Clinical trial NCT03697252
Conditions: Schizophrenia
Keywords: Schizophrenia
Sponsor: Karuna Therapeutics
Start date: 2018-09-18; Completion date: 2019-09-04
Enrollment: 182 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Xanomeline and Trospium Chloride Capsules intervention 2: Placebo Capsules
Intervention descriptions: intervention 1: Xanomeline 50 mg/trospium 20 mg BID on days 1-2 followed by xanomeline 100 mg/trospium 20 mg BID on days 3-7. The dose is increased to xanomeline 125 mg/trospium 30 mg BID on days 8-34 unless the subject is experiencing adverse events from the xanomeline 100 mg/trospium 20 mg dose. Subjects who were increased to xanomeline 125 mg/trospium 30 mg will have the option to return to xanomeline 100 mg/trospium 20 mg depending on clinical response and tolerability. Dosing must not change after Visit 7 of the study (at 21 ± 2 days of dosing) and may be decreased for tolerability reasons no more than once during the study. intervention 2: Placebo Capsules

Protocol documents:
Prot_000.pdf: 
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A Phase 2, Randomized, Double-blinded Study to Assess the Safety, 
Tolerability, and Efficacy of KarXT in Hospitalized Adults with DSM-5
Schizophrenia 
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NCT03697252


Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 2 of 127
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Karuna Pharmaceuticals 
13 Dec 2018 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 4 of 127
3
SYNOPSIS 
Protocol Number: 
KAR-004
Title: 
A Phase 2, Randomized, Double-blinded Study to Assess the Safety, Tolerability, and Efficacy of KarXT 
in Hospitalized Adults with DSM-5 Schizophrenia 
Investigational Product:
KarXT 
Study Centers: 
Approximately 12 study centers in the United States
Phase: 
Phase 2 
Objectives: 
Primary objective: 
The primary objective of the study is to assess the efficacy of KarXT (a fixed combination of xanomeline 
and trospium chloride) (xanomeline 125 mg/trospium 30 mg twice daily [BID]) versus placebo in 
reducing Positive and Negative Syndrome Scale (PANSS) total scores in adult inpatients with a 
Diagnostic and Statistical Manual‒Fifth Edition (DSM-5) diagnosis of schizophrenia. 
Secondary objectives:  
The secondary objectives of the study are to assess overall safety and tolerability of KarXT in adult 
inpatients with a DSM-5 diagnosis of schizophrenia: 
x
To assess spontaneously reported adverse events (AEs) in subjects treated with KarXT versus 
placebo 
x
To assess spontaneously reported cholinergic symptoms in subjects treated with KarXT versus 
placebo 
x
To assess orthostatic vital signs in subjects treated with KarXT versus placebo 
x
To assess electrocardiogram (ECG) parameters in subjects treated with KarXT versus placebo 
x
To assess reduction of PANSS positive score in subjects treated with KarXT versus placebo 
x
To assess reduction of PANSS Marder Factor score in subjects treated with KarXT versus 
placebo 
x
To assess the pharmacokinetics (PK) of xanomeline and trospium following administration of 
KarXT in adult subjects with a DSM-5 diagnosis of schizophrenia 
x
To assess Clinical Global Impression-Severity (CGI-S) results in subjects with KarXT versus 
placebo 
Study Design: 
The study will be an inpatient study in adult subjects with DSM-5 schizophrenia. Subjects will be 
randomized to receive either placebo or KarXT (xanomeline 125 mg/trospium 30 mg BID) for a treatment 


Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 5 of 127
period of 5 weeks. Subjects will start on a lead-in dose of xanomeline 50 mg/trospium 20 mg 2 times per 
day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of 
Week 1 (Days 3 to 7). On Day 8, dosing will be titrated upwards to xanomeline 125 mg/trospium 30 mg 
BID unless the subject is continuing to experience AEs from the previous dose increase of xanomeline 
100 mg/trospium 20 mg BID. All subjects who were increased to xanomeline 125 mg/trospium 30 mg 
BID, depending on clinical response and tolerability, will have the option to return to xanomeline 
100 mg/trospium 20 mg BID for the remainder of the treatment period. Dosing must not change after 
Visit 7 of the study and may be decreased for tolerability reasons no more than once during the study.
Number of Subjects:  
A total of approximately 180 subjects planned to be randomized in a 1:1 ratio to either KarXT or placebo. 
Treatment: 
x
Fixed dose Xanomeline 50 mg/Trospium 20 mg BID, oral 
x
Fixed dose Xanomeline 100 mg/Trospium 20 mg BID oral 
x
Fixed dose Xanomeline 125 mg/Trospium 30 mg BID oral 
x
Matching placebo BID oral 
Study Duration: 
Total study duration is up to 7 weeks, including a 7-day screening phase (up to a 7-day extension of the 
screening phase is allowed, if necessary) and a 5-week treatment period. 
Inclusion Criteria: 
1.
Subject is aged 18-60 years, inclusive, at screening. 
2.
Subject has a primary diagnosis of schizophrenia established by a comprehensive psychiatric 
evaluation based on the DSM-5 (American Psychiatric Association 2013) criteria and confirmed 
by Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorder 
Studies (MINI) version 7.0.2. 
3.
Subject is experiencing an acute exacerbation or relapse of symptoms, with onset less than 
2 months before screening. 
a.
The subject requires hospitalization for this acute exacerbation or relapse of 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. 
4.
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) 
5.
There should not be a change (improvement) in PANSS total score between screening and 
baseline of more than 20%. 
6.
Subject will have been off lithium therapy for at least 2 weeks before baseline and free of all oral 
antipsychotic medications for at least 2 weeks before baseline. 
7.
Subjects taking a depot antipsychotic could not have received a dose of medication for at least 
1 and a half injection cycles before baseline (eg, 3 or more weeks off for a 2-week cycle). 
8.
Subject is capable of providing informed consent. 
a.
A signed informed consent form must be provided before any study assessments are 
performed. 
b.
Subject must be fluent (oral and written) in English to consent 
9.
Subject is willing and able to be confined to an inpatient setting for the study duration, follow 
instructions, and comply with the protocol requirements. 
10. Subject has a CGI-S score of ≥ 4 at screening and baseline visits. 
11. Body mass index (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. 


Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
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13. Both females of child-bearing potential and males with partners of child-bearing potential must 
be willing to use a double-barrier method of birth control (ie, any double combination of male or 
female condom with spermicidal gel, diaphragm, sponge, or cervical cap with spermicidal gel) 
during the study and for 7 days after the last dose of study drug.  
14. Subject has an identified reliable informant. An informant 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 may not be necessary if the subject has 
been the patient of the investigator for ≥ 1 year.
Exclusion Criteria 
1. Any primary DSM-5 disorder other than schizophrenia within 12 months before screening 
(confirmed using MINI version 7.0.2 at screening). 
2. History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, 
gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or oncologic disease or any 
other condition that, in the opinion of the investigator, would jeopardize the safety of the subject 
or the validity of the study results, to exclude patients with human immunodeficiency virus 
(HIV), cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma, and/or active hepatic viral 
infections based on the liver function test results. 
3. History or high risk of urinary retention, gastric retention, or narrow-angle glaucoma. 
4. History of irritable bowel syndrome (with or without constipation) or serious constipation 
requiring treatment within the last 6 months 
5. Has a DSM-5 diagnosis of moderate to severe substance abuse disorder (except tobacco use 
disorder) within the 12 months before screening (confirmed using MINI version 7.0.2 at 
screening), or current abuse as determined by urine toxicology screen or alcohol test. A
screening subject with mild substance abuse disorder within the 12 months before screening 
must be discussed and agreed upon with the medical monitor before he/she can be allowed into 
the study. 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. 
6. Risk for suicidal behavior during the study as determined by the investigator’s clinical assessment 
and Columbia Suicide Severity Rating Scale (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 2 weeks of baseline) be receiving oral antipsychotic medications, 
MAO 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. Sperm donation is not allowed for 90 days 
after the final dose of study drug. 
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 their ability to adhere to the protocol visit 
schedule or fulfill visit requirements.
11. Subject has had psychiatric hospitalization(s) for more than 30 days (cumulative) during the 
90 days before screening. 
12. 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. 
13. Risk of violent or destructive behavior. 
14. Current involuntary hospitalization or incarceration. 
15. Participation in another clinical study in which the subject received an experimental or 
investigational drug agent within 3 months of screening. 


Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 9 of 127
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Visit 9 (Day 35 í 2 days; After 5 Weeks of DoubleEOLQG
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 10 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 11 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 12 of 127 
5
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation
Definition
AE
adverse event
AESI
adverse event of special interest
AIMS
Abnormal Involuntary Movement Scale
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
BID
twice daily
BMI
body mass index
CFR
Code of Federal Regulations
CGI-S
Clinical Global Impression‒Severity
C-SSRS
Columbia-Suicide Severity Rating Scale
DILI
drug-induced liver injury 
DSM-5
Diagnostic and Statistical Manual‒Fifth Edition
EDC
electronic data capture
ECG
electrocardiogram
eCRF
electronic case report form
ET
early termination
FDA
US Food and Drug Administration
GCP
Good Clinical Practice
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IWRS
interactive web response system
MCC
microcrystalline cellulose
MINI
Mini International Neuropsychiatric Interview
MMRM
mixed model for repeated measures
PANSS
Positive and Negative Syndrome Scale
PK
pharmacokinetic
SAE
serious adverse event
SAP
statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
ULN
upper limit of the normal range


Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 13 of 127 
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INTRODUCTION
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(or other indications such as Alzheimer’s disease) KDVEHHQRXWZHLJKHGE\WKH
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 14 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 17 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 20 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 21 of 127 
7
STUDY OBJECTIVES AND ENDPOINTS 
7.1
Objectives 
7.1.1
Primary Objective 
The primary objective of the study is to assess the efficacy of KarXT (a fixed 
combination of xanomeline and trospium chloride; xanomeline 125 mg/trospium 
30 mg) versus placebo in reducing PANSS total score in adult inpatients with a 
Diagnostic and Statistical Manual‒Fifth Edition (DSM-5) diagnosis of schizophrenia. 
7.1.2
Secondary Objectives 
The secondary objectives of the study are to assess overall safety and tolerability of 
KarXT in adult inpatients with a DSM-5 diagnosis of schizophrenia: 
x
To assess spontaneously reported AEs in subjects treated with KarXT versus 
placebo 
x
To assess spontaneously reported cholinergic symptoms in subjects treated with 
KarXT versus placebo 
x
To assess orthostatic vital signs in subjects treated with KarXT versus placebo 
x
To assess ECG parameters in subjects treated with KarXT versus placebo 
x
To assess reduction of PANSS positive score in subjects treated with KarXT 
versus placebo 
x
To assess reduction of PANSS Marder Factor score in subjects treated with 
KarXT versus placebo 
x
To assess the pharmacokinetics (PK) of xanomeline and trospium following 
administration of KarXT in adult subjects with a DSM-5 diagnosis of 
schizophrenia 
x
To assess Clinical Global Impression‒Severity (CGI-S) scale results in subjects 
with KarXT versus placebo 
7.2
Endpoints 
7.2.1
Primary Endpoint 
x
Change in PANSS total score at Week 5 
7.2.2
Secondary Endpoints
x
Efficacy Endpoints: 


Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 22 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 23 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 24 of 127 
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. 


Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 25 of 127 
8.1.1
Study Design 
Phase:
Screening
Inpatient Treatment
End of 
Treatment
Day:
Day -7 to -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 35 −2
days
Visit:
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Xanomeline/ 
trospium 
(KarXT):
N/A
50 mg/20 
mg BID
100 mg/20 
mg BID
100 mg/20 
mg BID
125 mg/30 
mg BID
(Option: 100 
mg/20 mg 
BID)a
125 mg/30 
mg BID
(Option: 100 
mg/20 mg 
BID)a
125 mg/30 
mg BID
(Option: 100 
mg/20 mg 
BID)a
125 mg/30 
mg BID
(Option: 100 
mg/20 mg 
BID)b
N/A
Comment:
Up to a 7-day 
extension to 
the screening 
phase is 
allowed.
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)
BID = twice daily. 
a 
All subjects who were increased to xanomeline 125 mg/trospium 30 mg, depending on clinical response and tolerability, will have the option to return to 
xanomeline 100 mg/trospium 20 mg 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 xanomeline and trospium at Visit 7. 


Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 26 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 27 of 127 
7DEOH
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 28 of 127 
PROCEDURE 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 29 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 30 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 31 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 32 of 127 
2. 
The investigator will be provided with a Study Site Binder for storing study 
related regulatory and study site documentation; eg, study logs and forms. 
3. 
The investigator must review all eCRF entries for completeness and accuracy.  
4. 
Periodic monitoring visits will be conducted on a regular basis by the Sponsor or 
designee in order to verify the accuracy of data entered on each eCRF against the 
raw data from source documents at the site. Items needing correction/clarification 
will be identified and brought to the attention of the study site personnel and 
principal investigator, and corrections will be made as appropriate. 
5.  
The Sponsor or designee will perform a final review and data management of the 
eCRF. The study database will be validated using appropriate validation processes. 
6. 
The Sponsor or designee may perform a regulatory audit of the study site, and 
may include a complete review of the overall study conduct, regulatory 
documentation, and selected subject eCRFs and source documents. 
8.3
Selection of Study Population 
8.3.1
Number of Planned Subjects  
A total of approximately 180 study subjects and approximately 12 sites in the United 
States are planned. Subjects who are randomized into the double-blind treatment phase 
but discontinue or withdraw will not be replaced. 
8.3.2
Inclusion Criteria 
To be eligible for enrollment, subjects must satisfy all of the following criteria: 
Subject is aged 18-60 years, inclusive, at screening. 
1.
Subject has a primary diagnosis of schizophrenia established by a comprehensive 
2.
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. 
Subject is experiencing an acute exacerbation or relapse of symptoms, with onset 
3.
less than 2 months before screening. 
a.
The subject requires hospitalization for this acute exacerbation or relapse of 
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. 
Positive and Negative Syndrome Scale total score between 80 and 120, inclusive, at 
4.
screening. 
a.
Score of ≥4 (moderate or greater) for ≥ 2 of the following Positive Scale (P) 
items at screening: 
i. Item 1 (P1; delusions) 
ii. Item 2 (P2; conceptual disorganization) 
iii. Item 3 (P3; hallucinatory behavior) 
iv. Item 6 (P6; suspiciousness/persecution) 


Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 33 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 34 of 127 
Has a DSM-5 diagnosis of moderate to severe substance abuse disorder (except 
5.
tobacco use disorder) within the 12 months before screening (confirmed using MINI 
version 7.0.2 at screening), or current abuse as determined by urine toxicology 
screen or alcohol test. A screening subject with mild substance abuse disorder 
within the 12 months before screening must be discussed and agreed upon with the 
medical monitor before he/she can be allowed into the study. 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. 
Risk for suicidal behavior during the study as determined by the investigator’s
6.
clinical assessment and the 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.
Clinically significant abnormal finding on the physical examination, medical history, 
7.
ECG, or clinical laboratory results at screening. 
Subjects cannot currently (within 2 weeks of baseline) be receiving oral 
8.
antipsychotic medications, MAO inhibitors, anticonvulsants (eg, lamotrigine, 
Depakote), tricyclic antidepressants (eg, imipramine, desipramine), selective 
serotonin reuptake inhibitors, or any other psychoactive medications except for 
anxiolytics (eg, lorazepam, chloral hydrate) taken as needed.  
Pregnant, lactating, or less than 3 months postpartum. Sperm donation is not 
9.
allowed for 90 days after the final dose of study drug. 
If, in the opinion of the investigator (and/or Sponsor), subject is unsuitable for 
10.
enrollment in the study or subject has any finding that, in the view of the 
investigator (and/or Sponsor), may compromise the safety of the subject or affect 
their ability to adhere to the protocol visit schedule or fulfill visit requirements. 
Subject has had psychiatric hospitalization(s) for more than 30 days (cumulative) 
11.
during the 90 days before screening. 
Subject has a history of treatment resistance to schizophrenia medications defined as 
12.
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. 
Risk of violent or destructive behavior. 
13.
Current involuntary hospitalization or incarceration. 
14.
Participation in another clinical study in which the subject received an experimental 
15.
or investigational drug agent within 3 months of screening. 
8.3.4
Removal of Subjects from Therapy or Assessments 
The availability of any new adverse safety information related to KarXT may result in 
stopping the study. An investigator, Sponsor, or Institutional Review Board (IRB) may 
take such actions. If the study is terminated for safety reasons, subjects will be notified 
immediately and assured that appropriate treatment and follow-up will be available. If 
an investigator terminates the study, the Sponsor, subjects, and IRB will be informed 


Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 35 of 127 
about the reason for such action. Similarly, if the Sponsor terminates the study, it will 
inform the investigators, the IRB, and the subjects of the reason for such an action. 
Similar notifications will be sent by the IRB if it takes such an action. 
8.3.5
Subject Withdrawal 
Subjects who are randomized into the double-blind treatment phase but then discontinue 
or withdraw will not be replaced.  
Subjects may withdraw from the study at any time as stated in the ICF (given to the 
subject at the time of enrollment) and without prejudice to further treatment. Subjects 
may be withdrawn or be discontinued from the study by the study investigator or the 
Sponsor for the following reasons: 
1. 
Violation of entry criteria; ie, subjects who are enrolled but are later discovered 
not to meet entry criteria 
2. 
Adverse event(s) 
3. 
Protocol noncompliance (eg, if a study subject is off study drug for >5 days in a 
row). 
4. 
Pregnancy (females of childbearing potential). 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. 
5. 
Development of suicidal or assaultive behavior 
6. 
Alcohol or illegal drug use 
7. 
Development of an intercurrent systemic illness requiring significant medical 
intervention or a clinically significant change in laboratory testing as per the 
investigator. 
8.
Sponsor’s decision to discontinue study
9. 
Subject withdraws consent 
10. 
Subject has need for a medication prohibited by the protocol. 
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 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 


Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 36 of 127 
treatment of subjects impossible. In this event, the investigator(s) will be informed of 
the reason for study termination. 
The reason for withdrawal or discontinuation must be recorded on the subject’s eCRFs. 
If a subject discontinues the study prematurely, for any reason, all procedures that 
would have been completed at the study discharge should be performed before subject 
study discontinuation, and the termination eCRF is to be completed. 
All subjects withdrawn from the study because of an emergent adverse experience will 
continue to be followed until the AE(s) resolve or stabilize. 
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, participation of women of childbearing potential in this study must be 
willing to use a double-barrier method of birth control (ie, any double combination of 
male or female condom with spermicidal gel, diaphragm, sponge, or cervical cap with 
spermicidal gel) during the study and for 7 days after the last dose of study drug. 
Females of childbearing potential will have a serum pregnancy test at screening and a 
urine pregnancy test on Day 1 (before receiving xanomeline and/or trospium) and 
Day 35. Should a woman become pregnant or suspects she is pregnant while 
participating in this study, she should inform study staff and her primary care physician 
immediately. 
Definition of women of childbearing potential: For the purpose of this study, a woman 
is considered of childbearing potential following menarche and until confirmed post-
menopausal state, unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.  
Pregnant women are excluded from this study because the effects of xanomeline and 
trospium 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 xanomeline or trospium, women who are breastfeeding 
must not be enrolled in the study. 
The effects of study drug on sperm are unknown. Men who agree to enroll in the study 
must agree to use a double-barrier method of birth control (ie, any double combination 


Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 37 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 38 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 39 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 40 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 41 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 42 of 127 
If unblinding is necessary for the welfare of a subject who has experienced an AE, 
unblinding of study drug may occur for just that subject. 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 appropriate course of action is to 
stop the investigational drug, and treat the signs and symptoms resulting from the AE. 
8.4.10 Prior and Concomitant Therapy 
8.4.10.1 Prior 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.  
8.4.10.2 Prohibited Medication/Therapy 
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 approval of the principal investigator. The administration of 
any other concomitant medications during the study period is prohibited without the 
prior approval of the principal investigator unless its use is deemed necessary in a 
medical emergency. Any medication taken by a subject during the course of the study 
and the reason for its use will be documented in the source documents and eCRF. 
Within 2 weeks of baseline, 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). 
Intramuscular antipsychotic medications taken before baseline should not have been 
taken within 1 and a half cycles from baseline (eg, 3 or more weeks off for a 2-week 
cycle). Please direct questions relating to prohibited medications to the assigned 
Medical Monitor. 
Subjects are not to have alcohol or illegal drug abuse within the prior 12 months of 
screening (unless medical monitor provided approval at screening), or at any time 
during the study.  


Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 43 of 127 
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Note: Written informed consent (IC) must be obtained before performing any study-
related procedure, including screening evaluations. 
6FUHHQLQJVKRXOGEHSHUIRUPHGIURP'D\WR'D\7KHVFUHHQLQJSKDVHLVDOORZHG
WREHH[WHQGHGXSWRDQDGGLWLRQDOGD\VLIQHFHVVDU\
6WXG\FDQGLGDWHVZLOOEHVFUHHQHGWRDVVHVVHOLJLELOLW\IRUHQUROOPHQWLQWRWKHVWXG\$
VFUHHQLQJORJZLOOEHPDLQWDLQHGIRUDOOFRQVHQWHGVWXG\FDQGLGDWHV$VFUHHQIDLOXUHLV
DQ\VWXG\FDQGLGDWHZKRVLJQVWKH,&DQGKDVFRPSOHWHGWKHVFUHHQLQJHYDOXDWLRQEXW
GRHVQRWTXDOLI\IRUWKHVWXG\RUGLVFRQWLQXHVWKHVWXG\EHIRUHVWXG\HQUROOPHQW7KH
study candidate’s initLDOVGDWHVFUHHQHGDQGUHDVRQVIRUVFUHHQLQJIDLOXUHPXVWEH
UHFRUGHGRQWKHVFUHHQLQJORJ
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 44 of 127 
Review the study candidate’s medical DQGSV\FKLDWULFKLVWRU\ DQGSULRUDQG
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 49 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 50 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 51 of 127 
with the use of a medicinal (investigational) product, whether or not it is related to the 
medicinal (investigational) product. This includes an exacerbation of pre-existing 
conditions or events, intercurrent illnesses, drug interaction or the significant worsening 
of the indication under investigation that is not recorded elsewhere in the eCRF under 
specific efficacy assessments. Anticipated fluctuations of pre-existing conditions, 
including the disease under study that does not represent a clinically significant 
exacerbation or worsening need not be considered AEs. 
In accordance with the protocol, the investigator and/or clinic staff will elicit AEs and 
inter-current illness during and at the end of the study period and these will be recorded 
on the appropriate page of the eCRF. Adverse events will be elicited by asking the 
subject a nonleading question, for example, “Have you experienced any new or changed 
symptoms since we last asked?” The eCRF will be completed at the end of the study as 
soon as the results of the final lab tests are available.  
The reporting period for AEs is the period immediately following the administration of 
study product on Visit 2/Day 1 and up to the time of discharge (Visit 9/Day 35) of the 
subject from the study. 
Adverse events will be reported on the AE eCRF using a recognized medical term or 
diagnosis that accurately reflects the event. Adverse events will be assessed by the 
investigator for severity, relationship to the study product, possible etiologies and 
whether the event meets criteria as a SAE and therefore requires immediate notification 
of the Sponsor, the IRB, and the FDA. If the event has not resolved at the end of the 
study reporting period it will be documented as still present on the eCRF. If an AE 
evolves into a condition that becomes “serious” it will also be reported as an SAE. 
Assessment of Severity 
Each AE will be assigned a category by the investigator as follows: 
Mild:
An AE that is easily tolerated by the subject, causes minimal discomfort,
and does not interfere with everyday activities.
Moderate:
An AE that is sufficiently discomforting to interfere with normal 
everyday activities; intervention may be needed.
Severe:
An AE that prevents normal everyday activities; treatment or other 
intervention usually needed.
If there is a change in severity of an AE, it must be recorded as a separate event. 
Assessment of Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, 
to the study drug. Causality should be assessed using the categories presented in the 
following table: 


Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 52 of 127 
Unrelated:
Clinical event with an incompatible time relationship to study drug
administration, and that could be explained by underlying disease or 
other drugs or chemicals or is incontrovertibly not related to the study 
drug.
Unlikely:
Clinical event whose time relationship to study drug administration 
makes a causal connection improbable, but that could plausibly be 
explained by underlying disease or other drugs or chemicals.
Possible:
Clinical event with a reasonable time relationship to study drug
administration, but that could also be explained by concurrent disease 
or other drugs or chemicals.
Probable:
Clinical event with a reasonable time relationship to study drug
administration, and is unlikely to be attributed to concurrent disease 
or other drugs or chemicals.
Very 
Likely/Certain:
Clinical event with plausible time relationship to study drug
administration, and that cannot be explained by concurrent disease or 
other drugs or chemicals.
Action Taken 
The investigator will describe the action taken in the appropriate section of the eCRF, as 
follows: 
x None 
x Study drug stopped 
x Study drug temporarily interrupted 
x Concomitant medication 
x Other, specify 
Follow-up of Adverse Events 
Subjects with AEs/SAEs will be treated if necessary and followed by the investigator 
until the event resolves or until, in the opinion of the investigator, the event is stabilized 
or determined to be chronic. The investigator will provide or arrange for appropriate 
follow-up (if required) for subjects, and document the course of the subject’s condition. 
Additional medical evaluation and treatment will be arranged as appropriate. Details of 
AE resolution must be documented in the eCRF. 
Documentation and Reporting of Adverse Events 
AEs should be reported and documented in accordance with the procedures outlined 
below. All AEs occurring during the study must be documented on the relevant eCRF 
pages. The following data should be documented for each AE: 


Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 53 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 54 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 55 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 56 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 57 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 58 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 59 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 60 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 61 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 62 of 127 
11.2 Analysis Populations 
11.2.1 Intent-To-Treat Population 
Intent-to-treat (ITT) population is defined as subjects who are randomized to the study. 
11.2.2 Modified Intent-To-Treat Population 
Modified Intent-to-treat (mITT) population is defined as randomized subjects who 
receive at least 1 dose of study drug and have a baseline assessment. The mITT 
population will be used for efficacy analyses. 
11.2.3 Safety Population 
Safety population is defined as subjects who receive at least 1 dose of study drug. The 
safety population will be used for safety analyses.
11.2.4 Pharmacokinetic Population 
Pharmacokinetic population is defined as randomized subjects who receive at least 
1 dose of study drug and have at least 1 measurable serum concentration of study 
medication. PK population will be used for PK analyses.
11.3 Statistical Analyses 
11.3.1 Subject Disposition  
The number of subjects in each analysis population and the reasons for discontinuation 
will be summarized. In addition, subjects’ status with regard to study treatment and 
follow-up will also be summarized. 
11.3.2 Demographic and Other Baseline Characteristics 
Subject disease and baseline characteristics will be summarized using frequency 
distribution or descriptive statistics as appropriate. 
11.3.3 Efficacy Analyses 
The primary 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 observed 
change from baseline PANSS total score at Week 2, 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, gender, and baseline 


Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 63 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 64 of 127 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 65 of 127 
x For the primary efficacy analysis, likelihood-based modeling approach will be 
used to handle incomplete data. For this purpose, an MMRM will be applied. 
x 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.  
x
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.  
11.4 Determination of Sample Size 
Assuming a PANSS total score difference of 9 between drug and placebo and standard 
deviation of 18, a sample size of approximately 180 (90 evaluable subjects per arm) will 
result in a power of 91% for a 2-sided alpha of 0.05. 
11.5 Protocol Deviations 
All protocol deviations will be tracked in the eCRF/electronic data capture (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. 
12 QUALITY ASSURANCE AND QUALITY CONTROL 
12.1 Audit and Inspection 
Study centers and study documentation may be subject to a Quality Assurance audit 
during the course of the study by the Sponsor or its nominated representative. In 
addition, inspections may be conducted by regulatory authorities at their discretion.
The study site personnel and principal investigator must make all study records 
(including source data and documentation) available to US and International regulatory 
agency personnel, the IRB and the study Sponsor or designee, for the purposes of 
monitoring, auditing, inspection, and copying. In addition, disclosure of study 
information to third parties may be required by law. 
12.2 Monitoring 
The study will be monitored by the Sponsor or its designee on a regular basis 
throughout the study period. Data for each subject will be recorded on an eCRF. Data 
collection must be completed for each subject who signs an ICF and is administered 
study drug. Some data such as scale assessments and laboratory results will be 
maintained in the vendor systems.  


Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 67 of 127 
13 RECORDS AND SUPPLIES 
13.1 Drug Accountability 
The accountability for the study drug at the study site rests with unblinded study 
monitors. These persons will maintain records of all the investigational products (drug 
and placebo), including their delivery and receipt, inventory at the site, use by each 
subject, and the destruction of unused study drug according to the directions of the 
Sponsor or designee. The investigators will assure that drug and placebo are used 
according to the protocol. The investigators will assure that the study drug and the 
records described in this paragraph will be stored in a locked area suitable for storage of 
pharmaceutical products, and in accordance with the conditions specified on the study 
drug label. Further, the investigators assure that the study drug and the records will be 
available for examination by the unblinded study monitor on periodic visits.  
All unused study drug supplies and equipment will be destroyed according to directions 
of the Sponsor or designee at the end of the study. 
On receipt of the study drug, an unblinded pharmacist at the study site will conduct an 
inventory of the supplies and verify that study drug supplies are received intact and in 
the correct amounts before completing a supplies receipt. The unblinded pharmacist will 
retain a copy of this receipt at the study center and it will be reviewed by the unblinded 
study monitor. The unblinded study monitor may check the study supplies at each study 
center at any time during the study.
It is the responsibility of the unblinded study monitor to ensure that the unblinded 
pharmacist has correctly documented the amount of the study drug received, dispensed, 
and returned on the dispensing log that will be provided. A full drug accountability log 
will be maintained at the study center at all times. The unblinded study monitor will also 
perform an inventory of study drug at the close-out visit to the study center. All
discrepancies must be accounted for and documented.


Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
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14
ETHICS 
14.1 Independent Ethics Committee or Institutional Review Board 
The protocol, informed consent, and other written material given to the subjects, and 
any other relevant study documentation will be reviewed and approved by the governing 
IRB of the participating center before study initiation and/or before the study drug is 
released to the investigator, and the investigator will keep the IRB informed as to the 
progress of the study. 
Modifications or changes to the protocol, the informed consent, or other study 
documentation may not be initiated without prior written IRB approval except when 
necessary to eliminate immediate hazards to the subjects or when the change(s) involves 
only logistical or administrative aspects of the study. Such modifications will be 
submitted to the IRB and written verification that the modification was submitted 
should be obtained. 
The IRB must be informed by the principal investigator of informed consent changes or 
revisions of other documents originally submitted for review; serious and/or unexpected 
adverse experiences occurring during the study; new information that may affect 
adversely the safety of the subjects or the conduct of the study; an annual update and/or 
request for re-approval; and when the study has been completed. 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and 
other records will be identified by a coded number and initials only; on some specimen 
collection records, the subject’s birth date may also appear. All study records will be 
kept in a locked file cabinet and code sheets linking a subject’s name to a subject 
identification number will be stored separately in another locked file cabinet. Clinical 
information will not be released without written permission of the subject, except as 
necessary for monitoring by the FDA or the Sponsor of the clinical study. 
14.2 Regulatory Authorities 
Relevant study documentation will be submitted to the US regulatory authorities, 
according to local/national requirements, for review and approval before the beginning 
of the study. On completion of the study, the regulatory authorities will be notified that 
the study has ended. 
14.3 Ethical Conduct of the Study 
The study will be conducted in accordance with the ethical principles set forth in the 
Declaration of Helsinki, the Guideline for GCP (ICH E6), the United States CFR 
governing the protection of human subjects (21CFR§50), IRBs (21CFR§56),  the 
requirements for conducting clinical investigations (21CFR§312), and all applicable 
local, state and federal government regulations and laws. 


Karuna Pharmaceuticals 
13 Dec 2018 
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Version 4.0 
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14.4 Informed Consent 
Written informed consent must be obtained before any protocol-specified procedures or 
interventions are carried out. Subjects will be counseled about the study before giving 
their written informed consent. The investigator or designated personnel will inform the 
subject of the objectives, methods, anticipated benefits, potential risks, and 
inconveniences of the study. The subject should be given every opportunity to ask for 
clarification of any points s/he does not understand and, if necessary, ask for more 
information. Subjects must be given ample opportunity to inquire about details of the 
study. The process of obtaining informed consent must be in accordance with applicable 
regulatory requirement(s) and must adhere to GCP. 
The investigator will explain the nature of the study and will inform the subject that 
participation is voluntary and that they can withdraw at any time. Written informed 
consent will be obtained from each subject before entry into the study. A copy of the 
signed consent form will be given to every participant and the original will be 
maintained with the subject’s records. The Informed Consent should be translated and 
certified into the local language of the respondent, as deemed necessary.   
It should be emphasized that the subject may refuse to enter the study or to withdraw 
from the study at any time, without consequences for their further care or penalty or loss 
of benefits to which the subject is otherwise entitled. Subjects who refuse to give or who 
withdraw written informed consent should not be included or continue in the study. 
The consent form must be approved by the IRB and be acceptable to the Sponsor. 
Consent forms must be written so as to be understood by the prospective subject. 
Informed consent will be documented by the use of a written consent form approved by 
the IRB and signed and dated by the subject and by the person who conducted the 
informed consent discussion. The signature confirms the consent is based on 
information that has been understood. Each signed ICF must be kept on file by the 
investigator for possible inspection by Regulatory Authorities and/or the Sponsor or its 
designee. The subject should receive a copy of the signed and dated written ICF and any 
other written information provided to the subjects, and should receive copies of any 
signed and dated consent form updates and any amendments to the written information 
provided to subjects.  
If new information becomes available that may be relevant to the subject’s willingness 
to continue participation in the study, a new ICF will be approved by the IEC(s)/IRB(s) 
(and regulatory authorities, if required). The study subjects will be informed about this 
new information, and reconsent will be obtained. 
14.5 Conflict of Interest 
The investigators will be partially paid by the Sponsor of this study for the study related 
expenses, but they will not profit from results, either positive or negative, with regard to 


