Clinical trial NCT05643170
Conditions: Schizophrenia
Sponsor: Karuna Therapeutics
Start date: 2022-11-08; Completion date: 2023-03-08
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 3b, 3-year, open-label, multi-center study in which patients with DSM-5 diagnosis of schizophrenia whose current medication(s) is not well tolerated and/or clinical symptoms are not well controlled will be switched to receive KarXT.

The primary objectives of the study are to assess the long-term safety and tolerability of KarXT and assess effectiveness, persistence, and durability of effect of KarXT through the Investigator Assessment Questionnaire (IAQ) and Clinical Global Impression - Severity of Illness (CGI-S) scale in patients with a diagnosis of schizophrenia.

The secondary objectives are to further assess the effectiveness using the Clinical Global Impression, Global Improvement (CGI-I), long-term safety and tolerability of KarXT, and evaluation of scores from multiple additional patient scales and assessments throughout the study.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Xanomeline and Trospium Chloride Capsules
Intervention descriptions: intervention 1: KarXT 50 mg/20 mg BID KarXT 100mg/20 mg BID KarXT 125mg/30 mg BID

Protocol documents:
Prot_SAP_000.pdf: 
Official Title of Study: 
A Multi-center, Open-label Study to Assess the Effectiveness, Long-term Safety, 
Tolerability, and Durability of Effect of KarXT in Patients With DSM-5 Diagnosis of 
Schizophrenia 
 
PROTOCOL(S) KAR-014 
 
NCT Number: NCT05643170 
  
Document Date (Date in which document was last revised): July 1, 2022 


KarXT 
Karuna Therapeutics 
Abbreviated Clinical Study Report  
KAR-014 v1.0 
 
Confidential 
Page 1 
16.1.1 
PROTOCOL AND AMENDMENTS 
Protocol KAR-014, Version 1.0, 01 July 2022 
Clarification Memorandum 20 October 2022 
 


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TITLE PAGE 
CLINICAL STUDY PROTOCOL 
A Multi-center, Open-label Study to Assess the Effectiveness, Long-term Safety, 
Tolerability, and Durability of Effect of KarXT in Patients With DSM-5 Diagnosis of 
Schizophrenia 
 
Protocol Number: KAR-014 
 
IND Number: 
127471 
EudraCT Number: 
Not applicable 
Name of Investigational Product: 
KarXT 
Phase of Development: 
Phase 3b 
Indication: 
Schizophrenia 
Sponsor: 
Karuna Therapeutics 
99 High Street 
26th Floor  
Boston, MA 02110 
Tel: (857) 449-2244 
Email: info@karunatx.com 
Protocol Version:  
v1.0  
Protocol Date: 
01 JUL 2022 
 
 
 
 
 
 
 


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PROTOCOL APPROVAL SIGNATURES 
Protocol Title: 
A Multi-center, Open-label Study to Assess the Effectiveness, 
Long-term Safety, Tolerability, and Durability of Effect of KarXT 
in Patients With DSM-5 Diagnosis of Schizophrenia 
Protocol Number: 
KAR-014 
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Council for Harmonisation (ICH) guidelines for current Good 
Clinical Practice (GCP), and applicable regulatory requirements. 
Sponsor Signatory 
 MD 
 
Karuna Therapeutics 
Date (DD-MMM-YYYY) 
MD, MBA 
 
Karuna Therapeutics 
Date (DD-MMM-YYYY) 
 


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INVESTIGATOR SIGNATURE PAGE 
Protocol Title: A Multi-center, Open-label Study to Assess the Effectiveness, Long-term Safety, 
Tolerability, and Durability of Effect of KarXT in Patients With DSM-5 Diagnosis of 
Schizophrenia  
Protocol Number: KAR-014 
Confidentiality and GCP/E6(R2) Compliance Statement 
• I, the undersigned, have reviewed this protocol. I will conduct the study as described in 
compliance with this protocol and relevant ICH guidelines, including GCP and applicable 
regulatory requirements. 
• I am thoroughly familiar with the appropriate use of the study drug, as described in this 
protocol, and any other information provided by Karuna Therapeutics, including, but not 
limited to, the current investigator’s brochure. 
• Prior to initiating the trial, I will provide the independent ethics committee 
(IEC)/institutional review board (IRB) all items subject to review and will obtain a 
written and dated approval/favorable opinion. Once the protocol has been approved by 
IEC/IRB, I will not modify this protocol without obtaining prior approval from Karuna 
Therapeutics and of the IEC/IRB. I will submit the protocol amendments and/or any 
informed e-consent form modifications to Karuna Therapeutics and the IEC/IRB, and 
approval will be obtained before any amendments are implemented. 
• I ensure that all persons or parties assisting me with the study are adequately qualified 
and informed about the Karuna Therapeutics study drug and of their delegated 
study-related duties and functions as described in the protocol. I will supervise these 
delegated persons or parties in the conduct of this trial.  
• I ensure that source documents and trial records that include all pertinent observations on 
each site’s trial subjects will be attributable, legible, contemporaneous, original, accurate, 
and complete.  
• I understand that all information obtained during the conduct of the study with regard to 
the subjects’ state of health will be regarded as confidential. No subjects’ names will be 
disclosed. All subjects will be identified by assigned numbers on all case report forms, 
laboratory samples, or source documents forwarded to the Sponsor. Clinical information 
may be reviewed by the Sponsor or its agents or regulatory agencies. An agreement must 
be obtained from the subject before disclosure of subject information to a third party. 
• Information developed in this clinical study may be disclosed by Karuna Therapeutics to 
other clinical investigators, regulatory agencies, or other health authorities or government 
agencies as required. 
Name: 
Signature: 
Title: 
Institution: 
Date (DD-MMM-YYYY) 


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1. 
PROTOCOL SYNOPSIS 
Title of Study: 
A Multi-center, Open-label Study to Assess the Effectiveness, 
Long-term Safety, Tolerability, and Durability of Effect of KarXT in 
Patients With DSM-5 Diagnosis of Schizophrenia 
Protocol Number: 
KAR-014 
Investigators/Study 
Sites: 
Approximately 25 study sites in the United States (US) 
Phase of 
Development: 
Phase 3b 
Rationale: 
To collect long-term (up to 3-years) safety data in patients with 
schizophrenia requiring a change in antipsychotic medication because 
their current medication(s) is not well tolerated and/or clinical 
symptoms are not well controlled. Patients will be switched to receive 
KarXT based on the investigator’s judgment to optimize treatment for 
each individual patient in a naturalistic trial.   
Objective(s): 
Primary Objectives: 
• Assess the long-term safety and tolerability of KarXT,  
• Assess effectiveness, persistence, and durability of effect of 
KarXT through the Investigator Assessment Questionnaire 
(IAQ) and Clinical Global Impression – Severity of Illness 
(CGI-S) scale in patients with a diagnosis of schizophrenia. 
Secondary Objectives: 
To further assess: 
• Effectiveness using the Clinical Global Impression - Global 
Improvement (CGI-I) at week 2 through week 24.  
• Long-term safety and tolerability of KarXT.  
• Evaluation of total scores from multiple economic patient 
scales and caregiver burden throughout the study. 
Endpoint(s): 
Primary Endpoints:  
• The primary safety endpoint is the incidence of 
treatment-emergent adverse events (TEAEs) leading to 
discontinuation.   


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• The primary efficacy endpoints are persistence and durability 
of effect of KarXT via IAQ and CGI-S scores at clinical visits 
throughout the study.   
Secondary Safety Endpoints: 
• Incidence of serious TEAEs (TESAEs). 
• Incidence of TEAEs of special interest.  
Secondary Efficacy Endpoints: 
• CGI-I scores at week 2 through week 24.   
• MSQ throughout the study. 
Other Endpoints: 
Safety: 
• Incidence of spontaneously reported TEAEs of special interest. 
• Incidence of spontaneously reported anticholinergic and 
procholinergic symptoms. 
• Change from baseline in clinical laboratory assessments (with 
emphasis on monitoring metabolic syndrome; waist 
circumference, blood pressure, fasting [preferred] blood 
glucose, high-density lipoprotein [HDL] cholesterol, and 
triglyceride levels).  
• Change from baseline in physical examinations, vital signs, 
body weight, and body mass index (BMI).   
• Barnes Akathisia Rating Scale (BARS). 
• Abnormal Involuntary Movement Scale (AIMS).  
Other: 
• Adherence to KarXT at different timepoints. 
• Time to treatment discontinuation for any reason.  
• Accountable Health Communities Health-Related Social 
Needs (AHC HRSN) screening tool.  
• Zarit Caregiver Burden Interview (ZBI-22). 
• EQ-5D-3L questionnaire.  
• Brief Cognitive Assessment Tool for Schizophrenia (B-CATS) 
(1. digit symbol substitution test, 2. trail making test part B, 
and 3. category fluency). 


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• Single nucleotide polymorphisms (SNPs) related to 
schizophrenia subtypes and drug metabolism. 
Study Design: 
This is a Phase 3b, 3-year, open-label, multi-center study in which 
patients with schizophrenia requiring a change in antipsychotic 
medication because their current medication(s) is not well tolerated 
and/or clinical symptoms are not well controlled will be switched to 
receive KarXT based on the investigator’s judgment for need of 
treatment optimization for the individual patient. The study’s 
objectives are to assess the effectiveness, long-term safety, 
tolerability, and durability of effect of KarXT in patients with 
Diagnostic and Statistical Manual‒Fifth Edition (DSM-5) diagnosis 
of schizophrenia.  
A suitable number of patients with schizophrenia (age 18 to 65 years) 
will be screened to enroll approximately 380 patients. To be eligible, 
patients will have experienced symptoms during screening that 
require treatment with an antipsychotic medication, demonstrated a 
previous response to antipsychotic medication (other than clozapine), 
and require a change of medication regimen because current 
medication is not well-tolerated and/or clinical symptoms are not 
well-controlled as judged by the investigator.  
The patients can be adequately managed in outpatient settings (do not 
require hospitalization) across approximately 25 study sites in the 
United States via a decentralized, site-centric model.  
Screening Phase: 
The screening phase will be up to 21 days (up to 7 day screening 
extension is permitted with medical monitor approval). 
Baseline Visit: 
Patients who meet the screening criteria will participate in a study 
baseline visit. It is preferred that all baseline assessments are 
completed in one visit. 
Treatment Phase: 
In this open-label study, all patients will receive KarXT for up to 
3 years.  
All patients will start on a lead in dose of KarXT 50/20 mg (50 mg 
xanomeline/20 mg trospium) twice daily (BID) for 7 days (Day 1 to 
Day 7). A telephone check-in will occur on Day 7 to determine if the 
patient will titrate to the KarXt 100/20 mg BID dose for the 2nd week 
(Day 8 to Day 14) or remain on the lead in dose (50/20 mg BID). At 
Clinic Visit 2 (end of week 2/Day 14), the dose may be titrated 
upwards to either KarXT 100/20 mg BID if the patient had remained 


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on the 50/20 mg BID dose through Day14, or the dose will increase 
to KarXT 125/30 mg BID if the patient was on the 100/20 mg BID 
through Day 14.  If the patient continues to experience adverse events 
(AEs) from the 50/20 mg BID dose of such severity that they are not 
able to titrate up at Day 14 (end of week 2), the patient must be 
discontinued. If the patient experiences AEs from the 100/20 mg BID 
dose and is not able to titrate up and/or, in the opinion of the 
investigator, a longer period on the 100/20 mg BID dose is necessary, 
patients may continue this dose. Thus, all patients will attempt 100/20 
mg BID dosing for at least 1 week. All patients who are increased to 
KarXT 125/30 mg BID or 100/20 mg BID, depending on tolerability, 
will have the option to return to KarXT 100/20 mg BID or 50/20 mg 
BID throughout the study. Re-escalation to 125/30 mg BID or 
100/20 mg BID or re-titration in cases in which the patient has been 
off KarXT for a longer period of time (at least 7 days) is allowed and 
will require a discussion between the investigator and the medical 
monitor. Additional changes to KarXT dosing (e.g., temporary dose 
reductions) may be permitted as clinically indicated per investigator 
discretion.     
In summary, upward titration is expected to optimize efficacy; 
however, if efficacious and better tolerated, any of the available doses 
could be used for maintenance. Unscheduled (UNS) visits, which can 
be conducted in-clinic or by telemedicine, may occur between 
required clinic visits as deemed necessary by the investigator to 
facilitate patient retention and ensure compliance with study 
objectives. (See Schedule of Assessments Table 1).  
End of Study (EoS) Safety Follow-up Visit: 
An EoS safety follow-up visit will be performed for all patients who 
have been dosed with KarXT. The EoS visit will take place 7 to 
28 days after the last dose of KarXT for patients who complete the 
treatment phase (End of Treatment [EoT]) and for patients who 
choose to discontinue from the study early (early termination [ET]), 
at the discretion of the investigator, per sponsor request, or if the 
sponsor terminates the study.(See Schedule of Assessments Table 1). 
Entry criteria: 
Inclusion Criteria: 
Individuals must meet all the following criteria to be included in the 
study: 
1. Patient is aged 18 to 65 years, inclusive, at screening.
2. Patient can provide informed consent.
a.
A signed informed consent form (ICF) must be provided
before any study assessments are performed.


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b. Patient must be fluent (oral and written) in the language of 
the ICF to consent. 
3. Patient has a primary diagnosis of schizophrenia established 
by a comprehensive psychiatric evaluation based on the 
DSM-5 (American Psychiatric Association, 2013) criteria 
and has been in the continuous care of the clinician or 
practice for at least 6 months prior to entering the study.   
4. The patient is dissatisfied with the side effects or general 
tolerability of their current antipsychotic medication, and for 
this reason, desires to change medications. Or, the patient is 
dissatisfied with the overall effectiveness or benefit of their 
current antipsychotic medication, and for this reason, desires 
to change medications.  
5. The patient has not required psychiatric hospitalization, acute 
crisis intervention, or other increase in their level of care due 
to symptom exacerbation within 4 weeks of screening, and in 
the opinion of the investigator, is psychiatrically stable to be 
managed in an outpatient setting.   
6. The patient has a CGI-S score of ≤4 (moderately severe or 
less) at screening and baseline visits.   
7. For at least 30 days prior to screening, the patient must have 
been prescribed and have taken an oral antipsychotic 
medication daily at a dose and frequency consistent with the 
drug label.  
8. The patient is willing and able, and in the opinion of the 
investigator it is clinically appropriate, to discontinue all 
antipsychotic medications prior to the baseline visit or to 
taper their current antipsychotic medication(s) with 
cross-over administration for up to two weeks (14 days) of 
dosing with KarXT (unless the patient is on olanzapine or 
quetiapine, which require discontinuation before KarXT 
initiation).  
In summary: 
a. Patients may washout antipsychotic medication during the 
screening phase (21 to 28 days prior to baseline) at the 
discretion of the investigator. Thus, the patient would have 
discontinued all antipsychotic medication prior to 
baseline.  
b. Or patient may down taper or continue down taper 
(washout) antipsychotic medication through the initial 
2 weeks of KarXT dosing (excluding olanzapine or 


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quetiapine, which require discontinuation before KarXT 
initiation). 
c. All patients must be washed out (discontinued) of all 
antipsychotic medication other than KarXT by end of 
week 2 (Day 14). 
9. Patient has an identified, reliable caregiver/informant that is 
willing (by informed consent) and able to respond to the 
ZBI-22 caregiver burden scale at specified visits. The 
caregiver/informant must be consistent throughout the 
duration of the study. If the patient has been the patient of the 
investigator for ≥6 months and, in the opinion of the 
investigator, the patient is self-sufficient, then a 
caregiver/informant may not be necessary.  
10. At the time of the Baseline Visit, the patient will have been 
off lithium therapy for at least 2 weeks. 
11. If taking a long-acting injectable (LAI) antipsychotic, the 
patient has not received a dose of the medication for at least 
12 weeks (24 weeks for INVEGA TRINZA®) before the 
Baseline Visit. 
12. Patient BMI must be ≥18.0 and ≤45.0 kg/m2. 
13. Patient resides in a stable living situation and is anticipated to 
remain in a stable living situation for the duration of the 
study, in the opinion of the investigator. 
14. If a woman of childbearing potential (WOCBP) or a man 
whose sexual partner(s) is a WOCBP, the patient must be 
willing and able to adhere to the contraception guidelines as 
defined in Section 12.1 Appendix 1. 
Exclusion Criteria: 
If any of the following exclusion criteria apply, a patient may not 
participate in the study: 
1. Any primary DSM-5 disorder diagnosis other than 
schizophrenia within 12 months before screening. 
Exclusionary disorders include, but are not limited to, 
bipolar I or II disorder and schizoaffective disorder. 
Symptoms of mild mood dysphoria or anxiety are allowed, as 
long as these symptoms are not the primary focus of 
treatment. 
2. The patient has a history of moderate to severe alcohol use 
disorder or a substance (other than nicotine or caffeine) use 
disorder within the past 12 months or has a positive urine 


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drug screen (UDS) for a substance other than cannabis at 
screening and baseline. 
a. A patient with mild substance abuse disorder within the 12 
months before screening must be discussed and agreed 
upon with the medical monitor before he/she can be 
allowed into the study. 
b. Patients with a positive UDS for cannabis are permitted to 
enroll in the study provided that the patient’s pattern of 
use is not indicative of a substance use disorder. 
3. The patient has a history of or presence of a 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, is likely to 
jeopardize the safety of the patient or the validity of the study 
results. 
4. Patient has human immunodeficiency virus (HIV) unless 
they are considered stable for 12 months prior to screening 
on highly active antiretroviral therapy (HAART) therapy 
(CD4 >500 and undetectable viral load); cirrhosis; biliary 
duct abnormalities; hepatobiliary carcinoma; and/or active 
hepatic viral infections based on either medical history or 
liver function test results. 
5. Patient has a history of or is at high risk of urinary retention, 
gastric retention, or narrow-angle glaucoma. 
6. Patient has a history of irritable bowel syndrome (with or 
without constipation) or constipation requiring treatment for 
more than 30 days within the last 6 months. 
7. Patient is at 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. Patient answers “Yes” on items 4 or 5 
(C-SSRS – ideation) with the most recent episode 
occurring within the 2 months before screening, or patient 
answers “Yes” to any of the 5 items (C-SSRS behavior) 
with an episode occurring within the 12 months before 
screening. Non-suicidal self-injurious behavior is not 
exclusionary. 


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8. Patient is at risk of violent or destructive behavior or serious 
harm to others, as determined by the investigator’s clinical 
assessment. 
9. Clinically significant abnormal finding on the physical 
examination, medical history, electrocardiogram (ECG), or 
clinical laboratory results at screening.  (Aspartate 
aminotransferase (AST) or alanine transaminase (ALT) 
>2x upper limit of normal (ULN) or total bilirubin (Tbili) 
>2x ULN (unless due to suspected Gilbert’s), hemoglobin 
<10 g.dL, white blood cell (WBC) <3 K, absolute neutrophil 
count (ANC) <1000, platelets <100 K, QTc >450 msec in 
males and >470 msec in females.)  
10. Currently and within 2 weeks before the Baseline Visit, 
patients cannot be receiving monoamine oxidase inhibitors, 
anticonvulsants (e.g., lamotrigine, Depakote), tricyclic 
antidepressants (e.g., imipramine, desipramine), centrally 
active anticholinergics (benztropine, trihexyphenidyl, 
diphenhydramine), or any other psychoactive medications 
other than daily antipsychotic maintenance therapy.  
a. As needed (PRN) anxiolytics and/or sleep aids are 
permitted (e.g., lorazepam, zolpidem). 
b. Selective serotonin reuptake inhibitors (SSRI’s)/ serotonin 
and norepinephrine reuptake inhibitors (SNRIs) taken at 
stable dose for at least 4 weeks before screening and that 
are anticipated to be continued at the same dose 
throughout the study are permitted. 
c. Benztropine (Cogentin) or similar medications used for 
extrapyramidal symptoms (EPS) will need to be tapered 
down slowly as withdrawal symptoms are likely. The 
suggested approach is a maximum 50% reduction per 
week until a 0.25 mg dose is reached. 
d. PRN second generation antihistamines, e.g., fexofenadine, 
loratadine, and cetirizine (that do not readily cross the 
blood-brain barrier [BBB]), could be used after the first 
month of the study for temporary symptom management 
of allergies. 
11. Patient has a history of treatment resistance to schizophrenia 
medications defined as:  
a. Failure to respond to 3 adequate courses of 
pharmacotherapy (a minimum of 4 weeks at an adequate 
dose per the label) within the past 12 months, OR 
b. Having received clozapine within the past 3 years. 


