 
group. Two toxicology animals had evidence of gavage accidents. For the third, the cause of 
death was undetermined, and a test article-related effect cannot be ruled out, but 
degeneration/regeneration of esophageal muscular is indicated some dosing-related trauma. If 
gavage accidents were involved, then they were not detected at gross necropsy. There was no 
evidence of target organ microscopic findings in GI tract or any other tissue of any animal, 
including the early death toxicity animals. 
A pharmacodynamics-mediated reduction in GI motility is consistent with the anti-muscarinic 
effects of trospium on intestinal musculature. Fecal retention, malabsorption, cessation of eating, 
dehydration, and rapid deterioration followed with continued dosing. Cessation of dosing in the 
high dose combination animals that survived led to rapid recovery, implying the deleterious 
effects had been pharmacodynamics-related. No effects on food consumption were seen in any 
xanomeline-alone group. The lack of microscopic findings in the GI tract of any early death or 
surviving animal implies that the adverse effects were pharmacologically mediated rather than 
direct target organ toxicity. 
Twenty-eight Day Repeat-Dose Studies with Xanomeline in Rats and Monkeys: Rats were fed 
xanomeline tartrate at 0%, 0.05%, 0.1%, or 0.2% daily and monkeys were fed xanomeline 
tartrate daily at 0, 5, 12.5, or 30 mg/kg. All animals survived until necropsy. Safety findings in 
rats included reduced body weight in the high dose group, increases in gamma-glutamyl-
transferase, cholesterol, and bilirubin, slight decreases in triglycerides, bile duct hyperplasia, 
higher serum potassium (males), and lower serum globulin (females). Findings in monkeys were 
dose related and included signs of intolerance such as emesis, salivation, diarrhea, hypoactivity, 
weight loss, and treatment-related tachycardia in the high-dose animals. 
Forty-Day Repeat Dose Study of KarXT in Rats (KarXT-302): Six groups of 15 rats/sex/group 
were given vehicle, xanomeline alone at 75 or 150 mg/kg/day, trospium alone at 100 mg/kg/day, 
or xanomeline/trospium combination at doses of 75/50 mg/kg/day or 150/100 mg/kg/day, with 
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all doses split into BID doses. Satellite rats (TK animals) were included for collection of plasma 
after the first and last doses to determine concentrations of each drug. Dosing was initially 
planned to be 90 days but was terminated after 40 days because of unexpected deaths in the TK 
animals. No target organ toxicity was seen. Safety findings included pharmacologically mediated 
constipation in the trospium alone and combination groups and mild biliary hyperplasia in the 
high-dose xanomeline alone and combination groups. There were 4 unscheduled deaths in TK 
animals; 2 in the high-dose xanomeline alone group (150 g/kg/day) and 2 in the high-dose 
combination group (150 mg/kg/day xanomeline plus 100 mg/kg/day trospium). Both 
xanomeline-only animals had necropsy gross findings of a gavage accident, and cause of death 
could not be determined. All toxicology animals survived to their scheduled sacrifice. Sponsor 
considers that the volume depletion and trauma of multiple bleeds (3 per animal), followed by 
reduced absorption of fluids and nutrients secondary to reduced GI motility with continued BID 
dosing explains the greater demise of TK animals relative to toxicity animals. 
Based on the results of the 90-day rat toxicology study, oral administration of trospium chloride 
and xanomeline tartrate alone or in combination to Crl:CD (SD) rats BID (12 hours ± 60 minutes 
apart) at dosage levels of 25 and 50 mg/kg/dose trospium chloride, 37 and 75 mg/kg/dose 
xanomeline tartrate, and a combination of 37/25, 75/25, and 75/50 mg/kg/dose xanomeline 
tartrate/trospium chloride for a minimum of 90 days resulted in minimal to moderate bile duct 
hyperplasia in the livers of the xanomeline tartrate and combination (xanomeline tartrate and 
trospium chloride) group males. Although there were no notable differences in the incidence of 
bile duct hyperplasia when comparing the single vs combination groups, there was an increased 
severity observed in the combination group males (specifically the 75/25 and 75/50 mg/kg/dose 
combination group males) when compared with the xanomeline tartrate group males at the 
terminal euthanasia. The bile duct hyperplasia was considered adverse in the high-dose 
xanomeline tartrate group males and in the 75/25 and 75/50 mg/kg/dose combination group 
males due to instances of moderate severity. Therefore, the no-observed-adverse-effect level was 
considered to be 50 mg/kg/dose for trospium chloride, 37 mg/kg/dose for xanomeline tartrate, 
and 37/25 mg/kg/dose for the combination of xanomeline tartrate/trospium chloride. At these 
doses for males, mean plasma AUC0-24 values were 27,700 pg•hr/mL for trospium, 
146,000 pg•hr/mL for xanomeline, and 4510 + 111,000 pg•hr/mL for trospium + xanomeline, 
respectively, on Day 91. At these dosages for females, mean plasma AUC0-24 values were 
9230 pg•hr/mL for trospium; 267,000 pg•hr/mL for xanomeline; and 16,700 + 171,000 pg•hr/mL 
for trospium + xanomeline, respectively, on Day 91. The absence of bile duct hyperplasia in 
females cannot be explained from differences in drug exposure. At the recovery euthanasia, bile 
duct hyperplasia was still present but was limited to minimal severity, and there was a decreased 
incidence in both the xanomeline tartrate and combination group males. There was also no 
notable difference in severity between the single vs combination groups at the recovery 
euthanasia. Given the decreased incidence/severity, in combination with the improved histologic 
appearance of bile ducts at the recovery euthanasia (i.e., smaller/flattened epithelium, 
noninflammatory, and an absence of portal bridging), changes at the recovery euthanasia were 
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consistent with a partial resolution of bile duct hyperplasia. With an absence of correlating serum 
liver enzyme elevations, bile acid alterations or hepatocellular degeneration, necrosis or 
regeneration, and with the apparent reversibility after cessation of treatment, these findings 
appear to have been tolerable by the affected animals. Therefore, the maximum tolerated dose 
was considered to be 50 mg/kg/dose for trospium chloride, 75 mg/kg/dose for xanomeline 
tartrate, and 75/50 mg/kg/dose for the combination of xanomeline tartrate/trospium chloride. For 
males, corresponding mean plasma AUC0-24 values were 27,700 pg•hr/mL for trospium; 
822,000 pg•hr/mL for xanomeline; and 133,000 + 276,000 pg•hr/mL for trospium + xanomeline, 
respectively, on Day 91. For females, corresponding mean plasma AUC0-24 values were 
9230 pg•hr/mL for trospium; 2,090,000 pg•hr/mL for xanomeline; and 17,600 + 
950,000 pg•hr/mL for trospium + xanomeline, respectively, on Day 91. 
In summary, no new findings on the “combination” of xanomeline and trospium (KarXT) were 
discovered; toxicology studies revealed the familiar exaggerations of systemic and CNS 
muscarinic effects that had previously been seen with xanomeline or trospium at high doses. 
Target organ findings with xanomeline alone were limited to biliary hyperplasia in the 28-day rat 
study but not the 28-day or 12-month monkey study, though similar findings were described in a 
6-month monkey study. With KarXT, biliary hyperplasia was not observed in the 14-day rat
study but was reported in the 40-day rat study. Notably, these hyperplastic findings are not
thought to represent pre-neoplastic lesions, because they were of low severity; no fibrosis or
associated hepatocellular changes, and no significant effects were seen on hepatobiliary-related
serum chemistry.
Completed Clinical Studies 
Refer to the IB for complete information regarding previous clinical studies conducted with 
xanomeline by Eli Lilly, and studies KAR-001, KAR-002, KAR-003, and KAR-004 conducted 
by Karuna Therapeutics using xanomeline with trospium. 
To date, more than 840 subjects or volunteers have been exposed to xanomeline tartrate (oral 
formulation, either alone, in combination with trospium, or as the combination drug KarXT) in 
19 completed clinical studies conducted either by Eli Lilly or Karuna Therapeutics, some for as 
long as 3 years. In those studies, significant improvements in cognition and reduced psychotic 
symptoms were observed. 
A study of xanomeline monotherapy in subjects with schizophrenia was reported in 2008[18]. In 
this pilot study, the effects of xanomeline were examined in 20 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 
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. 
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These studies demonstrated the potential for xanomeline as a treatment for psychosis and 
cognition across multiple subject populations. 
Study H2Q-EW-E001, conducted by 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 mg, 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 in sitting and standing heart rate, slight increase in supine systolic 
BP, and postural hypotension. 
The clinical experience with KarXT initiated by Karuna Therapeutics to date includes 
3 completed Phase 1, clinical pharmacology studies in healthy volunteers (KAR-001, KAR-002, 
and KAR-003) and one completed Phase 2 study (KAR-004) in adult inpatients with DSM-5 
schizophrenia. 
The first study conducted by Karuna, KAR-001 was “A Phase 1, double-blind, randomized, 
multiple-dose, pilot study comparing xanomeline administered alone to xanomeline administered 
in combination with trospium chloride in normal healthy volunteers.” This study consisted of 
2 arms, in which xanomeline was administered TID, alone, at a total daily dose of 225 mg in one 
arm, and the second arm received the same dose of xanomeline in combination with trospium 
chloride 20 mg administered BID, a total daily dose of 40 mg. Subjects were treated for 7 days. 
The goal was to determine whether this dosing regimen would reduce the cholinergic side effects 
of xanomeline by co-administration of the muscarinic antagonist, trospium. 
Overall, treatment with xanomeline 225 mg daily + trospium 40 mg daily administered over 
7 days was considered safe and well tolerated. The results of key and supportive endpoints 
showed a numerical reduction (although not statistically significant) in visual analog scale (VAS) 
scores for cholinergic events for the xanomeline + trospium treatment arm compared to the 
xanomeline alone treatment arm. Specifically, consistent numerical reduction in VAS scores for 
the xanomeline + trospium treatment arm was observed for the supportive endpoints of 
maximum weekly individual VAS scores and mean daily maximum composite VAS scores. 
Results of the clinician-administered scales were supportive of a reduction in vomiting, feelings 
of nausea, excess salivation, and sweating that interfered with daily activities in the 
xanomeline + trospium treatment arm compared to the xanomeline alone treatment arm. 
There were no meaningful differences between treatment groups in heart rate, resting BP, 
orthostatic BP or any electrocardiogram (ECG) parameters including QT. A small subset of 
subjects in both treatment arms had transient increases in heart rate and orthostatic BP changes 
which may have contributed to syncope and postural dizziness in those subjects. Two subjects 
(both in the xanomeline alone arm) experienced syncope. The incidence of orthostatic AEs in the 
KarXT group was approximately one-half that of subjects in the xanomeline alone group. 
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The most commonly reported treatment-emergent AEs (TEAEs) in KAR-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. 
Study KAR-002 was a Phase 1, double-blind, randomized, multiple-dose adaptive design pilot 
study to evaluate the safety and tolerability of KarXT in normal healthy volunteers. Subjects 
received either 100 mg xanomeline + 20 mg trospium BID or placebo. The first cohort of this 
study was stopped after 1.5 days when the US FDA put the program on hold due to a preliminary 
rat finding in the 14-day study. This study used a new formulation of KarXT in which 
xanomeline and trospium were combined into a single dose form and given BID. Safety findings 
included an increase in orthostatic complaints. Caution should be used in drawing conclusions 
from this study, as subjects did not have time to reach steady state plasma levels from dosing, as 
only 3 doses were given. 
Study KAR-003 was a Phase 1, double-blind, randomized, multiple-dose, adaptive design, 
inpatient pilot study to evaluate the safety and tolerability of KarXT in normal healthy 
volunteers. The primary objective of this study was to assess the safety and tolerability of 7 days 
of daily administration of KarXT at various dose combinations, administered BID. Subjects 
received either KarXT or placebo (3:1 ratio). All subjects on KarXT received 2 days of 50 mg 
xanomeline + 20 mg trospium BID, and then increased to different doses for Days 3 to 7. This 
study also used the new formulation of KarXT in which xanomeline and trospium were 
combined into a single dosage form and given BID. 
There was a relatively high degree of variability in xanomeline and trospium exposures between 
individuals in all cohorts, which is consistent with previous results with KarXT, 
xanomeline-alone, and trospium-alone. Peak plasma concentrations were observed at a median 
time of 2.0 hours for xanomeline and 1.0 hour for trospium across all treatment groups and study 
days. 
Although there was insufficient data to draw a definitive conclusion regarding the impact of 
trospium on the pharmacokinetics (PK) and bioavailability of xanomeline, or the impact of 
xanomeline on the PK and bioavailability of trospium, the PK results suggest that neither drug 
had a meaningful impact on the PK behavior of the other drug. 
During the 2-day lead-in phase, the most common AEs (≥20% of subjects) when all the subjects 
completed dosing were dry mouth, nausea, and constipation. For the treatment groups that 
completed dosing, although the incidence of TEAEs was lower in the KarXT 100/20 BID 
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(66.7%) group compared to KarXT 125/40 group (88.9%), the incidence of cholinergic TEAEs 
(nausea, vomiting, diarrhea, sweating, and excess salivation) was similar between the 2 groups. 
The most commonly reported TEAEs (20% of subjects in either treatment group) in these 
groups were dizziness, nausea, dry mouth, headache, vomiting, dyspepsia, somnolence, vision 
blurred, and dysuria. For the treatment groups that did not complete dosing (KarXT 150/20 BID 
group and KarXT 150/40 BID group), the cholinergic TEAEs were generally higher compared to 
the treatment groups that completed dosing. 
Overall, anticholinergic TEAEs appeared to occur primarily in the treatment groups that were 
dosed with 40 mg trospium BID (KarXT 150/40 BID and KarXT 125/40 BID groups), 
particularly when paired with 125 mg xanomeline BID, suggesting to consider slightly lowering 
the trospium dose from 40 mg BID in future studies. All TEAEs were mild or moderate in 
severity, and there were no SAEs or deaths. Treatment-emergent AEs were primarily cholinergic 
or orthostatic (and a few anticholinergic). Doses of 100 mg and 125 mg BID of xanomeline were 
well tolerated when paired with 20 mg and 40 mg BID of trospium, respectively. The safety and 
tolerability profile of KarXT 100/20 BID and KarXT 125/40 BID was acceptable and supports 
further evaluation at similar doses in future studies. Doses of KarXT 150/20 BID and 
150/40 BID were not well tolerated in this study. A pairing of 150 mg xanomeline with 40 mg 
trospium appeared to be better tolerated than 150/20, but some subjects still experienced 
tolerability issues. 
Study KAR-004 was a Phase 2 randomized, double-blinded study to assess the safety 
tolerability, and efficacy of KarXT in adults with DSM-5 schizophrenia, hospitalized with acute 
psychosis. The primary objective of the study was to assess the efficacy of KarXT 125/30 BID 
versus placebo in reducing PANSS total scores in adult inpatients with a DSM-5 diagnosis of 
schizophrenia. Subjects received either KarXT or placebo (1:1 ratio) for a treatment period of 
5 weeks. All subjects on KarXT received a lead-in dose of KarXT 50/20 BID for the first 2 days 
followed by KarXT 100/20 BID on Days 3 to 7. On Day 8, dosing was titrated upwards to 
KarXT 125/30 BID unless the subject was continuing to experience AEs from previous dose 
increase of 100/20 BID. The clinical portion of this study was completed and clinical study 
report is in progress. No new safety concerns have arisen during this study. 
The KAR-004 trial results are unambiguous regarding efficacy, where not only the primary 
outcome measure showed a robust separation from placebo, but the additional sensitivity and 
secondary outcome measures were consistently robust as well. 
KarXT demonstrated statistically significant and clinically meaningful mean reductions in total 
PANSS scores at 5 weeks compared to placebo (P < 0.0001) in the modified intent-to-treat 
(mITT) population. The KarXT group showed an adjusted mean improvement of 17.40 points at 
Week 5 compared to an adjusted mean 5.85 point improvement in the placebo group for a 
difference of 11.56 points in the total PANSS score (Figure 1). Substantial significant differences 
were also seen between KarXT and placebo at Weeks 2 and 4; moreover, the difference appears 
to be widening with each successive time point. In addition, sensitivity analyses of the primary 
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outcome measure all showed the same strong differences from placebo attesting to the robustness 
of the finding in Completer, last observation carried forward, and Per Protocol populations (all 
with p < 0.0001). Also, analyses exploring missingness via imputation for missing data at 
random or not missing at random also showed strong separation (both with p < 0.0001). The 
Cohen’s d effect size observed in this trial was 0.75. 
Figure 1 
Change from Baseline in PANSS Total Scores (KAR-004) 
 