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requested, the subject’s identity will remain confidential to the extent permitted by the 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
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Karuna Pharmaceuticals 
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KAR-004 Amendment 3 
Version 4.0 
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Karuna Pharmaceuticals 
13 Dec 2018 
KAR-004 Amendment 3 
Version 4.0 
Page 73 of 127 
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SAP_001.pdf: 
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6SRQVRU1DPHKaruna Pharmaceuticals, Inc.
3URWRFRO1XPEHUKAR-004
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3URWRFRO7LWOHA Phase 2, Randomized, Double-blinded Study to Assess the Safety, Tolerability, and 
Efficacy of KarXT in Hospitalized Adults with DSM-5 Schizophrenia
3URWRFRO9HUVLRQDQG'DWH''0PP<<<<Version 4.0 Amendment 3/11Dec2018
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The information contained in this document is confidential belonging to Karuna Pharmaceuticals, Inc.
Acceptance of this document constitutes agreement by the recipient that no information contained herein 
will be published or disclosed without prior written authorization from an official of Karuna
Pharmaceuticals, Inc.  However, this document may be disclosed to appropriate Institutional Review 
Board and Ethics Committees or duly authorized representatives of a national regulatory authority under 
the condition that they are requested to keep it confidential. In the event of an actual or suspected breach 
of this obligation, 
 should be notified promptly.
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Revision History.......................................................................................................................... 2 
$SSURYDOV .................................................................................................................................. 3 
1. 
Glossary of Abbreviations................................................................................................... 8 
2. 
Purpose............................................................................................................................10 
2.1. 
Responsibilities.....................................................................................................10 
2.2. 
Timings of Analyses..............................................................................................10 
3. 
Study Objectives ..............................................................................................................11 
3.1. 
Primary Objective .................................................................................................11 
3.2. 
Secondary Objectives...........................................................................................11 
3.3. 
Brief Description ...................................................................................................11 
3.4. 
Subject Selection..................................................................................................12 
3.4.1. 
Inclusion Criteria ..................................................................................................12 
3.4.2. 
Exclusion Criteria ................................................................................................. 13 
3.5. 
Determination of Sample Size...............................................................................14 
3.6. 
Treatment Assignment & Blinding.........................................................................14 
3.7. 
Administration of Study Medication.......................................................................15 
3.8. 
Study Procedures and Flowchart ..........................................................................15 
4. 
Endpoints .........................................................................................................................19 
4.1. 
Primary Efficacy Endpoint.....................................................................................19 
4.2. 
Secondary Efficacy Endpoints ..............................................................................19 
4.3. 
Pharmacokinetic Endpoints...................................................................................19 
4.4. 
Safety Endpoints...................................................................................................19 
4.5. 
Exploratory Endpoints...........................................................................................19 
5. 
Analysis Populations ........................................................................................................20 
5.1. 
Intent-to-Treat (ITT) Population.............................................................................20 
5.2. 
Safety Population..................................................................................................20 
5.3. 
Modified Intent-to-Treat (MITT) Population ...........................................................20 
5.4. 
PK Population.......................................................................................................20 
5.5. 
Completer Population ...........................................................................................20 
5.6. 
Per-Protocol (PP) Population................................................................................20 
6. 
General Aspects for Statistical Analysis ...........................................................................21 
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Page  of 
6.1. 
General Methods ..................................................................................................21 
6.2. 
Key Definitions......................................................................................................21 
6.2.1. 
First Dose Date ....................................................................................................21 
6.2.2. 
Last Dose Date ....................................................................................................21 
6.2.3. 
Study Day.............................................................................................................21 
6.2.4. 
Baseline and Change from Baseline ...................................................................21 
6.3. 
Missing Data.........................................................................................................22 
6.4. 
Visit Windows .......................................................................................................23 
6.5. 
Pooling of Centers ................................................................................................23 
7. 
Demographic, Other Baseline Characteristics and Medication .........................................24 
7.1. 
Subject Disposition and Withdrawals ....................................................................24 
7.2. 
Inclusion/Exclusion Criteria...................................................................................24 
7.3. 
Protocol Deviations...............................................................................................24 
7.4. 
Demographic and Other Baseline Characteristics.................................................25 
7.5. 
Medical History .....................................................................................................25 
7.6. 
Other Baseline Characteristics..............................................................................25 
7.7. 
Prior and Concomitant Medication ........................................................................25 
7.7.1. 
Prior Medication ...................................................................................................25 
7.7.2. 
Concomitant Medication ......................................................................................25 
8. 
Efficacy Analyses .............................................................................................................26 
8.1. 
Primary Efficacy Endpoint and Analysis................................................................26 
8.1.1. 
Primary Analysis ..................................................................................................26 
8.1.3. 
Sensitivity Analyses of Primary Endpoint ............................................................28 
8.2. 
Secondary Efficacy Endpoints and Analyses ........................................................30 
8.2.1. 
Hierarchical test for efficacy evaluation ...............................................................30 
8.2.2. 
Change from Baseline in PANSS Positive Score ................................................30 
8.2.3. 
Change in CGI-S score........................................................................................31 
8.2.4. 
Change from Baseline in PANSS Negative Score...............................................31 
8.2.5. 
Change in PANSS Marder Factor Score .............................................................31 
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8.2.6. 
CGI-S responders ................................................................................................32 
8.3. 
Exploratory Efficacy Endpoints and Analyses .......................................................32 
9. 
Pharmacokinetics Analysis...............................................................................................33 
9.1. 
PK Sampling Schedule .........................................................................................33 
9.3. 
Presentation of Concentration Data ......................................................................34 
9.3.1. 
Handling of missing data......................................................................................34 
9.5. 
Population PK Analysis.........................................................................................37 
10. 
Safety Analyses................................................................................................................38 
10.1. 
Extent of Exposure ...............................................................................................38 
10.2. 
Treatment Compliance..........................................................................................38 
10.3. 
Adverse Events.....................................................................................................38 
10.4. 
Laboratory Evaluations .........................................................................................39 
10.5. 
Height, Weight, BMI, and Waist Circumference ....................................................40 
10.6. 
Orthostatic Vital Signs...........................................................................................40 
10.7. 
ECG......................................................................................................................40 
10.8. 
Physical Examination............................................................................................40 
10.9. 
Other Safety Analyses ..........................................................................................40 
10.9.1. 
A Simpson-Angus Rating Scale...........................................................................40 
10.9.2. 
Barnes Rating Scale for Akathisia .......................................................................41 
10.9.3. 
Abnormal Involuntary Movement Scale (AIMS)...................................................41 
10.9.4. 
C-SSRS................................................................................................................41 
11. 
Interim Analyses...............................................................................................................42 
12. 
Changes from Analysis Planned in Protocol.....................................................................43 
13. 
Reference List..................................................................................................................44 
 
 
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15. 
Quality Control .................................................................................................................50 
 
 
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Abbreviation
Description
AE
adverse event
AESI
adverse event of special interest
AIMS
Abnormal Involuntary Movement Scale
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
ATC
Anatomical Therapeutic Chemical
BID
twice daily
BLQ
Below the Limit of Quantification
BMI
body mass index
CI
confidence interval
CGI-S
Clinical Global ImpressionಥSeverity
CM
concomitant medication
Cmax
maximum observed plasma concentration
CRF
case report form
C-SSRS 
Columbia-Suicide Severity Rating Scale
CV
coefficient of variation
ECG
electrocardiogram
ET 
early termination
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HEENT
head/eyes/ears/nose/throat
ICF 
informed consent form
ICH
International Conference on Harmonization
ISMC
Independent Safety Monitoring Committee
IWRS 
interactive web response system
LLOQ
lower limit of quantification
Max
maximum
MedDRA
Medical Dictionary for Regulatory Activities
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Abbreviation
Description
MI
multiple imputation
Min
minimum
MINI
Mini International Neuropsychiatric Interview
MMRM 
mixed model for repeated measures
N/A
not applicable
NA
not applicable
PANSS 
Positive and Negative Syndrome Scale
PK
pharmacokinetic
PT
preferred term
QTc
corrected QT interval
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SI
standard international system of units
SOC
System Organ Class
SOP
standard operating procedure
TEAE
treatment emergent adverse event
TLF
table, listing and figure
WHO
World Health Organization
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The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables and 
figures which will be produced, and the statistical methodologies that will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives.
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will perform the statistical analyses and are responsible for the production and quality control 
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The primary analysis of safety, efficacy and pharmacokinetics is planned after all subjects complete the 
final study visit or terminate early from the study.
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The primary objective of the study is to assess the efficacy of KarXT (a fixed combination of xanomeline
and trospium chloride) (xanomeline 125 mg/trospium 30 mg twice daily [BID]) versus placebo in reducing 
Positive and Negative Syndrome Scale (PANSS) total scores in adult inpatients with a Diagnostic and 
Statistical Manual௅Fifth Edition (DSM-5) diagnosis of schizophrenia.