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12. Patient is pregnant, lactating, or less than 3 months 
postpartum. 
13. Patient has any other medical, psychiatric, or social condition 
that, in the opinion of the investigator, is likely to 
unfavorably alter the risk-benefit of patient participation, to 
interfere with protocol compliance, or to confound safety or 
efficacy assessments.   
14. Patient has tested positive for coronavirus disease 2019 
(COVID-19) within 2 weeks of screening and/or baseline or 
patients who have prolonged symptoms of past infection, 
long COVID, that, in the opinion of the investigator, may 
interfere with the interpretation of safety during the study.  
15. Patient with extreme concerns relating to global pandemics, 
such as COVID-19, that precludes study participation. 
16. Patient is currently or recently (within 4 weeks of screening) 
involuntary hospitalization or incarceration. 
17. Patient participated in another clinical study in which they 
received an experimental or investigational drug agent within 
30 days prior to screening. 
Planned Sample 
Size: 
Approximately 380 patients (age 18 to 65 years) are planned to be 
enrolled in this study. 
Investigational 
Therapy: 
• Lead in fixed dose KarXT 50/20 mg BID (50 mg 
xanomeline/20 mg trospium) oral (Day 1 to Day 7) that can be 
extended beyond week 1. 
• Fixed dose KarXT 100/20 mg BID (100 mg xanomeline/20 mg 
trospium) oral (Day 8 to Day 14) that can be extended 
throughout the study.  
• Fixed dose KarXT 125/30 mg BID (125 mg xanomeline/30 mg 
trospium) oral (Day 15 to 3 years) if tolerated or deemed 
appropriate beginning no earlier than Day 15.  
Throughout the study, the investigator will have the flexibility of 
managing (up or down-titrating) doses in accordance with their 
clinical judgement for best patient outcomes. If patients cannot 
tolerate KarXT 50/20 mg BID dose by the end of week 2 (Day 14) as 
to allow for up-titration to 100/20 mg BID, they must be early 
terminated from the study. 
Patients who cannot maintain 65% adherence to the study drug over 
any 8 week period throughout the study, unless there is 


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hospitalization involved, will be discontinued from the study. The 
adherence assessments will be based on pill counts, patient recall, and 
caregiver report, if applicable.  
Reference Therapy: 
Not applicable. 
Treatment Duration: Treatment duration is approximately 3 years. 
Safety Assessments: 
• Adverse Events 
• Spontaneously reported TEAEs of special interest 
• Spontaneously reported anticholinergic and procholinergic 
symptoms 
• Clinical laboratory assessments (with an emphasis on 
monitoring metabolic syndrome; waist circumference, blood 
pressure, fasting (preferred) blood glucose, HDL cholesterol, 
and triglyceride levels) 
• Physical examinations, vital signs, body weight, and BMI   
• BARS 
• AIMS 
Efficacy 
Assessments: 
• CGI-S scores  
• IAQ  
• CGI-I scores  
• MSQ 
Other Assessments: 
• AHC HRSN screening tool to be completed by the patient, 
caregiver, or patient with help from caregiver 
• ZBI-22 
• Adherence to KarXT at different timepoints 
• EQ-5D-3L questionnaire  
• B-CATS (1. digit symbol substitution test, 2. trail making test 
part B, and 3. category fluency) 
• SNPs related to schizophrenia subtypes and drug metabolism   
Statistical Methods 
and Planned 
Analyses: 
Study Populations: 
Enrolled population: All patients who give informed consent for 
KAR-014 will be included in the enrolled population. 


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Safety population: All patients who receive at least 1 dose of KarXT 
in study KAR-014 will be included in the safety population and will 
be used in the safety analyses. 
Modified intent-to-treat (mITT) population: All patients who are 
enrolled and received KarXT through week 8, will be included in the 
mITT population and will be used in the efficacy and other analyses. 
Descriptive statistics will be used to provide an overview of the 
safety and efficacy results. For continuous parameters, descriptive 
statistics will include n, mean, median, standard deviation, minimum, 
and maximum. For categorical parameters, the number and 
percentage of patients in each category will be presented. The 
denominator for percentages will be based on the number of patients 
appropriate for the purposes of analysis. No statistical hypothesis 
testing will be performed. 


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Table 1: 
Schedule of Assessments 
Screening and Baseline 
DAY
-21 to -1 
0 
VISIT
Screening1 
Baseline 
Visit 12 
TYPE OF VISIT
C 
C 
PROCEDURE 
 
 
Written informed consent3 
X 
 
Collect demographic information (date of birth, age, sex, race, ethnicity) 
X 
 
Patient eligibility verification process 
X 
 
Medical, psychiatric, and medication history 
X 
 
Urine pregnancy test (WOCBP only)4 
X 
X 
Urine drugs of abuse and alcohol testing5 
X 
X 
Review of inclusion/exclusion criteria 
X 
X 
Height, body weight, BMI, waist circumference6 
X 
X 
Complete Physical Examination7 
X 
 
Targeted Physical Examination8 
 
X 
Spontaneous AEs9 
 
X 
Review of concomitant medications 
X 
X 
Vital signs: BP and HR10 
X 
X 
Resting ECG (12-lead)11 
X 
X 
Blood samples for clinical laboratory tests12 
X 
X 
Blood sample for viral serology13 
X 
 
Blood sample for DNA testing 
 
X 


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Abbreviations: AE = adverse event; AHC HRSN = Accountable Health Communities Health-Related Social Needs; AIMS = Abnormal Involuntary Movement 
Scale; BARS = Barnes Akathisia Rating Scale; BMI = body mass index; BP = blood pressure; C= Clinic visit; CGI-I = Clinical Global Impression – Global 
Improvement; CGI-S = Clinical Global Impression‒Severity Scale; C-SSRS = Columbia-Suicide Severity Rating Scale; d = day; DNA = deoxyribonucleic 
acid; ECG = electrocardiogram; EQ-5D-3L = Euroqol-5D-3L; HBV= hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
HR = heart rate; IAQ= Investigator Assessment Questionnaire; MSQ = Medication Satisfaction Questionnaire; NIDA-5 = National Institute on Drug Abuse-5; 
PI = principal investigator; QTcF = QT interval corrected by Fridericia; WOCBP = women of childbearing potential; ZBI-22 = Zarit Caregiver Burden 
Interview. 
1. Screening period of 21 days (up to 28 days).  7-day extension permitted with medical monitor approval. 
2. Baseline visit may be up to 7 days.  Preference is for baseline visit to be completed in one (1) day. 
3. Informed Consent to be obtained from patient and patient’s caregiver, if applicable.  See inclusion criteria 9. 
4. A urine pregnancy test for WOCBP should be performed at scheduled visits. In case of a positive urine pregnancy test result, a serum sample should be sent to 
the central laboratory for confirmation of the result. 
5. A NIDA-5 urine drug screen (cannabinoids or marijuana, phencyclidine, amphetamines, opiates, and cocaine) and test for alcohol (breathalyzer or urine 
alcohol level) will be performed locally at scheduled visits. A sample should be sent to the central lab at screening. Thereafter, if positive, except for 
cannabinoids or marijuana, a sample should be sent to the central laboratory for confirmation of the result.  
6. Height is recorded at screening only. 
7. 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. 
COVID-19 Rapid Test  
 
X 
C-SSRS14 
X 
X 
CGI-S 
X 
X 
IAQ 
 
X 
MSQ 
X 
 
AHC HRSN15  
 
X 
EQ-5D-3L 
 
X 
AIMS 
 
X 
BARS 
 
X 
ZBI-22 
 
X 
Brief Cognitive Assessment Tool for Schizophrenia 
 
X 
KarXT dispensed16 
 
X 


Karuna Therapeutics 
KAR-014 
KarXT 
v1.0 01 JUL 2022 
 
 
 
Page 17 of 78 
8. A targeted physical examination includes at a minimum body temperature, a check of general appearance, examination of organ systems that are relevant to 
the investigator based on review of the patient’s reported AEs, review of systems, and concomitant medication use. These also include symptom-driven 
physical examinations, which will be performed as clinically indicated at any study visit. 
9. AEs as reported by patients or observed by clinical staff and occurs after informed consent.   
10. Vital signs measurements should be taken at scheduled in-clinic visits, which include systolic and diastolic BP and HR. Per PI discretion, orthostatic vital 
signs may be assessed, but are not mandatory. 
11. ECG should be obtained before blood collection for any safety laboratory tests whenever possible. During the ECG, ventricular rate (bpm), PR (msec), QRS 
(msec), QT (msec), and QTcF (msec) measurements should be obtained. 
12. Refer to Section 8.2.12 (Table 2) for individual laboratory tests. For urinalysis, a urine dipstick will be performed locally. In the event of abnormalities, the 
sample will be sent to the central laboratory for full microscopic urinalysis. 
13. All patients must have the following viral serology tests completed at Screening:  anti-HCV antibody, HBV surface antigen, HBV core antibody, HIV-1 
antibody, and HIV-2 antibody. If the patient tests positive for anti-HCV antibody, then HCV RNA via polymerase chain reaction should be performed to 
confirm or rule out active infection. 
14. C-SSRS past 12-months version will be utilized at screening.   
15. AHC HRSN to be self-administered (preferred) or administered by site staff.  Form of administration to be consistent throughout the study. 
16. See Pharmacy Manual for dispensing details. All patients will start on a lead-in dose of KarXT 50/20 mg BID beginning on Day 1/week 0. At Baseline, 
dispense 2 week blister pack of KarXT 50/20 mg BID and 1 week blister pack of KarXT 100/20 mg BID. A telephone check-in at Day 7 (end of week 1) will 
determine if patients will titrate to the 100/20 mg BID dose beginning Day 8 through Day 14/end of week 2 or remain on the lead in dose 50/20 mg BID. At 
Visit 2 (Day 14), dosing will be titrated upwards to KarXT 100/20 mg BID or 125/30 mg BID (depending on previous week’s dose) unless the patient is 
experiencing AEs or, in the opinion of the investigator, a longer period on 100/20 mg BID is necessary, they may continue that dose. If the patient is not able to 
titrate up from 50/20 mg BID to 100/20 mg BID at Day 14, the patient must be discontinued. 


Karuna Therapeutics 
KAR-014 
KarXT 
v1.0 01 JUL 2022 
 
 
 
Page 18 of 78 
Week 0/Day 1 through Week 48/Day 336 (Year 1) 
Day 
All visit windows ± 2d unless otherwise indicated 
1 
7 
(+/- 1d) 
14 
(+/-1d) 
28 
42 
56 
84 
112 
140 
168 
224 
280 
336 
End of WEEK 
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
32 
40 
48 
VISIT 
n/a 
n/a 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
TYPE OF VISIT 
n/a 
T 
C 
C 
T 
C 
C 
C 
C 
C 
C 
C 
C 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient self-administration of KarXT 
BID1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Determination of dose titration2 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Dispense KarXT3 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Spontaneous AEs4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of concomitant medications5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs: BP and HR6 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Resting ECG (12-lead)7 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Body weight, BMI, waist 
circumference 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Complete physical exam8 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
AHC HRSN9  
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Blood samples for clinical laboratory 
tests10 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
Urine pregnancy test (WOCBP 
only)11 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urine drugs of abuse & alcohol12 
 
 
 
X 
 
X 
 
X 
 
 
X 
  
X 


Karuna Therapeutics 
KAR-014 
KarXT 
v1.0 01 JUL 2022 
 
 
 
Page 19 of 78 
C-SSRS13 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
CGI-S 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
IAQ 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
MSQ 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
EQ-5D-3L 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
BARS 
 
 
 
X 
 
X 
X 
 
 
X 
 
 
X 
AIMS 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
ZBI-2214 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Brief Cognitive Assessment Tool for 
Schizophrenia 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Abbreviations: AE = adverse event; AHC HRSN = Accountable Health Communities Health-Related Social Needs; AIMS = Abnormal Involuntary Movement 
Scale; BARS = Barnes Akathisia Rating Scale; BID = twice daily; BMI = body mass index; BP = blood pressure; C= Clinic visit; CGI-I = Clinical Global 
Impression – Global Improvement; CGI-S = Clinical Global Impression‒Severity scale; C-SSRS = Columbia-Suicide Severity Rating Scale; d = day; ECG = 
electrocardiogram;  EQ-5D-3L = Euroqol-5D-3L; HR = heart rate; IAQ= Investigator Assessment Questionnaire; MSQ = Medication Satisfaction 
Questionnaire; NIDA-5 = National Institute on Drug Abuse-5; PI = principal investigator; QTcF = QT interval corrected by Fridericia; T = Telephone Call; 
WOCBP = women of childbearing potential; ZBI-22 = Zarit Caregiver Burden Interview. 
1. The first dose of study drug is taken at home on the morning of Day 1. Patients will continue self-administration of KarXT BID throughout the treatment 
period of the study (at the appropriate dose level). Study drug should preferably be taken on an empty stomach, i.e., at least 1 hour before a meal or at least 2 
hours after a meal. 
2. See Pharmacy Manual for dispensing details. All patients will start on a lead-in dose of KarXT 50/20 mg BID beginning on Day 1/week 0. At Baseline, 
dispense 2 week blister pack of KarXT 50/20 mg BID and 1 week blister pack of KarXT 100/20 mg BID. A telephone check-in at Day 7 (end of week 1) will 
determine if patients will titrate to the 100/20 mg BID dose beginning Day 8 through Day 14/end of week 2 or remain on the lead in dose 50/20 mg BID. At 
Visit 2 (Day 14), dosing will be titrated upwards to KarXT 100/20 mg BID or 125/30 mg BID (depending on previous week’s dose) unless the patient is 
experiencing AEs or, in the opinion of the investigator, a longer period on 100/20 mg BID is necessary, they may continue that dose. If the patient is not able to 
titrate up from 50/20 mg BID to 100/20 mg BID at Day 14, the patient must be discontinued. 
3. At Visit 2 (Day 14/end of week 2), dispense a 2 week blister pack supply of KarXT. Beginning at Visit 3 (Day 28/end of week 4), dispense a 1 month bottle 
supply of KarXT at each clinic visit through week 24. Beginning at week 24, dispense a 2 month bottle supply of KarXT through week 152.   
4. AEs as reported by patients or observed by clinical staff are to be collected after informed consent. For telephone call visits, spontaneous AEs may be collected 
by telemedicine. 
5. Concomitant medications must be reviewed at every visit, including telephone visits (telemedicine). 


Karuna Therapeutics 
KAR-014 
KarXT 
v1.0 01 JUL 2022 
 
 
 
Page 20 of 78 
6. Vital sign measurements should be taken at scheduled in-clinic visits, which include systolic and diastolic BP and HR. Per PI discretion, orthostatic vital signs 
may be assessed, but are not mandatory. 
7. ECG should be obtained before blood withdrawal for any safety laboratory tests whenever possible. During the ECG, ventricular rate (bpm), PR (msec), QRS 
(msec), QT (msec), and QTcF (msec) measurements should be obtained. 
8. 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. 
9. AHC HRSN to be self-administered (preferred) or administered by site staff.  Form of administration to be consistent throughout the study. 
10. Refer to Section 8.2.12 (Table 2) for individual laboratory tests. For urinalysis, a urine dipstick will be performed locally. In the event of abnormalities, the 
sample will be sent to the central laboratory for full microscopic urinalysis. 
11. A urine pregnancy test for WOCBP should be performed at scheduled visits. In case of a positive urine pregnancy test result, a serum sample should be sent 
to the central laboratory for confirmation of the result. 
12. A NIDA-5 urine drug screen (cannabinoids or marijuana, phencyclidine, amphetamines, opiates, and cocaine) and test for alcohol (breathalyzer or urine 
alcohol level) will be performed locally at scheduled visits. A sample should be sent to the central lab at screening. Thereafter, if positive, with the exceptions 
of cannabinoids or marijuana, a sample should be sent to the central laboratory for confirmation of the result.  
13. C-SSRS “since last visit” version will be conducted at all scheduled study clinic visits (other than screening). At an Unscheduled visit, the C-SSRS should be 
performed to monitor patients for suicidality. 
14. ZBI-22 to be completed by a reliable caregiver/informant, if applicable. 


Karuna Therapeutics 
KAR-014 
KarXT 
v1.0 01 JUL 2022 
 
 
 
Page 21 of 78 
Week 56/Day 392 through Week 152/Day 1064 (Year 2-3) 
Day 
All visit windows ± 2d unless otherwise indicated 
392 
448 
504 
560 
616 
672 
728 
784 
840 
896 
952 
1008 
1064 
End of WEEK 
56 
64 
72 
80 
88 
96 
104 
112 
120 
128 
136 
144 
152 
VISIT 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
TYPE OF VISIT 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense KarXT1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spontaneous AEs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of concomitant medications3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs: BP and HR4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Resting ECG (12-lead)5 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Body weight, BMI, waist circumference 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete physical exam6 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
AHC HRSN7 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Blood samples for clinical laboratory 
tests8 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Urine pregnancy test (WOCBP only)9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine drugs of abuse & ETOH 10   
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
C-SSRS11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IAQ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Karuna Therapeutics 
KAR-014 
KarXT 
v1.0 01 JUL 2022 
 
 
 
Page 22 of 78 
MSQ  
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
EQ-5D-3L 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
BARS 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
AIMS 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
ZBI-2212 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Brief Cognitive Assessment Tool for 
Schizophrenia 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Abbreviations: AE = adverse event; AHC HRSN = Accountable Health Communities Health-Related Social Needs; AIMS = Abnormal Involuntary Movement 
Scale; BARS = Barnes Akathisia Rating Scale; BID = twice daily; BMI = body mass index; BP = blood pressure; C= Clinic visit; CGI-I = Clinical Global 
Impression – Global Improvement; CGI-S = Clinical Global Impression‒Severity scale; C-SSRS = Columbia-Suicide Severity Rating Scale; d = day; ECG = 
electrocardiogram;  EQ-5D-3L = Euroqol-5D-3L; HR = heart rate; IAQ= Investigator Assessment Questionnaire; MSQ = Medication Satisfaction 
Questionnaire; NIDA-5 = National Institute on Drug Abuse-5; PI = principal investigator; QTcF = QT interval corrected by Fridericia; T = Telephone Call; 
WOCBP = women of childbearing potential; ZBI-22 = Zarit Caregiver Burden Interview. 
1. See Pharmacy Manual for dispensing details. All patients will start on a lead-in dose of KarXT 50/20 mg BID beginning on Day 1/week 0. At Baseline, 
dispense 2 week blister pack of KarXT 50/20 mg BID and 1 week blister pack of KarXT 100/20 mg BID. A telephone check-in at Day 7 (end of week 1) will 
determine if patients will titrate to the 100/20 mg BID dose beginning Day 8 through Day 14/end of week 2 or remain on the lead in dose 50/20 mg BID. At 
Visit 2 (Day 14), dosing will be titrated upwards to KarXT 100/20 mg BID or 125/30 mg BID (depending on previous week’s dose) unless the patient is 
experiencing AEs or, in the opinion of the investigator, a longer period on 100/20 mg BID is necessary, they may continue that dose. If the patient is not able to 
titrate up from 50/20 mg BID to 100/20 BID at Day 14, the patient must be discontinued. At Visit 2 (Day 14/end of week 2), dispense a 2 week blister pack 
supply of KarXT. Beginning at Visit 3 (Day 28/end of week 4), dispense a 1 month bottle supply of KarXT at each clinic visit through week 24. Beginning at 
week 24, dispense a 2 month bottle supply of KarXT through week 152.  
2. AEs as reported by patients or observed by clinical staff are to be collected after informed consent. For telephone call visits, spontaneous AEs may be collected 
by telemedicine. 
3. Concomitant medications must be reviewed at every visit including telephone visits (telemedicine). 
4. Vital sign measurements should be taken at scheduled in-clinic visits. Includes systolic and diastolic BP and HR. Per PI discretion, orthostatic vital signs may 
be assessed, but are not mandatory. 
5. ECG should be obtained before blood withdrawal for any safety laboratory tests whenever possible. During the ECG, ventricular rate (bpm), PR (msec), QRS 
(msec), QT (msec), and QTcF (msec) measurements should be obtained. 
6. 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. 
7. AHC HRSN to be self-administered (preferred) or administered by site staff.  Form of administration to be consistent throughout the study. 
8. Refer to Section 8.2.12 (Table 2) for individual laboratory tests. For urinalysis, a urine dipstick will be performed locally. In the event of abnormalities, the 
sample will be sent to the central laboratory for full microscopic urinalysis. 
9. A urine pregnancy test for WOCBP should be performed at scheduled visits. In case of a positive urine pregnancy test result, a serum sample should be sent to 
the central laboratory for confirmation of the result. 