Abbreviations: LS = least squares; mITT = modified intent-to-treat; PANSS = Positive and Negative Syndrome 
Scale; SEM = standard error of the mean. 
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 timepoints (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. 
In regards to the Clinical Global Impression – Severity of Illness (CGI-S), subjects in the KarXT 
group overall significantly improved in ratings compared with placebo, with a P value of <0.001 
at Week 5. At Week 5, 8% of subjects on placebo improved (decreased) their CGI-S ratings by 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 with 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 
• Most common TEAEs were constipation, nausea, dry mouth, dyspepsia, and vomiting. 
None of these TEAEs were rated as severe, and none led to discontinuations 
• 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. 
• No syncope or mean changes in BP were seen 
• A 5.5 bpm peak mean placebo adjusted resting heart rate increase with a downward trend 
after week 2 was seen 
• One subject (on KarXT) was discontinued due to an elevated gamma-glutamyl 
transpeptidase 
• There were no new safety findings associated with KarXT that have not been observed 
with either xanomeline-alone or trospium-alone in previous trials 
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•
KarXT did not show evidence of many of the kinds of AEs that often occur in currently
available antipsychotics for the treatment of schizophrenia.
•
The rates of the following AEs were similar for KarXT and placebo: somnolence, weight
gain, and extrapyramidal symptoms.
Another Phase 3 study (KAR-007) is planned at approximately 20 study sites in the US. 
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 with all available 
APDs. 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 with placebo, demonstrated highly significant reduction in PANSS total scores 
(P < 0.0001) at all post randomization time points (Weeks 2, 4, and, 5) with a calculated effects 
size (Cohen’s d) of 0.75. KarXT, as compared to placebo, demonstrated significant improvement 
at all post randomization time points for PANSS positive symptom subscores, PANSS negative 
symptom subscores, PANSS Marder Factor negative symptom subscores, and CGI-S scores. 
More than 840 subjects or volunteers have been exposed to xanomeline tartrate (oral 
formulation, either alone, in combination with trospium, or as the fixed dose combination drug 
KarXT) in clinical studies. These early clinical studies, as well as nonclinical pharmacology and 
toxicology studies, have not revealed any specific contraindications to the use of xanomeline. 
The most common side effects/symptoms are the cholinergic related effects: nausea, vomiting, 
excess salivation, excess sweating, and diarrhea. In addition, subjects treated with xanomeline 
alone have reported both syncope and orthostatic dizziness. The addition of trospium decreases 
the peripheral cholinergic effect of xanomeline creating a better tolerated therapy. In addition, a 
titration phase also increases the tolerability of KarXT. 
Trospium chloride has been marketed in the US for 12 years. The most frequently reported AEs 
reported in pivotal trials were dry mouth, constipation, abdominal pain, headache, urinary 
retention, and abnormal vision and accommodation. For additional information, the package 
insert for trospium chloride tablets for oral use can be found in the IB. 
In a Phase 2 (KAR-004) clinical study, KarXT (100/20 and 125/30) significantly reduced the 
symptoms of schizophrenia in subjects with acute psychosis after treatment for 28 days. KarXT 
also showed an acceptable safety profile with the most common TEAEs being constipation, 
nausea, dry mouth, dyspepsia, and vomiting. All the reported TEAEs were mild or moderate in 
intensity. One SAE (psychotic disorder) was reported by a single subject and no deaths were 
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reported in the study. KarXT was generally well-tolerated and found to be safe in this patient 
population. 
KarXT represents a novel approach to the treatment of patients with schizophrenia that will 
provide an important and meaningful alternative to current therapies. The current tolerability and 
AE profile and the efficacy of KarXT justify further development of KarXT in this patient 
population by advancing to Phase 3 trials. 
Subjects assigned to active study drug may benefit by improvement in schizophrenia symptoms. 
Since subjects will be having an acute psychotic event, subjects will be hospitalized where the 
clinical staff is available to help them 24 hours a day. In addition, the inpatient setting represents 
an important venue for research, examining the effects of KarXT and helps to eliminate or 
reduce to the extent possible, subjectivity and bias. Furthermore, this inpatient setting will also 
enhance measurable quality standards as well as increased adherence. 
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6 
STUDY OBJECTIVES AND ENDPOINTS 
6.1 
Study Objectives 
 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of KarXT 125/30 BID versus 
placebo in reducing PANSS total scores in adult inpatients with a DSM-5 diagnosis of 
schizophrenia. 
 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the reduction of PANSS positive score in subjects treated with KarXT versus 
placebo 
• To evaluate the improvement in CGI-S results in subjects treated with KarXT versus 
placebo 
• To evaluate the reduction of PANSS negative score in subjects treated with KarXT 
versus placebo 
• To evaluate the reduction of PANSS Marder Factor negative symptoms score in subjects 
treated with KarXT versus placebo 
• To evaluate the safety and tolerability of KarXT 
• To assess the PK of xanomeline and trospium after administration of KarXT in adults 
who are acutely psychotic with a DSM-5 diagnosis of schizophrenia 
 
Exploratory Objectives 
The exploratory objectives of this study are: 
• To evaluate change in cognition measuring core domains of cognitive impairment in 
schizophrenia using the Cambridge Neuropsychological Test Automated Battery 
(CANTAB) 
• To evaluate the change in prolactin levels after administration of KarXT 
• To evaluate the single nucleotide polymorphisms (SNPs) regarding schizophrenia 
subtypes and SNPs related to drug metabolism 
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6.2 
Study Endpoints 
 
Primary Endpoint 
The primary endpoint of this study is change from baseline in PANSS total score at Week 5 
 
Secondary Endpoints 
6.2.2.1 
Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
• Change from baseline in PANSS positive score at Week 5 
• Change from baseline in PANSS negative score at Week 5 
• Change from baseline in PANSS Negative Marder Factor score at Week 5 
• CGI-S score at Week 5 
• Percentage of PANSS responders (a 30% change in PANSS total score) at Week 5 
6.2.2.2 
Safety Endpoints 
The safety endpoints of this study are as follows: 
• Spontaneously reported AEs including AEs of special interest (AESI) 
• Spontaneously reported procholinergic and anticholinergic symptoms 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
• Body weight, body mass index (BMI), waist circumference 
• Orthostatic vital signs (supine and standing after 2 minutes): BP (systolic and diastolic) 
and heart rate 
• Clinical laboratory evaluations: hematology, clinical chemistry, coagulation, urinalysis, 
and drug screen 
• 12-lead ECG 
• Physical examination 
• Suicidal ideation scale with the use of Columbia Suicide Severity Rating Scale (C-SSRS) 
 
Pharmacokinetic Endpoints 
The PK endpoints of this study are as follows: 
• Area under the plasma concentration-time curve (AUC) 
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• Maximum observed plasma concentration (Cmax) 
• Time to maximum observed plasma concentration (Tmax) 
 
Exploratory Endpoints 
• Change in cognition measuring core domains of cognitive impairment in schizophrenia 
using CANTAB 
• Change from baseline in prolactin levels at Week 5 
• Prediction of response based on SNP schizophrenia subtypes, and SNPs related to KarXT 
metabolism for both efficacy and tolerability 
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7 
INVESTIGATIONAL PLAN 
7.1 
Description of Overall Study Design and Plan 
This Phase 3, randomized, double-blind, parallel-group, placebo-controlled, multicenter, 
inpatient clinical study in adults who are acutely psychotic with a DSM-5 diagnosis of 
schizophrenia is designed to test the hypothesis that treatment with KarXT will result in 
significantly greater reduction (ie, improvement) in the primary and secondary endpoints at 
Week 5 from baseline compared with placebo. Total study duration is up to 8 weeks, including a 
7-day screening phase (up to a 7-day extension of the screening phase is allowed, if necessary), a 
5 week treatment period, and a 7-day follow-up period (only for subjects who do not rollover to 
KAR-008 study). Subjects completing this study will have the option of rolling over into a 
long-term open-label study (KAR-008) in which every subject will receive KarXT. Study staff 
should discuss KAR-008 protocol participation with potential subjects prior to the final day of 
participation in the acute study, via use of the provided recruitment materials. 
Screening Period: 
Screening of subjects will take place in 7 days or less before Day -1 (Days -8 to -2). Up to a 
7-day extension of the screening time is allowed, if necessary. 
A suitable number of subjects will be screened to randomize approximately 246 subjects across 
approximately 10 sites in the US and 10 sites in Ukraine. Subjects will be randomized through 
the IWRS in a 1:1 ratio to receive either KarXT or placebo for a treatment duration of 5 weeks. 
Treatment Period: 
In the treatment period, all subjects assigned to KarXT will start on a lead-in dose of 
KarXT 50/20 (xanomeline 50 mg/trospium 20 mg) BID for the first 2 days (Days 1 and 2) 
followed by KarXT 100/20 (xanomeline 100 mg/trospium 20 mg) BID for the remainder of 
Week 1 (Days 3 to 7). On Day 8, dosing will be titrated upwards to KarXT 125/30 BID unless 
the subject is continuing to experience AEs from the previous dose of KarXT 100/20 BID. All 
subjects who are increased to KarXT 125/30 BID, depending on clinical response and 
tolerability, will have the option to return to KarXT 100/20 BID for the remainder of the 
treatment period. Dosing must not change after Visit 7 (Day 21) of the study and may be 
decreased for tolerability reasons no more than once during the study. In addition, dose 
escalation to KarXT 125/30 BID may not occur outside of the permitted visit window for 
Visit 5/Day 8. 
All randomized 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. 
Efficacy assessments (PANSS scores and CGI-S score) will be assessed at scheduled visits. 
Refer to Section 11 for more details. 
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Safety will be assessed through spontaneous AEs including AESIs, procholinergic and 
anticholinergic symptoms, cognition testing, SAS, BARS, AIMS, body weight, BMI, waist 
circumference, orthostatic vital signs, ECG, clinical laboratory assessments (hematology, clinical 
chemistry, coagulation, urinalysis, and drug screen), prolactin levels, physical examination, and 
C-SSRS will be evaluated throughout the study as scheduled. Section 12 provides complete 
details on these safety assessments. 
Details on PK assessments are provided in Section 13. 
Safety Follow-up Period: 
A safety follow-up visit (Visit 11/ Day 42 + 5 days) will be performed for all those subjects who 
do not rollover into the long-term open-label study KAR-008. 
An Independent Safety Monitoring Committee (ISMC) will be responsible for reviewing on a 
periodic basis the safety data from this study and confirming that the study may continue. 
Table 1 presents the study design.
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Table 1 
Study Design 
 