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The secondary objectives of the study are to assess overall safety and tolerability of KarXT in adult
inpatients with a DSM-5 diagnosis of schizophrenia:
x
To assess spontaneously reported adverse events (AEs) in subjects treated with KarXT versus 
placebo
x
To assess spontaneously reported cholinergic symptoms in subjects treated with KarXT versus 
placebo
x
To assess orthostatic vital signs in subjects treated with KarXT versus placebo
x
To assess electrocardiogram (ECG) parameters in subjects treated with KarXT versus placebo
x
To assess reduction of PANSS positive score in subjects treated with KarXT versus placebo
x
To assess reduction of PANSS negative score in subjects treated with KarXT versus placebo
x
To assess reduction of PANSS Marder Factor score in subjects treated with KarXT versus placebo
x
To assess the pharmacokinetics (PK) of xanomeline and trospium following administration of 
KarXT in adult subjects with a DSM-5 diagnosis of schizophrenia
x
To assess Clinical Global Impression-Severity (CGI-S) results in subjects with KarXT versus 
placebo
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The study will be an inpatient study in adult subjects with DSM-5 schizophrenia. Subjects will be randomized 
to receive either placebo or KarXT (xanomeline 125 mg/trospium 30 mg BID) orally for a treatment period 
of 5 weeks. Subjects will start on a lead-in dose of xanomeline 50 mg/trospium 20 mg BID for the first 2 
days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On 
Day 8, dosing will be titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the subject is 
continuing to experience AEs from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. 
All subjects who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response 
and tolerability, will have the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder 
of the treatment period. Dosing must not change in the last 14 days of the study and may be decreased for 
tolerability reasons no more than once during the study.
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A total of approximately 180 study subjects and approximately 12 sites in the United States are planned. 
Subjects who are randomized into the double-blind treatment phase but discontinue or withdraw will not be 
replaced.
3.4.1.
Inclusion Criteria
To be eligible for enrollment, subjects must satisfy all of the following criteria:
1.
Subject is aged 18-60 years, inclusive, at screening.
2.
Subject has a primary diagnosis of schizophrenia established by a comprehensive psychiatric 
evaluation based on the DSM-5 (American Psychiatric Association 2013) criteria and confirmed by 
Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorder Studies (MINI) 
version 7.0.2.
3.
Subject is experiencing an acute exacerbation or relapse of symptoms, with onset less than 2 months 
before screening.
a.
The subject requires hospitalization for this acute exacerbation or relapse of 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.
4.
Positive and Negative Syndrome Scale total score between 80 and 120, inclusive, at screening.
a.
Score of  4 (moderate or greater) for  2 of the following Positive Scale (P) items at screening:
i.
Item 1 (P1; delusions)
ii.
Item 2 (P2; conceptual disorganization)
iii.
Item 3 (P3; hallucinatory behavior)
iv.
Item 6 (P6; suspiciousness/persecution)
5.
There should not be a change (improvement) in PANSS total score between screening and baseline 
of more than 20%.
6.
Subject will have been off lithium therapy for at least 2 weeks before baseline and free of all oral 
antipsychotic medications for at least 2 weeks before baseline.
7.
Subjects taking a depot antipsychotic could not have received a dose of medication for at least 1 and 
a half injection cycles before baseline (eg, 3 or more weeks off for a 2-week cycle).
8.
Subject is capable of providing informed consent.
a.
A signed ICF must be provided before any study assessments are performed.
b.
Subject must be fluent (oral and written) in English in order to consent.
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9.
Subject is willing and able to be confined to an inpatient setting for the study duration, follow 
instructions, and comply with the protocol requirements.
10. Subject must have CGI-S score of  4 at screening and baseline visits.
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. Both females of child bearing potential and males with partners of child bearing potential must be 
willing to use a double-barrier method of birth control (ie, any double combination of male or female 
condom with spermicidal gel, diaphragm, sponge, or cervical cap with spermicidal gel) during the 
study and for 7 days after the last dose of study drug.
14. Subject has an identified reliable informant. An informant 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 may not be necessary if the subject has been the 
patient of the investigator for  1 year.
3.4.2.
Exclusion Criteria
Subjects will be excluded from the study if one or more of the following criterion is applicable:
1.
Any primary DSM-5 disorder other than schizophrenia within 12 months before screening (confirmed 
using MINI version 7.0.2 at screening).
2.
History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, 
gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or oncologic disease or any other 
condition that, in the opinion of the investigator, would jeopardize the safety of the subject or the 
validity of the study results, to exclude patients with human immunodeficiency virus (HIV), cirrhosis, 
biliary duct abnormalities, hepatobiliary carcinoma, and/or active hepatic viral infections based on the 
liver function test results. 
3.
History of or high risk of urinary retention, gastric retention, or narrow-angle glaucoma.
4.
History of irritable bowel syndrome (with or without constipation) or serious constipation requiring 
treatment within the last 6 months 
5.
Has a DSM-5 diagnosis of moderate to severe substance abuse disorder (except tobacco use 
disorder) within the 12 months before screening (confirmed using MINI version 7.0.2 at screening), or 
current abuse as determined by urine toxicology screen or alcohol test. A screening subject with mild 
substance abuse disorder within the 12 months before screening must be discussed and agreed 
upon with the medical monitor before he/she can be allowed into the study. 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.
6.
Risk for suicidal behavior during the study as determined by the investigator’s clinical assessment 
and the C-SSRS as confirmed by the following:
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SAP Version: Final v2.0
, Effective Date 30-Apr-2018
Page  of 
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 2 weeks of baseline) be receiving oral antipsychotic medications, 
MAO inhibitors, anticonvulsants (eg, lamotrigine, Depakote), tricyclic antidepressants (eg, imipramine, 
desipramine), selective serotonin reuptake inhibitors, or any other psychoactive medications except 
for anxiolytics (eg, lorazepam, chloral hydrate) taken as needed.
9.
Pregnant, lactating, or less than 3 months postpartum. Sperm donation is not allowed for 90 days 
after the final dose of study drug.
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 their ability to adhere to the protocol visit schedule or fulfill visit 
requirements.
11. Subject has had psychiatric hospitalization(s) for more than 30 days (cumulative) during the 90 days 
before screening.
12. 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.
13. Risk of violent or destructive behavior.
14. Current involuntary hospitalization or incarceration.
15. Participation in another clinical study in which the subject received an experimental or investigational 
drug agent within 3 months of screening.

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Assuming a PANSS total score difference of 9 between drug and placebo and standard deviation of 18, a 
sample size of 180 (90 evaluable subjects per arm) will result in a power of 91% for a 2-sided alpha of 0.05.

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Subjects will be randomly assigned in a 1:1 ratio to either KarXT or placebo with stratification by site. A
randomization number can only be assigned to one subject and cannot be reused once assigned.
An IWRS will allocate treatment based on a prespecified randomization list. Active and placebo study drug 
will be provided to each site. 
Study subjects, informants, investigators, site personnel involved in subject evaluation, and the Sponsor’s 
medical monitor will be blinded to the subject treatment assignment. Both active study drug and placebo 
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Sponsor: Karuna Pharmaceuticals, Inc.; Protocol No.: KAR-004
SAP Version: Final v2.0
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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.
The Sponsor’s authorized designee will generate and maintain the security of the randomization code. The 
blinding code will be broken early only when information is needed to maintain the health and well-being of 
subjects such as for treatment of an AE. 
The reasons for any premature unblinding (either accidental or due to a serious adverse event [SAE] that
appears related to the investigational product) will be properly documented in the study file. Unblinding 
according to the protocol will occur only after completion of the study.
A list of treatment numbers for each treatment group will be generated by the vendor selected by the 
Sponsor to perform this function, and the treatment prepared in accordance with this list. Numbers will not 
be reused regardless of the status of the use of the corresponding study drug.
The members of the Independent Safety Monitoring Committee (ISMC) will be unblinded as they review 
the safety data from the study. There will be an unblinded pharmacist to manage study drug inventory for 
each site and an unblinded study monitor for drug accountability and review of documentation of drug 
inventory.
If unblinding is necessary for the welfare of a subject who has experienced an AE, unblinding of study drug 
may occur for just that subject. 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 
appropriate course of action is to stop the investigational drug, and treat the signs and symptoms resulting 
from the AE.
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Because this is an inpatient study, treatment compliance will be assured. All study drugs will be 
administered by study staff and recorded in the eCRF.
Study drug accountability will be assessed periodically by the assigned unblinded study monitor.
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SAP Version: Final v1.1
, Effective Date 30-Apr-2018
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Table 1. 
Schedule of Assessments
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Written informed consent
X
Collect demographic 
information (date of birth, 
gender, race)
X 
Pregnancy test (females of 
childbearing potential only)c
Xc
Xc
Xc
Urine drugs of abuse test and 
alcohol testingd
X 
Review of inclusion/exclusion 
criteria
X 
X 
Subject eligibility verification 
process
X 
Medical, psychiatric, and 
medication history
X 
Complete physical 
examinatione
Xe
Xe
Spontaneous AEs and 
medical statusf
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of concomitant 
medications
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height (Screening only) and 
body weight, BMI, waist 
circumference
X 
X 
X 
Orthostatic vital signs: blood 
pressure and heart rateg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Resting ECG (12-lead)h
X
X
Blood samples for 
hematology, coagulation, and 
serum chemistry and urine 
sample for urinalysisi
X 
X 
X 
Admission of subject to 
inpatient unitk
X 
Randomization/assignment of 
subject ID
X 
Determination of dose 
adjustment 
X 
X 
X 
X 
Study drug provided 
(randomized, double-
blind) and administered daily 
BIDl
X 
X 
X 
X 
X 
X 
X 
X 
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Sponsor: Karuna Pharmaceuticals, Inc.; Protocol No.: KAR-004
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Blood samples for PK 
analysism
Xm
Xm
Xm
Xm
MINI version 7.0.2.
X
Positive and Negative 
Syndrome Scale (PANSS) for 
schizophrenian
X 
X 
X 
X 
X 
C-SSRSo
X
X
X
X
X
X
X
CGI-S Scale
X
X
X
X
X
X
X
Simpson-Angus Rating Scale
X
X
Barnes Rating Scale for 
Akathisia
X 
X 
Abnormal Involuntary 
Movement Scale (AIMS)
X 
X 
Abbreviations: AE = adverse event; BID = twice daily; BMI = body mass index; CGI-6 &OLQLFDO*OREDO,PSUHVVLRQ௅6HYHULW\VFDOH
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
If a subject leaves the unit, he/she should have a urine drug screen and test for alcohol (breathalyzer or blood alcohol level) 
upon returning to the unit.
e 
A complete physical examination includes body temperature (°C), general appearance, head/eyes/ears/nose/throat (HEENT), 
examination of thorax and abdomen, assessment of cardiac, musculoskeletal, and circulatory systems, palpations for 
lymphadenopathy, and limited neurological examination. A brief physical examination is performed at Visit 9/Day 35.
f
Adverse events as reported by subjects or observed by clinical staff and occurs after dosing. One PK blood sample should be 
drawn if an AE is reported during a scheduled visit or if there is a dose adjustment or AE reported during an unscheduled visit 
(no multiple draws).
g
Vital signs taken supine and standing after 2 minutes. Blood pressure includes systolic and diastolic blood pressure. Heart rate 
is beats/minute. During treatment, beginning with Visit 2, vital signs should occur 2 (± 1) hours after dosing. At investigator 
discretion, additional orthostatic vital signs are allowed to be conducted as needed. 
h
During the ECG, ventricular rate (bpm), PR (msec), QRS (msec), QT (msec), and QTcF (msec).
i
Refer to Protocol Section 10.1.3.1.4 for individual laboratory tests.
k 
If an eligible subject is not already an inpatient, the subject should be admitted to the inpatient unit.
l 
Starting on Day 1, study drug is administered daily BID by the study staff, with the last dose administered on the evening of 
Day 34.
m 
For Visit 5/Day 8 and Visit 8/Day 28, 6 PK blood draws are required: before the morning dose, and at 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. For Visit 
9/ET, a single PK blood sample should be drawn prior to discharge (preferably in the morning) for completed (and early 
termination) subjects. One PK blood sample should also be drawn if an AE is reported during a scheduled visit or if there is a 
dose adjustment or AE reported during an unscheduled visit (no multiple draws).
n 
It is recommended, if at all possible, that the PANSS assessment should be performed first of all the other assessments at all
visits it is performed. The PANSS assessment includes the Marder Factor.
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Sponsor: Karuna Pharmaceuticals, Inc.; Protocol No.: KAR-004
SAP Version: Final v2.0
, Effective Date 30-Apr-2018
Page  of 
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C-SSRS first time use lifetime, other times use “since last visit” version.
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Sponsor: Karuna Pharmaceuticals, Inc.; Protocol No.: KAR-004
SAP Version: Final v2.0
, Effective Date 30-Apr-2018
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x
Change in PANSS total score at Visit 9

6HFRQGDU\(IILFDF\(QGSRLQWV
x
Change in PANSS positive score
x
Change in CGI-S score
x
Change in PANSS negative score
x
Change in PANSS Marder Factor score
x
Percent of CGI-S responders (with CGI-S scale equal to 1 or 2)

6DIHW\(QGSRLQWV
x
Spontaneous AEs
x
Orthostatic vital signs (supine and standing after 2 minutes): blood pressure (systolic and diastolic) 
and heart rate (beats/minute)
x
Clinical laboratory evaluations: hematology, clinical chemistry, coagulation, urinalysis, and drug 
screen
x
12-lead ECG
x
Physical examination
x
Suicidal ideation with the use of Columbia Suicide Severity Rating Scale (C-SSRS)

([SORUDWRU\(QGSRLQWV
x
Simpson-Angus Rating Scale
x
Barnes Rating Scale for Akathisia
x
Abnormal Involuntary Movement Scale (AIMS)
x
Body weight, body mass index (BMI), waist circumference
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Sponsor: Karuna Pharmaceuticals, Inc.; Protocol No.: KAR-004
SAP Version: Final v2.0
, Effective Date 30-Apr-2018
Page  of 
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The ITT population will include all subjects who are randomized to the study. Subjects will be analyzed 
according to randomized treatment.