Karuna Therapeutics 
KAR-014 
KarXT 
v1.0 01 JUL 2022 
 
 
 
Page 23 of 78 
10. A NIDA-5 urine drug screen (cannabinoids or marijuana, phencyclidine, amphetamines, opiates, and cocaine) and test for alcohol (breathalyzer or urine 
alcohol level) will be performed locally at scheduled visits. A sample should be sent to the central lab at screening. Thereafter, if positive, with the exceptions 
of cannabinoids or marijuana, a sample should be sent to the central laboratory for confirmation of the result.  
11. C-SSRS “since last visit” version will be conducted at all scheduled study clinic visits (other than screening). At an Unscheduled visit, the C-SSRS should be 
performed to monitor patients for suicidality. 
12. ZBI-22 to be completed by a reliable caregiver/informant if applicable. 


Karuna Therapeutics 
KAR-014 
KarXT 
v1.0 01 JUL 2022 
 
 
 
Page 24 of 78 
Week 156/Day 1092 (EoT) through Week 157/Day 1099 (EoS)/Early Termination (ET)/Unscheduled Visit (UNS) 
Day 
All visit windows ± 2d unless otherwise indicated 
1092 
1099 
(+7 to 28d) 
 
 
End of WEEK 
156 
157-160 
n/a 
n/a 
VISIT 
26/EoT 
27/EoS1 
ET 
UNS2 
TYPE OF VISIT 
C 
C 
C 
C 
PROCEDURE 
 
 
 
 
Record final dose of KarXT3 
X 
 
X 
 
Spontaneous AEs4 
X 
X 
X 
X 
Review of concomitant medications 
X 
X 
X 
X 
Vital signs: BP and HR5 
X 
X 
X 
X 
Resting ECG (12-lead)6 
X 
 
X 
 
Body weight, BMI, waist circumference 
X 
X 
X 
X 
Complete physical exam7 
X 
 
X 
 
AHC HRSN8 
X 
 
 
 
Blood samples for clinical laboratory tests9 
X 
 
X 
 
Urine pregnancy test (WOCBP only10)  
X 
 
X 
X 
Urine drugs of abuse and alcohol testing11 
 
 
 
X 
C-SSRS12 
X 
 
X 
X 
BARS 
X 
 
X 
 
CGI-S 
X 
 
X 
X 
Brief Cognitive Assessment Tool for Schizophrenia 
X 
 
 
 


Karuna Therapeutics 
KAR-014 
KarXT 
v1.0 01 JUL 2022 
 
 
 
Page 25 of 78 
IAQ 
X 
 
X 
X 
MSQ 
X 
 
 
 
EQ-5D-3L 
X 
 
 
 
AIMS 
X 
 
X 
 
Abbreviations: AE = adverse event; AHC HRSN = Accountable Health Communities Health-Related Social Needs; AIMS = Abnormal Involuntary Movement 
Scale; BARS = Barnes Akathisia Rating Scale; BMI = body mass index; BP = blood pressure; C= Clinic visit; CGI-S = Clinical Global Impression‒Severity 
scale; C-SSRS = Columbia-Suicide Severity Rating Scale; d = day; ECG = electrocardiogram; EoS = end of study; EoT = end of treatment; ET = early 
termination; EQ-5D-3L = Euroqol-5D-3L; HR = heart rate; MSQ = Medication Satisfaction Questionnaire; NIDA-5 = National Institute on Drug Abuse-5; PI = 
principal investigator; QTcF = QT interval corrected by Fridericia; UNS = unscheduled visit; WOCBP = women of childbearing potential. 
1. EoS to be completed 7 to 28 days after last dose of KarXT (following EoT or ET Visits). 
2. Unscheduled Visits (UNS) may be conducted as needed via telemedicine or in clinic to facilitate retention and ensure compliance with study objectives. 
Review of AEs and concomitant medications are required. Assessments (with an italic X) should be performed if an in clinic UNS visit occurs. All other 
assessments to be performed per PI discretion. 
3. Patients will self-administer the morning dose of KarXT on Day 1092. Patients will self-report their last administered dose during the EoT visit (or ET visit). 
At the EoT/ET visit, patients will return all study drug. Patients may receive only 1 dose of KarXT on Day 1092/EoT. 
4. AEs as reported by patients or observed by clinical staff and occurs after informed consent.  
5. Vital signs measurements should be taken at scheduled in-clinic visits, which include systolic and diastolic BP and HR. Per PI discretion, orthostatic vital signs 
may be assessed, but are not mandatory. 
6. ECG should be obtained before blood withdrawal for any safety laboratory tests whenever possible. During the ECG, ventricular rate (bpm), PR (msec), QRS 
(msec), QT (msec), and QTcF (msec) measurements should be obtained. 
7. 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. 
8. AHC HRSN to be self-administered (preferred) or administered by site staff.  Form of administration to be consistent throughout the study. 
9. Refer to Section 8.2.12 (Table 2) for individual laboratory tests. For urinalysis, a urine dipstick will be performed locally. In the event of abnormalities, the 
sample will be sent to the central laboratory for full microscopic urinalysis. 
10. A urine pregnancy test for WOCBP should be performed at scheduled visits. In case of a positive urine pregnancy test result, a serum sample should be sent 
to the central laboratory for confirmation of the result. 
11. A NIDA-5 urine drug screen (cannabinoids or marijuana, phencyclidine, amphetamines, opiates, and cocaine) and test for alcohol (breathalyzer or urine 
alcohol level) will be performed locally at scheduled visits. A sample should be sent to the central lab at screening. Thereafter, if positive, with the exceptions 
of cannabinoids or marijuana, a sample should be sent to the central laboratory for confirmation of the result.  
12. C-SSRS “since last visit” version will be conducted at all scheduled study clinic visits (other than screening). At an Unscheduled visit, the C-SSRS should be 
performed to monitor patients for suicidality. 
 


Karuna Therapeutics 
KAR-014 
KarXT 
v1.0 01 JUL 2022 
 
 
 
Page 26 of 78 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
PROTOCOL APPROVAL SIGNATURES ....................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
1. 
PROTOCOL SYNOPSIS .............................................................................................4 
2. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................31 
3. 
INTRODUCTION ......................................................................................................34 
3.1. 
Study Rationale ...........................................................................................................34 
3.2. 
Background .................................................................................................................34 
3.2.1. 
Schizophrenia .............................................................................................................34 
3.2.2. 
KarXT .........................................................................................................................35 
3.2.3. 
Clinical Studies ...........................................................................................................36 
3.3. 
Risk/Benefit Assessment ............................................................................................37 
3.3.1. 
Known Potential Risks ...............................................................................................37 
3.3.2. 
Known Potential Benefits ...........................................................................................37 
3.3.3. 
Assessment of Potential Risks and Benefits ...............................................................37 
4. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................38 
4.1. 
Study Objectives .........................................................................................................38 
4.1.1. 
Primary Objectives .....................................................................................................38 
4.1.2. 
Secondary Objectives .................................................................................................38 
4.2. 
Study Endpoints ..........................................................................................................38 
4.2.1. 
Primary Endpoints ......................................................................................................38 
4.2.2. 
Secondary Safety Endpoints .......................................................................................38 
4.2.3. 
Secondary Efficacy Endpoints ....................................................................................38 
4.2.4. 
Other Safety Endpoints ...............................................................................................38 
4.2.5. 
Other Endpoints ..........................................................................................................39 
5. 
STUDY DESIGN .......................................................................................................40 
5.1. 
Description of Overall Study Design ..........................................................................40 
5.1.1. 
Screening ....................................................................................................................40 
5.1.2. 
Baseline .......................................................................................................................40 
5.1.3. 
Open-Label Treatment Phase .....................................................................................40 
5.1.3.1. 
Dosing with KarXT ....................................................................................................40 


Karuna Therapeutics 
KAR-014 
KarXT 
v1.0 01 JUL 2022 
 
 
 
Page 27 of 78 
5.1.4. 
Safety Follow-up Visit ................................................................................................41 
5.1.5. 
End of Study ...............................................................................................................41 
5.2. 
Safety and Efficacy .....................................................................................................41 
5.3. 
Scientific Rationale for Study Design ........................................................................42 
5.4. 
Justification for Dose ..................................................................................................42 
6. 
SELECTION OF AND WITHDRAWAL OF PATIENTS ........................................43 
6.1. 
Inclusion Criteria ........................................................................................................43 
6.2. 
Exclusion Criteria .......................................................................................................44 
6.3. 
Patient Discontinuation Criteria .................................................................................46 
6.4. 
Patient Replacement ...................................................................................................47 
6.5. 
Lost to Follow-Up.......................................................................................................47 
7. 
STUDY TREATMENT ..............................................................................................48 
7.1. 
Study Treatment Administration ................................................................................48 
7.1.1. 
Study Treatment Description ......................................................................................48 
7.1.2. 
Dosing and Administration .........................................................................................48 
7.2. 
Preparation/Handling/Storage/Accountability ............................................................48 
7.2.1. 
Acquisition and Accountability ..................................................................................48 
7.2.2. 
Formulation and Appearance ......................................................................................49 
7.2.3. 
Packaging and Labeling ..............................................................................................49 
7.2.4. 
Study Drug Storage .....................................................................................................50 
7.3. 
Blinding ......................................................................................................................50 
7.4. 
Randomization ............................................................................................................50 
7.5. 
Dose Modification ......................................................................................................50 
7.6. 
Study Treatment Adherence .......................................................................................50 
7.7. 
Concomitant Therapy .................................................................................................50 
7.7.1. 
Concomitant Medications for Anxiety and/or Sleep Aid ...........................................51 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................52 
8.1. 
Efficacy Assessments and Diagnostic Scales .............................................................52 
8.1.1. 
Clinical Global Impression‒Severity (CGI-S) ............................................................52 
8.1.2. 
Clinical Global Impression – Improvement (CGI-I) ..................................................52 
8.1.3. 
Investigator’s Assessment Questionnaire (IAQ) ........................................................52 
8.1.4. 
Medication Satisfaction Questionnaire (MSQ) ..........................................................53 


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8.1.5. 
Brief Cognitive Assessment Tool for Schizophrenia (B-CATS) ...............................53 
8.2. 
Safety Scales and Other Assessments .........................................................................53 
8.2.1. 
Barnes Akathisia Rating Scale (BARS) .....................................................................53 
8.2.2. 
Abnormal Involuntary Movement Scale (AIMS) .......................................................53 
8.2.3. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................54 
8.2.4. 
EQ-5D-3L ...................................................................................................................54 
8.2.5. 
Accountable Health Communities Health-Related Social Needs (AHC 
HRSN) ........................................................................................................................54 
8.2.6. 
Zarit Caregiver Burden Interview (ZBI-22) ...............................................................54 
8.2.7. 
Demographics and Medical and Psychiatric History ..................................................54 
8.2.8. 
Vital Signs ..................................................................................................................55 
8.2.9. 
Physical Examination .................................................................................................55 
8.2.10. 
Weight, Height, and Body Mass Index .......................................................................55 
8.2.11. 
Electrocardiograms (ECG) .........................................................................................55 
8.2.12. 
Laboratory Assessments .............................................................................................55 
8.2.13. 
Other Laboratory Assessments ...................................................................................57 
8.2.14. 
Blood Sampling for Pharmacogenetics ......................................................................57 
8.3. 
Adverse Events and Serious Adverse Events .............................................................57 
8.3.1. 
Definition of Adverse Events (AEs) ...........................................................................57 
8.3.2. 
Adverse Events of Special Interest (AESIs) ...............................................................59 
8.3.3. 
Definition of Serious Adverse Events (SAEs)............................................................59 
8.3.4. 
Serious Adverse Event Reporting ...............................................................................60 
8.3.5. 
Pregnancy and Pregnancy Reporting ..........................................................................60 
8.3.6. 
Drug-Induced Liver Injury (DILI) ..............................................................................61 
8.3.7. 
Trial Discontinuation Criteria Other than Pregnancy .................................................62 
8.3.7.1. 
Individual Stopping Criteria .......................................................................................62 
8.3.7.2. 
Trial Stopping Rules ...................................................................................................62 
8.3.8. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) ..................................63 
8.3.9. 
Overdose .....................................................................................................................63 
8.3.10. 
Warnings and Precautions ..........................................................................................63 
9. 
STATISTICAL CONSIDERATIONS .......................................................................65 
9.1. 
Statistical Hypothesis ..................................................................................................65 


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9.2. 
Sample Size Determination ........................................................................................65 
9.3. 
Populations for Analyses ............................................................................................65 
9.4. 
Statistical Analyses .....................................................................................................65 
9.4.1. 
General Approach .......................................................................................................65 
9.4.2. 
Safety Analysis ...........................................................................................................66 
9.4.3. 
Efficacy Analysis ........................................................................................................66 
9.4.4. 
Planned Interim Analysis ............................................................................................66 
9.5. 
Handling of Missing Data ...........................................................................................67 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................68 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................68 
10.1.1. 
Regulatory Guidelines ................................................................................................68 
10.1.2. 
Independent Ethics Committee/Institutional Review Board ......................................68 
10.1.3. 
Informed Consent Process ..........................................................................................68 
10.1.4. 
Data Handling .............................................................................................................68 
10.1.5. 
Source Documents ......................................................................................................69 
10.1.6. 
Record Retention ........................................................................................................69 
10.1.7. 
Monitoring ..................................................................................................................69 
10.1.8. 
Quality Control and Quality Assurance ......................................................................70 
10.1.9. 
Ethical Considerations ................................................................................................70 
10.1.10. 
Financing and Insurance .............................................................................................70 
10.1.11. 
Publication Policy/Disclosure of Data ........................................................................70 
10.2. 
Protocol Amendment and Protocol Deviation ............................................................71 
10.2.1. 
Protocol Amendment ..................................................................................................71 
10.2.2. 
Protocol Deviations ....................................................................................................71 
11. 
LIST OF REFERENCES ............................................................................................72 
12. 
APPENDICES ............................................................................................................76 
12.1. 
Appendix 1 ..................................................................................................................76 
12.2. 
Appendix 2 ..................................................................................................................77 
 
 
 


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LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................15 
Table 2: 
Laboratory Assessments .............................................................................................56 
Table 3: 
Classification of Adverse Events by Intensity ............................................................58 
Table 4: 
Classification of Adverse Events by Relationship to Study Drug ..............................58 
Table 5: 
Populations for Analyses Descriptions .......................................................................65 
 
 


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2. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AD 
Alzheimer’s disease 
AE 
adverse event 
AESI 
adverse event of special interest 
AHC HRSN 
Accountable Health Communities Health-Related Social Needs 
AIMS 
Abnormal Involuntary Movement Scale 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
APD 
antipsychotic drug 
AST 
aspartate aminotransferase 
BARS 
Barnes Akathisia Rating Scale 
BBB 
blood-brain barrier 
B-CAT 
Brief Cognitive Assessment Tool for Schizophrenia 
BID 
2 times a day 
BMI 
body mass index 
BP 
blood pressure 
BPM 
beats per minute 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression‒Severity 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
D2 
dopamine receptor 2 
DILI 
drug induced liver injury 
DSM-5 
Diagnostic and Statistical Manual‒Fifth Edition 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 


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Abbreviation 
Definition 
EoS 
End of Study 
EoT 
End of Treatment 
EPS 
extrapyramidal symptoms 
ET 
early termination 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
HAART 
Highly Active Antiretroviral Therapy 
HDL 
high-density lipoprotein 
HIPAA 
Health Insurance Portability Accountability Act 
HIV 
Human Immunodeficiency Virus 
HPMC 
hydroxypropyl methylcellulose 
HR 
heart rate 
IAQ 
Investigator Assessment Questionnaire 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
Karuna 
Karuna Therapeutics 
KarXT 
combination of the muscarinic agonist xanomeline and the peripheral 
anticholinergic agent trospium 
LAI 
long-acting injectable 
LFT 
liver function test 
M1, M4 
muscarinic receptor subtypes 
MCC 
microcrystalline cellulose 
mITT 
modified intent-to-treat 
MSQ 
Medication Satisfaction Questionnaire 
NF 
National Formulary 
OLE 
open-label extension 
PANSS 
Positive and Negative Syndrome Scale 


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Abbreviation 
Definition 
PK 
pharmacokinetic(s) 
PRN 
as needed 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SNP 
single nucleotide polymorphisms 
SNRI 
serotonin and norepinephrine reuptake inhibitors 
SoA 
schedule of assessments 
SSRI 
selective serotonin reuptake inhibitors 
SUSAR 
suspected unexpected serious adverse reaction 
Tbili 
total bilirubin  
TD 
tardive dyskinesia 
TDD 
total daily dose 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
UDS 
urine drug screen 
ULN 
upper limit of normal  
UNS 
unscheduled visit 
US 
United States 
USP 
United States Pharmacopeia 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 
ZBI-22 
Zarit Caregiver Burden Interview 