Phase: 
Screening 
Inpatient Treatment 
End of 
Treatment 
/Early 
Termination 
Safety 
Follow-up 
Day: 
Days -8 
to -2 
Day -1 
Day 1 
Day 3 
+1 day 
Day 7 
±2 days 
Day 8 
-1/+2 
days 
Day 14 
±2 days 
Day 21 
±2 days 
Day 28 
±2 
days 
Day 32 
+1 day 
Day 35 
-2 daysc 
Day 42 
+5 days 
Visit: 
Visit 1 
Visit 2a 
Visit 
2b 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Xanomeline
/ trospium 
(KarXT)*: 
N/A 
 
50/20 
BID 
100/20 
BID 
100/20 
BID 
125/30 
BID 
(Option: 
100/20 
BID)a 
125/30 
BID 
(Option: 
100/20 
BID)a 
125/30 
BID 
(Option: 
100/20 
BID)a 
125/30 
BIDb 
125/30 
BIDb 
125/30 BIDb 
 
Comment: 
Up to a 
7-day 
extension 
to the 
screening 
phase is 
allowed. 
Baseline 
2-day 
lead-in 
dose 
Upwar
d 
titratio
n of 
dose 
 
Upward 
titration 
of dose 
Downward dose 
adjustment allowed 
according to clinical 
response/tolerability 
No dose 
adjustment 
allowed (after 
Day 21) 
 
For 
subjects 
who do 
not enter 
in to 
rollover 
Study 
(KAR-
008) 
Abbreviation: BID = twice daily. 
* All the KarXT doses are in mg. 
a. 
All subjects who are increased to KarXT 125/30, depending on clinical response and tolerability, will have the option to return to KarXT 100/20 BID for 
the remainder of the treatment period. 
b. No dose adjustment will be allowed after Visit 7. All subjects will continue taking the doses chosen for KarXT at Visit 7. 
c. The last dose of study drug will be administered the morning of Visit 10. 
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7.2 
Discussion of Study Design 
A randomized, double-blind, parallel-group, placebo-controlled study design is suitable for 
conducting any interventional studies. This design will minimize bias and provide reference data 
for comparison of efficacy and safety parameters of the investigational drug. 
Schizophrenia is a long-term mental disorder which requires a chronic therapy. A 5-week 
treatment duration is considered an acceptable treatment duration to observe clinically significant 
response (ie. primary endpoint can be achieved). The 5-week treatment duration is substantiated 
by the statistically significant outcome of the KAR-004 study of the same duration.  
7.3 
End of Study 
A subject will have fulfilled the requirements for study completion when the subject has 
completed all study periods, including the End of Study visit (Visit 10/Day 35 [End of 
Treatment/Early Termination] for subjects who roll over into KAR-008 or Visit 11/Day 42 
[Follow-up] for subjects who do not roll over into the KAR-008 study) as indicated in the 
Schedule of Assessments (Table 2) in accordance with the protocol. 
Subjects completing this study will have the option of rolling over into a long-term open-label 
study (KAR-008) in which every subject will receive KarXT, following completion of 
Visit 10/Day 35 of the current study (KAR-009). 
Note: A safety follow-up visit will be performed 1 week after the End of Treatment/Early 
Termination visit (Visit 10) for subjects who have completed Visit 10/Day 35 but do not rollover 
in to the long-term open-label study KAR-008. 
7.4 
Independent Safety Monitoring Committee 
For the purpose of this study, the ISMC is an independent group of individuals with pertinent 
expertise that reviews on a regular basis accumulating safety and tolerability data from the 
clinical study. The ISMC will include 3 clinicians and a reporting statistician. This committee 
will be responsible, on a periodic basis, for confirming the safety and tolerability of KarXT 
throughout the study, with particular focus on assessing for any new toxicities that might be 
involved with KarXT. 
The reviews will be of unblinded data to allow a comparison of event rates and detection of 
safety signals across treatment groups to identify important safety information. The ISMC 
charter will contain the details of the types of data to be reviewed, the defined triggers for 
review, the minimum frequency of meetings (timed, if no triggers), and the communication plan 
for disseminating review recommendations. 
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8 
SELECTION OF STUDY POPULATION 
Section 7.1 provides information regarding number of subjects planned to be randomized. 
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 must be provided before any study assessments are 
performed. 
b. Subject must be fluent (oral and written) in English (applicable to the US) or local 
language (Ukrainian or Russian applicable to Ukraine) 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 for 
Schizophrenia and Psychotic Disorder Studies (MINI) version 7.0.2. 
4. Subject is experiencing an acute exacerbation or relapse of psychotic symptoms, 
with onset less than 2 months before screening. 
a. The subject requires hospitalization for this acute exacerbation or relapse of psychotic 
symptoms. 
b. If already an inpatient at screening, has been hospitalized for less than 2 weeks for 
the current exacerbation at the time of screening. 
5. Positive and Negative Syndrome Scale total score between 80 and 120, inclusive. 
a. Score of ≥4 (moderate or greater) for ≥2 of the following Positive Scale (P) items: 
i. Item 1 (P1; delusions) 
ii. Item 2 (P2; conceptual disorganization) 
iii. Item 3 (P3; hallucinatory behavior) 
iv. Item 6 (P6; suspiciousness/persecution) 
6. Subjects with no change (improvement) in PANSS total score between screening and 
baseline (Day -1) of more than 20%. 
7. Subject has a CGI-S score of ≥4 at screening and baseline (Day -1) visits. 
8. Subject will have been off lithium therapy for at least 2 weeks before baseline and free 
of all oral antipsychotic medications for at least 5 half-lives or 1 week, whichever is 
longer, before baseline (Day -1). 
9. Subjects taking a long-acting injectable antipsychotic could not have received a dose of 
medication for at least 12 weeks (24 weeks for INVEGA TRINZA®) before baseline 
visit (Day -1). 
10. Subject is willing and able to be confined to an inpatient setting for the study duration, 
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follow instructions, and comply with the protocol requirements. 
11. BMI must be ≥18 and ≤40 kg/m2. 
12. Subject resides in a stable living situation and is anticipated to return to that same stable 
living situation after discharge, in the opinion of the investigator. 
13. Subject has an identified reliable informant/caregiver. An informant/caregiver is 
needed at the screening and baseline visits as well as at the end of the study for 
relevant assessments (site staff may act as informant while the subject is an inpatient). 
An informant/caregiver may not be necessary if the subject has been the patient of the 
investigator for ≥1 year. 
14. 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 
Individuals meeting any of the following criteria at screening or baseline are ineligible to 
participate in this study: 
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, moderate to severe alcohol use disorder (within the past 
12 months), substance (other than nicotine or caffeine) use disorder within the past 
12 months (use of cannabis at screening will result in screen failure with the allowance 
to rescreen at a later date if no moderate to severe substance use disorder is determined), 
major depressive disorder, bipolar I or II disorder, schizoaffective disorder, obsessive 
compulsive disorder, and post-traumatic stress disorder. Symptoms of mild mood 
dysphoria or anxiety are allowed as long as these symptoms are not the primary focus of 
treatment. 
a. A screening subject with mild substance abuse disorder within the 12 months before 
screening must be discussed and agreed upon with the medical monitor before they 
can be allowed into the study. 
2. Subjects who are newly diagnosed or are experiencing their first treated episode of 
schizophrenia. 
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 
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. 
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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. 
9. Subjects cannot currently (within 5 half-lives or 1 week, whichever is longer, before 
baseline [Day -1]) be receiving oral antipsychotic medications; monoamine oxidase 
inhibitors; anticonvulsants (eg, lamotrigine, Depakote); tricyclic antidepressants (eg, 
imipramine, desipramine); selective serotonin reuptake inhibitors; or any other 
psychoactive medications except for as needed anxiolytics (eg, lorazepam, chloral 
hydrate). 
10. Pregnant, lactating, or less than 3 months postpartum. 
11. If, in the opinion of the investigator (and/or Sponsor), subject is unsuitable for 
enrollment in the study or subject has any finding that, in the view of the investigator 
(and/or Sponsor), may compromise the safety of the subject or affect his/her ability to 
adhere to the protocol visit schedule or fulfill visit requirements. 
12. Positive test for coronavirus (COVID-19) within 2 weeks before screening and at 
screening. 
13. Subjects with extreme concerns relating to global pandemics, such as COVID-19, that 
preclude study participation. 
14. Subject has had psychiatric hospitalization(s) for more than 30 days (cumulative) 
during the 90 days before screening. 
15. Subject has a history of treatment resistance to schizophrenia medications defined as 
failure to respond to 2 adequate courses of pharmacotherapy (a minimum of 4 weeks 
at an adequate dose per the label) or required clozapine within the last 12 months. 
16. Subjects with prior exposure to KarXT. 
17. Subjects who experienced any adverse effects due to xanomeline or trospium. 
18. Participation in another clinical study in which the subject received an experimental or 
investigational drug agent within 3 months before screening. 
19. Risk of violent or destructive behavior. 
20. Current involuntary hospitalization or incarceration. 
8.3 
Rescreening 
Individuals who sign the informed consent form (ICF) to participate in the study but who do not 
subsequently meet all the requirements for safety laboratory assessments and therefore do not 
enroll (screen failures) may be rescreened, upon approval of the medical monitor on a case by 
case basis. Such individuals may be allowed to rescreen up to 1 time. When re-testing within the 
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same screening procedure, only the exclusionary laboratory tests will be repeated once in case 
the exclusionary laboratory result was not due to a pathological condition and was occasional 
(except for individuals who have positive serology results).  
8.4 
Study Withdrawal, Removal, and Replacement of Subjects 
If a subject discontinues study treatment and is withdrawn from the study for any reason, the 
study site must immediately notify the medical monitor. The date and the reason for study 
discontinuation must be recorded on the electronic case report form (eCRF). Subjects who 
complete or discontinue early from the study will be discharged from the study site, if clinically 
warranted after completing all the Visit 10/early termination assessments as indicated in the 
Schedule of Assessments (Table 2). 
Note: A safety follow-up visit will be performed 1 week after the End of Treatment/Early 
Termination visit (Visit 10) for those subjects who do not roll over into the long-term open-label 
study KAR-008. 
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 will 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. The reason for subject withdrawal will be noted on the 
eCRF 
• on the basis of the investigator’s clinical judgement 
• intercurrent illness: a condition, injury, or disease unrelated to the primary diagnosis that 
became apparent during treatment and necessitated the subject’s termination from the 
study 
• general or specific changes in the subject’s condition that renders him/her ineligible for 
further treatment according to the inclusion/exclusion criteria (eg, subject has need for a 
medication prohibited by the protocol) 
• subject fails to adhere to the protocol requirements (eg, drug noncompliance [if a study 
subject is off study drug for >5 days in a row])  
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• violation of entry criteria; ie, subjects who are enrolled but are later discovered not to 
meet entry criteria 
• development of suicidal or assaultive behavior 
• alcohol or illegal drug use 
• pregnancy, as indicated in Section 12.7.8. Any study subject who becomes pregnant 
while participating in the study will be unblinded to study treatment randomization. If she 
is found to be on active treatment assignment, she will be followed until her pregnancy 
reaches term 
• Sponsor’s decision to discontinue study 
Subjects withdrawing 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 leave the unit or are lost to follow-up. 
These efforts must be documented in the subject’s file. Subjects with AEs ongoing at end of 
study will be followed until the AE is resolved (regardless of whether they enroll in the 
long-term open-label study KAR-008) or the subject is considered to be in stable condition. 
The Sponsor has the right to terminate the study at any time in case of SAEs or if special 
circumstances concerning the study drug 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 study drug. WOCBP will have a serum 
pregnancy test at screening and a urine pregnancy test on Day -1 (before receiving KarXT) and 
thereafter, as designated at other scheduled visits (Table 2). In case of positive urine pregnancy 
test result, a serum 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. 
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Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment 
of the mother with KarXT, women who are breastfeeding must not be enrolled in the study. 
The effects of study drug on sperm are unknown. Men whose sexual partners are WOCBP must 
agree to use a highly effective method of birth control (see APPENDIX 1 for a list of acceptable 
highly effective methods of contraception) and must not impregnate a sexual partner during or 
for 30 days after the last dose of study drug. They must also agree to refrain from sperm donation 
for 30 days after the last dose of study drug. 
WOCBP will be instructed that known or suspected pregnancy occurring during the study should 
be confirmed and reported to the investigator. If a female subject becomes pregnant, the 
investigator must withdraw her from the study without delay. The subject must not receive any 
further doses of the study drug. Upon discontinuation from the study, only those procedures that 
would not expose the pregnant female subject to undue risk will be performed. See Section 
12.7.8 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 report 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 SAE (Section 12.7.4). 
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 leave the facility and are lost to 
follow-up to obtain end of study 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 Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB) may take such actions. If the study is terminated for safety reasons, subjects 
will be notified immediately and assured that appropriate treatment and follow-up will be 
available. If an investigator terminates the study, the Sponsor, subjects, and IEC/IRB will be 
informed about the reason for such action. Similarly, if the Sponsor terminates the study, it will 
inform the investigators, the IEC/IRB, and the subjects of the reason for such an action. Similar 
notifications will be sent by the IEC/IRB if it takes such an action. 
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9 
TREATMENTS 
9.1 
Details of Study Treatments 
KarXT is formulated as hard hydroxypropyl methylcellulose oral capsules containing 2 distinct 
populations of drug beads, one of which is loaded with xanomeline tartrate and the other of 
which is loaded with trospium chloride. Each capsule contains the freebase equivalent of 
xanomeline and trospium according to the desired dose strength. In addition to the active 
ingredients, the drug beads contain microcrystalline cellulose (MCC). The beads are not coated 
and are formulated for immediate release of the active ingredients. 
 