6DIHW\3RSXODWLRQ
The Safety population will include all subjects who receive at least one dose of study medication. Subjects 
will be analyzed according to treatment received. The Safety population will be used for all analyses of 
safety endpoints
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The MITT population will include all subjects who were randomized, received at least one dose of study 
medication, and have a baseline and at least one post-baseline PANSS assessment. The MITT population 
will be used for all analyses of efficacy endpoints.
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The PK population will include all subjects who received at least one dose of the study drug and have at 
least one measurable PK concentration. If any subjects are found to be noncompliant with respect to dosing, 
have incomplete data, or other clinical events potentially interfering with the pharmacokinetic profile, a
decision will be made on a case-by-case basis as to their inclusion in the analysis of PK parameters. The 
PK population will be used for PK analyses.
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The Completer population will include all MITT subjects who have a valid PANSS total score at Visit 9. The 
Completer population will be used for a sensitivity analysis of the primary efficacy endpoint.
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All protocol deviations will be tracked in the clinical study 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.
The PP population will include all subjects who were randomized, received at least one dose of study 
medication, have a baseline and at least one post-baseline PANSS assessment, and have no major 
protocol deviations. The PP population will be used for a sensitivity analysis of the primary efficacy endpoint.
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Sponsor: Karuna Pharmaceuticals, Inc.; Protocol No.: KAR-004
SAP Version: Final v2.0
, Effective Date 30-Apr-2018
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x
Unless otherwise specified, summaries will be presented for each treatment and overall.
x
Continuous variables will be summarized using the number of observations (n), mean, standard 
deviation (SD), median, minimum, and maximum. Categorical variables will be summarized using 
number of observations (n), frequency and percentages of subjects
x
All relevant subject data will be included in listings.
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6.2.1.
First Dose Date
First dose date is defined as the date of first dose of study medication received after randomization.
6.2.2.
Last Dose Date
Last dose date is defined as the date of last dose of study medication. 
6.2.3.
Study Day
The study day is determined relative to the date of first dose of study medication. The day of the first dose 
of study medication will be defined as study Day 1. The day prior to the first dose of study medication is 
study Day -1. There is no study Day 0.
6.2.4.
Baseline and Change from Baseline
Baseline value is defined as the last value prior to the first dose of study medication administration. This 
value could be the pre-dose assessment on the first dose date or the assessment at the screening visit. If 
multiple values are present for the same date, the values from the last assessment will be used as the 
baseline unless otherwise specified. 
Change from baseline = (post-baseline value – baseline value). 
For the purpose of tabulations, the unscheduled post-baseline values generally will be excluded from 
summary tables presented by visit, but will be included in the listings. Unscheduled visits will be considered 
for analyses of shift from Baseline to worst value (low-normal-high).
6.2.5.
Low dose and High dose group
Based on the dosage of KarXT received during the treatment period, subjects will be separated into a low 
dose group and high dose group. Subjects who never took doses more than Xanomeline 100 mg/Trospium 
20 mg BID or who were down-titrated after getting to Xanomeline 125 mg/Trospium 30 mg BID but then 
remained on 100 mg/20 mg for the rest of the study are categorized as low dose group; subjects who took 
Xanomeline 125 mg/Trospium 30 mg BID after the first week of “titration” and then throughout the study 
are categorized as high dose group.  
Safety data including adverse events, laboratory tests and vital sign assessments will be summarized by 
low dose group and high dose group.
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6WDWLVWLFDO$QDO\VLV3ODQIRU,QWHUYHQWLRQDO6WXGLHV
Sponsor: Karuna Pharmaceuticals, Inc.; Protocol No.: KAR-004
SAP Version: Final v2.0
, Effective Date 30-Apr-2018
Page  of 
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All available data for the subjects who withdraw from the study for any reasons will be analyzed. Missing 
assessment data will be assumed to be missing at random. There will be no imputation of missing data for 
analysis purposes unless otherwise specified. Subjects with missing PK data will be evaluated on a case-
by-case basis to determine if sufficient data are available for meaningful PK analysis.
The partial/missing AE or concomitant medication (CM) start/end dates will be imputed for study period and 
study day determination purpose.
If the date and/or time that an AE is incomplete, the event will be considered a TEAE unless the partial 
start/end dates/times give sufficient detail in order to prove that the AE started or stopped prior to the first 
dose in the study. In such cases the event will not be considered a TEAE.
If the date that a medication started is incomplete, the medication will be considered as concomitant unless 
the partial date(s) give sufficient detail in order to prove that the medication was stopped prior to the day of 
first dose in the study. In such a case, the medication will be considered as prior medication. A medication 
started prior to the first dose date and ongoing as of the first dose date will be considered both prior and 
concomitant.
,QFRPSOHWH6WDUW'DWH
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x
If the year is the same as the year of the first dosing date, then the day and month of the first 
dosing date will be assigned to the missing fields.
x
If the year is prior to the year of first dosing date, then December 31 will be assigned to the 
missing fields.
x
If the year is after the year of first dosing, then January 1 will be assigned to the missing fields.
0LVVLQJGD\RQO\
x
If the month and year are the same as the year and month of first dosing date, then the first 
dosing date will be assigned to the missing day.
x
If either the year of the partial date is before the year of the first dosing date or the year of the 
partial date and the first dosing date are the same but the month of partial date is before the 
month of the first dosing date, then the last day of the month will be assigned to the missing day.
x
If either the year of the partial date is after the year of the first dosing date or the year of the 
partial date and the first dose date are the same but the month of partial date is after the month of 
the first dosing date, then the first day of the month will be assigned to the missing day. 
x
If the stop date is not missing, and the imputed start date is after the stop date, the start date will 
be imputed by the stop date. 
0LVVLQJGD\PRQWKDQG\HDU
x
No imputation is needed, and the corresponding AE will be included as TEAE and the 
corresponding CM will be included as a concomitant medication.
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Sponsor: Karuna Pharmaceuticals, Inc.; Protocol No.: KAR-004
SAP Version: Final v2.0
, Effective Date 30-Apr-2018
Page  of 
If the imputed stop date is before the start date, then the imputed stop date will be equal to the start date.
0LVVLQJGD\DQGPRQWK
x
If the year of the incomplete stop date is the same as the year of the last dosing date, then the 
day and month of the last dosing date will be assigned to the missing fields. 
x
If the year of the incomplete stop date is prior to the year of the last dosing date or prior to the 
year of the first dosing date, then December 31 will be assigned to the missing fields. 
x
If the year of the incomplete stop date is prior to the year of the last dosing date but is the same 
as the year of the first dosing date, then the first dosing date will be assigned to the missing date. 
x
If the year of the incomplete stop date is after the year of the last dosing date, then January 1 will 
be assigned to the missing fields.
0LVVLQJGD\RQO\
x
If the month and year of the incomplete stop date are the same as the month and year of the last 
dosing date, then the day of the last dosing date will be assigned to the missing day. 
x
If either the year of the partial date is not equal to the year of the last dosing date or the year of 
the partial date and the last dosing date are the same but the month of partial date is not equal to 
the month of the last dosing date, then the last day of the month will be assigned to the missing 
day. 

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Unscheduled visits will not be windowed to protocol-specified visits—nominal visits will be used for all by 
visit summaries.  Data collected at unscheduled visits will be included in the data listings but will not be 
included in the analyses unless otherwise stated.
Early termination visits for efficacy and safety endpoints (PANSS, CGI, C-SSRS scores and vital signs) will 
be reassigned to the next applicable scheduled visit for each assessment. Otherwise, no visit windowing 
will be performed.
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For analyses not stratified by site, data from all study centers will be combined. For analyses stratified by 
site, study centers with two or fewer subjects of any treatment group will be combined and considered as 
one ‘Other’ site in the analysis.
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Sponsor: Karuna Pharmaceuticals, Inc.; Protocol No.: KAR-004
SAP Version: Final v2.0
, Effective Date 30-Apr-2018
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The number of subjects in each analysis population (ITT population, Safety population, MITT population, 
PK population, Completer population, and PP population), the number of subjects who completed the study, 
and the number of subjects who withdrew early from the study and the reasons for discontinuation will be 
summarized by treatment group and overall. 
The reasons for early discontinuation include: 
x
Adverse Event
x
Consent Withdrawn
x
Lost to follow-up
x
Investigator decision
x
Death
x
Pregnancy
x
Other
Subjects’ completion/discontinuation status will be listed, including subject identifier, informed consent date, 
date of completion/early discontinuation and, for those who discontinued early, the specific reason(s) for 
discontinuation.
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Inclusion/exclusion criteria definitions and violations will be listed. If no inclusion/exclusion violations are 
reported, this will be noted in place of the listing.

