Clinical trial NCT04659161
Conditions: Schizophrenia Schizophrenia; Psychosis
Sponsor: Karuna Therapeutics
Start date: 2020-12-16; Completion date: 2022-05-24
Enrollment: 252 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Xanomeline and Trospium Chloride Capsules intervention 2: Placebo
Intervention descriptions: intervention 1: Oral xanomeline 50 mg/trospium chloride 20 mg BID (twice a day) for the first 2 days (Days 1 and 2) followed by xanomeline 100 mg/trospium chloride 20 mg BID for the remainder of Week 1 (Days 3 to 7). At Visit 5 (Day 8), dosing was to be titrated upwards to xanomeline 125 mg/trospium chloride 30 mg BID unless the subject was continuing to experience adverse events (AEs) from the previous dose of KarXT 100/20 BID. All subjects who were increased to KarXT 125/30 BID, depending on clinical response and tolerability, had the option to return to KarXT 100/20 BID for the remainder of the treatment period. intervention 2: Placebo Capsules twice a day (BID)

Protocol documents:
Prot_000.pdf: 
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1 
FINAL CLINICAL STUDY PROTOCOL 
 
Karuna Therapeutics 
Protocol Title: A Phase 3, Randomized, Double-blind, Parallel-group, Placebo-controlled, 
Multicenter Study to Evaluate the Efficacy and Safety of KarXT in Acutely Psychotic 
Hospitalized Adults with DSM-5 Schizophrenia 
Protocol Number: KAR-007 
 
IND Number: 
127471 
EudraCT Number: 
Not applicable 
Name of Investigational Product: 
KarXT 
Phase of Development: 
Phase 3 
Indication: 
Schizophrenia 
Sponsor: 
Karuna Therapeutics 
33 Arch Street 
Suite 3110 
Boston, MA 02110 
Tel: 
(857) 449-2244 
Email: 
info@karunatx.com 
Protocol Version:  
1.4 
Protocol Date: 
09 August 2021 
 
-
 
 
 
 
 




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INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
A Phase 3, Randomized, Double-blind, Parallel-group, 
Placebo-controlled, Multicenter Study to Evaluate the Efficacy and 
Safety of KarXT in Acutely Psychotic Hospitalized Adults with 
DSM-5 Schizophrenia 
Protocol Number: 
KAR-007 
Confidentiality and Current Good Clinical Practice (GCP)/E6(R2) Compliance Statement 
• I, the undersigned, have reviewed this protocol (and amendments, including 
appendices, and I will conduct the study as described in compliance with this protocol 
(and amendments) and relevant International Council for Harmonisation (ICH) 
guidelines including GCP and applicable regulatory requirements. 
• I am thoroughly familiar with the appropriate use of the study drug, as described in 
this protocol and any other information provided by Karuna Therapeutics including, 
but not limited to, the current investigator’s brochure. 
• Prior to initiating the trial, I will provide the independent ethics committee 
(IEC)/institutional review board (IRB) all items subject to review and will obtain a 
written and dated approval/favorable opinion. Once the protocol has been approved 
by IEC/IRB, I will not modify this protocol without obtaining prior approval of 
Karuna Therapeutics and of the IEC/IRB. I will submit the protocol amendments 
and/or any informed consent form modifications to Karuna Therapeutics and the 
IEC/IRB, and approval will be obtained before any amendments are implemented. 
• I ensure that all persons or party assisting me with the study are adequately qualified 
and informed about the Karuna Therapeutics study drug and of their delegated study-
related duties and functions as described in the protocol. I will supervise these 
delegated persons or parties in the conduct of this trial. 
• I ensure that source documents and trial records that include all pertinent observations 
on each of the site’s trial subjects will be attributable, legible, contemporaneous, 
original, accurate, and complete. 
• I understand that all information obtained during the conduct of the study with regard 
to the subjects’ state of health will be regarded as confidential. No subjects’ names 
will be disclosed. All subjects will be identified by assigned numbers on all case 
report forms, laboratory samples, or source documents forwarded to the Sponsor. 
Clinical information may be reviewed by the Sponsor or its agents or regulatory 
agencies. Agreement must be obtained from the subject before disclosure of subject 
information to a third party. 
• Information developed in this clinical study may be disclosed by Karuna Therapeutics 
to other clinical investigators, regulatory agencies, or other health authority or 
government agencies as required. 