Identity of Study Treatments 
Active study agents for treatment group will be size 0, Swedish-orange hydroxypropyl 
methylcellulose hard capsules. Placebo will be prepared in matching capsules; therefore, an 
unblinded pharmacist will be required to dispense study drug in a blinded fashion to personnel 
who will be responsible for administration of IP to the subject. For the 2-day lead-in period 
(Days 1 and 2), subjects randomized to active drug will receive capsule strength KarXT 50/20 
BID, followed by 2 capsules of KarXT 50/10 mg BID or a dosage of 100/20 BID for a total daily 
dosage of 200/40 mg xanomeline/trospium chloride for the remainder of Week 1 (Days 3 to 7). 
At the beginning of Week 2, dosing may be increased to 2 capsules of KarXT 62.5/15 mg or a 
dosage of 125/30 BID for a total daily dosage of 250/60 mg xanomeline/trospium chloride, 
depending on clinical response and tolerability. Investigators have the option to return a subject 
to KarXT 100/20 BID for the remainder of the treatment period, but dosing must not change 
after Visit 7 of the study. 
KarXT 50/10 mg is composed of 44.4% xanomeline tartrate, 5.8% trospium chloride, excipients 
37.59% MCC, 11.5% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a size 0, 
Swedish-orange, hydroxypropyl methylcellulose hard capsule. 
KarXT 50/20 mg is composed of 33.4% xanomeline tartrate, 8.7% trospium chloride, excipients 
39.8% MCC, 17.3% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a size 0, 
Swedish-orange, hydroxypropyl methylcellulose hard capsule. 
KarXT 62.5/15 mg is composed of 41.7% xanomeline tartrate, 6.5% trospium chloride, 
excipients 38.1% MCC, 12.9% lactose monohydrate, 0.3% ascorbic acid and 0.5% talc in a 
size 0, Swedish-orange, hydroxypropyl methylcellulose hard capsule. 
Placebo is composed of sugar spheres pf011, 850/1000 suglets, 99.05% colorcon, and 10.05% 
talc in a size 0, Swedish-orange, hydroxypropyl methylcellulose hard capsule. 
All investigational agents are to be stored according to requirements. 
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Packaging and Labelling 
The study packaging and labelling will be performed by Corealis Pharma, located in Laval, 
Quebec, Canada, Catalent Pharma Solutions, located in Winchester, Kentucky (labelling for the 
US sites), and Catalent Pharma Solutions, located in Philadelphia, Pennsylvania (labelling for 
Ukrainian sites). All packaging and labelling operations will be performed according to Good 
Manufacturing Practice for Medicinal Products and the relevant regulatory requirements. 
Bulk supply bottles are labeled with the name of the drug, recommended storage conditions, the 
name and address of the manufacturer, and the Investigational Use Statement (“Caution: New 
Drug – Limited by Federal [US] Law to Investigational Use”). 
Further details on labelling of investigational products will be provided in the Pharmacy Manual. 
 
Study Drug Storage 
KarXT and placebo must be stored at controlled room temperature 15°C-25°C in a secured 
location with no access to unauthorized personnel. 
 
Study Drug Retention 
Study drug not used in KAR-009 may be used for the long-term extension study (KAR-008). 
Therefore, unused study drug for this particular study must be retained until completion or 
termination of the KarXT program, and written authorization from the Sponsor has been 
received. The unused study drug can be reassigned in the IWRS to subjects in the KAR-008 
study. All unused and used study drug must be destroyed at the site or returned, as specified by 
Sponsor. It is the investigator’s responsibility to ensure that the Sponsor has provided written 
authorization prior to return or destruction, and that appropriate records of the disposal are 
documented and maintained. No used or unused study drug may be disposed until fully 
accounted for by the study monitor. 
9.2 
Dose Schedule 
The first dose of the study drug will be administered in the morning of Day 1. The last dose will 
be administered in the morning of Visit 10 (Day 35 -2 days). The study drug should be 
administered daily BID on an empty stomach ie, at least 1 hour before a meal or 2 to 3 hours 
after a meal. Some considerations for dosing and PK blood withdrawals are provided in the 
subsections below. 
 
Visit 2b/Day 1 Randomization and Dosing 
• The first dose will be administered in the morning, and the evening dose will be 
administered 12 ± 0.5 hours after the morning dose. 
• All subjects must be administered 4 dosages of the KarXT 50/20 or placebo before dose 
escalation to KarXT 100/20 or placebo BID. 
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Visit 3/Day 3 and/or Visits Occurring on Weekends/Holidays 
• If dose escalation to the KarXT 100/20 or placebo level is confirmed by investigator 
order on Visit 3/Day 3, that dose is to be administered in the morning. 
• When Day 3 occurs on a weekend, it is expected that the complete Visit 3 will be 
performed, and the subject’s dose will be escalated on Day 3. 
• If completion of the visit is not possible on Day 3, the +1-day visit window may be used. 
In this instance, the dose will not be escalated until the study visit occurs. In all cases, the 
subject must have had at least 4 doses of KarXT 50/20 or placebo before escalating to 
KarXT 100/20 or placebo. 
• This may result in only 4 days of the KarXT 100/20 or placebo dose at Visit 5/Day 8, 
which is acceptable. 
• All subjects must be administered 8 doses of the KarXT 100/20 or placebo before dose 
escalation to KarXT 125/30 or placebo BID. 
 
Visit 5/Day 8 Dosing and PK Considerations and Visit 8/Day 28 PK 
Considerations 
• If dose escalation to the KarXT 125/30 or placebo level is confirmed by investigator 
order on Visit 5/Day 8, that dose is to be administered in the morning (after the predose 
PK blood draw) to allow for serial postdose PK blood draws per protocol (Table 2, 
Footnote p). 
• Should the use of visit windows be necessary, serial PK sampling must accompany the 
actual day of dose escalation for Visit 5.  
• For Visit 8, serial PK sampling is meant to capture the PK profile of the subject’s final 
KarXT dose level (125/30 or 100/20) after multiple doses; therefore, there must be no 
changes in dose for at least 7 days prior to Visit 8. PK sampling must accompany the 
actual day of Visit 8 if a window is used. 
 
Visit 10/Day 35 Dosing 
• All subjects will receive their final dose of KarXT or placebo on the morning of 
Visit 10/Day 35. 
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 
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number will consist of a 3-digit study code and a 3-digit site identification followed by a 3-digit 
subject number assigned sequentially within each site, starting at 
. 
On Day -1, all eligible subjects will be randomly assigned in a 1:1 ratio to either KarXT or 
placebo groups. Subjects will be assigned a randomization number through the IWRS, in 
accordance with the randomization code generated by the authorized personnel at VERISTAT. 
At the study site, the randomization schedule will only be accessible to authorized unblinded 
pharmacy personnel or designee. Once a randomization number is allocated to one subject, it 
may not be assigned to another subject even if the former discontinued the study. 
 
Blinding 
An IWRS will allocate treatment based on a prespecified randomization list generated by 
VERISTAT. Active and placebo study drug will be provided in bulk to each site participating in 
the study. For each dose, study drug and packaging will be identical in size, shape, color, and 
appearance (see Section 9.1.2). No other study site personnel (except the pharmacist or other 
designated unblinded individual), subjects, informants/caregivers, Sponsor personnel, or Sponsor 
designees (eg, Sponsor’s Medical Monitor) will be unblinded to treatment assignment throughout 
the duration of the study unless unblinding is required. Both active study drug and placebo will 
be supplied as identical matching capsules. This prevents bias on the part of the study staff and 
the subject to influence the results of the study. 
If an investigator becomes unblinded to a given subject’s study treatment, that subject will be 
discontinued from the study unless there are ethical reasons for that subject not to be 
discontinued; approval from the Sponsor/medical monitor must be obtained in such instances. 
VERISTAT will generate and maintain the security of the randomization code. In the event that 
emergency unblinding is required for a given subject because of AEs or concerns for the 
subject’s safety or wellbeing, the investigator may break the randomization code for just that 
subject via the IWRS, by which system the unblinding will be captured after consultation and 
agreement with the medical monitor/Sponsor. The unblinding and its cause will also be 
documented in the eCRF. Unblinding according to the protocol will occur only after completion 
of the study. 
If an AE is thought to be related to the study drug and poses a safety risk, the investigator must 
decide whether to stop investigational treatment and/or treat the subject. Subject withdrawal 
should be avoided, if possible. If discontinuation of treatment occurs, every attempt should be 
made to restart study drug if medically appropriate, whatever the duration of discontinuation. 
When a subject has an AE that requires that the investigator be unblinded, the investigator can 
obtain the treatment assignment from the IWRS system. The site is expected to notify the study 
medical monitor before breaking the study blind unless it is in the subject’s best interest if the 
blind is broken immediately. Note: In most circumstances, it is not necessary to unblind a 
subject, even if an SAE has occurred. For many drugs there is no specific therapy for AEs. The 
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appropriate course of action is to stop the investigational drug and treat the signs and symptoms 
resulting from the AE. 
The members of the ISMC will be unblinded as they review the safety data from the study. 
9.4 
Dose Modification 
Subjects will be dosed as described in Section 7.1 and in accordance with the Schedule of 
Assessments (Table 2). The study drug 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 at Visits 5, 6, and 7 and at unscheduled visits. No dose adjustments are allowed after 
Visit 7. No other dose modifications are permissible in this study except those specified in this 
protocol. 
9.5 
Treatment Accountability and Compliance 
The pharmacist or other designated unblinded 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 study drug will be supervised by study site personnel to ensure compliance. 
Investigators will maintain records that adequately document that the subjects were provided 
with the correct study treatment bulk supply and reconcile the products received from the drug 
dispensing center. Investigational product will not be returned to the Sponsor or designee until 
accountability has been fully monitored through the end of the study. Study drug accountability 
will be assessed periodically by the assigned unblinded study monitor. 
9.6 
Prior and Concomitant Therapy 
 
Prior and Concomitant Medications 
Subjects will be asked for all prior medications they were taking up to 6 months before the study, 
up to the time of the first dose of study medication on Day 1. All prior medications will be 
recorded on the eCRF. 
Restricted prior therapies are provided in Section 8.2.  
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 (ie, from the time of screening visit until study completion), subjects will 
refrain from the use of any new concomitant medications without the specific prior approval of 
the investigator. The administration of any other concomitant medications during the study 
period is prohibited without the prior approval of the investigator unless its use is deemed 
necessary in a medical emergency. Any medication or therapy that is taken by or administered to 
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the subject during the course of the study must be recorded in the eCRF. The entry must include 
the dose, regimen, route, indication, dates of use, and time of use (only for concomitant 
medications used on an as-needed [PRN] basis). 
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. 
• Within 5 half-lives or 1 week, whichever is longer, before baseline (Day -1), subjects 
could not have taken oral antipsychotic medications, MAO inhibitors, mood stabilizers 
(ie, lithium), anticonvulsants (eg, lamotrigine, Depakote), tricyclic antidepressants (eg, 
imipramine, desipramine), selective serotonin reuptake inhibitors, or any other 
psychoactive medications except for anxiolytics that were taken on an as needed basis 
(eg, lorazepam, chloral hydrate).  
• Subjects taking a long acting injectable antipsychotic could not have received a dose of 
medication for at least 12 weeks (24 weeks for INVEGA TRINZA®). 
Note: Please direct questions relating to prohibited medications to the Medical Monitor. 
 