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3.
INTRODUCTION
3.1. 
Study Rationale
Schizophrenia is a long-term mental disorder that requires chronic therapy. There is a significant 
unmet medical need in the treatment of patients with schizophrenia. Many patients with 
schizophrenia have an inadequate response to antipsychotic therapy and continue to be 
symptomatic, including positive symptoms, such as hallucinations, delusions, and other disabling 
psychotic symptoms, as well as negative and cognitive symptoms. Interventions to treat 
inadequate responders include dosing above the high end of the therapeutic range, switching to 
another first-line antipsychotic, combining the current antipsychotic with another class of 
psychotropic medication (e.g., mood stabilizer) in the hopes of augmenting the response to the 
current antipsychotic, or switching to clozapine if patients are treatment-resistant.  
All antipsychotics currently approved for the treatment of schizophrenia have dopamine receptor 
(D2) affinities that mediate antipsychotic activity. In the Phase 2 study (KAR-004), KarXT, a 
M1/M4 muscarinic agonist, demonstrated statistically significant results on the Positive and 
Negative Syndrome Scale (PANSS) positive subscale, the PANSS total score, and the PANSS 
negative subscale (Brannan et al., 2021). KarXT is a combination of the muscarinic agonist 
xanomeline and the peripheral anticholinergic agent trospium. Given that KarXT has no direct 
dopaminergic activity and differs from the D2 antagonists risperidone, paliperidone, quetiapine 
(IR/XR), ziprasidone, and lurasidone and the D2 partial agonist aripiprazole, adjunctive KarXT 
may provide additional efficacy (particularly on positive symptoms) in patients with an 
inadequate response to risperidone, paliperidone, aripiprazole, or their long-acting injectables 
(LAIs); quetiapine (IR/XR); ziprasidone; or lurasidone.  
The proposed study, KAR-014, is an open-label, multi-center, long-term study to evaluate the 
effectiveness, long-term safety, tolerability, and durability of effect of KarXT in patients with a 
Diagnostic and Statistical Manual‒Fifth Edition (DSM-5; American Psychiatric Association, 
2013) diagnosis of schizophrenia that require a change in their antipsychotic medication because 
their current medication(s) is not well tolerated and/or clinical symptoms are not well controlled. 
3.2. 
Background 
3.2.1. 
Schizophrenia 
Schizophrenia is a long-term mental disorder involving a breakdown in the relation between 
thought, emotion, and behavior that leads to faulty perception, inappropriate actions and feelings, 
withdrawal from reality and personal relationships into fantasy and delusion, and a sense of 
mental fragmentation. Symptoms include delusions, hallucination, disorganized speech or 
behavior, and impaired cognitive ability (Patel et al., 2014). The prevalence of schizophrenia is 
between 0.6% and 1.9% in the United States (US) population (van Os and Kapur, 2009). 
Moreover, a claims analysis estimated that the annual prevalence of diagnosed schizophrenia in 
the US is 5.1 per 1000 lives (Wu et al., 2006). It is found equally in males and females, with 
males usually having an earlier onset of symptoms (Crismon et al., 2014).  
The mainstay for treating schizophrenia is antipsychotic drugs (APDs) (Green et al., 2004). All 
currently available antipsychotics act through blockage of all or subsets of dopamine receptors in 


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the brain. First generation APDs, particularly high D2 potency therapies, such as haloperidol, 
were marked by high rates of parkinsonian extrapyramidal symptoms (EPS) and tardive 
dyskinesia (TD). They consequently have limited use today. The second-generation agents, 
including risperidone, paliperidone, aripiprazole, olanzapine, quetiapine (IR/XR), lurasidone, and 
lumateperone, tend to have lower levels of EPS or TD. They are currently the most commonly 
prescribed APD class; however, the second-generation drugs also have problematic side effects, 
including significant weight gain, metabolic disturbances, sedation, and akathisia (Huhn et al., 
2019; Leucht et al., 2013; Lieberman et al., 2005). These side effects have contributed to poor 
medication adherence, resulting in frequent relapses and hospitalizations (Emsley et al., 2013; 
Kahn et al., 2015). Thus, there is a need for new medications for schizophrenia that act through 
alternative mechanisms. 
Central muscarinic receptors have been hypothesized to be therapeutic treatments for 
schizophrenia based on several converging lines of evidence, including both animal and human 
studies (Sellin et al., 2008; Wess et al., 2007). There are 5 subtypes of muscarinic receptors 
(M1-M5). The therapeutic effect of central muscarinic receptor agonism is thought to be due to 
the agonism of M1 and M4 receptors in the central nervous system (CNS) (Mirza et al., 2003). 
However, compounds that agonize M1 and M4 receptors are often not specific enough to not also 
agonize M2 and M3 receptors outside of the CNS, leading to adverse events (AEs) related to 
activation of these peripheral receptors. Thus, any potential benefit of muscarinic agonists in 
schizophrenia (or other indications, such as Alzheimer’s disease [AD]) has been outweighed by 
the occurrence of AEs associated with peripheral cholinergic side effects, such as nausea, 
vomiting, diarrhea, sweating, and excess salivation. 
3.2.2. 
KarXT 
KarXT is a novel combination of xanomeline tartrate and trospium chloride. Xanomeline tartrate 
is a muscarinic-cholinergic receptor agonist. It has agonistic activity at all 5 muscarinic 
receptors, but it preferentially stimulates M1 and M4 receptors. KarXT’s potential therapeutic 
effects are thought to be mediated through its binding to M1 and M4 receptors in the CNS. A 
recent study reported that xanomeline is a potent M4 muscarinic agonist in vivo as measured by 
various second messenger assays (Thorn et al., 2019). Xanomeline also rapidly enters the brain, 
achieving a brain-to-plasma ratio greater than 10, making it an attractive CNS drug candidate 
(Farde et al., 1996). Xanomeline does not have any direct binding activity on dopaminergic 
receptors, suggesting that its mechanism of action is unrelated to direct dopamine involvement. 
Previous double-blind, placebo-controlled clinical trials provided evidence that xanomeline has 
clinically relevant antipsychotic efficacy. In a multicenter, outpatient trial in AD (N = 343), 
3 dose levels of xanomeline (up to 225 mg/day) and placebo were assessed for 26 weeks. 
Significant dose-dependent improvements in psychotic symptoms relative to placebo were 
observed. Moreover, psychotic symptoms resolved quite rapidly in subjects who were 
symptomatic at baseline, and a dose-dependent reduction in the emergence of psychotic 
symptoms versus placebo was found. In a completer analysis, cognitive improvement was also 
found, suggesting that longer treatment intervals may be necessary for cognitive enhancement 
(Bodick et al., 1997a; Bodick et al., 1997b). In a subsequent small, double-blind, placebo 
controlled inpatient trial in 20 treatment-resistant subjects with schizophrenia, xanomeline 
(225 mg/day) demonstrated robust and relatively rapid improvement in psychosis compared to 


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placebo. Improvement in both negative symptoms and cognitive impairment was observed 
(Shekhar et al., 2008). 
In the AD trials, schizophrenia trials, and healthy volunteer studies, dose dependent 
“cholinergic” AEs were reported, including vomiting, nausea, diarrhea, sweating, and 
hypersalivation. These side effects were frequent and, at the higher doses of xanomeline, led to 
significant rates of discontinuation in the AD studies. This “procholinergic” AE profile curtailed 
further development of xanomeline as a single agent.  
The procholinergic AEs associated with xanomeline appear to be mediated by xanomeline’s 
stimulation of peripheral rather than central muscarinic receptors, which would make these AEs 
theoretically amenable to counteracting with peripheral anticholinergic treatment. Trospium 
chloride is a peripherally acting muscarinic antagonist that binds to and antagonizes all five 
muscarinic receptor subtypes. Several studies in humans demonstrated that trospium does not 
appreciably cross the blood-brain barrier (BBB), which is consistent with the drug’s quaternary 
ammonium structure (Scheife and Takeda, 2005).  
Karuna Therapeutics (Karuna) hypothesized that adding trospium to xanomeline will mitigate 
peripheral procholinergic side effects, and thus, provide a strategy to allow xanomeline to be 
used to stimulate brain muscarinic receptors with a decreased side effect burden. Xanomeline is 
currently not approved or marketed in any country. Trospium has been approved for over 
10 years by the Food and Drug Administration (FDA) and by European authorities to treat 
overactive bladder, and it is generally well tolerated (Staskin et al., 2010). The most frequently 
reported AEs for trospium are dry mouth, constipation, abdominal pain, headache, urinary 
retention, and abnormal vision and accommodation. The package insert for trospium chloride 
tablets for oral use can be found in the KarXT Investigator’s Brochure (IB) for additional 
information. 
KarXT significantly reduced the symptoms of schizophrenia in subjects with acute psychosis 
after inpatient treatment for 5 weeks (Study KAR-004; Brannan et al., 2021). KarXT also 
showed an acceptable safety profile; the most common treatment-emergent adverse events 
(TEAEs) were constipation, nausea, dry mouth, dyspepsia, and vomiting (for completed clinical 
studies, see Section 3.2.3). 
3.2.3. 
Clinical Studies 
To date, across 19 completed clinical studies (conducted by Eli Lilly or Karuna) with durations 
up to 3 years of exposure, more than 840 subjects have been exposed to xanomeline tartrate (oral 
formulation; either alone, in combination with trospium, or as the combination drug KarXT). In 
completed studies, significant improvements in cognition and reduced psychotic symptoms were 
observed.  
The clinical experience to date with KarXT includes 4 completed Phase 1 studies in healthy 
volunteers (KAR-001, KAR-002, KAR-003 and KAR-020) and 1 completed Phase 2 study 
(KAR-004) in adult patients with DSM-5 schizophrenia (Refer to KarXT IB for details). 
Multiple other Phase 1 and Phase 3 studies are ongoing. 


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3.3. 
Risk/Benefit Assessment 
The risks and benefits of KarXT in humans are not fully known. The Phase 2 study, KAR-004, 
showed that KarXT monotherapy had statistically significant efficacy compared to placebo with 
an acceptable safety profile that appeared unique compared to available APDs. In this 5-week 
trial, treatment with KarXT was not associated with weight gain, sedation, or meaningful EPS 
changes. In contrast, these AEs pose a significant risk with other APD treatments for 
schizophrenia, which can lead to discontinuation of treatment and to significant morbidity. 
3.3.1. 
Known Potential Risks 
The most common risks are procholinergic-related effects (e.g., nausea, vomiting, tremor, excess 
salivation, excess sweating, and diarrhea) and anticholinergic symptoms (e.g., dry mouth, blurred 
vision, dry eyes, constipation, urinary retention, etc.). The frequently observed AEs increased 
liver function test (LFT), tachycardia, fatigue, and chills have also been reported. In addition, 
patients treated with xanomeline alone have reported both syncope and orthostatic dizziness. The 
addition of trospium appears to decrease the peripheral cholinergic effect of xanomeline, creating 
a better tolerated therapy. 
3.3.2. 
Known Potential Benefits 
Patients who are inadequate responders to their current APD may benefit from switching from 
their current therapy to KarXT. 
3.3.3. 
Assessment of Potential Risks and Benefits 
KarXT represents a novel approach to the treatment of patients with schizophrenia that could 
provide an important and meaningful alternative to currently available therapies. The efficacy of 
KarXT, coupled with its apparently acceptable tolerability and AE profile, will potentially render 
significant benefits when used as an adjunctive therapy to currently prescribed APDs. Multiple 
study design elements are in place to minimize the risk to the study participants. The Sponsor 
believes the risk-benefit ratio is favorable, and continuous risk-benefit assessments will be 
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4.
STUDY OBJECTIVES AND ENDPOINTS
4.1. 
Study Objectives 
4.1.1. 
Primary Objectives 
The primary objectives of the study are to assess the long-term safety and tolerability of KarXT 
as well as its effectiveness, persistence, and durability of effect through the Investigator 
Assessment Questionnaire (IAQ) and Clinical Global Impression – Severity of Illness (CGI-S) 
scale in patients with a diagnosis of schizophrenia. 
4.1.2. 
Secondary Objectives 
The secondary objectives of the study are to further assess: 
•
Effectiveness using the Clinical Global Impression - Global Improvement (CGI-I) at
week 2 through week 24.
•
Long-term safety and tolerability of KarXT.
•
Evaluation of total scores from multiple economic patient scales and caregiver burden
throughout the study.
4.2. 
Study Endpoints
4.2.1. 
Primary Endpoints
•
The primary safety endpoint is the incident of TEAEs leading to discontinuation.
•
The primary efficacy endpoints are persistence and durability of effect of KarXT via
IAQ and CGI-S scores at clinical visits throughout the study.
4.2.2. 
Secondary Safety Endpoints 
The secondary safety endpoints are as follows: 
•
Incidence of serious TEAEs (TESAEs).
•
Incidence of TEAEs of special interest.
4.2.3. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
•
CGI-I scores at week 2 through 24 weeks.
•
MSQ throughout the study.
4.2.4. 
Other Safety Endpoints 
The other safety endpoints are: 
•
Incidence of spontaneously reported TEAEs of special interest.


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• Incidence of spontaneously reported anticholinergic and procholinergic symptoms. 
• Change from baseline in clinical laboratory assessments (with emphasis on 
monitoring metabolic syndrome; waist circumference, blood pressure, fasting 
[preferred] blood glucose, high-density lipoprotein [HDL] cholesterol, and 
triglyceride levels).  
• Change from baseline in physical examinations, vital signs, body weight and body 
mass index (BMI).   
• Barnes Akathisia Rating Scale (BARS). 
• Abnormal Involuntary Movement Scale (AIMS). 
4.2.5. 
Other Endpoints 
• Adherence to KarXT at different timepoints. 
• Time to treatment discontinuation for any reason. 
• Accountable Health Communities Health-Related Social Needs (AHC HRSN) 
screening tool.  
• ZBI-22. 
• EQ-5D-3L questionnaire.  
• Brief Cognitive Assessment Tool for Schizophrenia (B-CATS) (1. digit symbol 
substitution test, 2. trail making test part B, and 3. category fluency). 
• Single nucleotide polymorphisms (SNPs) related to schizophrenia subtypes and drug 
metabolism. 


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5. 
STUDY DESIGN 
5.1. 
Description of Overall Study Design 
This is a Phase 3b, 3-year, open-label, multi-center study in which patients with schizophrenia 
requiring a change in antipsychotic medication because their current medication(s) is not well 
tolerated and/or clinical symptoms are not well controlled will be switched to receive KarXT 
based on the investigator’s judgment for need of treatment optimization for the individual 
patient. The study’s objectives are to assess the effectiveness, long-term safety, tolerability, and 
durability of effect of KarXT in patients with DSM-5 diagnosis of schizophrenia. 
5.1.1. 
Screening 
The study consists of a screening phase of up to 21 days (up to a 7 day screening extension is 
permitted with medical monitor approval).  (See Table 1) 
5.1.2. 
Baseline 
Patients who meet the screening criteria will participate in a study baseline visit. It is preferred 
that all baseline assessments are completed in one (1) visit; however, they may be done over 
7 days.  (See Table 1) 
5.1.3. 
Open-Label Treatment Phase 
The open-label treatment phase is 3 years (156 weeks).  (See Table 1) 
5.1.3.1. 
Dosing with KarXT 
The dosing of the study medication (KarXT) is described below. KarXT is expressed as mg 
xanomeline as the tartrate salt/mg trospium chloride.   
• Week 1 (Days 1 to 7) – KarXT 50/20 mg, 2 times a day (BID).  
• Week 2 (Days 8 to 14) – KarXT 100/20 mg, BID or remain on 50/20 mg, BID. 
• Week 3 (Days 15 to 21) – KarXT 125/30 mg, BID or 100/20 mg, BID. 
• Weeks 4 to 156 (Days 28 to 1092) – Flexible dosing based on tolerability and clinical 
response to KarXT 50/20 mg, KarXT 100/20 mg, and KarXT 125/30 mg doses, BID.  
The dosing of KarXT is flexible; however, in the absence of tolerability issues, patients should 
have their dose increased if efficacy has not been observed (based on the clinical judgment of the 
investigator). The expectation is that most patients will respond to KarXT 100/20 mg, BID or 
KarXT 125/30 mg, BID. 
Below is a more detailed breakdown of the early dosing and titration recommendations. 
All patients will start on a lead in dose of KarXT 50/20 mg (50 mg xanomeline/20 mg trospium) 
BID for 7 days (Day 1 to Day 7). A telephone check-in will occur on Day 7 to determine if the 
patient will titrate to the KarXT 100/20 mg BID dose for the 2nd week (Day 8 to Day 14) or 
remain on the lead in dose (50/20 mg BID). At Clinic Visit 2 (end of week 2/Day 14), the dose 
may be titrated upwards to either KarXT 100/20 mg BID if the patient had remained on the 


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50/20 mg dose through Day14, or the dose will increase to KarXT 125/30 mg BID if the patient 
was on the 100/20 mg through Day 14. If the patient continues to experience AEs from the 
50/20 mg BID dose of such severity that they are not able to titrate up at Day 14 (end of week 2), 
the patient must be discontinued. If the patient experiences AEs from the 100/20 mg BID dose 
and is not able to titrate up and/or, in the opinion of the investigator, a longer period on the 
100/20 mg BID dose is necessary, patients may continue this dose. Thus, all patients will attempt 
100/20 mg BID dosing for at least 1 week. All patients who are increased to KarXT 125/30 mg 
BID or 100/20 mg BID, depending on tolerability, will have the option to return to KarXT 
100/20 mg BID or 50/20 mg BID throughout the study. Re-escalation to 125/30 mg BID or 
100/20 mg BID or re-titration in cases in which the patient has been off KarXT for a longer 
period of time (at least 7 consecutive days) is allowed and will require a discussion between the 
investigator and the medical monitor. Additional changes to KarXT dosing (e.g., temporary dose 
reductions) may be permitted as clinically indicated per investigator discretion.    
Patients who cannot maintain 65% adherence to the study drug over any 8 week period 
throughout the study, unless there is hospitalization involved, will be discontinued from the 
study. The adherence assessments will be based on pill counts, patient recall, and caregiver 
report if applicable.  
In summary, upward titration is expected to optimize efficacy; however, if efficacious and better 
tolerated, any of the available doses could be used for maintenance. Unscheduled (UNS) visits, 
which can be conducted in-clinic or by telemedicine, may occur between required clinic visits as 
deemed necessary by the investigator to facilitate patient retention and ensure compliance with 
study objectives. (See Table 1) 
5.1.4. 
Safety Follow-up Visit 
An End of Study (EoS) safety follow-up visit will be performed for all patients who have been 
dosed with KarXT. The EoS visit will take place 7 to 28 days after the last dose of KarXT for 
patients who complete the treatment phase (End of Treatment [EoT]), and for patients who 
choose to discontinue from the study early (early termination [ET]), at the discretion of the 
investigator, per sponsor request, or if the sponsor terminates the study. (See Table 1) 
5.1.5. 
End of Study 
A patient will have fulfilled all the requirements for the trial when the patient has completed all 
study visits, including the EoT visit (Visit 26) and the EoS visit (Visit 27), in accordance with 
the protocol (Table 1). 
5.2. 
Safety and Efficacy 
Safety will be assessed through spontaneous TEAEs, including TEAEs of special interest, 
TESAEs, and TEAEs leading to discontinuation of the study drug; cholinergic (pro- and anti-) 
symptoms; BARS; AIMS; body weight; BMI; orthostatic vital signs; clinical safety laboratory 
assessments (hematology, clinical chemistry, prolactin levels, coagulation, urinalysis, and drug 
screen); 12-lead electrocardiogram (ECG); physical examination; and Columbia-Suicide Severity 
Rating Scale (C-SSRS) will be evaluated throughout the study as scheduled.  


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Efficacy will be assessed through: 
• Effectiveness using the CGI-I at week 2 through week 24 and persistence and 
durability of effect with IAQ and CGI-S scale throughout the study 
• MSQ 
5.3. 
Scientific Rationale for Study Design 
Many patients with schizophrenia have an inadequate response to their antipsychotic therapy and 
either continue to be symptomatic, which includes positive symptoms, such as hallucinations and 
delusions, or they have to deal with unwanted side effects related to the D2 receptor blockade, 
some of which could be permanent (e.g., TD). Given that KarXT has a different mechanism of 
action from D2 antagonists (risperidone, paliperidone, quetiapine, ziprasidone, or lurasidone) or 
D2 partial agonist (aripiprazole) and KarXT, as a monotherapy, has shown successful clinical 
data for both efficacy and safety from its Phase 2 study (KAR-004), KarXT therapy may provide 
efficacy with a side effect profile that could represent a more beneficial risk-benefit ratio than 
existing approved therapeutics for the treatment of schizophrenia symptoms and syndromes.  
This current study aims to evaluate long-term safety, efficacy, persistence, and durability of 
effect in a close to real-world clinical setting; providing naturalistic, real-world evidence-like 
data to complement the ongoing registrational programs with KarXT in schizophrenia.    
5.4. 
Justification for Dose 
The Phase 2 study (KAR-004) was a 5 week inpatient trial that used flexible dosing of KarXT in 
subjects with acute psychosis. KarXT 100/20 mg BID or 125/30 mg BID significantly reduced 
the symptoms of schizophrenia. KarXT showed an acceptable safety profile; the most common 
TEAEs were constipation, nausea, dry mouth, dyspepsia, and vomiting. All reported TEAEs 
were mild or moderate in intensity. One SAE (psychotic disorder) was reported by a single 
subject, and no deaths were reported. KarXT was generally well tolerated and found to be safe in 
this patient population (Brannan et al., 2021). 
That is the reason why, in the current study, all patients will attempt 100/20 mg BID dosing for 
at least 1 week. All patients who are increased to KarXT 125/30 mg BID or 100/20 mg BID, 
depending on tolerability, will have the option to return to KarXT 100/20 mg BID or 50/20 mg 
BID throughout the study with the lowest dose allowed to accommodate cases of restarting the 
medication as well as ones where patients may be low metabolizers.   