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<Name> 
<Title> 
Date (DD-Mmm-YYYY) 
Institution 
 
 






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BID may not occur outside of the permitted visit window for 
Visit 5/Day 8. 
A safety follow-up visit (Visit 11/ Day 42 + 5 days) will be performed 
for all those subjects who do not rollover in to the long-term open-label 
study KAR-008. 
The study is designed to test the hypothesis that treatment with KarXT 
in adult schizophrenia subjects with acute psychosis will result in 
significantly greater reduction (ie, improvement) in the primary and 
secondary endpoints at Week 5 from baseline compared with placebo. 
The endpoints are set up as a hierarchical list and step down through 
the statistical testing of each endpoint using an alpha of 0.05. Statistical 
testing of change from baseline to Week 5 in PANSS positive score, 
PANSS negative score, and PANSS Negative Marder Factor score, 
CGI-S score at Week 5, and percentage of PANSS responders will be 
performed only if the primary endpoint is significant at the 0.05 alpha 
level (P ≤ 0.05), and testing would continue through a preordered list 
of key secondary efficacy endpoints. If at any point P > 0.05, then 
formal statistical testing would stop. This will control the overall Type 
1 error rate across all hypotheses/endpoints being tested. 
Selection of Subjects: 
Inclusion Criteria: 
Individuals must meet all of the following criteria to be included in the study: 
1. Subject is aged 18 to 65 years, inclusive, at screening. 
2. Subject is capable of providing informed consent. 
a. 
A signed informed consent form must be provided before 
any study assessments are performed. 
b. Subject must be fluent (oral and written) in English to consent 
3. Subject has a primary diagnosis of schizophrenia established by a 
comprehensive psychiatric evaluation based on the DSM-5 
(American Psychiatric Association 2013) criteria and confirmed 
by Mini International Neuropsychiatric Interview for 
Schizophrenia and Psychotic Disorder Studies (MINI) version 
7.0.2. 
4. Subject is experiencing an acute exacerbation or relapse of 
psychotic symptoms, with onset less than 2 months before 
screening. 
a. 
The subject requires hospitalization for this acute exacerbation or 
relapse of psychotic symptoms. 
b. If already an inpatient at screening, has been hospitalized 
for less than 2 weeks for the current exacerbation at the 
time of screening. 
5. Positive and Negative Syndrome Scale total score between 80 and 120, 
inclusive. 
a. 
Score of ≥4 (moderate or greater) for ≥2 of the following Positive 
Scale (P) items: 
i. Item 1 (P1; delusions) 
ii. Item 2 (P2; conceptual disorganization) 
iii. Item 3 (P3; hallucinatory behavior) 
iv. Item 6 (P6; suspiciousness/persecution) 
6. Subjects with no change (improvement) in PANSS total score between 
screening and baseline (Day -1) of more than 20%. 


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7. Subject has a CGI-S score of ≥4 at screening and baseline (Day -1) 
visits. 
8. Subject will have been off lithium therapy for at least 2 weeks 
before baseline and free of all oral antipsychotic medications for at 
least 5 half-lives or 1 week, whichever is longer, before baseline 
(Day -1). 
9. Subjects taking a long-acting injectable antipsychotic could not 
have received a dose of medication for at least 12 weeks (24 
weeks for INVEGA TRINZA®) before baseline visit (Day -1). 
10. Subject is willing and able to be confined to an inpatient setting 
for the study duration, follow instructions, and comply with the 
protocol requirements. 
11. Body mass index must be ≥18 and ≤40 kg/m2. 
12. Subject resides in a stable living situation and is anticipated to 
return to that same stable living situation after discharge, in the 
opinion of the investigator. 
13. Subject has an identified reliable informant. An informant is 
needed at the screening and baseline visits as well as at the end 
of the study for relevant assessments (site staff may act as 
informant while the subject is an inpatient). An informant may 
not be necessary if the subject has been the patient of the 
investigator for ≥1 year. 
14. Women of childbearing potential (WOCBP) or men whose sexual 
partners are WOCBP must be willing and able to adhere to the 
contraception guidelines as defined in Section 8.4.1
. 
Exclusion Criteria: 
1. Any primary DSM-5 disorder other than schizophrenia within 
12 months before screening (confirmed using MINI version 7.0.2 
at screening). Exclusionary disorders include, but are not limited 
to, moderate to severe alcohol use disorder (within the past 
12 months), substance (other than nicotine or caffeine) use disorder 
within the past 12 months (use of cannabis at screening will result 
in screen failure with the allowance to rescreen at a later date if no 
moderate to severe substance use disorder is determined), major 
depressive disorder, bipolar I or II disorder, schizoaffective 
disorder, obsessive compulsive disorder, and post-traumatic stress 
disorder. Symptoms of mild mood dysphoria or anxiety are 
allowed as long as these symptoms are not the primary focus of 
treatment. 
a. 
A screening subject with mild substance abuse disorder within 
the 12 months before screening must be discussed and agreed 
upon with the medical monitor before they can be allowed into 
the study. 
2. Subjects who are newly diagnosed or are experiencing their first treated 
episode of schizophrenia. 
3. History or presence of clinically significant cardiovascular, 
pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, 
immunologic, dermatologic, neurologic, or oncologic disease or 
any other condition that, in the opinion of the investigator, would 
jeopardize the safety of the subject or the validity of the study 
results. 
4. Subjects with HIV, cirrhosis, biliary duct abnormalities, 
hepatobiliary carcinoma, and/or active hepatic viral infections 