Concomitant Medications for Anxiety and/or Sleep aid 
Subjects are allowed to take benzodiazepines (up to 6 mg lorazepam/day or equivalent) for 
anxiety, agitation, and insomnia on a PRN basis. Subjects may also use non-benzodiazepine 
medications (eg, zolpidem, zaleplon) as a sleep aid also on a PRN basis. Study sites must record 
the use of such medications in the eCRF on a per-administration basis and subject’s source 
document. Note: Cognition testing should not be done within 8 hours of receiving a 
benzodiazepine or sleep medication. 
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10 STUDY PROCEDURES 
Table 2 outlines the timing of procedures and assessments to be performed throughout the study. 
Section 12.6 specifies laboratory assessment samples to be obtained. See Sections 11, 12, and 13 
for additional details regarding efficacy, safety, and PK assessments, respectively. 
 
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Table 2. 
Schedule of Assessments 
PROCEDURE 
SCREENING 
PHASE 
TREATMENT PHASE 
SAFETY 
FOLLOW-UPv 
Unscheduled 
Visit(s)b 
VISIT 
1 
(Day -8 
to -2)a 
2a 
(Day 
-1) 
2b 
(Day 
1) 
3 
(Day 
3 +1 
day) 
4 
(Day 
7 ±2 
days) 
5 
(Day 
8  
-1/+2 
days) 
6 
(Day 
14 ±2 
days) 
7 
(Day 
21 ±2 
days) 
8 
(Day 
28 ±2 
days)u 
9 
(Day 
32 +1 
day) 
10/ET 
(Day 35  
-2 days) 
11 
(Day 42 
+5 days) 
WEEKS PAST 
RANDOMIZATION 
NA 
0 
 
 
1 
 
2 
3 
4 
 
5 
6 
 
Written informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Collect 
demographic 
information (date of 
birth, sex, race) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(females of 
childbearing 
potential only)c 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Urine test for 
drugs of abuse 
and alcohol 
testingd 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Review of 
inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Subject eligibility 
verification process 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, 
psychiatric, and 
medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examinatione 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
Spontaneous AEsf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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PROCEDURE 
SCREENING 
PHASE 
TREATMENT PHASE 
SAFETY 
FOLLOW-UPv 
Unscheduled 
Visit(s)b 
VISIT 
1 
(Day -8 
to -2)a 
2a 
(Day 
-1) 
2b 
(Day 
1) 
3 
(Day 
3 +1 
day) 
4 
(Day 
7 ±2 
days) 
5 
(Day 
8  
-1/+2 
days) 
6 
(Day 
14 ±2 
days) 
7 
(Day 
21 ±2 
days) 
8 
(Day 
28 ±2 
days)u 
9 
(Day 
32 +1 
day) 
10/ET 
(Day 35  
-2 days) 
11 
(Day 42 
+5 days) 
WEEKS PAST 
RANDOMIZATION 
NA 
0 
 
 
1 
 
2 
3 
4 
 
5 
6 
 
Review of 
concomitant 
medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height (Screening 
only) and body 
weight, BMI, waist 
circumference 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Orthostatic vital 
signs: BP and heart 
rateg 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Resting 12-lead ECGh 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
Blood samples for 
hematology, 
coagulation, and 
serum chemistry and 
urine sample for 
urinalysisi 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
COVID-19 
testingj 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Blood sample 
for prolactink 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Blood sample 
for viral 
serologyl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample 
for DNA testing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
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PROCEDURE 
SCREENING 
PHASE 
TREATMENT PHASE 
SAFETY 
FOLLOW-UPv 
Unscheduled 
Visit(s)b 
VISIT 
1 
(Day -8 
to -2)a 
2a 
(Day 
-1) 
2b 
(Day 
1) 
3 
(Day 
3 +1 
day) 
4 
(Day 
7 ±2 
days) 
5 
(Day 
8  
-1/+2 
days) 
6 
(Day 
14 ±2 
days) 
7 
(Day 
21 ±2 
days) 
8 
(Day 
28 ±2 
days)u 
9 
(Day 
32 +1 
day) 
10/ET 
(Day 35  
-2 days) 
11 
(Day 42 
+5 days) 
WEEKS PAST 
RANDOMIZATION 
NA 
0 
 
 
1 
 
2 
3 
4 
 
5 
6 
 
Functional 
constipation inquirym 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Admission of subject 
to inpatient unitn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization/
assignment of 
subject 
randomization 
number 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Determination of dose 
adjustment 
 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
Study drug provided 
(randomized, double- 
blind) and 
administered daily 
BIDo 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Blood samples for PK 
analysisp 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
MINI version 7.0.2q 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Positive and Negative 
Syndrome Scale 
(PANSS) for 
schizophreniar 
X 
X 
 
 
 
 
X 
X 
X 
 
X 
X 
 
C-SSRSs 
X 
X 
 
 
X 
 
X 
X 
X 
 
X 
X 
X
CGI-S Scale 
X 
X 
 
 
X 
 
X 
X 
X 
 
X 
 
 
Cognition testingt 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
Simpson-Angus 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
X 
 
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PROCEDURE 
SCREENING 
PHASE 
TREATMENT PHASE 
SAFETY 
FOLLOW-UPv 
Unscheduled 
Visit(s)b 
VISIT 
1 
(Day -8 
to -2)a 
2a 
(Day 
-1) 
2b 
(Day 
1) 
3 
(Day 
3 +1 
day) 
4 
(Day 
7 ±2 
days) 
5 
(Day 
8  
-1/+2 
days) 
6 
(Day 
14 ±2 
days) 
7 
(Day 
21 ±2 
days) 
8 
(Day 
28 ±2 
days)u 
9 
(Day 
32 +1 
day) 
10/ET 
(Day 35  
-2 days) 
11 
(Day 42 
+5 days) 
WEEKS PAST 
RANDOMIZATION 
NA 
0 
 
 
1 
 
2 
3 
4 
 
5 
6 
 
Rating Scale 
Barnes Rating Scale 
for Akathisia 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
X 
 
Abnormal 
Involuntary 
Movement Scale 
(AIMS) 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
X 
 
Discuss participation 
in KAR-008w 
 
 
 
 
 
 
 
X 
 
 
 
Abbreviations: AE = adverse event; BID = twice daily; BMI = body mass index; BP = blood pressure; CGI-S = Clinical Global Impression‒Severity scale; 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ET = early termination; ID = identification; MINI = Mini International 
Neuropsychiatric Interview; PK = pharmacokinetic; QTcF = QT interval corrected by Fridericia. 
a. 
Up to a 7-day extension of the screening phase is allowed, if needed. 
b. 
Other assessments as needed. 
c. 
A serum pregnancy test for females of childbearing potential should be done at screening, and urine pregnancy tests should be done at other visits. 
d. 
A National Institute on Drug Abuse-5 urine drug screen (cannabinoids or marijuana, phencyclidine, amphetamines, opiates, and cocaine) will be 
performed at screening and at Visit 2a (baseline). If a subject leaves the study site, they should have a urine drug screen and test for alcohol (breathalyzer 
or urine alcohol level) upon returning to the study site.  
e. 
A complete physical examination includes body temperature (°C), general appearance, head/eyes/ears/nose/throat, examination of thorax and 
abdomen, assessment of cardiac, musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited neurological 
examination. 
f. 
AEs as reported by subjects or observed by clinical staff and occurs from Day -1. One PK blood sample may be drawn if a relevant/significant AE 
(based on medical judgement) is reported during a scheduled visit or if there is a dose adjustment or a relevant/significant AE reported during an 
unscheduled visit (no multiple draws). 
g. 
Vital signs taken supine and standing after 2 minutes. BP includes systolic and diastolic BP and is to be taken in the same arm for the duration of the 
study. Heart rate is measured in beats/minute. During treatment, beginning with Day 1, orthostatic vital signs should occur 2 (±1) hours after morning 
dosing. Orthostatic vital signs are only required after the morning dose of the specified visit days, but additional orthostatic vital sign monitoring is 
allowed at the investigator’s discretion. It would be acceptable, for example, to do orthostatic vital signs BID after dosing increases for a day or 2 for 
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subjects where it seems warranted, but this should not be done automatically. 
h. 
ECG on Day 1 will be done at 2 hours + 15 minutes post morning dose. ECGs at all other scheduled visits will be performed before blood withdrawal for 
any safety laboratory tests and/or PK analysis. During the ECG, ventricular rate (bpm), PR (msec), QRS (msec), QT (msec), and QTcF (msec) 
measurements should be obtained. 
i. 
Refer to Table 3 for individual laboratory tests. For urinalysis, a urine dipstick will be performed at the site, and the sample will be sent to the central 
laboratory in case of abnormalities. 
j. 
Optional COVID-19 test may be performed at unscheduled visits based on the Investigator’s discretion. 
k. 
Blood sample for prolactin must be obtained before the morning dose of the study drug at scheduled visits (except at Visit 2a). 
l. 
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. 
m. Functional constipation inquiry: At specified visits, subjects will be asked whether they have experienced constipation (per the ROME III criteria and 
Bristol Stool Form scale; see APPENDIX 2) since the last visit and if yes, whether the constipation required intervention. If the subject answers yes, 
sites are instructed to ask subjects to provide event date and ensure the event is documented as an AE and treatment is documented as concomitant 
medication.  
n. 
If an eligible subject is not already an inpatient, the subject should be admitted to the inpatient unit. 
o. 
Starting on Day 1, study drug is administered daily BID (first dose of study will be administered in the morning of Day 1, and evening dose will be 
administered 12 ± 0.5 hours after the morning dose and after last PK sampling [for Visits 5 and 8] is completed), on an empty stomach ie, at least 1 hour 
before a meal or 2 to 3 hours after a meal by the study staff, with the last dose administered on the morning of Visit 10. All subjects must receive at 
least 4 dosages of the 50/20 BID before dose escalation to KarXT 100/20 BID. 
p. 
For Visit 5/Day 8 and Visit 8/Day 28, 7 PK blood draws are required: before the morning dose, and at 0.5 hour ± 5 minutes, 1 hour ± 5 minutes, 
2 hours ± 10 minutes, 4 hours ± 10 minutes, 8 hours ± 10 minutes, and 12 hours ± 10 minutes after the morning dose (Note: The 12-hour samples must 
be collected before administration of the evening dose). PK blood draws at Visit 5 must be drawn in relation to the first dose of KarXT 125/30 for 
subjects who are escalated in the morning of Visit 5/Day 8 -1/+2 days. PK blood must also be drawn in relation to the morning dose for subjects who 
are not escalated at Visit 5/Day 8 -1/+2 days. For Visit 10/ET, a single PK blood sample should be withdrawn before discharge (preferably in the 
morning after the last dose of the study drug). One PK blood sample may also be drawn if a relevant/ significant AE is reported during a scheduled visit 
or if there is a dose adjustment or a relevant/significant AE reported during an unscheduled visit (no multiple draws). For an ET Visit that is related to 
an AE, the collection of a PK blood sample is not optional and should be drawn before discharge. 
q. 
MINI should be performed before PANSS assessment. 
r. 
It is recommended, if at all possible, that the PANSS assessment should be performed before all the other scale assessments (except MINI) for 
all visits at which it is performed. The PANSS assessment includes the Marder Factor. 
s. 
C-SSRS first time use lifetime, other times use “Since Last Visit” version. At the Unscheduled visit, the C-SSRS should be performed to monitor subjects 
for suicidality. 
t. 
During screening, subjects will complete each of the CANTAB tests for familiarization purposes. These same tests will then be administered on Visits 
2a, 7, and 9. Note: Cognition testing cannot be done within 8 hours of receiving benzodiazepine or sleep medications. 
u. 
There must be no changes in dose for at least 7 days leading up to Visit 8. 
v. 
Safety follow-up visit will be performed 1 week (Day 42 +5 days) after Visit 10/ET for subjects who do not rollover in to the long-term open-label study 
KAR-008. 
w. Study staff should discuss KAR-008 protocol participation with potential subjects prior to the final day of participation in the acute study, via use of the 
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provided recruitment materials. 
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10.1 Informed Consent 
Informed consent forms must be approved for use by the reviewing IEC/IRB. Before performing 
any study-related procedures, the investigator (or designee) will obtain written informed consent 
from the subject.  
10.2 Study Procedures 
Assessments and their timings are to be performed as outlined in the Schedule of Assessments 
(Table 2). Section 12.6 specifies laboratory assessment samples to be obtained.  
Assessments and procedures scheduled at a visit where study drug is administered should be 
performed before administration of treatment unless otherwise indicated in the Schedule of 
Assessments (Table 2). 
Efficacy assessments are described in Section 11 and include PANSS and CGI-S scores. 
Safety assessments are described in Section 12 and include spontaneous AEs; AESIs, 
procholinergic and anticholinergic symptoms; cognition testing (CANTAB); SAS; BARS; 
AIMS; body weight; BMI; waist circumference; orthostatic vital signs; ECG; clinical laboratory 
assessments (hematology, clinical chemistry, coagulation, urinalysis, and drug screen); prolactin 
levels; physical examination; and C-SSRS. 
PK assessments are described in Section 13 and include estimation of AUC, Cmax, and Tmax. 
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 study drug. 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 after discussion with the 
medical monitor. 
Study discontinuation procedures are described in Sections 8.4 and 8.6. 
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11 EFFICACY ASSESSMENTS 
The Schedule of Assessments (Table 2) outlines the efficacy assessments to be performed 
throughout the study and their timing. 
11.1 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[22]. 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. The PANSS assessment includes the Marder Factor. 
It is recommended, if at all possible, that the PANSS assessment should be performed before all 
the other scale assessments (except MINI at screening) for all visits at which it is performed.  
11.2 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 modified CGI-S 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[23]. 
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 previous 7 days. 
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12 SAFETY ASSESSMENTS 
Safety assessments (spontaneous AEs; AESIs; procholinergic and anticholinergic symptoms; 
cognition testing [CANTAB]; SAS; BARS; AIMS; body weight; BMI; waist circumference; 
orthostatic vital signs; ECG; clinical laboratory assessments [hematology, clinical chemistry, 
coagulation, urinalysis, prolactin, and drug screen]; physical examination; and C-SSRS) are to be 
performed at protocol-specified visits, as specified in the Schedule of Assessments (Table 2). 
12.1 Demographics, and Medical 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 and psychiatric 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 12.7. All 
changes not present at baseline or described in the past medical history and identified as 
clinically noteworthy must be recorded as AEs. 
12.2 Vital Signs 
Orthostatic vital signs (systolic and diastolic BP and heart rate measurements) will be evaluated 
at the 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, beginning with Day 1, orthostatic vital signs should 
occur 2 (±1) hours after morning dosing. Orthostatic vital signs are only required after the 
morning dose of the specified visit days, but additional orthostatic vital sign monitoring is 
allowed at the investigator’s discretion. 
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. 
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12.3 Physical Examination 
A complete physical examination (body temperature, general appearance, 
head/eyes/ears/nose/throat, examination of thorax and abdomen, assessment of cardiac, 
musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited 
neurological examination) will be performed at visits as specified in Table 2. Physical 
examinations will be performed by a physician or qualified designee. 
12.4 Weight, Height, Body Mass Index, 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. 
12.5 Electrocardiograms 
A 12-lead, resting ECG will be obtained at the visits indicated in the Schedule of Assessments 
(Table 2). During the ECG, ventricular rate (bpm), PR (msec), QRS (msec), QT (msec), and 
QTcF (msec) measurements will be obtained. ECG at Day 1 will be performed 2 hours 
(+ 15 minutes) post morning dose. ECGs at all other scheduled visits will be performed before 
blood withdrawal for any safety laboratory tests and/or PK analysis. 
All the ECGs obtained will be interpreted by experienced independent blinded reader(s) at the 
central reading facility. 
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 on the eCRF. ECGs will be 
repeated if clinically significant abnormalities are observed or artifacts are present. 
12.6 Laboratory Assessments 
Laboratory assessment samples (Table 3) are to be obtained at designated visits as detailed in the 
Schedule of Assessments (Table 2). 
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Table 3. 
Laboratory Assessments 
Hematology 
Serum Chemistry 
Urine Analysis (Dipstick) 
Full and differential blood count 
Hct 
Hb 
MCH 
MCHC 
MCV 
Platelet count 
RBC count 
WBC count with differential 
ALT 
ALP 
AST 
Albumin 
Uric acid 
BUN or urea 
Carbon dioxide 
Creatinine 
Creatine kinase and subtypes 
Electrolytes (sodium, 
potassium, chloride, calcium, 
phosphorus) 
GGT 
Glucose 
LDH 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Triglycerides 
Total protein 
Appearance 
pH 
Protein 
Glucose 
Ketone bodies 
Indicators of blood and WBCs 
Specific gravity 
Urobilinogen 
Occult blood 
WBCs 
Prolactin 
Coagulation 
Serologya 
COVID-19 
PT 
Activated PTT 
Fibrinogen 
HBV 
HCV 
HIV 
 