3URWRFRO'HYLDWLRQV
All protocol deviations will be tracked in the clinical study management system. Deviations considered major 
will be identified as such before study unblinding during medical monitor periodic review.
Major protocol deviations will be summarized by the following categories for all subjects in the ITT 
Population, including the number of subjects with at least one major protocol deviation. All protocol 
deviations related to study inclusion or exclusion criteria, conduct of the trial, subject management, or 
subject assessment will be listed. 
Protocol deviation category includes:
x
Inclusion Criteria
x
Exclusion Criteria
x
Randomization Error
x
ICF
x
SAE Not Reported
x
Visit Out of Window
x
Missed Study Visit
x
Procedure Not Per Protocol
x
Concomitant Medication
x
Lab Sample
x
IP Preparation or Dosing Error
x
Other
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Sponsor: Karuna Pharmaceuticals, Inc.; Protocol No.: KAR-004
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Age (years), height (cm), weight (kg), and BMI (kg/m2) will be summarized descriptively by treatment group 
and overall for the ITT Population, Safety Population, MITT Population, Completer Population, and Per-
Protocol Population. Sex, race, ethnicity, and child-bearing potential status will be summarized by frequency 
counts. Body mass index is calculated based on weight and height at baseline.
Demographic data and baseline characteristics (as detailed above) as well as informed consent data will 
be listed. 
The following calculations will be utilized:
Height (in cm) = height (in inches) * 2.54
Weight (in kg) = weight (in lbs) * 0.4536
BMI (kg/m2) = Weight(kg)/[Height(m)2] 
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The medical or psychiatric history are recorded and coded with Medical Dictionary for Regulatory Activities
(MedDRA) version 21.0. 
A summary of medical history will be presented by MedDRA System Organ Class (SOC) and Preferred
Term (PT) by treatment group and overall for the ITT Population. A listing of medical history by subject will
be provided.
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Baseline MINI test assessment will be listed.
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Subjects will be asked to report all prior and concomitant medications. Prior medications taken up to 6 
months before the study will be recorded. Prior and concomitant medications will be coded with World 
Health Organization (WHO) Drug Dictionary WHO-DD - B3 Enhanced version March 2018.
7.7.1.
Prior Medication
Prior medications are defined as any medications with a start date up to 6 months before the first dose date. 
The number and percentage of subjects using each medication will be summarized by treatment group and 
overall using the ITT Population by Anatomical Therapeutic Chemical class level 2 (ATC2) and preferred 
term together with the number and percentage of subjects using at least one medication within each 
treatment group.
7.7.2.
Concomitant Medication
Concomitant medications are defined as medications either ongoing as of the first dose date or which 
started on or after the first dose date. A medication may be considered both prior and concomitant. The 
number and percentage of subjects using each medication will be summarized by treatment group and 
overall using the ITT Population by ATC2 and preferred term together with the number and percentage of 
subjects using at least one medication within each treatment group.
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The PANSS is a medical scale used for measuring symptom severity of subjects with schizophrenia and is 
widely used in the study of antipsychotic therapy.[Kay 1987] 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. PANSS total score is the sum of 
all 30 items with a minimum score of 30 and a maximum score of 210. If a patient has a PANSS assessment 
recorded, but any of the 30 items are missing, the last nonmissing score for the respective item from 
previous assessments will be carried forward. Missing item score at baseline will not be imputed and the 
total score will be missing. If the total has > 30% of the items missing at a particular visit, the respective 
total score at the visit will not be calculated and will be treated as missing data in the analysis.
The PANSS assessed prior to the first dose taken will be used as the baseline score. PANSS assessed at 
Visit 6, Visit 8, and Visit 9 will be used as post-baseline scores.
8.1.1.
Primary Analysis
The primary endpoint of the study is the change from baseline in PANSS total score at Visit 9. The difference 
between KarXT and placebo at Visit 9 will be estimated using a mixed model for repeated measures 
(MMRM). The model will include the observed change from baseline PANSS total score at Visit 6, Visit 8,
and Visit 9 as the response variable. The treatment difference at Visit 9 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. Baseline PANSS total score, site, age, and gender will be used 
as covariates in the model. Any site with two or fewer subjects in any treatment group will be combined into 
an “Other” site for analysis.
An unstructured covariance structure will be applied for the MMRM analysis. In the event that the model 
does not converge with the unstructured covariance structure, the following covariance structures will be 
attempted in the following order: heterogeneous Toeplitz structure (TOEPH) and then heterogeneous 
compound symmetry (CSH). The denominator degrees of freedom will be computed using the Kenward-
Roger method.
The least square (LS) mean, standard error (SE), and LS mean difference between KarXT and placebo 
group at Visit 9 along with the 95% confidence interval (CI) will be provided. The p-value for the hypothesis 
testing will also be provided. Treatment difference will be assessed with a 2-sided alpha level of 0.05.  The 
SAS code planned for the analysis is outlined below.
proc mixed data=&data;
class trtp avisit site usubjid gender;
model chg= trtp avisit trtp*avisit base site age gender / ddfm=kr;
repeated avisit / subject=usubjid type=un;
lsmeans trtp*avisit / cl;
run;
The MITT population will be used for the primary efficacy analysis. Observed and change from baseline 
PANSS total scores will be summarized by visit for the MITT population.
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Estimated mean changes (with SE) from baseline PANSS total score will be graphed by treatment group 
and visit. The x-axis will include the visit (Visit 6, Visit 8, or Visit 9) and the y-axis will represent the change 
from baseline. LS mean estimates and SEs of these estimates from the primary MMRM will be used for the 
display.
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8.1.3.
Sensitivity Analyses of Primary Endpoint
The following sensitivity analyses will be performed for the primary endpoint:
x
Completer analysis: The primary efficacy analysis will be repeated for the Completer population. 
x
Per Protocol analysis: The primary efficacy analysis will be repeated for the PP population.  
x
Last observation carried forward (LOCF):  In this analysis, the missing PANSS total scores will be 
replaced by the previous post-baseline visit assessment values carried forward. The LOCF-imputed 
values at Visit 9 will be compared using an Analysis of Covariance (ANCOVA) model with treatment 
group as a fixed factor and baseline PANSS total score and site will be used as a covariate in the 
model. This analysis will be performed in the MITT population.
x
Multiple Imputation (MI) analysis with Missing At Random assumption:
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MI techniques based on Pattern Mixture Models (PMM) will be applied as a sensitivity analysis 
in the MITT population. This methodology will structure data based on missing data patterns. 
The method will be based on a missingness pattern having a monotone structure, i.e. if among 
the observations over time the PANSS total score at a visit is missing, the PANSS total socre 
at all the following visits will also be treated as missing. For subjects with intermittent missing 
values, before performing MI based on the PMM, it will be necessary to create a monotone 
missingness pattern. Intermittent missing values will be imputed using the Markov Chain Monte 
Carlo (MCMC) methodology which assumes a multivariate normal distribution over all variables 
included in the imputation model. The MI procedure in SAS will be used for this purpose and 
this first MI step is planned to be repeated 100 times, creating several different datasets with a 
monotone missing data structure. A seed value of 201809 will be used in the MI procedure. 
The imputation is based on the missing at random (MAR) assumption, i.e. the missing data are 
assumed to follow the same model as the other subjects in their respective treatment group. 
R
After this, the remaining missing data can be imputed using a method for monotone 
missingness, also based on the MAR assumption. Thus, for each of the created datasets with 
a monotone missing data pattern, the MI procedure in SAS will be used to impute missing 
values based on a sequential procedure reflecting the monotone missing data pattern. Subjects 
with the first missing value occurring at Visit 6 will have their missing Visit 6 value replaced by 
an imputed value from a regression model with treatment group, site, and the change from 
baseline PANSS score as explanatory variables. In the next step, subjects with their Visit 8
value missing will have their missing Visit 8 value replaced by an imputed value from a 
regression model with treatment group, the change from baseline PANSS total score at 
baseline and the Visit 6 value as explanatory variables. A similar procedure will be used to 
impute the missing values at Visit 9. 
R
The imputed datasets generated with the approach described above do contain only non-
missing values and are used as input in the model for the sensitivity analysis of the primary 
endpoint. MMRM models similar as described above will thus be run on each of the generated 
imputed datasets and the difference between the treatment groups at Visit 6, Visit 8, and Visit 
9 will be estimated. The MMRM model will be similar to the primary analysis. Finally, the 
MIANALYZE procedure in SAS will be applied to combine the results from these several 
datasets to derive an overall estimate of the treatment difference at Visit 9. In addition to the 
estimates, corresponding 95% confidence intervals and p-values will be calculated.
x
MI analysis with Missing Not At Random assumption (Placebo group based imputation):  Another MI 
analysis will be performed with the assumption that the data is not missing at random. Placebo group 
based assumption will be used, i.e. the trajectories of the subjects are assumed to follow the placebo
group after the discontinuation. Methods similar to the procedure described above will be used in the 
MITT population. However, the missing values will be imputed using Placebo based imputation.
x
MI analysis with Missing Not At Random assumption (Tipping point based imputation):  If the primary 
analysis significantly favors KarXT, another MI analysis will be performed in the MITT population with 
the assumption that the data in the KarXT group is not missing at random. A tipping point based 
assumption will be used, i.e. the trajectories of the subjects in the KarXT group after withdrawal are 
assumed to be worse by an amount of delta. After the MI using the MAR assumption, as defined 
above has been done, the amount of delta will be added to each imputed value in the KarXT group. 
Successively harsher deltas will be imposed on the imputed values in the KarXT group, starting with 
a PANSS total score increment (worsening) of 0.5 points. The delta is further increased in the steps 
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of 0.5 points (1.0, 1.5, 2.0, …) until the statistical significance is lost, i.e. until the p-value becomes 
>0.05. For the placebo group, the MI using MAR assumption will be used.
8.1.4.
Additional Analyses of Primary Endpoint
x
Observed and change from baseline results will be provided by visit
x
LS mean (SE), 95% CIs, and p-values of each treatment group and LS differences will be provided 
for Visit 6 and Visit 8
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8.2.1.
Hierarchical test for efficacy evaluation
If the primary efficacy endpoint is statistically significant, the secondary efficacy endpoints will be 
analyzed using hierarchical hypothesis tests in a fixed sequence procedure based on the following order:
a. 
PANSS Positive Score
b. 
CGI change from baseline
c. 
PANSS Negative Score
d. 
PANSS Marder Factor Score
e. 
Percentage of CGI responders (defined as a score of 1 or 2)
The efficacy tests will stop if the previous test shows no statistical siginificance in favor of KarXT at the 
alpha level 0.05. 
8.2.2. 
Change from Baseline in PANSS Positive Score
PANSS positive score is the sum of all PANSS 7 positive symptom scales with a minimum score of 7 and 
a maximum score of 49. If a patient has a PANSS assessment recorded, but any of the 7 positive symptom 
scales are missing, the last nonmissing score for the respective item from previous assessments will be 
carried forward. If > 30% of the 7 positive symptom scale items missing at a particular visit, the respective 
positive score at the visit will not be calculated and will be treated as missing data in the analysis.
The PANSS positive score will be analyzed using a model similar to the MMRM used for the primary 
endpoint.
The model will include the observed change from baseline PANSS positive score at Visit 6, Visit 8, and 
Visit 9 as the response. The MMRM will include the treatment group (KarXT or placebo), visit, and the 
interaction between the treatment group and visit as fixed factors. Baseline PANSS positive score, site, age, 
and gender will be used as covariates in the model. 
Observed and change from baseline PANSS positive scores will be summarized by visit for the MITT
population.
Estimated mean changes (with SE) from baseline PANSS positive score will be graphed by treatment group 
and visit. The x-axis will include the visit (Visit 6, Visit 8, or Visit 9) and the y-axis will represent the change 
from baseline. LS means estimates and SEs of these estimates from the primary MMRM will be used for 
the display.
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8.2.3.
Change in CGI-S score
CGI-S will be assessed at screening, baseline (Day 1) and at the end of Visit 4, Visit 6, Visit 7, Visit 8, and 
Visit 9. The severity of the illness is categorized as: 1 = Normal, not at all ill; 2 = Borderline mentally ill; 3 = 
Mildly ill; 4 = Moderately ill; 5 = Markedly ill; 6 = Severely ill; and 7 = Among the most extremely ill patients. 
CGI-S scores will be summarized by visit using frequency counts for the MITT population.
In addition, shift tables from Baseline to worst value, last value, and at each scheduled post-Baseline visit 
will be provided by treatment group.
8.2.4. 
Change from Baseline in PANSS Negative Score
PANSS negative score is the sum of all PANSS 7 negative symptom scales with a minimum score of 7 and 
a maximum score of 49. If a patient has a PANSS assessment recorded, but any of the 7 negative symptom 
scales are missing, the last nonmissing score for the respective item from previous assessments will be 
carried forward. If > 30% of the 7 negative symptom scale items missing at a particular visit, the respective 
negative score at the visit will not be calculated and will be treated as missing data in the analysis.
The PANSS negative score will be analyzed using a model similar to the MMRM used for the primary 
endpoint.
The model will include the observed change from baseline PANSS negative score at Visit 6, Visit 8, and 
Visit 9 as the response. The MMRM will include the treatment group (KarXT or placebo), visit, and the 
interaction between the treatment group and visit as fixed factors. Baseline PANSS negative score, site, 
age, and gender will be used as covariates in the model. 
Observed and change from baseline PANSS negative scores will be summarized by visit for the MITT
population.
Estimated mean changes (with SE) from baseline PANSS negative score will be graphed by treatment 
group and visit. The x-axis will include the visit (Visit 6, Visit 8, or Visit 9) and the y-axis will represent the 
change from baseline. LS means estimates and SEs of these estimates from the primary MMRM will be 
used for the display.
8.2.5. 
Change in PANSS Marder Factor Score
PANSS Marder factor score is the sum of 5 negative scales and 2 general scales (N1. Blunted affect; N2. 
Emotional withdrawal; N3. Poor rapport; N4. Passive/apathetic social withdrawal; N6. Lack of spontaneity;  
G7. Motor retardation; and G16. Active social avoidance).  If a patient has a PANSS assessment recorded, 
but any of the item are missing, the last nonmissing score for the respective item from previous 
assessments will be carried forward. If > 30% of the items missing at a particular visit, the respective positive 
score at the visit will not be calculated and will be treated as missing data in the analysis.
The PANSS Marder Factor score will be analyzed using a model similar to the MMRM used for the primary 
endpoint.  
Observed and change from baseline PANSS Marder factor scores will be summarized by visit for the MITT
population.
Estimated mean changes (with SE) from baseline PANSS Marder factor score will be graphed by treatment 
group and visit. The x-axis will include the visit (Visit 6, Visit 8, or Visit 9) and the y-axis will represent the 
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change from baseline. LS means estimates and SEs of these estimates from the primary MMRM will be 
used for the display.
8.2.6.
CGI-S responders
A CGI-S responder is defined as a subject with CGI-S score equal to 1 or 2. A CGI-S non-responder is
defined as a subject with CGI-S scale equal to 3 to 7.
The percent of CGI-S responders at each visit will be compared between the treatment groups (KarXT and
placebo) using the Cochran-Mantel-Haenszel test stratified by site and baseline CGI-S score.  
Percentage of CGI-S responders at each visit will also be graphed by treatment group. The x-axis will 
include the visit (Visit 4, Visit 6, Week 3/Day 21, Visit 8, Visit 9) and the y-axis will represent the percentage
of subjects.
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PK analysis will be done for the PK population. PK parameters will be calculated using non-compartmental 
analysis (NCA) method for xanomeline and trospium using the validated software WinNonlin® (Version 8.0).
Actual sample collection times relative to dose administration will be used in the analysis. PK parameters 
will be estimated for an individual subject only if the subject exhibits measurable concentrations of drug at 
a minimum of three consecutive time points within a concentration-time profile (at least 50% of the subject 
concentrations data i.e. 3 out of 6 timepoints are not BLQ). 
PK concentrations are listed for all subjects in PK population. 
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PK samples to evaluate the exposure of xanomeline and trospium will be taken according to the following 
schedule and acceptable windows in Table 2. 
7DEOH3KDUPDFRNLQHWLF%ORRG6DPSOH&ROOHFWLRQDQG$FFHSWDEOH:LQGRZV
Visit/Day
Timepoints
Window
Visit 5/Day 8
Visit 8/Day 28
Predose morning
-
1 hour post morning dose
± 5 minutes
2 hour post morning dose
± 10 minutes
4 hour post morning dose
± 10 minutes
8 hour post morning dose
± 10 minutes
12 hour post morning dose
± 10 minutes (prior to evening dose)
Visit 9/ET
Single blood draw
Prior to discharge/ET
Unscheduled Visit/AE
Single blood draw
AE/dose adjustment
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9.3.1.
Handling of missing data 
Missing concentration data for all subjects who are administered scheduled study treatments will be 
considered as non-informative missing data and will not be imputed. No concentration estimates will be 
provided for missing sample values.
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In addition to standard non-compartmental analysis, the population PK modelling is planned for xanomeline 
and trospium, which will be performed as a two-step analysis. 
The details for population PK modelling will be described in a separate population PK SAP, and the results 
will be presented in a separate population PK modelling report.
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The population used for safety analyses will be the Safety population. Safety will be assessed on the 
basis of adverse events (AE), adverse events of special interest (AESI), clinical laboratory data, ECG 
parameters, physical examinations, and orthostatic vital signs
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The treatment duration (days) and cumulative dose taken (mg) will be summarized. The following 
calculation will be utilized:
Treatment duration (days) = last treatment date – first treatment date + 1
The number of subjects experiencing a dose reduction will be summarized.
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The number of doses planned to be taken, the number of doses actually taken, compliance (%), the number 
of doses missed, and the number of doses missed due to each cause will be summarized.  
The number of doses planned to be taken = (Last dose date – first dose date + 1) *2
Compliance (%) = number of doses actually taken/number of doses planned to be taken *100%
Treatment compliance data will listed based on drug administration data.
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Adverse events will be analyzed in terms of treatment-emergent adverse events (TEAEs) which are defined 
as AEs that are newly occurring or worsening from the time of the first dose of study medication. Reported 
AE terms will be coded using MedDRA version 21.0. 
The severity of AE is graded as mild, moderate, and severe. If the severity is missing, the TEAE will be 
considered to be severe for table summary purposes.
The relationship to study medication is evaluated as very likely/certain, probable, possible, unlikely, and 
unrelated. Events will be classified as related vs non-related. A related AE is an event with a relationship 
to treatment as very likely/certain, probable, or possible; a non-related AE is an event with relationship to 
treatment as unlikely, or unrelated. If the relationship to the study treatment is missing, the TEAE will be 
considered to be treatment-related for table summary purposes.
TEAEs will be summarized by SOC, PT and treatment group. TEAEs with onset after the last dose of the 
study treatment period are attributed to the treatment received during the treatment period. Both event and 
subject counts will be summarized. A subject with two or more AEs in an SOC or PT category is counted 
only once for the subject count. The counts will be complemented by percentages calculated for the subject 
counts unless otherwise specified.
The following summaries will be provided:
x
An overall summary of the number and percentage of subjects reporting TEAEs, serious TEAEs, 
severe TEAEs, treatment-related TEAEs, TEAEs leading to drug withdrawal, treatment-related 
TEAEs leading to drug withdrawal, and TEAEs leading to death.
x
TEAEs overall and by SOC and PT
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x
Treatment-related TEAEs overall and by SOC and PT
x
TEAEs by maximum severity, overall and by SOC and PT. A subject with two or more AEs in an 
SOC or PT category is counted only once at the maximum severity for the subject count.
x
TEAEs by maximum relationship (related vs. non-related) to study treatment, overall and by SOC 
and PT. A subject with two or more AEs in an SOC or PT category is counted only once at the 
maximum relationship to study treatment for the subject count.
x
Serious TEAEs, overall and by SOC and PT
x
Serious TEAEs by maximum relationship (related vs. non-related) to study treatment, overall and 
by SOC and PT
x
Non-Serious TEAEs, overall and by SOC and PT
x
TEAEs leading to study drug withdrawal, overall and by SOC and PT. This is a subset of the AEs 
where Action Taken with Study Treatment is checked as “Study Drug Stopped” is checked. 
x
TEAEs leading to death, overall and by SOC and PT. This is a subset of the AEs where SAE criteria
is checked as “Death”.  
The tables will be sorted by descending frequency of SOC according to KarXT column and then, within a 
SOC, by descending frequency of PT based on the subject count for the KarXT column. 
The original (non-imputed) date and time will be shown on all listings of AEs. Listings will be provided for 
all TEAEs, serious TEAEs, severe TEAE, Treatment-related TEAEs, TEAEs leading to study drug 
withdrawal, and TEAEs leading to death.Any TEAEs which code to a PT of “Syncope” and/or “Orthostasis” 
are AEs of special interest (AESI). They are already summarized in TEAEs overall and by SOC and PT 
table, and will not be summarized seperately. Treatment emergent AESI data will be listed.