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based on either medical history or liver function test results. 
5. History or high risk of urinary retention, gastric retention, or 
narrow-angle glaucoma. 
6. History of irritable bowel syndrome (with or without 
constipation) or serious constipation requiring treatment 
within the last 6 months 
7. Risk for suicidal behavior during the study as determined by the 
investigator’s clinical assessment and C-SSRS as confirmed by 
the following: 
a. 
Answers “Yes” on items 4 or 5 (C-SSRS – ideation) with 
the most recent episode occurring within the 2 months 
before screening or answers “Yes” to any of the 5 items 
(C-SSRS behavior) with an episode occurring within the 
12 months before screening. Nonsuicidal, self-injurious 
behavior is not exclusionary. 
8. Clinically significant abnormal finding on the physical 
examination, medical history, ECG, or clinical laboratory 
results at screening. 
9. Subjects cannot currently (within 5 half-lives or 1 week, 
whichever is longer, before baseline [Day -1]) be receiving oral 
antipsychotic medications; monoamine oxidase inhibitors; 
anticonvulsants (eg, lamotrigine, Depakote); tricyclic 
antidepressants (eg, imipramine, desipramine); selective serotonin 
reuptake inhibitors; or any other psychoactive medications except 
for as needed anxiolytics (eg, lorazepam, chloral hydrate). 
10. Pregnant, lactating, or less than 3 months postpartum. 
11. If, in the opinion of the investigator (and/or Sponsor), subject is 
unsuitable for enrollment in the study or subject has any finding 
that, in the view of the investigator (and/or Sponsor), may 
compromise the safety of the subject or affect his/her ability to 
adhere to the protocol visit schedule or fulfill visit requirements. 
12. Positive test for coronavirus (COVID-19) within 2 weeks before 
screening and at screening. 
13. Subjects with extreme concerns relating to global pandemics, 
such as COVID-19, that preclude study participation. 
14. Subject has had psychiatric hospitalization(s) for more than 
30 days (cumulative) during the 90 days before screening. 
15. Subject has a history of treatment resistance to schizophrenia 
medications defined as failure to respond to 2 adequate courses 
of pharmacotherapy (a minimum of 4 weeks at an adequate dose 
per the label) or required clozapine within the last 12 months. 
16. Subjects with prior exposure to KarXT. 
17. Subjects who experienced any adverse effects due to xanomeline 
or trospium. 
18. Participation in another clinical study in which the subject 
received an experimental or investigational drug agent within 
3 months before screening. 
19. Risk of violent or destructive behavior. 
20. Current involuntary hospitalization or incarceration. 
Planned Sample Size: 
A total of approximately 246 adult subjects (aged 18 to 65 years, inclusive) 
are planned to be randomized in a 1:1 ratio to 2 treatment groups, either 
KarXT or placebo. 
Investigational Therapy: 
1. Fixed dose KarXT 50/20 BID (50 mg xanomeline/20 mg trospium), 
oral (Days 1 to 2) 




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a total of 246 subjects 
are estimated to be enrolled. 




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8.4 
Study Withdrawal, Removal, and Replacement of Subjects ......................................45 
 
Pregnancy ...........................................................................................................46 
8.5 
Completion of the Study or Lost to Follow-up ..........................................................47 
8.6 
Study Termination ......................................................................................................47 
9 
TREATMENTS ...............................................................................................................48 
9.1 
Details of Study Treatments .......................................................................................48 
 
Identity of Study Treatments ..............................................................................48 
 
Packaging and Labelling ....................................................................................48 
 
Study Drug Storage ............................................................................................49 
 
Study Drug Retention .........................................................................................49 
9.2 
Dose Schedule ............................................................................................................49 
 
Visit 2b/Day 1 Randomization and Dosing .......................................................49 
 
Visit 3/Day 3 and/or Visits Occurring on Weekends/Holidays .........................49 
 
Visit 5/Day 8 Dosing and PK Considerations and Visit 8/Day 28 PK 
Considerations ....................................................................................................50 
 
Visit 10/Day 35 Dosing ......................................................................................50 
9.3 
Measures to Minimize Bias: Study Treatment Assignment .......................................50 
 
Method of Study Treatment Assignment ...........................................................50 
 
Blinding 51 
9.4 
Dose Modification ......................................................................................................51 
9.5 
Treatment Accountability and Compliance ................................................................52 
9.6 
Prior and Concomitant Therapy .................................................................................52 
 
Prior and Concomitant Medications ..................................................................52 
 
Concomitant Medications for Anxiety and/or Sleep aid ....................................53 
10 
STUDY PROCEDURES .................................................................................................54 
10.1 Informed Consent .......................................................................................................61 
10.2 Study Procedures ........................................................................................................61 
11 
EFFICACY ASSESSMENTS .........................................................................................62 
11.1 Positive and Negative Syndrome Scale ......................................................................62 
11.2 Clinical Global Impression‒Severity .........................................................................62 
12 
SAFETY ASSESSMENTS .............................................................................................63 
12.1 Demographics, and Medical and Psychiatric History ................................................63 
12.2 Vital Signs ..................................................................................................................63 
12.3 Physical Examination .................................................................................................64 
12.4 Weight, Height, Body Mass Index, Waist Circumference .........................................64 