Pregnancy test: A serum pregnancy test will be performed on all women of childbearing potential at 
screening and a urine pregnancy test (urine HCG) will be performed at other scheduled visits at the site. If a 
urine pregnancy test is positive, a serum sample should be sent to central laboratory for confirmation of the 
result. 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; GGT = gamma-glutamyl transpeptidase; Hb = hemoglobin; HBV = Hepatitis B; 
HCG = human chorionic gonadotropin; Hct = hematocrit; HCV = Hepatitis C; HIV = Human Immunodeficiency 
virus; LDH = lactate dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular 
hemoglobin concentration; MCV = mean corpuscular volume; PT = prothrombin time; PTT = partial 
thromboplastin time; RBC = red blood cell; WBC = white blood cell. 
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. 
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 urine volume of 10 mL will be obtained to perform urinalysis (if abnormalities 
observed on dipstick) and urine drug and alcohol screen at scheduled time points as per Table 2. 
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Blood and abnormal urine (microscopic analysis) samples will be analyzed at a central 
laboratory facility. Urine samples will first be analyzed by dipstick at the site. If the results of the 
dipstick indicate abnormalities to be further investigated, the sample will be sent to the central 
laboratory, and a microscopic analysis will be performed. All laboratory reports must be 
reviewed, signed, and dated by the investigator. A legible copy of all reports must be filed with 
both the subject’s eCRF and medical record (source document) for that visit. Any laboratory test 
result considered by the investigator to be clinically significant should be considered an AE 
(clinically significant AEs include those that require an intervention). Clinically significant 
abnormal values occurring during the study will be followed up with until repeat test results 
return to normal, stabilize, or are no longer clinically significant. 
All the study subjects will be closely monitored for drug-induced liver toxicity, detailed in 
Section 12.7.5, during the study. 
Other Laboratory Assessments: 
A National Institute on Drug Abuse-5 urine drug screen (cannabinoids or marijuana, 
phencyclidine, amphetamines, opiates, and cocaine) will be performed using a dipstick at 
screening and at Visit 2a (baseline). 
Alcohol testing is performed using a breathalyzer or urine alcohol test. 
If a subject leaves the study site, they should have a urine drug screen test and test for alcohol 
(breathalyzer or urine alcohol test) upon returning to the study site. 
 
Blood Sampling for Pharmacogenetics 
A blood sample may be collected at baseline (Day -1) for exploratory pharmacogenetic analysis. 
Approximately 9 mL of blood may be collected for subsequent DNA extraction. The samples 
will be stored at a central laboratory facility, where DNA will be extracted and retained. The 
collection, storage, shipping, processing of the blood samples, and the analytical methods to be 
used will be detailed in the laboratory manual.  
The genetic variants to be analyzed may include SNPs and any other variants as deemed 
necessary by the Sponsor.  
The details on the statistical analysis will be provided either in the statistical analysis plan (SAP) 
or the clinical study report. 
12.7 Adverse Events 
 
Adverse Events 
An AE is any symptom, physical sign, syndrome, or disease that either emerges during the study 
or, if present at screening, worsens during the study, regardless of the suspected cause of the 
event. All medical and psychiatric conditions (except those related to the indication under study) 
present at screening will be documented in the medical history eCRF. Changes in these 
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conditions and new symptoms, physical signs, syndromes, or diseases should be noted on 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 on 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 laboratory tests 
are available. 
Each AE is to be documented on the eCRF with reference to date of onset, duration, frequency, 
severity, relationship to study drug, action taken with study drug, treatment of event, and 
outcome. Furthermore, each AE is to be classified as being serious or nonserious. Changes in 
AEs and resolution dates are to be documented on the eCRF. 
For the purposes of this study, the period of observation for collection of AEs extends from the 
time immediately after the administration of study drug on Day 1 until the End of Study (Visit 10 
for subjects who roll over and Visit 11 for subjects who do not roll over to Study KAR-008 
study) or early termination. 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 study drug are given in 
Table 4 and Table 5. 
Table 4. 
Classification of Adverse Events by Intensity 
MILD: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with 
everyday activities. 
MODERATE: An event that is sufficiently discomforting to interfere with normal everyday activities. 
SEVERE: An event that prevents normal everyday activities. 
 
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Table 5. 
Classification of Adverse Events by Relationship to Study Drug 
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 study drug 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 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 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 reexposure to drug (if rechallenge occurs); and (4) it follows a known pattern 
of response to the test drug. 
Abbreviation: AE, adverse event. 
 
 
Adverse Events of Special Interest 
The AESIs will be monitored and include orthostasis and liver function test elevations inclusive 
of DILI. 
AEs of special interest should be recorded as AEs and reported as SAEs when appropriate. 
 
Serious Adverse Events 
A, 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 
(hospitalization for elective treatment of a pre-existing, nonworsening condition is not, 
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however, considered an SAE; the details of such hospitalizations must be recorded on the 
medical history or physical examination page of the eCRF), 
• results in persistent or significant disability/incapacity, and/or 
• is a congenital anomaly/birth defect. 
Other important medical events that may not be immediately life-threatening or result in death or 
hospitalization, based upon appropriate medical judgment, are considered SAEs if they are 
thought to jeopardize the subject and/or require medical or surgical intervention to prevent one 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 first dose of the study drug is administered, during the study, or 
within 1 week of stopping the treatment must be reported to the Catalyst Clinical Research 
Pharmacovigilance group and will be communicated to the Sponsor. Any such SAE due to any 
cause, whether or not related to the study drug, 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 is: 
 
The events must be recorded on the standard AE eCRF. Preliminary reports of SAEs must be 
followed up by detailed descriptions later on, including clear and anonymized photocopies of 
hospital case reports, consultant reports, autopsy reports, and other documents when requested 
and applicable. SAE reports must be made whether or not the investigator considers the event to 
be related to the investigational drug. 
Appropriate remedial measures should be taken to treat the SAE, and the response should be 
recorded. The investigator must report all additional follow-up evaluations to the Catalyst 
Clinical Research Pharmacovigilance group within 24 hours of becoming aware of the additional 
information or as soon as is practicable. All SAEs will be followed up until the investigator and 
Sponsor agree the event is satisfactorily resolved. 
Any SAE that is not resolved by the end of the study or upon discontinuation of the subject’s 
participation in the study is to be followed up until it either resolves, stabilizes, returns to 
baseline values (if a baseline value is available), or is shown to not be attributable to the study 
drug or procedures. 
 
Drug-Induced Liver Injury 
The sponsor has incorporated the following for monitoring of the drug induced liver injury: 
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• An increase of serum ALT or AST to >3 × upper limit of normal (ULN) should be 
followed by repeat testing within 48 to 72 hours of all 4 of the usual serum measures 
(ALT, AST, ALP, and total bilirubin) to confirm the abnormalities and to determine if 
they are increasing or decreasing. An inquiry should be made about the symptoms 
(fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, and rash). 
• Close observation should be initiated with ALT or AST >3 × ULN: 
o Repeat liver enzyme and serum bilirubin tests 2 or 3 times weekly. Frequency of 
retesting can decrease to once per week or less if abnormalities stabilize or the trial 
drug has been discontinued, and the subject is asymptomatic. 
o Obtain a more detailed history of symptoms and prior or concurrent diseases. 
o Obtain a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug 
use, and special diets. 
o Rule out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy; and biliary 
tract disease. 
o Obtain a history of exposure to environmental chemical agents. 
o Obtain additional tests to evaluate liver function, as appropriate (eg, international 
normalized ratio, direct bilirubin). 
o Consider gastroenterology or hepatology consultations. 
• Discontinuation of treatment should be considered if: 
o ALT or AST >8 × ULN 
o ALT or AST >5 × ULN for more than 2 weeks 
o ALT or AST >3 × ULN and (total bilirubin >2 × ULN or international normalized 
ratio >1.5) 
o ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or eosinophilia (>5%) 
• Hepatic adjudication of cases should include an evaluation for alternative causes such as 
viral, autoimmune, alcohol, hepatobiliary disorders, nonalcoholic steatohepatitis, 
concomitant medications, etc. 
• Follow up to resolution of elevated liver enzymes. 
• Gamma-glutamyl transpeptidase elevations alone should not prompt drug 
discontinuation. 
 