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6. 
SELECTION OF AND WITHDRAWAL OF PATIENTS 
6.1. 
Inclusion Criteria 
Individuals must meet all the following criteria to be included in the study: 
1. Patient is aged 18 to 65 years, inclusive, at screening. 
2. Patient can provide informed consent. 
a. A signed informed consent form (ICF) must be provided before any study 
assessments are performed. 
b. Patient must be fluent (oral and written) in the language of the ICF to consent. 
3. Patient has a primary diagnosis of schizophrenia established by a comprehensive 
psychiatric evaluation based on the DSM-5 criteria and has been in the continuous care 
of the clinician or practice for at least 6 months prior to entering the study.   
4. The patient is dissatisfied with the side effects or general tolerability of their current 
antipsychotic medication, and for this reason, desires to change medications. Or, the 
patient is dissatisfied with the overall effectiveness or benefit of their current 
antipsychotic medication, and for this reason, desires to change medications.  
5. The patient has not required psychiatric hospitalization, acute crisis intervention, or 
other increase in their level of care due to symptom exacerbation within 4 weeks of 
screening, and in the opinion of the investigator, is psychiatrically stable to be managed 
in an outpatient setting.   
6. The patient has a CGI-S score of ≤4 at screening and baseline visits.   
7. For at least 30 days prior to screening, the patient must have been prescribed and have 
taken an oral antipsychotic medication daily at a dose and frequency consistent with the 
drug label. 
8. The patient is willing and able, and in the opinion of the investigator it is clinically 
appropriate, to discontinue all antipsychotic medications prior to the baseline visit or to 
taper their current antipsychotic medication(s) with cross-over administration for up to 
two weeks (14 days) of dosing with KarXT (unless the patient is on olanzapine or 
quetiapine, which require discontinuation before KarXT initiation)  
In summary: 
a. Patients may washout antipsychotic medication during the screening phase (21 to 
28 days prior to baseline) at the discretion of the investigator. Thus, the patient would 
have discontinued all antipsychotic medication prior to baseline  
b. Or patient may down taper or continue down taper (washout) antipsychotic 
medication through the initial 2 weeks of KarXT dosing (excluding olanzapine or 
quetiapine). 
c. All patients must be washed out (discontinued) of all antipsychotic medication other 
than KarXT by end of week 2 (Day 14). 


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9. Patient has an identified, reliable caregiver/informant that is willing (by informed 
consent) and able to respond to the ZBI-22 caregiver burden scale at specified visits. 
The caregiver/informant must be consistent throughout the duration of the study. If the 
patient has been the patient of the investigator or the practice for ≥6 months and, in the 
opinion of the investigator, the patient is self-sufficient, then a caregiver/informant may 
not be necessary. 
10. At the time of the Baseline Visit, the patient will have been off lithium therapy for at 
least 2 weeks. 
11. If taking a LAI antipsychotic, the patient has not received a dose of the medication for at 
least 12 weeks (24 weeks for INVEGA TRINZA® [INVEGA TRINZA Package Insert, 
2021]) before the Baseline Visit. 
12. Patient BMI must be ≥18.0 and ≤45.0 kg/m2. 
13. Patient resides in a stable living situation and is anticipated to remain in a stable living 
situation for the duration of the study, in the opinion of the investigator. 
14. If a woman of childbearing potential (WOCBP) or a man whose sexual partner(s) is a 
WOCBP, the patient must be willing and able to adhere to the contraception guidelines 
as defined in Section 12.1 Appendix 1. 
6.2. 
Exclusion Criteria 
If any of the following exclusion criteria apply, a patient may not participate in the study: 
1. Any primary DSM-5 disorder diagnosis other than schizophrenia within 12 months 
before screening. Exclusionary disorders include, but are not limited to, bipolar I or II 
disorder and schizoaffective disorder. Symptoms of mild mood dysphoria or anxiety are 
allowed, as long as these symptoms are not the primary focus of treatment. 
2. The patient has a history of moderate to severe alcohol use disorder or a substance (other 
than nicotine or caffeine) use disorder within the past 12 months or has a positive urine 
drug screen (UDS) for a substance other than cannabis at screening and baseline. 
a. A patient with mild substance abuse disorder within the 12 months before screening 
must be discussed and agreed upon with the medical monitor before he/she can be 
allowed into the study. 
b. Patients with a positive UDS for cannabis are permitted to enroll in the study 
provided that the patient’s pattern of use is not indicative of a substance use disorder. 
3. The patient has a history of or presence of a 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 patient or the validity of 
the study results. 
4. Patient has human immunodeficiency virus (HIV) unless stable for 12 months prior to 
screening on highly active antiretroviral therapy (HAART) therapy (CD4 >500 and 
undetectable viral load); cirrhosis; biliary duct abnormalities; hepatobiliary carcinoma; 


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and/or active hepatic viral infections based on either medical history or liver function 
test results. 
5. Patient has a history of or is at high risk of urinary retention, gastric retention, or narrow 
angle glaucoma. 
6. Patient has a history of irritable bowel syndrome (with or without constipation) or 
serious constipation requiring treatment within the last 6 months. 
7. Patient is at risk for suicidal behavior during the study as determined by the 
investigator’s clinical assessment and C-SSRS as confirmed by the following: 
a. Patient answers “Yes” on items 4 or 5 (C-SSRS – ideation) with the most recent 
episode occurring within the 2 months before screening, or patient answers “Yes” to 
any of the 5 items (C-SSRS behavior) with an episode occurring within the 12 months 
before screening. Non-suicidal self-injurious behavior is not exclusionary. 
8. Patient is at risk of violent or destructive behavior or serious harm to others, as 
determined by the investigator’s clinical assessment. 
9. Clinically significant abnormal finding on the physical examination, medical history, 
ECG, or clinical laboratory results at screening. (Aspartate aminotransferase (AST) or 
alanine transaminase (ALT) >2x upper limit of normal (ULN) or total bilirubin (Tbili) 
>2x ULN (unless due to suspected Gilbert’s), hemoglobin <10 g.dL, white blood cell 
(WBC) <3 K, absolute neutrophil count (ANC) <1000, platelets <100 K, 
QTc >450 msec in males and >470 msec in females.)  
10. Currently and within 2 weeks before the Baseline Visit, patients cannot be receiving 
monoamine oxidase inhibitors, anticonvulsants (e.g., lamotrigine, Depakote® [Depakote 
Package Insert, 2021]), tricyclic antidepressants (e.g., imipramine, desipramine), 
centrally active anticholinergics (benztropine, trihexyphenidyl, diphenhydramine), or 
any other psychoactive medications other than daily antipsychotic maintenance therapy.  
a. As needed (PRN) anxiolytics and/or sleep aids are permitted (e.g., lorazepam, 
zolpidem). 
b. Selective serotonin reuptake inhibitors (SSRI’s)/serotonin and norepinephrine 
reuptake inhibitors (SNRIs) taken at stable dose for at least 4 weeks before screening 
and that are anticipated to be continued at the same dose throughout the study are 
permitted. 
c. Benztropine (Cogentin) or similar medications used for extrapyramidal symptoms 
(EPS) will need to be tapered down slowly as withdrawal symptoms are likely. The 
suggested approach is a maximum 50% reduction per week until a 0.25 mg dose is 
reached. 
d. PRN second generation antihistamines, e.g., fexofenadine, loratadine, and cetirizine 
(that do not readily cross the BBB), could be used after the first month of the study 
for temporary symptom management of allergies 
11. Patient has a history of treatment resistance to schizophrenia medications defined as:  
a. Failure to respond to 3 adequate courses of pharmacotherapy (a minimum of 4 weeks 
at an adequate dose per the label) within the past 12 months, OR 


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b. Having received clozapine within the past 3 years. 
12. Patient is pregnant, lactating, or less than 3 months postpartum. 
13. Patient has any other medical, psychiatric, or social condition that, in the opinion of the 
investigator, is likely to unfavorably alter the risk-benefit of patient participation, to 
interfere with protocol compliance, or to confound safety or efficacy assessments.   
14. Patients has tested positive for coronavirus disease 2019 (COVID-19) within 2 weeks of 
screening and/or baseline or patients who have prolonged symptoms of past infection, 
long COVID, that, in the opinion of the investigator, may interfere with the 
interpretation of safety during the study 
15. Patient with extreme concerns relating to global pandemics, such as COVID-19, that 
precludes study participation. 
16. Patient is currently or recently (within 4 weeks of screening) involuntary hospitalization 
or incarceration. 
17. Patient participated in another clinical study in which they received an experimental or 
investigational drug agent within 30 days prior to screening. 
6.3. 
Patient Discontinuation Criteria 
All patients are free to discontinue from participation in the study at any time and for any reason. 
The investigator must discontinue any patient from the study if the patient requests to stop 
participating in the study. The investigator, sponsor, or its designee may remove a patient from 
the study at any time and for any reason. In addition, patients may be discontinued if they: 
• Experience an intolerable AE; 
• Require a medication that is prohibited by the protocol; 
• Do not follow guidelines specified in the protocol (i.e., is noncompliant with protocol 
procedures); 
• Have any medically appropriate reason or significant protocol violation, in the 
opinion of the investigator; 
• Have a clinically significant investigational treatment-related hypersensitivity 
reaction; 
• Become pregnant; 
• Meet an exclusion criterion (either newly developed or not previously recognized) 
such that risk-benefit is unfavorably affected, or he/she no longer meets criteria for 
the intended study population; 
• Are lost to follow-up; 
• Continued study participation poses an unfavorable risk-benefit to the patient, in the 
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Discontinuation criteria related to adequately tolerating the investigational product are discussed 
in Section 5.1.3.1. 
Should a patient discontinue early from the study, the reason(s) for study discontinuation will be 
documented on the electronic case report form (eCRF). All reasonable efforts will be made to 
have the patient complete the ET assessments (Table 1). 
6.4. 
Patient Replacement 
If patients discontinue the study, they will not be replaced.  
6.5. 
Lost to Follow-Up 
The study will be completed when all patients complete their study-related procedures in 
accordance with the protocol. 
Reasonable efforts (3 documented phone calls and a certified letter) will be made to contact 
patients who are lost to follow-up. These efforts must be documented in the patient’s file. 
Patients with AEs ongoing at the EoS visit will be followed until the AE is resolved or the 
patient is considered to be in stable condition. 


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7. 
STUDY TREATMENT 
7.1. 
Study Treatment Administration 
7.1.1. 
Study Treatment Description  
KarXT is formulated as hard hydroxypropyl methylcellulose (HPMC) oral capsules containing 
2 distinct populations of drug beads. Each capsule contains xanomeline (as the tartrate salt) and 
trospium chloride in the stated dose strengths (Section 7.2.2). The main components of the drug 
beads are the active ingredients and microcrystalline cellulose (MCC). The beads are not coated 
and are formulated for immediate release of the active ingredients. 
7.1.2. 
Dosing and Administration  
The first dose of the study drug in this study will be taken at home on the morning of Day 1. The 
last dose will be taken at Visit 26 (week 156/Day 1092; the completion of the 3-year treatment 
period). The study drug should be taken daily BID, preferably on an empty stomach, i.e., at least 
1 hour before a meal or at least 2 hours after a meal.  
KarXT is expressed as mg xanomeline as the tartrate salt/mg trospium chloride. All patients will 
start on a lead in dose of KarXT 50/20 mg, BID Day 1 to Day 7.  
• Week 1 (Days 1 to 7) – KarXT 50/20 mg, BID.  
• Week 2 (Days 8 to 14) – KarXT 100/20 mg, BID or remain on 50/20 mg, BID. 
• Week 3 (Days 15 to 21) – KarXT 125/30 mg, BID or 100/20 mg, BID. 
• Weeks 4 to 156 (Days 28 to 1092) – Flexible dosing based on tolerability and clinical 
response KarXT 50/20 mg, KarXT 100/20 mg, and KarXT 125/30 mg doses, BID.  
The dosing of KarXT is flexible after week 4 (Day 28); however, in the absence of tolerability 
issues, patients should have their dose increased if efficacy has not been observed (based on the 
clinical judgment of the investigator). The expectation is that most patients will respond to 
KarXT 100/20 mg or KarXT 125/30 mg, BID. 
All investigational agents are to be stored according to requirements. 
7.2. 
Preparation/Handling/Storage/Accountability  
7.2.1. 
Acquisition and Accountability 
The pharmacist or other designated individual will maintain records of the study treatment 
delivered to the study site, the inventory at the study site, the distribution to each patient, and the 
return of materials to the Sponsor or designee for storage or disposal. These records should 
include dates, quantities, batch/serial numbers, expiration dates, ambient temperature log, and 
unique code numbers assigned to the product and study patients. 
The administration of KarXT will be supervised by study site personnel (during in-clinic visits) 
and by an interactive response technology (IRT) system, 4G.  


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Investigators will maintain records that adequately document that patients were provided the 
correct study treatment. Study drugs will be dispensed in prepackaged blister card wallets and 
bottles. The wallets will contain 8 days of doses of KarXT capsules for BID administration. The 
bottles will contain 30 days of doses of KarXT capsules for BID administration. Patients will be 
advised to return all blister card wallets and bottles to the site staff at each in-clinic visit for drug 
accountability. 
7.2.2. 
Formulation and Appearance 
The formulations of all the drug products (KarXT 50/20 mg, 100/20 mg, and 125/30 mg 
xanomeline as the tartrate salt/trospium chloride) are provided below.  
Note that xanomeline is formulated as the tartrate salt, but the tartrate moiety is not included in 
the nominal dose. Therefore, xanomeline doses reflect the dose of xanomeline, not the dose of 
xanomeline tartrate. Conversely, the nominal dose of trospium chloride reflects the combined 
weight of the trospium and the chloride. As an example, 50/20 mg KarXT contains 50 mg of 
xanomeline as the tartrate salt and 20 mg of trospium chloride. 
Excipients in KarXT capsules are MCC (National Formulary [NF]); lactose monohydrate (NF); 
talc (United States Pharmacopeia [USP]); ascorbic acid (USP/NF); and Swedish orange, opaque, 
size 0, hard HPMC capsule shells.  
• KarXT 50/20 mg is composed of 33.4% xanomeline tartrate, 8.7% trospium chloride. 
Excipients:  39.8% MCC, 17.3% lactose monohydrate, 0.3% ascorbic acid, and 0.5% 
talc in a size 0, Swedish orange, opaque, and HPMC hard capsule.  
• KarXT 100/20 mg is composed of 44.4% xanomeline tartrate, 5.8% trospium 
chloride. Excipients:  37.59% MCC, 11.5% lactose monohydrate, 0.3% ascorbic acid, 
and 0.5% talc in a size 0, Swedish orange, opaque, HPMC hard capsule. 
• KarXT 125/30 mg is composed of 41.7% xanomeline tartrate, 6.5% trospium 
chloride. Excipients:  38.1% MCC, 12.9% lactose monohydrate, 0.3% ascorbic acid, 
and 0.5% talc in a size 0, Swedish orange, opaque, and HPMC hard capsule.   
7.2.3. 
Packaging and Labeling 
The packaging and labeling will be done by Catalent Pharma Solutions, located in Philadelphia, 
Pennsylvania. All packaging and labeling operations will comply with Good Manufacturing 
Practice for Medicinal Products and the relevant regulatory requirements. 
Blister pack wallets of KarXT capsules will be provided at Baseline and week 2 (Day 14), and 
they will be labeled. The label will include “KarXT (Xanomeline/Trospium Cl)”, recommended 
storage conditions, the name and address of the manufacturer, and the Investigational Use 
Statement (“Caution: New Drug – Limited by Federal (or United States) law to investigational 
use.”). Bottles of KarXT capsules will be provided at week 4 (Day 14) through week 152 
(Day 1064), and they will be labeled. The label will include “KarXT (Xanomeline/Trospium 
Cl)”, recommended storage conditions, the name and address of the manufacturer, and the 
Investigational Use Statement (“Caution: New Drug – Limited by Federal Law to Investigational 
Use.”). 


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7.2.4. 
Study Drug Storage 
KarXT must be stored at controlled room temperature, 15°C to 25°C, in a secured location with 
no access to unauthorized personnel at the site. Patients should store study medication at room 
temperature. 
7.3. 
Blinding 
This is a single arm open-label study; therefore, blinding is not applicable. 
7.4. 
Randomization 
This is an open-label study; therefore, randomization is not applicable.  
The Patient Number (14-XXX-XXX) in this trial will consist of a 2-digit study code (14), a 
3-digit site identification, and a 3-digit patient number that will be assigned sequentially within 
each site, starting with 001. 
7.5. 
Dose Modification 
Patients will be dosed as described in Section 7.1.2 and in accordance with the schedule of 
assessments (SoA) (Table 1). KarXT doses were selected based on the results of previous 
clinical studies (see Section 3.2.3 and Section 5.4). Per the protocol, patients will be evaluated 
for dose adjustments at Day 7 (telephone visit) through Visit 25 and at unscheduled visits. 
7.6. 
Study Treatment Adherence 
Treatment adherence will be evaluated by on-site pill count/site drug accountability procedures. 
The number of pills dispensed and returned (for each dispensation visit) will be recorded on the 
appropriate electronic case report form (eCRF). Patients will be reminded to adhere to the BID 
medication schedule. 
Patients who cannot maintain 65% adherence to the study drug over any 8 weeks period, unless 
there is hospitalization involved, will be discontinued from the study. The adherence assessments 
will be based on pill counts, patient recall, and caregiver report, if applicable. 
7.7. 
Concomitant Therapy 
Concomitant medications ongoing as of the Baseline visit will be captured in the eCRF as 
baseline therapy. Thereafter, all medications and other treatments taken by the patient during the 
study, including those treatments initiated before the start of the study drug administration, must 
be recorded on the KAR-014 eCRF. 
All patients participating in this study must not take any other antipsychotic medication beyond 
KarXT during the study, except for oral antipsychotics that may be down titrated during the first 
2 weeks of KarXT. If there is a strong case to be made after first 6 months of treatment for 
augmentation or PRN therapy, it needs to be discussed with the Medical Monitor. 
During the study (i.e., from Day 1 [day of 1st dose] until study completion), patients will refrain 
from the use of any other new concomitant medication(s) without the specific prior approval of 


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the investigator, unless its use is deemed necessary as in a medical emergency. Over the counter 
medications, such as acetaminophen, paracetamol, ibuprofen, aspirin etc., are permitted during 
the study. 
Note:  Please direct questions relating to prohibited medications to the Medical Monitor. 
7.7.1. 
Concomitant Medications for Anxiety and/or Sleep Aid 
Patients are allowed to take benzodiazepines (up to 4 mg lorazepam/day or equivalent) for 
anxiety, agitation, and insomnia on a PRN basis. Patients may also use nonbenzodiazepine 
medications (e.g., zolpidem, zaleplon) as a sleep aid. 