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14.5 Safety Analysis ...........................................................................................................82 
14.6 Pharmacokinetic Analysis ..........................................................................................82 
14.7 Interim Analysis .........................................................................................................82 
14.8 Handling of Missing Data ..........................................................................................82 
15 
STUDY MANAGEMENT ..............................................................................................84 
15.1 Approval and Consent ................................................................................................84 
 
Regulatory Guidelines ........................................................................................84 
 
Independent Ethics Committee/Institutional Review Board ..............................84 
 
Informed Consent ...............................................................................................84 
15.2 Data Handling .............................................................................................................85 
15.3 Source Documents ......................................................................................................85 
15.4 Record Retention ........................................................................................................86 
15.5 Monitoring ..................................................................................................................86 
15.6 Quality Control and Quality Assurance .....................................................................86 
15.7 Protocol Amendment and Protocol Deviation ............................................................87 
 
Protocol Amendment .........................................................................................87 
 
Protocol Deviations ............................................................................................87 
15.8 Ethical Considerations ................................................................................................87 
15.9 Financing and Insurance .............................................................................................87 
15.10 Publication Policy/Disclosure of Data........................................................................88 
16 
REFERENCES ................................................................................................................89 
 
 
 
 
 
 


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3.1 
List of In-text Tables 
Table 1 
Study Design ...........................................................................................................40 
Table 2. Schedule of Assessments ........................................................................................55 
Table 3. Laboratory Assessments..........................................................................................65 
Table 4. Classification of Adverse Events by Intensity ........................................................67 
Table 5. Classification of Adverse Events by Relationship to Study Drug ..........................68 
Table 6 
Cognitive Tests and Cognitive Domains Assessed by the Cambridge 
Neuropsychological Test Automated Battery .........................................................74 
Table 7 
Statistical Testing Procedure ...................................................................................80 
 
 


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3.2 
List of In-text Figures 
Figure 1 Change from Baseline in PANSS Total Scores (KAR-004) ...................................29 
Figure 2 Change from Baseline in PANSS-Positive Scores (KAR-004) ..............................30 
Figure 3 Change from Baseline in CGI-S (KAR-004) ..........................................................31 
Figure 4 Change from Baseline in PANSS-Negative Scores (KAR-004) ............................32 
 


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4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AD 
Alzheimer’s disease 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
APD 
antipsychotic drug 
AUC 
area under the plasma concentration-time curve 
AUC0-12 
area under the plasma concentration-time curve from 0 to 12 hours 
AUC0-24 
area under the plasma concentration-time curve from 0 to 24 hours 
BARS 
Barnes Akathisia Rating Scale 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
 
 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression‒Severity 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTS 
CTCAE 
Clinical Trial Subject 
Common Terminology Criteria for Adverse Events 
DILI 
drug induced liver injury 
DSM-5 
Diagnostic and Statistical Manual‒Fifth Edition 
EDC 
electronic data capture 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EPS 
extrapyramidal symptoms 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability Accountability Act 
IB 
Investigator’s Brochure 


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Abbreviation 
Definition 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
MCC 
microcrystalline cellulose 
MINI 
Mini International Neuropsychiatric Interview 
mITT 
modified intent-to-treat 
MMRM 
mixed model repeated measures 
NCI 
National Cancer Institute 
PANSS 
Positive and Negative Syndrome Scale 
PK 
pharmacokinetic(s) 
PRN 
as needed 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson Angus Scale 
SNP 
single nucleotide polymorphism 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TID 
thrice daily 
TK 
toxicokinetic 
Tmax 
Time to maximum observed plasma concentration 
ULN 
upper limit of normal  
US 
United States 
VAS 
visual analog scale 
VCT 
Verified Clinical Trials Registry 
WOCBP 
women of child bearing potential 