Trial Discontinuation Criteria Other than DILI and Pregnancy 
12.7.6.1 
Individual Stopping Criteria 
Based on NCI CTCAE v5.0, the 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 12.7.5) will be at the discretion of the investigator. 
12.7.6.2 
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: 
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a.
continue the clinical study without modification; or
b. continue the clinical study with modification (listing the specific modifications
recommended); or
c.
terminate the study.
Suspected Unexpected Serious Adverse Reactions 
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 or not an event is causally related to study treatment. The 
Sponsor (or their designee Syneos Health) will consider the investigator’s assessment and 
determine whether the event meets the criteria for being reportable as a 7-day or 15-day safety 
report. SUSARs that are fatal or life-threatening must be reported to the regulatory authorities 
and the IEC/IRBs (where required) within 7 days after the Sponsor (or their designee) 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 their designee) first has knowledge of them. 
The Sponsor (or their designee) 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 
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should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a 
patent airway should be promptly provided. 
Decreased Gastrointestinal Motility: 
Trospium should be administered with caution to subjects with GI obstructive disorders because 
of the risk of gastric retention. Trospium chloride, like other antimuscarinic agents, may decrease 
GI motility and should be used with caution in subjects with conditions such as ulcerative colitis, 
intestinal atony, and myasthenia gravis. 
Controlled Narrow-angle Glaucoma: 
In subjects being treated for narrow-angle glaucoma, trospium chloride should only be used if 
the potential benefits outweigh the risks and in that circumstance only with careful monitoring. 
Central Nervous System Effects: 
Trospium chloride is associated with anticholinergic CNS effects. A variety of CNS 
anticholinergic effects have been reported, including dizziness, confusion, hallucinations, and 
somnolence. Subjects should be monitored for signs of anticholinergic CNS effects, particularly 
after beginning treatment or increasing the dose. Advise subjects not to drive or operate heavy 
machinery until they know how trospium chloride affects them. If a subject experiences 
anticholinergic CNS effects, dose reduction or drug discontinuation should be considered. 
Anticholinergic Adverse Reactions in Subjects with Moderate Renal Impairment: 
Trospium is substantially excreted by the kidney. The effects of moderate renal impairment on 
systemic exposure are not known but systemic exposure is likely increased. Therefore, 
anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract 
infection, and urinary retention) are expected to be greater in subjects with moderate renal 
impairment. 
Elevation of liver enzymes: 
Elevated liver enzymes have been reported in previous studies of xanomeline alone in patients 
with Alzheimer’s disease. It is notable, however, that hepatic enzyme elevations were not 
observed in the Phase 1 studies in healthy volunteers, and that the liver function test elevations 
observed in the Phase 2 schizophrenia study (KAR-004) with KarXT (a combination of 
xanomeline and trospium) were quite limited in contrast to the effects observed with xanomeline 
in the elderly Alzheimer’s population. Moreover, even in patients with Alzheimer disease who 
experienced more hepatic enzyme elevations, the data demonstrate reversibility even with 
continued xanomeline treatment in those patients for whom 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. 
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Pregnancy 
WOCBP must have a negative pregnancy test at screening. 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 in female subjects will 
be reported until the subject completes or withdraws from the study. The pregnancy will be 
reported immediately by faxing/emailing a completed pregnancy report to the Sponsor (or 
designee) within 24 hours of knowledge of the event. The pregnancy will not be processed as an 
SAE; however, the investigator will follow-up with the subject until completion of the pregnancy 
and must assess the outcome in the shortest possible time but not more than 30 days after 
completion of the pregnancy. 
If a female subject becomes pregnant, the investigator must withdraw her from the study without 
delay. The subject must not receive any further doses of the study drug. 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 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 study 
drug. Overdose should be managed with symptomatic and supportive care. 
12.8 Cambridge Neuropsychological Test Automated Battery 
The computerized CANTAB provides an objective measure of cognitive function correlated to 
neural networks (Table 6). A short cognitive battery measuring core cognitive domains of 
impairment in schizophrenia (ie, as per Brief Assessment of Cognition Schizophrenia key 
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cognitive domains) will be employed for this study, and it will take approximately 30 minutes to 
complete. These CANTAB tests meet MATRICS workshop criteria[24]. Subjects will have 
1 familiarization session with the CANTAB tests during the screening visit and will 
subsequently complete the same test battery on Visits 2a (baseline), Visit 7, and Visit 9. Subjects 
perform the test on a provisioned iPad with data immediately uploaded to the CANTAB Connect 
cloud-based platform (WiFi permitting). 
Cognition testing cannot be done within 8 hours of receiving benzodiazepine or sleep 
medications. 
Table 6 
Cognitive Tests and Cognitive Domains Assessed by the Cambridge 
Neuropsychological Test Automated Battery 
CANTAB Tests 
MATRICS Cognitive Domain 
Outcome Measures 
Rapid visual information 
processing 
Sustained attention/vigilance 
A’ Prime: Signal detection 
measure of how good the subject is 
at detecting the target sequence 
(string of three numbers); 
regardless of response tendency 
Verbal recognition memory 
Verbal memory and new learning 
Free Recall: The total number of 
words that are correctly recalled 
from the presentation phase by the 
subject during the immediate free 
recall stage 
Spatial Span 
Working memory 
Forward Span Length: The 
longest sequence of boxes 
successfully recalled by the subject 
One-touch stockings of Cambridge  
Executive Function 
Planning/Problem Solving 
Problems Solved on First Choice: 
The total number of assessed trials 
where the subject chose the correct 
answer on their first attempt 
Abbreviation: CANTAB = Cambridge Neuropsychological Test Automated Battery 
12.9 Simpson-Angus 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. 
12.10 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[25]. 
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12.11 Abnormal Involuntary Movement Scale 
The AIMS is a rating scale that is used to measure involuntary movements know as tardive 
dyskinesia, which can sometimes develop as a side effect of long-term treatment with 
antipsychotic medications. It is a 12-item scale to assess orofacial, extremity, and truncal 
movements as well as the overall severity, incapacitation, and the subject’s level of awareness of 
the movements. Items are scored from 0 (none) to 4 (severe). A higher score indicates more 
severe dyskinesia. 
12.12 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[26]. 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 “lifetime” version 
will be completed; for all subsequent visits the “Since Last Visit” version of the C-SSRS will be 
administered. 
12.13 Functional Constipation Inquiry 
Constipation refers to bowel movements that are infrequent or hard to pass[27]. The stool is 
often hard and dry[28]. Other symptoms may include abdominal pain, bloating, and feeling as if 
one has not completely passed the bowel movement[29]. The normal frequency of bowel 
movements in adults is between 3 per day and 3 per week[27]. Constipation will be defined per 
the Rome III criteria, as less than 3 bowel movements per week, APPENDIX 2 
(Longswreth,1486,C3)[30]. 
The Bristol Stool Form Scale has been correlated with a change in intestinal function, and had 
been shown to be a useful tool in clinical practice and research[31]. A sample Bristol Stool Form 
Scale is located in APPENDIX 2. 
As a measure of anticholinergic effects, at each visit (except at Visit 2a), 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 and pain with bowel 
movements secondary to straining, abdominal pain, abdominal bloating, and the sensation of 
incomplete bowel evacuation[29,32]. 
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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. 
12.14 Mini International Neuropsychiatric Interview Version 7.0.2 
The MINI is a short structured diagnostic interview developed for DSM-5 psychiatric disorders. 
With an administration time of approximately 15 minutes, it was designed to meet the need for a 
short but accurate structured psychiatric interview for multicenter clinical studies and 
epidemiology. 
12.15 Change in Prolactin 
Blood samples to assess the change in prolactin levels will be obtained on Visit 2a/Day -1, 
Visit 7/Day 21 ± 2 days, and Visit 10/Day 35 -2 days/Early Termination (ET). At each of these 
visits (except Visit 2a), blood sample must be collected before the morning dose of the study 
drug. 
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13 PHARMACOKINETICS 
13.1 Pharmacokinetic Sampling 
 
Blood Samples 
Blood samples for PK analysis of KarXT levels will be collected at the time points indicated in 
the Schedule of Assessments (Table 2). Approximately 6 mL of blood to be collected at each 
scheduled time point. The actual date and time of each blood sample collection will be recorded. 
Serial blood samples to measure plasma concentrations of xanomeline and trospium will be 
obtained on Visit 5/Day 8 -1/+2 days (first dose of fixed titration period) and Visit 8/Day 
28 ± 2 days. Blood samples will be obtained at the following time points on these days: 
PK Sample 
Timing of Collection 
Collection Window 
1 
Before morning dose 
 
 
After morning dose 
 
2 
0.5 hours 
± 5 min 
3 
1 hour 
± 5 min 
4 
2 hours 
± 10 min 
5 
4 hours 
± 10 min 
6 
8 hours 
± 10 min 
7 
12 hours after (but before the 
evening dose) 
± 10 min 
 
It is very important that the exact time of each PK draw and dosing times are recorded in the 
eCRF and that PK samples are collected within the specified times of collection. 
Should the use of visit windows be necessary, serial PK sampling must accompany the actual 
day of potential dose escalation for Visit 5. 
For Visit 8, serial PK sampling is meant to capture the PK profile of the subject’s final KarXT 
dose level (125/30 or 100/20) after multiple doses. If visit windows are used for Visit 8, the PK 
sampling should occur at least 7 days after Visit 7 is completed, and there must be no changes in 
dose for at least 7 days leading up to Visit 8. PK sampling must accompany the actual day of 
Visit 8. 
Note: A single PK sample should be drawn before discharge (preferably in the morning after the 
last dose of the study drug) at Visit 10/Day 35 -2 days or ET. In addition, one PK sample may be 
drawn if a relevant/significant AE is reported during a scheduled visit or if there is a dose 
adjustment or relevant/significant AE reported during an unscheduled visit (no multiple draws). 
For an ET Visit that is related to an AE, the collection of a PK blood sample is not optional and 
should be drawn before discharge. 
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Details of PK blood sample collection, processing, storage, and shipping procedures will be 
provided in a separate laboratory manual. 
13.2 Pharmacokinetic Analytical Methodology 
Concentrations of trospium and xanomeline will be determined from plasma PK samples using a 
validated analytical method. Details of the method validation and sample analysis will be 
included with the final clinical study report. 
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14 STATISTICAL ANALYSIS 
A 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 compliment to the protocol and supersedes it in case of 
differences. 
The statistical evaluation will be performed using SAS® software version 9.4 or higher 
(SAS Institute, Cary, NC). All data will be listed, and summary tables will be provided. 
Summary statistics will be presented by dose group. For continuous variables, data will be 
summarized with the number of subjects (N), mean and standard deviation, median, minimum, 
and maximum by treatment group. For categorical variables, data will be tabulated with the 
number and proportion of subjects for each category by treatment group. 
14.1 Determination of Sample Size 
Assuming treatment difference of change from baseline in PANSS total score at Week 5 is 
8 points between drug and placebo (standard deviation 16), a sample size of approximately 
172 (86 evaluable subjects per arm) will result in a power of 90.3% for a 2-sided alpha of 0.05 
(P ≤ 0.05). With a dropout rate of 30%, a total of 246 subjects are estimated to be enrolled. 
14.2 Analysis Populations 
Intent-to-Treat Population 
All subjects who are randomized to the study will be included in the intent-to-treat (ITT) 
population. 
Modified ITT Population 
All subjects who are randomized, received at least 1 dose of study drug, have a baseline PANSS 
assessment, and at least 1 post-baseline PANSS assessment will be included in the mITT 
population and will be used in the efficacy analysis. 
Safety Population 
All subjects who received at least 1 dose of study drug will be included in the safety population 
and will be used in the safety analysis. 
PK Population 
All subjects who have an evaluable PK profile will be included in the PK population and will be 
used in the PK analysis. Subjects must have received at least 1 dose of active study drug and 
have at least 1 measurable plasma concentration of study drug.  
14.3 General Statistical Considerations 
All efficacy analyses will be performed using the mITT population. The statistical analysis of the 
primary and key secondary efficacy variables will account for multiplicity by using a fixed 
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sequence testing procedure. The primary endpoint of change from baseline to Week 5 in PANSS 
total score will be evaluated first. The endpoints are set up as a hierarchical list and step down 
through the statistical testing of each endpoint using an alpha of 0.05. Statistical testing of 
change from baseline to Week 5 in PANSS positive score, PANSS negative score, and PANSS 
Negative Marder Factor score, CGI-S score at Week 5, and percentage of PANSS responders 
will be performed only if the primary endpoint is significant at the 0.05 alpha level (P ≤ 0.05), 
and testing would continue through a pre-ordered list of key secondary efficacy endpoints. If at 
any point P > 0.05, then formal statistical testing would stop. This will control the overall Type 1 
error rate across all hypotheses/endpoints being tested. Table 7 outlines the testing procedure. 
Table 7 
Statistical Testing Procedure 
KarXT vs Placebo 
1. Change from baseline in PANSS total score at Week 5 
2. Change from baseline in PANSS positive score at Week 5 
3. Change from baseline in PANSS negative score at Week 5 
4. Change from baseline in PANSS Negative Marder Factor score at Week 5 
5. CGI-S score at Week 5 
6. Percentage of PANSS responders (a 30% change in PANSS total score) at Week 5 
 