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8.
STUDY ASSESSMENTS AND PROCEDURES
The SoA (Table 1) outlines the efficacy and safety assessments to be performed throughout the 
study and their timing.  
The first dose of the study drug in this study will be self-administered by the patient at home the 
morning of Day 1, which is one day following the in-clinic Baseline Visit. The last dose will be 
taken at week 156 (the end of the 3-year treatment period). The study drug should be taken daily 
BID, preferably on an empty stomach, i.e., at least 1 hour before a meal or 2 hours after a meal.  
If completion of the visit is not possible on the scheduled day, the ± 2-day visit window (unless 
otherwise noted) may be used. 
8.1. 
Efficacy Assessments and Diagnostic Scales 
8.1.1. 
Clinical Global Impression‒Severity (CGI-S) 
The CGI-S is a rating scale completed independently by a clinician that is used to measure illness 
and symptom severity in subjects with mental disorders. It is used to rate the severity of a 
subject’s illness at the time of assessment. The modified CGI-S asks the clinician 1 question: 
“Considering your total clinical experience, how mentally ill is the subject at this time?” The 
clinician’s answer is rated on the following 7-point scale:  1 = normal, not at all ill; 
2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 
7 = among the most extremely ill subjects (Guy, 1976). 
This rating is based on observed and reported symptoms, behavior, and function in the past 
7 days. As symptoms and behavior can fluctuate over a week, the score should reflect the 
average severity level across the previous 7 days. 
8.1.2. 
Clinical Global Impression – Improvement (CGI-I) 
The CGI-I is a 7-point scale that requires the clinician to assess how much the patient's illness 
has improved or worsened relative to a baseline state at the beginning of the intervention. 
Clinicians are asked: “Compared to the patient’s condition at baseline, this patient’s [average] 
condition has...?”, and they rate as:  1 = Very much improved; 2 = Much improved; 
3 = Minimally improved; 4 = No change; 5 = Minimally worse; 6 = Much worse; 7 = Very much 
worse (Guy, 1976). 
8.1.3. 
Investigator’s Assessment Questionnaire (IAQ) 
The IAQ was developed to be a simple, easily used tool that simultaneously evaluates all health 
concerns associated with antipsychotic use in patients with schizophrenia or schizoaffective 
disorder. Effectiveness of treatment is assessed by the IAQ total score (primary endpoint), which 
is defined as the sum of 10 out of 12 items (positive symptoms, negative symptoms, somnolence, 
weight gain, signs and symptoms of prolactin elevation, akathisia, EPS, cognition, energy, and 
mood); each item is rated on a 5-point Likert scale (1 = Much better, 2 = Slightly better, 
3 = About the same, 4 = Slightly worse, and 5 = Much worse). 


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8.1.4. 
Medication Satisfaction Questionnaire (MSQ) 
The MSQ is a single-item questionnaire that evaluates satisfaction with antipsychotic medication 
in schizophrenia patients. Patient satisfaction with treatment can strongly influence health related 
behavior, pursuit and use of mental health services, treatment adherence, and long-term 
outcomes. Used for more than 20 years, the MSQ has different versions. The choice was made 
for utilizing the version with one single question rated on a 7-point scale; allowing for more 
nuanced responses to the question of overall how satisfied you are with your current 
antipsychotic therapy:  1 = Extremely dissatisfied, 2=Very dissatisfied, 3=Somewhat dissatisfied, 
4=Neither satisfied nor dissatisfied, 5=Somewhat satisfied, 6 = Very satisfied, 7 = Extremely 
satisfied. 
8.1.5. 
Brief Cognitive Assessment Tool for Schizophrenia (B-CATS) 
B-CATS is a brief measure composed of 3 cognitive tests (digital symbol substitution test; trail 
making test, part B; and category fluency) that provides a global cognition score. It is highly 
correlated with the global scores from comprehensive neuropsychological batteries that take 
between 6 and 20 times as long to administer. The B-CATS has been developed specifically for 
use by clinicians, and the 3 tests have straightforward and easy instructions for administration 
and scoring. 
• Digit symbol substitution:  a sheet with a 9-item key pairing digit 1 through 9 with a 
unique symbol; below are rows of numbers with blank squares beneath. The subject 
pairs each number with its unique symbol. The score is the number of correct 
number-symbol pairs completed in 120 seconds. 
• Trail making test, part B:  a sheet with scattered circles containing letters or numbers. 
Subjects draw a ‘‘trail’’ from number to letter (1-A-2-B, etc.) to number 13 without 
lifting the pencil from the article. The score is the time to completion. 
• Category fluency:  subjects orally list as many animals, fruits, and vegetables as they 
can in 60 seconds per category. The administrator tracks responses, and the score is 
the number of unique and appropriate answers per category. 
8.2. 
Safety Scales and Other Assessments 
Safety assessments are to be performed at protocol-specified visits, as specified in the SoA 
(Table 1). Table 2 describes all the safety laboratory tests required for this study. 
8.2.1. 
Barnes Akathisia Rating Scale (BARS) 
The BARS is a rating scale used to assess the severity of drug-induced akathisia, or restlessness; 
involuntary movements; and inability to sit still. The range of scores is 0 to 14, with higher 
scores indicating greater severity (Barnes, 1989). 
8.2.2. 
Abnormal Involuntary Movement Scale (AIMS) 
The AIMS is a rating scale used to measure involuntary movements known as TD, 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 


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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. 
8.2.3. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a tool designed to systematically assess and track suicidal AEs (suicidal behavior 
and suicidal ideation) throughout the study (Posner et al., 2011). The strength of this suicide 
classification system is its ability to comprehensively identify suicidal events while limiting the 
over-identification of suicidal behavior. The C-SSRS will be administered by a certified rater at 
the site and takes about 5 minutes to complete. 
This study will use the “Since Last Visit” version during scheduled visits. 
8.2.4. 
EQ-5D-3L 
EQ-5D-3L is an instrument that evaluates the generic quality of life developed in Europe, and it 
is widely used. The EQ-5D-3L descriptive system is a preference-based Health Related Quality 
of Life (HRQL) measure with one question for each of the five dimensions that include mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression. 
8.2.5. 
Accountable Health Communities Health-Related Social Needs (AHC HRSN) 
Developed by Centers for Medicare & Medicaid Services (CMS) Center for Medicare and 
Medicaid Innovation (CMMI), the AHC HRSN screening tool is used to assess the health-related 
social needs of patients and their effect on total health care costs and health outcomes. For this 
study, it will be important to also note the insurance status of patients, so changes will be tracked 
over the 3-year duration of the study. 
8.2.6. 
Zarit Caregiver Burden Interview (ZBI-22) 
The Zarit Burden Interview, a popular caregiver self-report measure used by many aging 
agencies, originated as a 29-item questionnaire (Zarit, Reever & Bach-Peterson, 1980). The 
revised version contains 22 items (ZBI-22). Each item on the interview is a statement that the 
caregiver is asked to endorse using a 5-point scale. Response options range from 0 (never) to 
4 (nearly always). For shorter administration, shorter versions, ranging from 1 to 18 items, have 
been developed. A study by Yu, Yap & Liew (2018) found that the 6-item version was the 
optimal short version as it provided similar diagnostic utility to the original 22-item version with 
the fewest items. 
8.2.7. 
Demographics and Medical and Psychiatric History 
Demographic data will be collected for all patients at the Screening visit of the KAR-014 study. 
The information to be captured includes the patient’s date of birth (alternatively year of birth if 
the full date of birth is not allowed to be collected for legal reasons), age, sex at birth, race, and 
ethnicity, which will be obtained from the patient and recorded in the eCRF. 
Medical and psychiatric history will be recorded at the Screening visit of the KAR-014 study. 
Investigators should document the occurrence, signs, and symptoms of the patient’s preexisting 
conditions, including all baseline symptoms, ongoing illnesses, other chronic conditions, and 
surgical history at the Screening visit of KAR-014. The medical history will also include a 


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history of drug, substance, or alcohol abuse/dependence within 1 year before the Screening visit 
of KAR-014. 
Illnesses first occurring or detected during the study and/or worsening of a concomitant illness 
during the study are to be documented as AEs on the eCRF in accordance with Section 8.3. All 
clinical abnormalities not present at baseline or described in the past medical history that are 
subsequently identified as clinically noteworthy must be recorded as AEs. 
8.2.8. 
Vital Signs 
Vital signs (systolic and diastolic blood pressure [BP] and heart rate [HR] measurements) will be 
evaluated at the visits as indicated in the SoA (Table 1). All vital signs will be measured supine 
or sitting after 2 minutes. Blood pressure includes systolic and diastolic BP, and it is to be taken 
in the same arm for the duration of the study. Heart rate is measured in beats/minute.  
Vital sign measurements will be repeated if clinically significant or if machine/equipment errors 
occur. Out-of-range BP or HR measurements will be repeated at the investigator’s discretion. 
Any confirmed, clinically significant vital sign measurements must be recorded as AEs. 
8.2.9. 
Physical Examination 
A complete physical examination (body temperature [orally collected, °C]; general appearance; 
head/eyes/ears/nose/throat; examination of thorax and abdomen; assessment of cardiac, 
musculoskeletal, and circulatory systems; palpations for lymphadenopathy; and limited 
neurological examination) will be performed at the visits specified in Table 1. Physical 
examinations will be performed by a physician. 
8.2.10. 
Weight, Height, and Body Mass Index 
Height (cm) and weight (kg) measurements will be obtained at the visits specified in the SoA 
(Table 1). BMI should be calculated at these visits. All findings should be recorded in the eCRF. 
8.2.11. 
Electrocardiograms (ECG) 
A 12-lead, resting ECG will be obtained at the visits indicated in the SoA (Table 1). During the 
ECG, ventricular rate (beats per minute [bpm]), PR (msec), QRS (msec), QT (msec), and QTcF 
(msec) measurements will be obtained. ECGs at all scheduled visits will be performed before 
blood withdrawal for any safety laboratory tests or pharmacokinetic (PK) analysis. 
All ECGs will be interpreted by experienced independent blinded reader(s) at a central reading 
facility. 
8.2.12. 
Laboratory Assessments 
Laboratory assessment samples (Table 2) are to be collected at designated visits as detailed in the 
SoA (Table 1). Fasting (preferred) blood laboratory samples will be analyzed at a central 
laboratory. Patients should be asked to present at the baseline visit in a fasting state (no eating or 
drinking except water for 8 to 12 hours). The state the patient presents at baseline should be 
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Table 2: 
Laboratory Assessments 
Hematology 
Serum Chemistry 
Urinalysis (Dipstick) 
Hct 
Hb 
MCH 
MCHC 
MCV 
Platelet count 
RBC count 
WBC count with differential 
 
ALT 
ALP 
AST 
Albumin 
Uric acid 
BUN or urea 
Carbon dioxide 
Creatinine 
Creatine kinase and subtypes 
Electrolytes (sodium, 
potassium, chloride, calcium, 
phosphorus) 
GGT 
Glucose 
LDH 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
HDL 
LDL 
Triglycerides 
Total protein 
Appearance 
pH 
Protein 
Glucose 
Ketone bodies 
Indicators of blood and WBCs 
Specific gravity 
Urobilinogen 
Occult blood 
WBCs 
UDS 
HbA1c (glycated Hb test) 
 
Prolactin 
COVID 19 Rapida 
Coagulation 
Serologyb 
PT 
Activated PTT 
Fibrinogen 
HBV 
HCV 
HIV 
Pregnancy test: A urine pregnancy test for WOCBP should be performed per the SoA (Table 1). In case of 
positive urine pregnancy test result, a serum sample should be sent to central laboratory to confirm the result. 
Full and microscopic urinalysis:  
Chemical exam: SG, pH, bilirubin, urobilinogen, protein, glucose, ketone, hemoglobin, leukocyte esterase, 
nitrite.  
Microscopic exam: RBCs, WBCs, epithelial cells, bacteria, yeasts, parasites, casts, crystals 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; COVID-19 = covid disease 2019; GGT = gamma-glutamyl transpeptidase; Hb = 
hemoglobin; HCG = human chorionic gonadotropin; Hct = hematocrit; LDH = lactate dehydrogenase; MCH = 
mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular 


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volume; PCR = polymerase chain reaction; PT = prothrombin time; PTT = partial thromboplastin time; RBC = red 
blood cell; UDS = urine drug screen; WBC = white blood cell. 
a COVID-19 Rapid test to be performed locally at Baseline.  If positive, PCR to be performed by central laboratory. 
b The following viral serology tests completed at Screening: anti-HCV antibody, HBV surface antigen, HBV core 
antibody, HIV 1 antibody, and HIV-2 antibody. If the patients tests positive for anti-HCV antibody, then HCV 
RNA via polymerase chain reaction should be performed to confirm or rule out active infection. 
Approximately 7 to 30 mL of venous blood will be withdrawn for the tests listed above at 
scheduled time points as per the SoA (Table 1).  
A minimum urine volume of 10 mL will be collected for urinalysis and a urine drug screen at 
scheduled time points as per the SoA (Table 1).  
Blood and abnormal urine samples will be analyzed at a central laboratory facility for 
microscopic analyses.  
All laboratory reports must be reviewed, signed, and dated by the investigator. A legible copy of 
all reports must be filed with both the patient’s eCRF and medical record (source document) for 
that visit. Any laboratory test result considered by the investigator to be clinically significant 
should be considered an AE (clinically significant AEs include those that require an 
intervention). Clinically significant abnormal values occurring during the study will be followed 
until repeat test results return to normal, stabilize, or are no longer clinically significant. 
8.2.13. 
Other Laboratory Assessments 
A urine drug screen (cannabinoids or marijuana, phencyclidine, amphetamines, opiates, and 
cocaine) will be performed at designated visits as detailed in the SoA (Table 1).  
Urine alcohol testing will be performed for alcohol content. 
8.2.14. 
Blood Sampling for Pharmacogenetics 
A blood sample may be collected at baseline for exploratory pharmacogenetic analysis if the 
patient provides consent for the procedure. Approximately 9 mL of blood may be collected for 
subsequent DNA extraction. The samples will be stored at a central laboratory facility where 
DNA will be extracted and retained. The collection, storage, shipping, processing of the blood 
samples, and the analytical methods to be used will be detailed in the laboratory manual. 
The genetic variants to be analyzed may include SNPs and any other variants as deemed 
necessary by the Sponsor. 
8.3. 
Adverse Events and Serious Adverse Events 
8.3.1. 
Definition of Adverse Events (AEs) 
An AE is any symptom, physical sign, syndrome, or disease that either emerges during the study 
or, if present at Screening, worsens during the study, regardless of the suspected cause of the 
event. All medical and psychiatric conditions present at Screening will be documented in the 
medical history eCRF. Clinically significant changes in these conditions and new symptoms, 
physical signs, syndromes, or diseases should be noted on the AE eCRF during the rest of the 
study. Clinically significant vital signs and laboratory abnormalities should also be recorded as 


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AEs. Surgical procedures that were planned before the patient enrolled in the study are not 
considered AEs if the conditions were known before study inclusion; the medical condition 
should be reported in the patient’s medical history. In addition, all COVID-19 related events 
should be reported as AEs. 
In accordance with the protocol, the investigator and/or study staff will elicit AEs and concurrent 
illness during and at the safety follow-up visit, and these will be recorded on the appropriate 
page of the eCRF. AEs will be elicited by asking the patient a nonleading question, for example, 
“Have you experienced any new or changed symptoms since we last asked?” 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the event should be noted. If the intensity category changes over a number of days, 
then those changes should be recorded separately with distinct onset dates. 
Specific guidelines for classifying AEs by intensity and relationship to study drug are provided 
in Table 3 and Table 4. 
Table 3: 
Classification of Adverse Events by Intensity 
MILD  
An event that is easily tolerated by the patient, causes minimal discomfort, and 
does not interfere with everyday activities. 
MODERATE  
An event that is sufficiently discomforting to interfere with normal everyday 
activities. 
SEVERE  
An event that prevents normal everyday activities. 
 
Table 4: 
Classification of Adverse Events by Relationship to Study Drug 
UNRELATED  
This category applies to adverse events (AEs) that are clearly and incontrovertibly 
due to extraneous causes (disease, environment, etc.). 
UNLIKELY   
This category applies to AEs that are judged to be unrelated to the test drug but for 
which no extraneous cause may be found. An AE may be considered unlikely to be 
related to the study drug when it meets 2 of the following criteria: (1) it does not 
follow a reasonable temporal sequence from the administration of the test drug; 
(2) it could readily have been produced by the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
patient; (3) it does not follow a known pattern of response to the test drug; or (4) it 
does not reappear or worsen when the drug is readministered. 
POSSIBLY  
This category applies to AEs for which a connection with the test drug appears 
unlikely but cannot be ruled out with certainty. An AE may be considered possibly 
related when it meets 2 of the following criteria: (1) it follows a reasonable 
temporal sequence from the administration of the drug; (2) it could not readily 
have been produced by the patient’s clinical state, environmental or toxic factors, 
or other modes of therapy administered to the patient; or (3) it follows a known 
pattern of response to the test drug. 
PROBABLY   
This category applies to AEs that the investigator believes with a high degree of 
certainty are related to the test drug. An AE may be considered probably related 
when it meets 3 of the following criteria:  (1) it follows a reasonable temporal 


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sequence from the administration of the drug; (2) it cannot be reasonably explained 
by the known characteristics of the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient; (3) it disappears or 
decreases upon cessation or reduction in dose (note that sometimes an AE does not 
disappear upon discontinuation of the drug yet drug-relatedness clearly exists; for 
example, bone marrow depression, fixed drug eruptions, or tardive dyskinesia); or 
(4) it follows a known pattern of response to the test drug. 
DEFINITELY  
This category applies to AEs that the investigator believes are incontrovertibly 
related to the test drug. An AE may be assigned an attribution of “definitely related 
when it meets all of the following criteria:  (1) it follows a reasonable temporal 
sequence from the administration of the drug; (2) it cannot be reasonably explained 
by the known characteristics of the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient; (3) it disappears or 
decreases upon cessation or reduction in dose and recurs with re-exposure to the 
drug (if rechallenge occurs); and (4) it follows a known pattern of response to the 
test drug. 
8.3.2. 
Adverse Events of Special Interest (AESIs) 
AESIs will be monitored, and they include orthostasis and LFT elevations (inclusive of drug 
induced liver injury [DILI]; Section 8.3.6). 
AESIs should be recorded as AEs and reported as SAEs when appropriate. 
Orthostasis will be defined as the patient being symptomatic with at least one of the following 
differences in orthostatic vitals between sitting position and standing after 2 minutes:  
• A decrease of systolic BP of 20 mmHg or more.  
• A decrease in diastolic BP of 10 mmHg or more.  
• An increase in HR of 30 bpm or more.  
Changes of the orthostatic vitals alone will not be considered an AESI without the patient being 
symptomatic. If the patient is asymptomatic with the above differences in orthostatic vitals, the 
event will be captured as an AE. 
Since BP and HR will be taken at each visit, orthostatic evaluation will be conducted when 
indicated and per the clinical judgement of the investigator with at least one such assessment 
within the first 2 months of drug initiation and at least one assessment every 6 months thereafter.   
8.3.3. 
Definition of Serious Adverse Events (SAEs) 
An SAE is any untoward medical occurrence that, in the view of either the investigator or 
Sponsor: 
• Results in death. 
• Is life-threatening. 
• Results in inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization for elective treatment of a pre-existing, non-worsening condition is 


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not; however, considered an SAE; the details of such hospitalizations must be 
recorded on the medical history or physical examination page of the eCRF). 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Other important medical events that may not be immediately life-threatening or result 
in death or hospitalization, based on appropriate medical judgment, are considered 
SAEs if they are thought to jeopardize the patient and/or require medical or surgical 
intervention to prevent one of the outcomes defining an SAE. SAEs are critically 
important for the identification of significant safety problems; therefore, it is 
important to consider both the investigator’s and the Sponsor’s assessments. If either 
the Sponsor or the investigator believes that an event is serious, the event must be 
considered serious and evaluated by the Sponsor for expedited reporting. 
8.3.4. 
Serious Adverse Event Reporting 
SAEs and AESIs will be classified as treatment-emergent as appropriate. SAEs and AESI 
reported by patients or observed by clinical staff after the patient has signed the ICF must be 
reported to the pharmacovigilance group of the Sponsor. Any such SAE or AESI due to any 
cause, whether related to the study drug or not, must be reported within 24 hours of occurrence 
or when the investigator becomes aware of the event. SAEs must be reported directly through 
the electronic data capture (EDC)/eSource system, but as a backup (in case the EDC/eSource 
system is not available), sites can use the email address Safety@catalystcr.com. 
Catalyst Clinical Research Pharmacovigilance email address is:  Safety@catalystcr.com. 
The events must be recorded on the standard AE eCRF. Preliminary reports of SAEs must be 
followed up by detailed descriptions, including clear and anonymized photocopies of hospital 
case reports, consultant reports, autopsy reports, and other documents when requested and 
applicable. SAE reports must be made whether the investigator considers the event to be related 
to the investigational drug or not. 
Appropriate remedial measures should be taken to treat the SAE, and the treatment procedure 
should be recorded. The investigator must report all additional follow-up evaluations to the 
pharmacovigilance group within 24 hours of becoming aware of the additional information or as 
soon as it is practicable. All SAEs will be followed up until the investigator and Sponsor agree 
the event is satisfactorily resolved. 
Any SAE that is not resolved by the safety follow-up visit or upon discontinuation of the 
patient’s participation in the study is to be followed up until it either resolves, stabilizes, returns 
to baseline values (if a baseline value is available), or is shown to not be attributable to the study 
drug or procedures. 
8.3.5. 
Pregnancy and Pregnancy Reporting 
WOCBP must have a negative pregnancy test at Screening and Baseline prior to receiving the 
first dose of study treatment for this study (KAR-014).  