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5 
INTRODUCTION 
5.1 
Background on Schizophrenia 
Schizophrenia is a long-term mental disorder involving a breakdown in the relation between 
thought, emotion, and behavior and leads to faulty perception, inappropriate actions and feelings, 
withdrawal from reality and personal relationships into fantasy and delusion, and a sense of 
mental fragmentation. Symptoms include delusions, hallucination, disorganized speech or 
behavior, and impaired cognitive ability[1]. The prevalence of schizophrenia is between 0.6% 
and 1.9% in the United States (US) population[2]. Moreover, a claims analysis has estimated that 
the annual prevalence of diagnosed schizophrenia in the US is 5.1 per 1000 lives[3]. It is found 
equally in males and females, with males usually having an earlier onset of symptoms[4]. 
The mainstay for treating schizophrenia is antipsychotic drugs (APDs)[5]. All currently available 
antipsychotics act through blockage of all or subsets of dopamine receptors in the brain. First-
generation APDs include chlorpromazine and haloperidol; treatment with these agents is marked 
by high rates of parkinsonian extrapyramidal symptoms (EPS) and tardive dyskinesia, and they 
consequently have limited use today. The second-generation agents that include risperidone, 
olanzapine, quetiapine, lurasidone, aripiprazole, and lumateperone tend to have lower levels of 
EPS or tardive dyskinesia and are currently the most commonly prescribed APD class. However, 
the second-generation drugs also have problematic side effects that include significant weight 
gain, metabolic disturbances, sedation, and akathisia[6,7,8]. These side effects contribute to poor 
medication adherence resulting in frequent relapses and hospitalizations[9,10]. Thus there is a 
need for medications for schizophrenia which act through alternative mechanisms. 
Central muscarinic receptors have been hypothesized to be therapeutic treatments for 
schizophrenia based on several converging lines of evidence including both animal and human 
studies[11,12]. There are 5 subtypes of muscarinic receptors (M1-M5). The therapeutic effect of 
central muscarinic receptor agonism is thought to be due to agonism of M1 and M4 receptors in 
the central nervous system (CNS)[13]. However, compounds that agonize M1 and M4 receptors 
are often not specific enough not to also agonize M2 and M3 receptors outside of the CNS due to 
the highly conserved allosteric binding sites that the receptors share, leading to adverse events 
(AEs) related to activation of these peripheral receptors. Thus, any potential benefit of 
muscarinic agonists in schizophrenia (or other indications such as Alzheimer’s disease [AD]) has 
been outweighed by the occurrence of AEs associated with peripheral cholinergic side effects 
(nausea, vomiting, diarrhea, sweating, and excess salivation). 
5.2 
Background on KarXT (Xanomeline Tartrate and Trospium Chloride) 
Xanomeline tartrate is a muscarinic-cholinergic receptor agonist. It has agonistic activity at all 
5 muscarinic receptors but preferentially stimulates M1 and M4 receptors and binding to M1 and 
M4 receptors in the CNS is thought to be responsible for the drug’s potential therapeutic effects 
(Roth, unpublished data). A recent study reports that xanomeline is a very potent M4 muscarinic 


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agonist in vivo, measured by various second messenger assays[14]. Xanomeline also enters the 
brain rapidly achieving a brain to plasma ratio of greater than 10 making it an attractive CNS 
drug candidate[15]. 
Xanomeline does not have any direct binding activity on dopaminergic receptors, suggesting that 
its mechanism of action is unrelated to direct dopamine involvement. 
Previous double-blind, placebo controlled clinical trials have provided strong evidence that 
xanomeline has clinically relevant antipsychotic efficacy. In a multicenter outpatient trial in AD 
(N = 343), 3 doses of xanomeline (up to 225 mg/day) and placebo were assessed for 
26 weeks[16,17]. Significant dose-dependent improvements in psychotic symptoms relative to 
placebo were observed. Moreover, psychotic symptoms resolved quite rapidly in subjects who 
were symptomatic at baseline and a dose dependent reduction in the emergence of psychotic 
symptoms versus placebo was also observed. In a completer analysis, cognitive improvement 
was also found suggesting longer treatment intervals may be necessary for cognitive 
enhancement[16,17]. In a subsequent small (N = 20) double-blind, placebo-controlled inpatient 
trial in treatment resistant subjects with schizophrenia, xanomeline (225 mg/day) demonstrated 
robust and relatively rapid improvement in psychosis compared to placebo. In addition, 
improvement in both negative symptoms and cognitive impairment was observed[18]. 
In both the AD and schizophrenia trials, as well as in previous healthy volunteer studies, dose 
dependent “cholinergic” AEs were also reported, namely vomiting, nausea, diarrhea, sweating 
and hypersalivation. These side effects were frequent and, at the higher doses of xanomeline led 
to significant rates of discontinuation in the AD studies. This “procholinergic” AE profile 
curtailed further development of xanomeline as a single agent. 
It is believed that the procholinergic AEs associated with xanomeline are mediated by 
xanomeline’s stimulation of peripheral rather than central muscarinic receptors, which would 
make these AEs theoretically amenable to counteracting peripheral anticholinergic treatment. 
Trospium chloride is a peripherally acting muscarinic antagonist which binds to and antagonizes 
all five muscarinic receptor subtypes[19]. It is a commonly used generic drug approved for over 
10 years by the Food and Drug Administration (FDA) and by European authorities to treat 
overactive bladder and is generally well tolerated[19]. Several human subject studies have 
demonstrated that trospium does not appreciably cross the blood brain barrier, consistent with the 
drug’s quaternary ammonium structure[20]. 
KarXT is a novel combination of xanomeline tartrate and trospium chloride. Karuna 
hypothesized that the addition of trospium would mitigate peripheral procholinergic side effects 
(vomiting, nausea, diarrhea, sweating and hyper-salivation) and thus provide a strategy to allow 
xanomeline to be administered and stimulate brain muscarinic receptors with a decreased side 
effect burden. Phase 1 studies in healthy volunteers of this combination demonstrated that 
KarXT reduced these side effects by 46% compared to xanomeline alone[21]. Moreover, the 
remaining cholinergic AEs were generally mild to moderate in severity and transient in nature, 
often lasting a few hours without recurrence and were generally single-episode. In general, 