14.4 Efficacy Analysis 
 
Primary Estimand 
The population of the primary estimand is among adult inpatients (aged 18-65 years) with a 
DSM-5 diagnosis of schizophrenia, confirmed by MINI for schizophrenia, who are acutely 
psychotic and hospitalized with PANSS score of 80 to 120 at time of enrollment, defined 
according to the inclusion/exclusion criteria. Subjects will receive flexible dose KarXT, whereby 
a subject receiving 100/20 (xanomeline 100 mg/trospium 20 mg) may be titrated upwards to 
KarXT 125/30 on Day 8. All subjects who are increased to 125/30 BID will have the option to 
return to KarXT 100/20, but may not change their dose after Visit 7 (Day 21) or decrease their 
dose for tolerability reasons more than once. The primary analysis will be executed on the mITT 
population, including all subjects with a baseline and at least 1 post-baseline PANSS 
measurement, grouped as randomized. 
The variable is the change from baseline in PANSS total score at Week 5. 
Intercurrent events: 
• Discontinuation from study treatment prior to the completion of the 5 weeks of efficacy 
assessments: While on treatment strategy where efficacy results recorded prior to subject 
discontinuation from the study will be included in the analysis 
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• Use of concomitant medication for anxiety and/or sleep aid: Treatment policy strategy 
where results will be used regardless of concomitant medications for anxiety and/or sleep 
aid 
The population level summary is the difference between treatment groups (KarXT vs placebo) in 
mean change from baseline in PANSS at Week 5, obtained from a mixed model repeated 
measures (MMRM). 
Robustness of the estimand will be assessed through sensitivity analyses using alternative 
methods for handling of missing data and accounting for use of concomitant medications for 
anxiety and/or sleep aid (eg, subgroup by use of concomitant medication or including use of such 
concomitant medications as time-varying covariate in the MMRM). 
 
Analysis of the Primary Efficacy Endpoint 
The primary efficacy endpoint of the study is the change from baseline in PANSS total score at 
Week 5. The difference between KarXT and placebo at Week 5 will be estimated using an 
MMRM. The model will include the change from baseline PANSS total scores at Week 2, Week 
3, Week 4, and Week 5 as the response. Within-subject correlation will be accounted for using 
an unstructured covariance matrix. Fixed effects will include the treatment group (KarXT or 
placebo), visit, and the interaction between the treatment group and visit, site, age, sex, and 
baseline PANSS total score. Low-enrolling sites may be pooled, if necessary, for modeling 
purposes. The algorithm for pooling sites will be specified in the SAP. 
Sensitivity analyses of the primary efficacy endpoint may be performed on an observed case 
basis, using multiple imputation techniques, and classifying treatment dropouts as treatment 
failures. Alternative time-varying parameterizations of dose level and use of concomitant 
medication for anxiety and/or sleep aid may also be included in sensitivity analyses. In addition, 
alternative covariance matrices for the MMRM may be investigated. The sensitivity analyses of 
the primary endpoint will be specified in the SAP. 
 
Analysis of Secondary Efficacy Endpoints 
The continuous secondary endpoints (change from baseline to Week 5 in PANSS positive score, 
PANSS negative score, PANSS Negative Marder Factor score, and CGI-S) will be analyzed in 
the same manner as the primary efficacy analysis (ie, using MMRM). 
The categorical secondary endpoint (percentage of PANSS responders at Week 5) will be 
compared between the treatment groups (KarXT and placebo) using the Cochran-Mantel-
Haenszel test. 
The statistical analysis of the primary and key secondary efficacy variables will account for 
multiplicity by using a fixed sequence testing procedure. This testing procedure will control the 
overall Type 1 error rate across all hypotheses/endpoints being tested. 
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14.5 Safety Analysis 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities version 
22.1 or higher. The incidence of TEAEs (events with onset dates on or after the start of the study 
drug) will be summarized for each treatment group separately by System Organ Class and 
Preferred Term. All AEs will be listed by subject, along with information regarding onset, 
duration, relationship and severity to study drug, action taken with study drug, treatment of 
event, and outcome. 
Orthostatic vital signs, clinical laboratory data, prolactin levels, ECG parameters, and physical 
examinations will be summarized using descriptive statistics, including observed and change 
from baseline values, as well as numbers of subjects with values outside limits of the normal 
range at each time point by treatment group. Similar descriptive summaries will be provided for 
SAS, BARS, change in cognition (CANTAB), AIMS, body weight, BMI, and waist 
circumference. 
14.6 Pharmacokinetic Analysis 
PK results will be listed for all subjects who received active treatment. The profiles or time 
points obtained with protocol deviations affecting PK results will be flagged and may be 
excluded from summaries and analyses. 
The data will be presented graphically via individual plots and mean plots summarized by actual 
treatment, visit, and time point.  
PK parameters for xanomeline and trospium will be derived from plasma concentration data 
using noncompartmental methods. Actual time elapsed from dosing will be used to estimate all 
individual PK parameters. The primary PK parameters of interest will include Cmax, Tmax, and 
AUC from 0 to 12 hours (or from 0 to the last measurable concentration). Additional parameters 
(not limited to the following) such as the elimination half-life, clearance, and volume of 
distribution will be determined if the data permit. 
The effect of dose on PK and other inferential analyses for exposure-response relationship may 
be performed. The details of the PK analysis will be described in the SAP. The 
noncompartmental analysis will be described as a part of final clinical study report. 
14.7 Interim Analysis  
No interim analysis is planned for this study. 
14.8 Handling of Missing Data 
Several different methods to handle the missing data in the primary efficacy endpoint analysis 
may be used. 
• For the primary efficacy analysis, likelihood-based modeling approach will be used to 
handle incomplete data. For this purpose, an MMRM will be applied. 
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• Sensitivity analysis for the primary efficacy endpoint will be conducted using the last 
observation carried forward approach. In this analysis, the missing values will be 
replaced by the previous visit PANSS total score carried forward. 
• Sensitivity analysis for the primary efficacy endpoint will be conducted using the 
Multiple Imputation approach (ie, by replacing each missing value with a set of plausible 
values that represent the uncertainty about the right value to impute). 
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15 STUDY MANAGEMENT 
15.1 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. 
Independent Ethics Committee/Institutional Review Board 
Conduct of the study must be approved by an appropriately 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 principal investigator 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 principal 
investigator 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 caregiver informed consent (Ukraine only) should be obtained before any data pertaining to 
him or her and the subject is collected. 
Subject Registry (for the US only): 
Clinical trial registries, such as clinical trial subject database (CTSdatabase) and Verified 
Clinical Trials (VCT), seek to reduce duplicate enrollment by identifying potential protocol 
violations and duplicate subjects before randomization. At the time of providing the informed 
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 screening visit, following informed consent and before any 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 reports will 
detail each protocol violation detected and specific washout period dates where applicable. 
Participants who are identified as verification failures by CTS or VCT should not be enrolled 
without documented approval from Karuna or Syneos Health. 
At the last subject contact, CTSdatabase and VCT staff will automatically close out the subject 
(safety follow-up, ET, or completer) based on interactive response system (IXRS). 
15.2 Data Handling 
Any data to be recorded directly on the eCRFs (to be considered as source data) will be 
identified at the start of the study. Data reported on the eCRF that are derived from source 
documents should be consistent with the source documents, or the discrepancies must be 
explained. See also Section 15.3. 
Clinical data will be entered by site personnel on eCRFs for transmission to the Sponsor. Data on 
eCRFs transmitted via the web-based data system must correspond to and be supported by source 
documentation maintained at the study site, unless the study site makes direct data entry to the 
databases for which no other original or source documentation is maintained. In such cases, the 
study site should document which eCRFs are subject to direct data entry and should have in 
place procedures to obtain and retain copies of the information submitted by direct data entry. 
All study forms and records transmitted to the Sponsor must only include coded identifiers such 
that directly identifying personal information is not transmitted. The primary method of data 
transmittal is via the secure, internet-based electronic data capture (EDC) system maintained by 
Syneos Health. Access to the EDC system is available to only authorized users via the study’s 
secured internet web site, where a user unique assigned username and password are required for 
access. 
Any changes made to data after collection will be made through the use of the EDC system. 
Electronic CRFs will be considered complete when all missing and/or incorrect data have been 
resolved. 
15.3 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 onto eCRFs. Copies of completed eCRFs 
will be provided to the Sponsor and the sites at the end of the study. The completed eCRFs will 
be retained by the investigator. 
15.4 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 
Health Insurance Portability Accountability Act of 1996 [HIPAA] 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. 
15.5 Monitoring 
The study will be monitored according to the KAR-009 monitoring plan to ensure that it is 
conducted and documented properly according to the protocol, GCP, and all applicable 
regulatory requirements. 
Monitoring visits, on-site and remote (telephone) or a combination and contacts will be made at 
appropriate times during the study. The Principal Investigator will assure him/her and adequate 
site personnel are available throughout the study to collaborate with clinical monitors. Clinical 
monitors must have direct access to source documentation in order to check the completeness, 
clarity, and consistency of the data recorded in the eCRFs for each subject. 
The investigator will make available to the clinical monitor all source documents and medical 
records necessary to review protocol adherence and eCRFs. In addition, the investigator will 
work closely with the clinical monitor and, as needed, provide them appropriate evidence that the 
study is being conducted in accordance with the protocol, applicable regulations, and GCP 
guidelines. 
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15.6 Quality Control and Quality Assurance 
The Sponsor or its designee will perform the quality assurance and quality control activities of 
this study; however, responsibility for the accuracy, completeness, security, and reliability of the 
study data presented to the Sponsor lies with the investigator generating the data. 
The Sponsor will arrange audits as part of the implementation of quality assurance to ensure that 
the study is being conducted in compliance with the protocol, standard operating procedures, 
GCP, and all applicable regulatory requirements. Audits will be independent of and separate 
from the routine monitoring and quality control functions. Quality assurance procedures will be 
performed at study sites and during data management to assure that safety and efficacy data are 
adequate and well documented. 
15.7 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. 
15.8 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. 
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IECs/IRBs will review and approve this protocol and the ICF. All subjects and/or caregivers are 
required to give written informed consent before participation in the study. 
15.9 Financing and Insurance 
Before the study commences, the Sponsor (or its designee) and the investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study. This agreement will 
be documented in a financial agreement that will be signed by the investigator (or the institution 
signatory) and the Sponsor (or its designee). 
The investigator is required to have adequate current insurance to cover claims for negligence 
and/or malpractice (US only). The Sponsor will provide no-exclusion insurance coverage for the 
clinical study as required by national regulations. 
15.10 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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16 REFERENCES 
 
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Brannan SK, Paul SM and Breier A. Xanomeline plus trospium: A novel strategy to 
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Buchanan RW, Davis M, Goff D, et al. A summary of the FDA-NIMH-MATRICS 
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Functional bowel disorders. Gastroenterology. 2006 Apr;130(5):1480–1491. 
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Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
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Locke GR III, Pemberton JH, Phillips SF. American Gastroenterological Association 
Medical Position Statement: guidelines on constipation. Gastroenterology. 2000 
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17 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 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[1]. 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. 
A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
Highly effective methods of contraception are those that have a failure rate of <1% (when 
implemented consistently and correctly) and include the following: 
•
combined (containing estrogen and progestogen) hormonal contraception associated with
inhibition of ovulation (administration may be oral, intravaginal, or transdermal)
•
progestogen-only hormonal contraception associated with inhibition of ovulation
(administration may be oral, injectable, or implantable)
•
intrauterine device
•
intrauterine hormone-releasing system
•
bilateral tubal ligation or occlusion
•
vasectomy (provided that the male has a medical assessment of surgical success)
All subjects will be strongly advised that they (or the female partners of male subjects) should 
not become pregnant before receiving study drug on Day 1 and continuing until 30 days after the 
last dose of study drug. A female subject will be advised that she must report immediately to the 
study site for pregnancy testing and appropriate management in the event that she may be 
pregnant. 
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APPENDIX 2. 
FUNCTIONAL CONSTIPATION INQUIRY 
 
 
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