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If a female patient becomes pregnant, the investigator must discontinue her from the study 
without delay. The patient must not receive any further doses of KarXT. Upon discontinuation 
from the study, only those procedures that would not expose the patient to undue risk will be 
performed. 
If the female patient or the female partner of the male patient is willing and able to consent to 
pregnancy follow-up, she will be followed until her pregnancy reaches term. Information 
regarding the pregnancy must only be submitted after obtaining informed consent from the 
pregnant partner. The investigator will arrange counseling for the pregnant partner with a 
specialist. The specialist will discuss the risks of continuing with the pregnancy and the possible 
effects on the fetus. 
The investigator must notify the Sponsor (or designee) of any female patient or female partner of 
a male patient that becomes pregnant while participating in the study. Any known cases of 
pregnancy will be reported until the patient completes or discontinues from the study.  
The pregnancy will be reported immediately by faxing/emailing a completed pregnancy report to 
the Sponsor (or designee) within 24 hours of knowledge of the event. The pregnancy will not be 
processed as an SAE; however, the investigator will follow-up with the patient until the 
completion of the pregnancy and must assess the outcome in the shortest possible time, but not 
more than 30 days after completion of the pregnancy.  
The investigator should notify the Sponsor (or designee) of the pregnancy outcome by 
submitting a follow-up pregnancy report. If the outcome of the pregnancy involved spontaneous 
or therapeutic abortion (any congenital anomaly detected in an aborted fetus is to be 
documented), stillbirth, neonatal death, or congenital anomaly, the investigator will report the 
event by faxing/emailing a completed pregnancy report form to the Sponsor (or designee) within 
24 hours of knowledge of the event, and the event will be considered an SAE. 
The investigator should also be notified of pregnancy that occurs during the study but is not 
confirmed until after completion of the study. In the event that a patient is subsequently found to 
be pregnant after inclusion in the study, any pregnancy will be followed to term, and the status of 
mother and child will be reported to the Sponsor after delivery. 
8.3.6. 
Drug-Induced Liver Injury (DILI) 
The sponsor has incorporated the following for monitoring of the DILI: 
• An increase of serum ALT or AST to >3 × ULN should be followed by repeat testing 
within 48 to 72 hours of all 4 of the usual serum measures (ALT, AST, alkaline 
phosphatase [ALP], and total bilirubin) to confirm the abnormalities and to determine 
if they are increasing or decreasing. An inquiry should be made about the symptoms 
(fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, and rash). 
• Close observation should be initiated with ALT or AST ≥3 × ULN. 
• Repeat liver enzyme and serum bilirubin tests 2 or 3 times weekly. The frequency of 
retesting can decrease to once per week or less if abnormalities stabilize or the trial 
drug has been discontinued and the patient is asymptomatic. 


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• Obtain a more detailed history of symptoms and prior or concurrent diseases. 
• Obtain a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets. 
• Rule out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy; and biliary 
tract disease. 
• Obtain a history of exposure to environmental chemical agents. 
• Obtain additional tests to evaluate liver function, as appropriate (e.g., international 
normalized ratio, direct bilirubin). 
• Consider gastroenterology or hepatology consultations. 
Discontinuation of treatment should be considered if: 
• ALT or AST >8 × ULN. 
• ALT or AST ≥5 × ULN for more than 2 weeks. 
• ALT or AST ≥3 × ULN and (total bilirubin > 2 × ULN or international normalized 
ratio >1.5). 
• ALT or AST ≥3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, or eosinophilia (> 5%). 
Gamma-glutamyl transpeptidase elevations alone should not prompt drug discontinuation.  
Hepatic adjudication of cases should include an evaluation for alternative causes, such as viral, 
autoimmune, alcohol, hepatobiliary disorders, nonalcoholic steatohepatitis, concomitant 
medications, etc.  
Follow-up is expected until resolution of elevated liver enzyme cases. 
8.3.7. 
Trial Discontinuation Criteria Other than Pregnancy 
8.3.7.1. 
Individual Stopping Criteria 
Based on Common Terminology Criteria for Adverse Events (CTCAE, 2017) v5.0, the study 
drug will be discontinued in any patient who has a ≥ Grade 4 AE. Discontinuation or dose 
reduction for Grade 3 AEs will be at the discretion of the investigator. 
8.3.7.2. 
Trial Stopping Rules 
The safety and tolerability aspects of KarXT will be overseen by the medical monitors and the 
study team of the Sponsor and the Contract Research Organization (CRO). They will be 
responsible for safeguarding the interests of clinical study patients. The study team is expected to 
recommend to the sponsor whether to: 
• Continue the clinical study without modification; or 


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• Continue the clinical study with modification (listing the specific modifications 
recommended); or 
• Terminate the study. 
8.3.8. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
AEs that meet all the following criteria will be classified as suspected unexpected serious 
adverse reactions (SUSARs) and reported to the appropriate regulatory authorities in accordance 
with applicable regulatory requirements for expedited reporting: 
• Serious.  
• Unexpected (i.e., the event is not consistent with the safety information in the KarXT 
IB, or package insert of generic trospium). 
• At least a reasonable possibility that there is a causal relationship between the event 
and the study treatment. 
The investigator will assess whether or not an event is causally related to study treatment. The 
Sponsor (or their designee CRO) will consider the investigator’s assessment and determine 
whether the event meets the criteria for being reportable as a 7-day or 15-day safety report. 
SUSARs that are fatal or life-threatening must be reported to the regulatory authorities and the 
Independent Ethics Committee (IEC)/ Institutional Review Board (IRBs) (where required) within 
7 days after the Sponsor (or their designee) has first knowledge of them with a follow-up report 
submitted within a further 8 calendar days. Other SUSARs must be reported to the relevant 
regulatory authorities and the IEC/IRBs within 15 calendar days after the Sponsor (or their 
designee) first has knowledge of them. 
The Sponsor (or their designee) is responsible for reporting SUSARs, and any other events 
required to be reported in an expedited manner, to the regulatory authorities and for informing 
investigators of reportable events in compliance with applicable regulatory requirements within 
specific timeframes. Investigators will notify the relevant IEC/IRBs of reportable events within 
the applicable timeframes. 
8.3.9. 
Overdose 
The investigator must immediately notify the Sponsor of any occurrence of overdose with the 
study drug. Overdose should be managed with symptomatic and supportive care. For the purpose 
of this study, an overdose is defined as any intentional or unintentional consumption of 
investigation medicinal product that exceeds the maximum TDD (total daily dose) specified in 
the protocol (250/60 mg TDD). 
8.3.10. 
Warnings and Precautions 
Risk of Urinary Retention 
Trospium chloride should be administered with caution to patients with clinically significant 
bladder outflow obstruction because of the risk of urinary retention. 
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Angioedema of the face, lips, tongue, and/or larynx has been reported with trospium chloride, an 
active ingredient in KarXT. In one case, angioedema occurred after the first dose of trospium 
chloride as SANCTURA® (SANCTURE Package Insert, 2012). Angioedema associated with 
upper airway swelling may be life-threatening. If the involvement of the tongue, hypopharynx, or 
larynx occurs, KarXT should be promptly discontinued and appropriate therapy and/or measures 
necessary to ensure an open patent airway should be promptly provided. 
Decreased Gastrointestinal Motility 
Trospium chloride should be used with caution in patients with gastrointestinal obstructive 
disorders because of the risk of gastric retention. Trospium chloride, like other antimuscarinic 
agents, may decrease gastrointestinal motility and should be used with caution in patients with 
conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis. 
Controlled Narrow-angle Glaucoma 
In patients being treated for narrow-angle glaucoma, trospium chloride should be used only if the 
potential benefits outweigh the risks and, in that circumstance, only with careful monitoring. 
Central Nervous System Effects 
Trospium chloride is associated with anticholinergic CNS effects. A variety of CNS 
anticholinergic effects have been reported, including dizziness, confusion, hallucinations, and 
somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly 
after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy 
machinery until they know how trospium chloride affects them. If a patient experiences 
anticholinergic CNS effects, dose reduction or drug discontinuation should be considered. 
Anticholinergic Adverse Reactions in Patients with Moderate Renal Impairment 
Trospium is substantially excreted by the kidney. The effects of moderate renal impairment on 
systemic exposure are not known, but systemic exposure is likely increased. Therefore, 
anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract 
infection, and urinary retention) are expected to be greater in patients with moderate renal 
impairment. 
Elevation of Liver Enzymes 
Elevated liver enzymes have been reported in previous studies of xanomeline as a monotherapy 
in AD patients. Elevations in hepatic enzymes have not been seen in Phase 1 studies with KarXT 
in healthy volunteers. The LFT elevations in the Phase 2 schizophrenia study (KAR-004) with 
KarXT were quite limited when compared to the effects of xanomeline alone in the elderly AD 
population. Moreover, even in the AD patients who experienced hepatic enzyme elevations, the 
elevations were reversible even with continued xanomeline treatment in patients who provided 
sufficient follow-up data. Importantly, there were no Hy’s law cases or elevations in total 
bilirubin to > 2 × upper limit of the reference range for either xanomeline or KarXT. 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypothesis 
No statistical hypothesis testing will be performed for this study. 
9.2. 
Sample Size Determination 
The primary objectives of this study are to assess the long-term safety and tolerability of KarXT 
as well as its effectiveness, persistence, and durability of effect through the IAQ and CGI-S scale 
in patients with a diagnosis of schizophrenia. Approximately 380 patients are planned to be 
enrolled in this study. The goal is to have at least 100 patients remain in the study after 2 years, 
which equates to an approximate 60% yearly retention rate, which would be higher than the 
average of 50% (including LAIs) adherence observed for patients living with schizophrenia. 
Thus, achieving the retention goal of this naturalistic study will position KarXT above the 
overall average for adherence amongst available therapies. 
9.3. 
Populations for Analyses 
Table 5: 
Populations for Analyses Descriptions 
Population 
Description 
Enrolled 
All patients who have given informed consent for KAR-014 will be 
included in the enrolled population. 
Safety 
All patients who receive at least 1 dose of KarXT in study KAR-014 
will be included in the safety population and will be used in the safety 
analyses. 
Modified Intent-to-Treat 
(mITT) 
All patients who are enrolled and received KarXT through week 8, 
will be included in the mITT population and will be used in the 
efficacy and other analyses. 
9.4. 
Statistical Analyses 
9.4.1. 
General Approach 
Descriptive statistics will be used to provide an overview of the safety and efficacy results. For 
continuous parameters, descriptive statistics will include n, mean, median, standard deviation, 
minimum, and maximum. For categorical parameters, the number and percentage of patients in 
each category will be presented. The denominator for percentages will be based on the number of 
patients appropriate for the purposes of analysis. No statistical hypothesis testing will be 
performed. For endpoints defined as change from baseline, the baseline is defined as the last 
measurement prior to the first dose of the study medication unless otherwise specified. Further 
methods pertaining to the summary and analyses of the efficacy and safety data are presented in 
the following sections and will be described in more detail in the Statistical Analysis Plan (SAP). 


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9.4.2. 
Safety Analysis 
Safety endpoints will be summarized for all patients in the safety population. The presentation of 
safety data will be based on the treatment received in KAR-014. 
The primary safety endpoint of the study is the incidence of TEAEs leading to discontinuation. 
Secondary safety endpoints are the incidence of TESAEs and the incidence of TEAEs of special 
interest. 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities version 
23.0 or higher. The incidence of TEAEs (events with onset dates on or after the start of the study 
drug in KAR-014) will be summarized by system organ class and preferred term. All AEs will be 
listed by patient, along with information regarding onset, duration, severity, relationship to study 
drug, action taken with the study drug, treatment of the event, and outcome. The incidence and 
severity of AEs, TEAEs leading to discontinuation, TEAEs, TEAEs of special interest, and 
TESAEs will be presented by defined study populations.   
Vital signs, clinical laboratory data, prolactin levels, ECG parameters, and physical examinations 
will be summarized using descriptive statistics, including observed and change-from-baseline 
values, as well as numbers of patients with values outside the limits of the normal range at each 
time point by treatment group. Similar descriptive summaries will be provided for BARS, AIMS, 
height, body weight, and BMI.   
Additional details pertaining to the summary of safety data will be provided in the SAP. 
9.4.3. 
Efficacy Analysis 
Efficacy analysis will be conducted for all patients in the modified intent-to-treat (mITT) 
population. 
The primary efficacy endpoints will be measured by IAQ and CGI-S, secondary efficacy 
endpoints will be assessed by CGI-I and MSQ, and a cognition endpoint will be assessed by 
B-CATS. 
Other endpoints of the study include functional and observed outcomes (EQ-5D-3L and ZBI-22), 
adherence to KarXT at different timepoints, AHC HRSN, and SNPs related to schizophrenia 
subtypes and drug metabolism.   
Descriptive statistics will be used for observed values and change from baseline (as applicable) 
of efficacy endpoints. For continuous parameters, descriptive statistics will include n, mean, 
median, standard deviation, minimum, and maximum. For categorical parameters, the number 
and percentage of patients in each category will be presented. The denominator for percentages 
will be based on the number of patients appropriate for the purposes of analysis. No statistical 
hypothesis testing will be performed. 
9.4.4. 
Planned Interim Analysis  
No interim analysis is planned for this study. 


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9.5. 
Handling of Missing Data 
Safety and efficacy analyses will be based on the observed case data. No missing data will be 
imputed. 


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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. 
Regulatory Guidelines 
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki and/or all relevant regulations, as set forth in Parts 50, 56, 312, Subpart D, of Title 21 of 
the US Code of Federal Regulations (CFR), in compliance with International Council for 
Harmonisation (ICH) and Good Clinical Practice (GCP) guidelines, and all applicable local, 
state, and federal government regulations and laws. 
10.1.2. 
Independent Ethics Committee/Institutional Review Board 
The conduct of the study must be approved by an appropriate IEC/IRB. Approval is required for 
the study protocol, protocol amendments (if applicable), IB, ICFs, recruitment material, patient 
information sheets, and other patient facing material. 
10.1.3. 
Informed Consent Process 
For each study patient, informed consent will be obtained before any protocol-related activities. 
As part of this procedure, the investigator or designee must explain orally and in writing the 
nature of the study, its purpose, procedures, expected duration, alternative therapy available, and 
the benefits and risks involved in study participation. The patient should be informed that they 
may discontinue from the study at any time, and the patient will receive all information that is 
required by local regulations and guidelines for ICH. The investigator will provide the Sponsor 
or its representative with a copy of the IEC/IRB-approved ICF before the start of the study. 
The ICF should be revised whenever there are substantial changes to procedures or when new 
information becomes available that may affect the willingness of a patient to participate. 
Revisions to the ICF required during the study must be approved by the Sponsor and IEC/IRB, 
and a copy of the revised consent form is provided to the Sponsor. For any updated or revised 
ICFs, the patients must be re-consented for continued participation in the study. 
10.1.4. 
Data Handling 
Any data to be recorded directly on the eCRFs (to be considered as source data) will be 
identified at the start of the study. Data reported on the eCRF that are derived from source 
documents should be consistent with the source documents, or the discrepancies must be 
explained. See also Section 10.1.5.  
Clinical data will be entered by site personnel on eCRFs for transmission to the Sponsor. Data on 
eCRFs transmitted via the web-based data system must correspond to and be supported by source 
documentation maintained at the study site, unless the study site makes direct data entry to the 
databases for which no other original or source documentation is maintained. In such cases, the 
study site should document which eCRFs are patient to direct data entry and should have in place 
procedures to obtain and retain copies of the information submitted by direct data entry. All 
study forms and records transmitted to the Sponsor must include only coded identifiers such that 
directly identifying personal information is not transmitted. The primary method of data 


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transmittal is via the secure, internet-based EDC system maintained by the CRO. Access to the 
EDC system is available only to authorized users via the study’s secured internet website, where 
a user-unique assigned username and password are required for access. 
Any changes made to data after collection will be made through the EDC system. Electronic 
CRFs will be considered complete when all missing and/or incorrect data have been resolved. 
10.1.5. 
Source Documents 
Source documents are considered to be all information in original records and certified copies of 
original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. The investigator will provide direct 
access to source documents and/or source data in the facilitation of trial-related monitoring, 
audits, review by IECs/IRBs, and regulatory inspections. 
The investigator/institution should maintain adequate and accurate source documents and trial 
records that include all pertinent observations on each of the site’s trial patients. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, should not obscure the original entry, and should be explained if 
necessary. 
Data recorded on source documents will be transcribed onto eCRFs. Copies of completed eCRFs 
will be provided to the Sponsor and the sites at the end of the study. The completed eCRFs will 
be retained by the investigator. 
10.1.6. 
Record Retention 
Study records and source documents must be preserved for at least 15 years after the completion 
or discontinuation from the study, at least 2 years after the drug being studied has received its 
last approval for sale, or at least 2 years after the drug development has stopped, and in 
accordance with the applicable local privacy laws, whichever is the longer time period. 
The investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of patient health information, including, but not limited to, the 
Standards for Individually Identifiable Health Information, 45 CFR, Parts 160 and 164 (the 
Health Insurance Portability Accountability Act of 1996 [HIPAA] Privacy Regulation). The 
investigator shall ensure that study patients authorize the use and disclosure of protected health 
information in accordance with HIPAA Privacy Regulation and a form satisfactory to the 
Sponsor. 
10.1.7. 
Monitoring 
The study will be monitored according to the KAR-014 monitoring plan to ensure that it is 
conducted and documented properly according to the protocol, GCP, and all applicable 
regulatory requirements. 
Monitoring visits, on-site, remote, and virtual (telephone) or a combination, and contacts will be 
made at appropriate times during the study. The investigator will assure that adequate site 
personnel are available throughout the study to collaborate with clinical monitors. Clinical 