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 Completed Clinical Studies 
Refer to the IB for complete information regarding previous clinical studies conducted with 
xanomeline by Eli Lilly, and studies KAR-001, KAR-002, KAR-003, and KAR-004 conducted 
by Karuna Therapeutics using xanomeline with trospium. 
To date, more than 840 subjects or volunteers have been exposed to xanomeline tartrate (oral 
formulation, either alone, in combination with trospium, or as the combination drug KarXT) in 
19 completed clinical studies conducted either by Eli Lilly or Karuna Therapeutics, some for as 
long as 3 years. In those studies, significant improvements in cognition and reduced psychotic 
symptoms were observed. 
A study of xanomeline monotherapy in subjects with schizophrenia was reported in 2008[18]. In 
this pilot study, the effects of xanomeline were examined in 20 subjects with schizophrenia 
utilizing a double-blind, placebo-controlled, 4-week study design. Subjects treated with 
xanomeline did significantly better than subjects in the placebo group on Brief Psychiatric 
Rating Scale total scores and PANSS total scores (ie, 24-point change over placebo, P = 0.04). In 
the cognitive test battery, subjects in the xanomeline group showed improvements relative to 
placebo in some of the cognitive domains of verbal learning and short-term memory function. 
These studies demonstrated the potential for xanomeline as a treatment for psychosis and 
cognition across multiple subject populations. 
















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5.3 
Clinical Risks/Benefits of KarXT and Study Rationale 
The risks and benefits of KarXT in humans are not fully known. KarXT is a fixed dose 
combination of xanomeline and trospium. The available clinical trial data indicate that KarXT 
has robust efficacy and a favorable safety profile that appears unique compared with all available 
APDs. Treatment with KarXT is not associated with weight gain, sedation, or meaningful EPS 
changes. In contrast, these serious side effects pose a significant risk with other APD treatments 
for schizophrenia and can lead to discontinuation of treatment and significant morbidity. A Phase 
2 registration quality pivotal trial in 182 subjects met the primary endpoint with the PANSS total 
score showing a 11.6 point mean improvement compared to placebo with a highly significant 
(P < 0.0001) separation from placebo (-17.4 KarXT vs -5.9 placebo) at Week 5. KarXT, as 
compared with placebo, demonstrated highly significant reduction in PANSS total scores 
(P < 0.0001) at all post randomization time points (Weeks 2, 4, and, 5) 
 
 KarXT, as compared to placebo, demonstrated significant improvement 
at all post randomization time points for PANSS positive symptom subscores, PANSS negative 
symptom subscores, PANSS Marder Factor negative symptom subscores, and CGI-S scores. 
More than 840 subjects or volunteers have been exposed to xanomeline tartrate (oral 
formulation, either alone, in combination with trospium, or as the fixed dose combination drug 
KarXT) in clinical studies. These early clinical studies, as well as nonclinical pharmacology and 
toxicology studies, have not revealed any specific contraindications to the use of xanomeline. 
The most common side effects/symptoms are the cholinergic related effects: nausea, vomiting, 
excess salivation, excess sweating, and diarrhea. In addition, subjects treated with xanomeline 
alone have reported both syncope and orthostatic dizziness. 
 
 
 
Trospium chloride has been marketed in the US for 12 years. The most frequently reported AEs 
reported in pivotal trials were dry mouth, 
 abdominal pain, headache, urinary 
retention, and abnormal vision and accommodation. For additional information, the package 
insert for trospium chloride tablets for oral use can be found in the IB. 
In a Phase 2 (KAR-004) clinical study, KarXT (100/20 and 125/30) significantly reduced the 
symptoms of schizophrenia in subjects with acute psychosis after treatment for 28 days. KarXT 
also showed an acceptable safety profile with the most common TEAEs being constipation, 


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nausea, dry mouth, dyspepsia, and vomiting. All the reported TEAEs were mild or moderate in 
intensity. One SAE (psychotic disorder) was reported by a single subject and no deaths were 
reported in the study. KarXT was generally well-tolerated and found to be safe in this patient 
population. 
KarXT represents a novel approach to the treatment of patients with schizophrenia that will 
provide an important and meaningful alternative to current therapies. The current tolerability and 
AE profile and the efficacy of KarXT justify further development of KarXT in this patient 
population by advancing to Phase 3 trials. 
Subjects assigned to active study drug may benefit by improvement in schizophrenia symptoms. 
Since subjects will be having an acute psychotic event, subjects will be hospitalized where the 
clinical staff is available to help them 24 hours a day. In addition, the inpatient setting represents 
an important venue for research, examining the effects of KarXT and helps to eliminate or 
reduce to the extent possible, subjectivity and bias. Furthermore, this inpatient setting will also 
enhance measurable quality standards as well as increased adherence. 