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Clinical laboratory data are collected at the visits specified in Table 1. The assessments include:
Hematology: hemoglobin, hematocrit, mean cell volume, red blood cell count, white blood cell count with 
differential, and platelet count.
Serum Chemistry: alkaline phosphatase, gamma-glutamyl transferase, AST, ALT, lactate dehydrogenase, 
total bilirubin, total protein, cholesterol, triglycerides, urea nitrogen, uric acid, glucose, calcium, chloride, 
creatinine, inorganic phosphate, potassium, sodium, albumin, and bicarbonate.
Coagulation: prothrombin time, partial thromboplastin time, and fibrinogen.
Urinalysis: color/appearance, pH, glucose, specific gravity, ketones, protein, urobilinogen, occult blood, 
white blood cells, microscopic.
Other Laboratory Assessments: 
A serum pregnancy test for females of childbearing potential will be performed at screening, and urine 
pregnancy tests will be performed at other visits.
A NIDA-5 urine drug screen (cannabinoids or marijuana, phencyclidine, amphetamines, opiates, and 
cocaine) will be performed at screening only.
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Alcohol testing is performed using a breathalyzer or blood alcohol test. If a subject leaves the unit, he/she 
should have a urine drug screen test and test for alcohol (breathalyzer or blood alcohol test) upon returning 
to the unit.
The hematology, coagulation, and chemistry laboratory parameters will be summarized with descriptive 
statistics for the observed values at each visit and change from baseline to post-baseline visits values by 
treatment group.
The number and percentage of subjects with low, normal, or high values at each visit for each hematology, 
chemistry, and coagulation parameter will be summarized. These values will be presented as a shift table; 
ie, the distribution of the 3 response categories at each post-baseline visit will be classified by the baseline 
category.
Listings will be provided for the hematology, coagulation, chemistry, urinalysis, pregnancy tests, urine drug 
screen, and alcohol test results. 
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Observed and change from baseline result for body weight, BMI, and waist circumference will be 
summarized by visit and treatment. 
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Observed and change from baseline orthostatic vital signs will be summarized by visit and treatment. Box 
plots will be generated for the observed values of orthostatic vital signs by visit and by high/low dose group 
and overall for each treatment group.
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The standard 12-lead ECGs will be performed at the visits specified in Table 1.
A summary of ECG parameters (ventricular rate, PR, QRS, QT, and QTcF interval) and change from 
baseline will be presented by visit. 
In addition, the investigator’s interpretation will be summarized by visit. 
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A complete physical examination is performed at Visit 1 and Visit 9 and includes body temperature (°C), 
general appearance, head/eyes/ears/ nose/throat (HEENT), examination of the thorax and abdomen, 
assessment of cardiac, musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and 
limited neurological examination.
A summary of physical examinations will be presented by visit.
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10.9.1. 
A Simpson-Angus Rating Scale
The Simpson-Angus Scale 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.
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Observed and change from baseline Simpson-Angus Rating Scale total score, subscale score (Simpson-
Angus Rating Scale Total Score (Excluding Item 10)), and individual item scores will be summarized by 
visit for the Safety population.
10.9.2.
Barnes Rating Scale for Akathisia
The Barnes Rating Scale for akathisia is a rating scale used to assess the severity of drug-induced
akathisia, or restlessness, involuntary movements and inability to sit still. The range of scores is 0 to 14,
with higher scores indicating greater severity.
Observed and change from baseline Barnes Rating Scale and the four individual scores will be summarized
by visit for the Safety population.
10.9.3.
Abnormal Involuntary Movement Scale (AIMS)
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.
Observed and change from baseline AIMS, subscales (AIMS total score for items 1-7, AIMS total score for
items 1-10), and individual item scores will be summarized by visit for the Safety population.
10.9.4. 
C-SSRS
The C-SSRS is a measure of suicidal ideation and behavior. The rating scale has 4 general categories: 
suicidal ideation, intensity of ideation, suicidal behavior, and actual attempts. The frequency and percentage 
of subjects with each response for suicidal ideation, intensity of ideation, and suicidal behavior items will 
be summarized as appropriate by treatment group and visit.
All C-SSRS data will be listed.
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No interim analysis is planned for this study.
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The following changes were made from the analyses planned in Protocol Version 4.0:
2.
Hierarchical testing procedure for secondary endpoints is specified in section 8.2.1.
3.
Secondary endpoint analysis for PANSS negative scores is added in section 8.2.4. 
4.
Low dose and high dose group definitions are added in section 6.2.5. 
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SAS programs are developed to produce output such as analysis data sets, summary tables, data listings,
figures or statistical analyses. An overview of the development of programs is detailed in 
SOPs Developing Statistical Programs 
 and Quality Deliveries (SDTM, ADaM, TLF) 
describes the quality control procedures that are performed for all SAS programs and output. Quality 
control is defined here as the operational techniques and activities undertaken to verify that the SAS 
programs produce the output by checking for their logic, efficiency and commenting and by review of the 
produced output.  
 SOP Pharmacokinetic and Related Data Analyses and Reporting
 describes the 
procedure for the generation and reporting of PK and pharmacodynamics data. 
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