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monitors must have direct access to source documentation to check the completeness, clarity, 
and consistency of the data recorded in the eCRFs for each patient. 
The investigator will make available to the clinical monitor all source documents and medical 
records necessary to review protocol adherence and eCRFs. In addition, the investigator will 
work closely with the clinical monitor and as needed, will provide appropriate evidence that the 
study is being conducted in accordance with the protocol, applicable regulations, and GCP 
guidelines. 
10.1.8. 
Quality Control and Quality Assurance 
The Sponsor or its designee will perform the quality assurance and quality control activities of 
this study; however, responsibility for the accuracy, completeness, security, and reliability of the 
study data presented to the Sponsor lies with the investigator generating the data. 
The Sponsor will arrange audits as part of the implementation of quality assurance to ensure that 
the study is being conducted in compliance with the protocol, standard operating procedures, 
GCP, and all applicable regulatory requirements. Audits will be independent of and separate 
from the routine monitoring and quality control functions. Quality assurance procedures will be 
performed at study sites and during data management to assure that safety and efficacy data are 
adequate and well documented. 
10.1.9. 
Ethical Considerations 
This study will be conducted in accordance with this protocol, the accepted version of the 
Declaration of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, 
Subpart D, of Title 21 of the CFR; and in compliance with GCP guidelines. 
IECs/IRBs will review and approve this protocol and the ICF. All patients are required to give 
informed consent before participation in the study. 
10.1.10. 
Financing and Insurance 
Before the study commences, the Sponsor (or its designee) and the investigator (or the 
institution, as applicable) will agree on the costs necessary to perform the study. This agreement 
will be documented in a financial agreement that will be signed by the investigator (or the 
institution signatory) and the Sponsor (or its designee). 
The investigator is required to have adequate current insurance to cover claims for negligence 
and/or malpractice. The Sponsor will provide no-exclusion insurance coverage for the clinical 
study as required by national regulations. 
10.1.11. 
Publication Policy/Disclosure of Data 
Both the use of data and the publication policy are detailed in the clinical study agreement. 
Intellectual property rights (and related matters) generated by the investigator and others 
performing the clinical study will be patient to the terms of the clinical study agreement, which 
will be agreed upon between the institution and the Sponsor or their designee. With respect to 
such rights, the Sponsor or its designee will solely own all rights and interests in any materials, 
data, and intellectual property rights developed by investigators and others performing the study 


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described in this protocol, patient to the terms of any such agreement. In order to facilitate such 
ownership, investigators will be required to assign all such inventions either to their institution or 
directly to the Sponsor or its designee, as will be outlined in the clinical study agreement. 
10.2. 
Protocol Amendment and Protocol Deviation 
10.2.1. 
Protocol Amendment 
Amendments to the protocol that entail corrections of typographical errors, clarifications of 
confusing wording, changes in study personnel, and minor modifications that have no effect on 
the safety of patients or the conduct of the study will be classified as administrative amendments 
and will be submitted to the IEC/IRB for informational use only. The CRO will ensure that 
acknowledgment is received and filed. Amendments that are classified as substantial 
amendments must be submitted to the appropriate regulatory authorities and the IECs/IRBs for 
approval and, except for urgent safety measures, will not be implemented at sites until such 
approvals are received. 
10.2.2. 
Protocol Deviations 
Should a protocol deviation occur, the Sponsor must be informed as soon as possible. Protocol 
deviations and/or violations and the reasons they occurred will be included in the clinical study 
report. Reporting of protocol deviations to the IEC/IRB and in accordance with applicable 
regulatory authority mandates is an investigator’s responsibility.   
• All protocol deviations will be tracked and evaluated on an ongoing basis. Deviations 
considered major will be identified as such during the Medical Monitor’s periodic 
review. 
• Minor deviations are those which do not affect the scientific soundness of the 
research study or the rights or safety of patient. One example is a visit outside a visit 
window by a day or 2. 
• Major deviations are those that do affect the scientific soundness of the research study 
or the rights or safety of patients. 
Major protocol deviations will be tabulated by type of deviation. 


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11. 
LIST OF REFERENCES 
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American Pharmaceutical, Inc. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021436s044s045,021713s035s036,0
21729s027s028,021866s029s030lbl.pdf 
ABILIFY MAINTENA® (aripiprazole) (2020). Package Insert, Highlights of Prescribing 
Information. Otsuka American Pharmaceutical, Inc. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202971s013lbl.pdf 
American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders 
(5th ed.) https://doi.org/10.1176/appi.books.9780890425596. 
ARISTADA® (aripiprazole lauroxil) (2020). Package Insert, Highlights of Prescribing 
Information. Alkermes, Inc. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/207533s017,209830s005lbl.pdf 
Barnes, T.R. (1989). A rating scale for drug-induced akathisia. Br J Psychiatry 154, 672-676. 
Bodick, N.C., Offen, W.W., Levey, A.I., Cutler, N.R., Gauthier, S.G., Satlin, A., Shannon, H.E., 
Tollefson, G.D., Rasmussen, K., Bymaster, F.P., et al. (1997a). Effects of xanomeline, a 
selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in 
Alzheimer disease. Arch Neurol 54, 465-473. 
Bodick, N.C., Offen, W.W., Shannon, H.E., Satterwhite, J., Lucas, R., van Lier, R., and Paul, 
S.M. (1997b). The selective muscarinic agonist xanomeline improves both the cognitive deficits 
and behavioral symptoms of Alzheimer disease. Alzheimer Dis Assoc Disord 11 Suppl 4, S16-
22. 
Brannan, S.K., Sawchak, S., Miller, A.C., Lieberman, J.A., Paul, S.M., and Breier, A. (2021). 
Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia. N Engl J 
Med 384, 717-726. 
Crismon, L., Argo, T.R., and Buckley, P.F. (2014). Schizophrenia, 9th edn (New York, New 
York: McGraw-Hill). 
CTCAE (2017). Common Terminology Criteria for Adverse Events; 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_refere
nce_5x7.pdf. 
Depakote (divalproex sodium) (2021). Package Insert, Highlights of Prescribing Information. 
AbbVie Inc. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/018723s065lbl.pdf 
Emsley, R., Chiliza, B., Asmal, L., and Harvey, B.H. (2013). The nature of relapse in 
schizophrenia. BMC Psychiatry 13, 50. 
Farde, L., Suhara, T., Halldin, C., Nyback, H., Nakashima, Y., Swahn, C.G., Karlsson, P., 
Ginovart, N., Bymaster, F.P., Shannon, H.E., et al. (1996). PET study of the M1-agonists 
[11C]xanomeline and [11C]butylthio-TZTP in monkey and man. Dementia 7, 187-195. 
GEODON® (ziprasidone) (2022). Package Insert, Highlights of Prescribing Information. Pfizer 
Inc. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020825s063lbl.pdf 


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Green, M.F., Kern, R.S., and Heaton, R.K. (2004). Longitudinal studies of cognition and 
functional outcome in schizophrenia: implications for MATRICS. Schizophr Res 72, 41-51. 
Guy, W. (1976). EDCEU Assessment Manual for Psychopharmacology – Revised., E. US 
Department of Health, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental 
Health Administration, NIMH Psychopharmacology Research Branch, Division of Extramural 
Research Programs, ed. (DHEW Publication No ADM 76 338.), pp. 534-537. 
HMA (2020). Heads of Medicines Agencies. Clinical Trial Facilitation Group page. 
Recommendations related to contraception and pregnancy testing in clinical trials.  
Huhn, M., Nikolakopoulou, A., Schneider-Thoma, J., Krause, M., Samara, M., Peter, N., Arndt, 
T., Backers, L., Rothe, P., Cipriani, A., et al. (2019). Comparative efficacy and tolerability of 32 
oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a 
systematic review and network meta-analysis. Lancet 394, 939-951. 
INVEGA® (paliperidone) (2021). Package Insert, Highlights of Prescribing Information. Janssen 
Pharmaceuticals, Inc. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021999Orig1s039lbl.pdf 
INVEGA SUSTENNA® (paliperidone palmitate) (2021). Package Insert, Highlights of 
Prescribing Information. Janssen Pharmaceuticals, Inc. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022264Orig1s033lbl.pdf 
INVEGA TRINZA® (paliperidone palmitate) (2021). Package Insert, Highlights of Prescribing 
Information. Janssen Pharmaceuticals, Inc. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/207946Orig1s011lbl.pdf 
Kahn, R.S., Sommer, I.E., Murray, R.M., Meyer-Lindenberg, A., Weinberger, D.R., Cannon, 
T.D., O'Donovan, M., Correll, C.U., Kane, J.M., van Os, J., et al. (2015). Schizophrenia. Nat 
Rev Dis Primers 1, 15067. 
LATUDA (lurasidone hydrochloride) (2019). Package Insert, Highlights of Prescribing 
Information. Sunovion Pharmaceuticals Inc. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/200603s035lbl.pdf 
Leucht, S., Cipriani, A., Spineli, L., Mavridis, D., Orey, D., Richter, F., Samara, M., Barbui, C., 
Engel, R.R., Geddes, J.R., et al. (2013). Comparative efficacy and tolerability of 15 
antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 382, 951-962. 
Lieberman, J.A., Stroup, T.S., McEvoy, J.P., Swartz, M.S., Rosenheck, R.A., Perkins, D.O., 
Keefe, R.S., Davis, S.M., Davis, C.E., Lebowitz, B.D., et al. (2005). Effectiveness of 
antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353, 1209-1223. 
Mirza, N.R., Peters, D., and Sparks, R.G. (2003). Xanomeline and the antipsychotic potential of 
muscarinic receptor subtype selective agonists. CNS Drug Rev 9, 159-186. 
Patel, K.R., Cherian, J., Gohil, K., and Atkinson, D. (2014). Schizophrenia: overview and 
treatment options. P T 39, 638-645. 
PERSERIS™ (risperidone) (2019). Package Insert, Highlights of Prescribing Information. 
Indivior Inc. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210655s004lbl.pdf 


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Posner, K., Brown, G.K., Stanley, B., Brent, D.A., Yershova, K.V., Oquendo, M.A., Currier, 
G.W., Melvin, G.A., Greenhill, L., Shen, S., et al. (2011). The Columbia-Suicide Severity Rating  
RISPERDAL CONSTA® ((risperidone) (2021). Package Insert, Highlights of Prescribing 
Information. Janssen Pharmaceuticals, Inc. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020272Orig1s083,020588Orig1s071
,021444Orig1s057,021346Orig1s061lbl.pdf#page=60 
Scale: initial validity and internal consistency findings from three multisite studies with 
adolescents and adults. Am J Psychiatry 168, 1266-1277. 
SANCTURA® (trospium chloride) (2012). Package Insert, Highlights of Prescribing 
Information. Allergan, Inc. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021595s009lbl.pdf 
Scheife, R., and Takeda, M. (2005). Central nervous system safety of anticholinergic drugs for 
the treatment of overactive bladder in the elderly. Clin Ther 27, 144-153. 
Sellin, A.K., Shad, M., and Tamminga, C. (2008). Muscarinic agonists for the treatment of 
cognition in schizophrenia. CNS Spectr 13, 985-996. 
SEROQUEL® (quetiapine) (2022). Package Insert, Highlights of Prescribing Information. 
AstraZeneca. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020639s072lbl.pdf 
SEROQUEL XR® (quetiapine) (2022). Package Insert, Highlights of Prescribing Information. 
AstraZeneca. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/022047s046lbl.pdf 
Shekhar, A., Potter, W.Z., Lightfoot, J., Lienemann, J., Dube, S., Mallinckrodt, C., Bymaster, 
F.P., McKinzie, D.L., and Felder, C.C. (2008). Selective muscarinic receptor agonist xanomeline 
as a novel treatment approach for schizophrenia. Am J Psychiatry 165, 1033-1039. 
Staskin, D., Kay, G., Tannenbaum, C., Goldman, H.B., Bhashi, K., Ling, J., and Oefelein, M.G. 
(2010). Trospium chloride has no effect on memory testing and is assay undetectable in the 
central nervous system of older patients with overactive bladder. Int J Clin Pract 64, 1294-1300. 
Thorn, C.A., Moon, J., Bourbonais, C.A., Harms, J., Edgerton, J.R., Stark, E., Steyn, S.J., Butter, 
C.R., Lazzaro, J.T., O'Connor, R.E., et al. (2019). Striatal, Hippocampal, and Cortical Networks 
Are Differentially Responsive to the M4- and M1-Muscarinic Acetylcholine Receptor Mediated 
Effects of Xanomeline. ACS Chem Neurosci 10, 1753-1764. 
van Os, J., and Kapur, S. (2009). Schizophrenia. Lancet 374, 635-645. 
Wess, J., Eglen, R.M., and Gautam, D. (2007). Muscarinic acetylcholine receptors: mutant mice 
provide new insights for drug development. Nat Rev Drug Discov 6, 721-733. 
Wu, E.Q., Shi, L., Birnbaum, H., Hudson, T., and Kessler, R. (2006). Annual prevalence of 
diagnosed schizophrenia in the USA: a claims data analysis approach. Psychol Med 36, 1535-
1540. 
Yu J, Yap P, Liew TM. (2019) The optimal short version of the Zarit Burden Interview for 
dementia caregivers: diagnostic utility and externally validated cutoffs. Aging Ment Health. 
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Zarit, S.H., Reever, K.E. and Bach-Peterson, J. (1980) Relatives of the impaired elderly: 
correlates of feelings of burden. The gerontologist, 20(6), pp.649-655. 


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12.
APPENDICES
12.1. 
Appendix 1
Contraception Guidelines 
Female patients of childbearing potential with a non-sterilized male sexual partner must agree to 
use at least 1 highly effective method of contraception beginning >30 days before receiving 
study drug on Day 1 and continuing until 30 days after the last dose of study drug. If oral 
contraceptives are used, the patient must have been on a stable dose for >6 months.  
A woman is considered to be WOCBP following menarche and until becoming postmenopausal, 
unless she is permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy (HMA, 2020). Female patients who are 
postmenopausal, which is defined as 12 consecutive months with no menses without an 
alternative medical cause, must have been postmenopausal for >1 year if they wish to not use 
contraceptives. Postmenopausal status must be confirmed by a test of the patient’s follicle-
stimulating hormone (FSH) level which must be elevated and consistent with postmenopausal 
levels (ie, >40 IU/L); otherwise, these patients must agree to use contraceptives listed below. 
Female patients who are surgically sterile (ie, hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy) will not need to undergo the FSH level test.  
A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
Highly effective methods of contraception are those which have a failure rate of <1% (when 
implemented consistently and correctly) and include:  
•
combined (containing estrogen and progestogen) hormonal contraception associated with
inhibition of ovulation (administration may be oral, intravaginal, or transdermal)
•
progestogen-only hormonal contraception associated with inhibition of ovulation
(administration may be oral, injectable, or implantable)
•
intrauterine device
•
intrauterine hormone-releasing system
•
bilateral tubal ligation or occlusion
•
vasectomy (provided that the male has a medical assessment of surgical success)
All patients will be strongly advised that they (or the female partners of male patients) should not 
become pregnant while on study treatment or for 30 days after the last dose. A female patient 
will be advised that she must report immediately to the study site for pregnancy testing and 
appropriate management in the event that she may be pregnant.  Male patients should refrain 
from sperm donation for 30 days after the last dose of study drug. 


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12.2. 
Appendix 2 
Background Antipsychotic Dosing Regimen 
Antipsychotic 
drugs 
Trade name 
Dosing Recommendations 
Paliperidone  
INVEGA®  
(Schizophrenia) 
Recommended Dose: 3to 12 mg/day 
Maximum Dose: 12 mg/day  
INVEGA SUSTENNA® 
 
Dose range is 117 mg, 156 mg, or 234 mg (IM 
injection every month) 
INVEGA TRINZA® 
Dose range is 410 mg, 546 mg, or 819 mg (IM 
injection every 3 months) 
 
Invega Trinza® Doses for Adult Patients 
Adequately Treated with Invega Sustenna® 
Invega Sustenna of 117 mg the Invega 
Trinza = 410 mg  
Invega Sustenna of 156 mg the Invega 
Trinza = 546 mg  
Invega Sustenna of 234 mg the Invega 
Trinza = 819 mg  
Risperidone  
 
Risperidone (oral) 
Target dose Schizophrenia: 4 to 6 mg / day 
Effective Dose Range Schizophrenia: 4 to 16 
mg /day 
RISPERDAL CONSTA®  
Dose range is 25 mg, 37.5 mg, or 50 mg (IM 
injection every 2 weeks) 
PERSERIS™ 
Dose range is 90 to 120 mg monthly (SQ 
injection) 
90 mg (0.6 mL) equivalent to 3 mg oral 
risperidone  
120 mg (0.8 mL) equivalent to 4 mg oral 
risperidone 
Aripiprazole 
Aripiprazole (oral) 
Dose range: 10 mg to 30 mg / day 
ABILIFY MAINTENA® 
(Aripiprazole 
monohydrate) 
300 mg, 400 mg every month (IM injection) 
ARISTADA®(Aripiprazole 
lauroxil) 
441 mg, 662 mg, or 882 mg every month (IM 
injection) 
882 mg every 6 weeks 


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1064 mg every 2 months 
Quetiapine IR 
SEROQUEL® (oral) 
(Schizophrenia; Adults) 
Dose range: 300 to 750 mg/day 
Quetiapine XR SEROQUEL XR® (oral) 
(Schizophrenia; Adults) 
Dose range: 400 to 800 mg/day 
Ziprasidone 
GEODON® (oral) 
(Schizophrenia; Adults) 
Dose range: 40 to 160 mg/day 
Lurasidone 
LATUDA (oral) 
(Schizophrenia) 
Dose range: 40 to 160 mg/day 
Abbreviations: IM = intramuscular; SQ = subcutaneous 
 


October 20, 2022 
 
Advarra IRB 
6100 Merriweather Dr. 
Suite 600 
Columbia, MD 21044 
 
RE:   Karuna Therapeutics KAR-014 [Pro00065534] 
A Multi-center, Open-label Study to Assess the Effectiveness, Long-term Safety, 
Tolerability, and Durability of Effect of KarXT in Patients With DSM-5 Diagnosis of 
Schizophrenia 
 
Please accept this KAR-014 Protocol Clarification Memorandum to document the below noted protocol 
clarifications that will be incorporated in a forthcoming amendment. 
 
 
Remove the Brief Cognitive Assessment tool for Schizophrenia (B-CATS) and replace with Brief 
Assessment of Cognition in Schizophrenia Symbol Coding (BACS SC) test. 
o The B-CATS consists of three (3) parts; 1. digit symbol substitution test, 2. trail making 
test, and 3. category fluency 
o Karuna decided to proceed with the BACS SC for cognition endpoint.  This reduces 
patient and site burden by two (2) tests 
   
 
Remove NIDA-5 UDS (cannabinoids or marijuana, phencyclidine, amphetamines, opiates, and 
cocaine) and replace with 12 Panel UDS (AMP (amphetamines), BAR (barbituates) BUP 
(Buprenorphine), BZO (Benzodiazepines), COC (cocaine), mAMp (Methamphetamine), MDMA 
(molly), MTD (methodone), OPI (opiates), OXY (oxycodone), PCP (Phencyclidine), THC 
(marijuana)).  The 5 panel UDS was not able to be sourced through the central laboratory.   
 
 
Clarify that all patients who titrate from 50/20mg BID to 100/20mg BID are not required to 
remain on 100/20mg BID for ‘at least 1 week’.  Further details on dose titration are specified 
in the protocol.   
 
 
Clarify that C-SSRS is to be performed at Unscheduled ‘in clinic’ visits to monitor patients for 
suicidality.  C-SSRS is not performed if via telemedicine. 
 
 
Revise Laboratory Assessments Table 2  
o Urinalysis (Dipstick) section; add bilirubin 
o Full and microscopic urinalysis section; remove parasites 
 
Karuna is committing to revising the protocol to incorporate these revisions and clarifications within 
60 days.    
 
 
Regards, 


 
99 High Street | Floor 26 | Boston, MA 02110 
Direct: (857) 338-1227 Cell: (617) 548-5686 
 
www.karunatx.com