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6 
STUDY OBJECTIVES AND ENDPOINTS 
6.1 
Study Objectives 
 Primary Objective 
The primary objective of the study is to evaluate the efficacy of KarXT 125/30 BID versus 
placebo in reducing PANSS total scores in adult inpatients with a DSM-5 diagnosis of 
schizophrenia. 
 Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the reduction of PANSS positive score in subjects treated with KarXT versus 
placebo 
• To evaluate the improvement in CGI-S results in subjects treated with KarXT versus 
placebo 
• To evaluate the reduction of PANSS negative score in subjects treated with KarXT 
versus placebo 
• To evaluate the reduction of PANSS Marder Factor negative symptoms score in subjects 
treated with KarXT versus placebo 
• To evaluate the safety and tolerability of KarXT 
• To assess the PK of xanomeline and trospium after administration of KarXT in adults 
who are acutely psychotic with a DSM-5 diagnosis of schizophrenia 


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6.2 
Study Endpoints 
 Primary Endpoint 
The primary endpoint of this study is change from baseline in PANSS total score at Week 5 
 Secondary Endpoints 
6.2.2.1 
Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
• Change from baseline in PANSS positive score at Week 5 
• Change from baseline in PANSS negative score at Week 5 
• Change from baseline in PANSS Negative Marder Factor score at Week 5 
• CGI-S score at Week 5 
• Percentage of PANSS responders (a 30% change in PANSS total score) at Week 5 
6.2.2.2 
Safety Endpoints 
The safety endpoints of this study are as follows: 
• Spontaneously reported AEs including AESIs 
• Spontaneously reported procholinergic and anticholinergic symptoms 
• Simpson-Angus Scale (SAS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
• Body weight, body mass index (BMI), waist circumference 
• Orthostatic vital signs (supine and standing after 2 minutes): BP (systolic and diastolic) 
and heart rate 
• Clinical laboratory evaluations: hematology, clinical chemistry, coagulation, urinalysis, 
and drug screen 
• 12-lead ECG 
• Physical examination 
• Suicidal ideation scale with the use of Columbia Suicide Severity Rating Scale (C-SSRS) 
 Pharmacokinetic Endpoints 
The PK endpoints of this study are as follows: 
• Area under the plasma concentration-time curve (AUC) 
• Maximum observed plasma concentration (Cmax) 




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7 
INVESTIGATIONAL PLAN 
7.1 
Description of Overall Study Design and Plan 
This Phase 3, randomized, double-blind, parallel-group, placebo-controlled, multicenter, 
inpatient clinical study in adults who are acutely psychotic with a DSM-5 diagnosis of 
schizophrenia is designed to test the hypothesis that treatment with KarXT will result in 
significantly greater reduction (ie, improvement) in the primary and secondary endpoints at 
Week 5 from baseline compared with placebo. Total study duration is up to 8 weeks, including a 
7-day screening phase (up to a 7-day extension of the screening phase is allowed, if necessary), a 
5 week treatment period, and a 7-day follow-up period (only for subjects who do not rollover to 
KAR-008 study). Subjects completing this study will have the option of rolling over into a 
long-term open-label study (KAR-008) in which every subject will receive KarXT. Study staff 
should discuss KAR-008 protocol participation with potential subjects prior to the final day of 
participation in the acute study, via use of the provided recruitment materials. 
Screening Period: 
Screening of subjects will take place in 7 days or less before Day -1 (Days -8 to -2). Up to a 
7-day extension of the screening time is allowed, if necessary. 
A suitable number of subjects will be screened to randomize approximately 246 subjects across 
approximately 20 sites in the US. Subjects will be randomized through the IWRS in a 1:1 ratio to 
receive either KarXT or placebo for a treatment duration of 5 weeks. 
Treatment Period: 
In the treatment period, all subjects assigned to KarXT will start on a lead-in dose of 
KarXT 50/20 (xanomeline 50 mg/trospium 20 mg) BID for the first 2 days (Days 1 and 2) 
followed by KarXT 100/20 (xanomeline 100 mg/trospium 20 mg) BID for the remainder of 
Week 1 (Days 3 to 7). On Day 8, dosing will be titrated upwards to KarXT 125/30 BID unless 
the subject is continuing to experience AEs from the previous dose of KarXT 100/20 BID. All 
subjects who are increased to KarXT 125/30 BID, depending on clinical response and 
tolerability, will have the option to return to KarXT 100/20 BID for the remainder of the 
treatment period. Dosing must not change after Visit 7 (Day 21) of the study and may be 
decreased for tolerability reasons no more than once during the study. In addition, dose 
escalation to KarXT 125/30 BID may not occur outside of the permitted visit window for 
Visit 5/Day 8. 
All randomized subjects will have structured diagnostic interview sessions and questionnaires 
administered throughout the study (see Schedule of Assessments Table 2). Analyses of change 
from baseline in diagnostic measures will be performed. 
Efficacy assessments (PANSS scores and CGI-S score) will be assessed at scheduled visits. 
Refer to Section 11 for more details. 


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Safety will be assessed through spontaneous AEs including AESIs, procholinergic and 
anticholinergic symptoms,
 SAS, BARS, AIMS, body weight, BMI, waist 
circumference, orthostatic vital signs, ECG, clinical laboratory assessments (hematology, clinical 
chemistry, coagulation, urinalysis, and drug screen), 
, physical examination, and 
C-SSRS will be evaluated throughout the study as scheduled. Section 12 provides complete 
details on these safety assessments. 
Details on PK assessments are provided in Section 13. 
Safety Follow-up Period: 
A safety follow-up visit (Visit 11/ Day 42 + 5 days) will be performed for all those subjects who 
do not rollover into the long-term open-label study KAR-008. 
An Independent Safety Monitoring Committee (ISMC) will be responsible for reviewing on a 
periodic basis the safety data from this study and confirming that the study may continue. 
Table 1 presents the study design.


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Table 1 
Study Design 
 
Phase: 
Screening 
Inpatient Treatment 
End of 
Treatment 
/Early 
Termination 
Safety 
Follow-up 
Day: 
Days -8 
to -2 
Day -1 
Day 1 
Day 3 
+1 day 
Day 7 
±2 days 
Day 
8 -1/+2 
days 
Day 14 
±2 days 
Day 21 
±2 days 
Day 28 
 ±2 days 
Day 32 
+1 day 
Day 35 
-2 daysc 
Day 42 
+5 days 
Visit: 
Visit 1 
Visit 2a 
Visit 
2b 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Xanomeline
/ trospium 
(KarXT)*: 
N/A 
 
50/20 
BID 
100/20 
BID 
100/20 
BID 
125/30 
BID 
(Option: 
100/20 
BID)a 
125/30 
BID 
(Option: 
100/20 
BID)a 
125/30 
BID 
(Option: 
100/20 
BID)a 
125/30 
BIDb 
125/30 
BIDb 
125/30 BIDb 
 
Comment: 
Up to a 
7-day 
extension 
to the 
screening 
phase is 
allowed. 
Baseline 
2-day 
lead-in 
dose 
Upward 
titration 
of dose 
 
Upward 
titration 
of dose 
Downward dose 
adjustment allowed 
according to clinical 
response/tolerability 
No dose 
adjustment 
allowed (after 
Day 21) 
 
For 
subjects 
who do 
not enter 
in to 
rollover 
Study 
(KAR-
008) 
Abbreviation: BID = twice daily. 
* All the KarXT doses are in mg. 
a. 
All subjects who are increased to KarXT 125/30, depending on clinical response and tolerability, will have the option to return to KarXT 100/20 BID for 
the remainder of the treatment period. 
b. No dose adjustment will be allowed after Visit 7. All subjects will continue taking the doses chosen for KarXT at Visit 7. 
c. The last dose of study drug will be administered the morning of Visit 10. 


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7.4 
Independent Safety Monitoring Committee 
For the purpose of this study, the ISMC is an independent group of individuals with pertinent 
expertise that reviews on a regular basis accumulating safety and tolerability data from the 
clinical study. The ISMC will include 3 clinicians and a reporting statistician. This committee 
will be responsible, on a periodic basis, for confirming the safety and tolerability of KarXT 
throughout the study, with particular focus on assessing for any new toxicities that might be 
involved with KarXT. 
The reviews will be of unblinded data to allow a comparison of event rates and detection of 
safety signals across treatment groups to identify important safety information. The ISMC 
charter will contain the details of the types of data to be reviewed, the defined triggers for 
review, the minimum frequency of meetings (timed, if no triggers), and the communication plan 
for disseminating review recommendations. 


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8 
SELECTION OF STUDY POPULATION 
Section 7.1 provides information regarding number of subjects planned to be randomized. 
8.1 
Inclusion Criteria 
Individuals must meet all of the following criteria to be included in the study: 
1. Subject is aged 18 to 65 years, inclusive, at screening. 
2. Subject is capable of providing informed consent. 
a. A signed informed consent form must be provided before any study assessments are 
performed. 
b. Subject must be fluent (oral and written) in English to consent 
3. Subject has a primary diagnosis of schizophrenia established by a comprehensive 
psychiatric evaluation based on the DSM-5 (American Psychiatric Association 2013) 
criteria and confirmed by Mini International Neuropsychiatric Interview for 
Schizophrenia and Psychotic Disorder Studies (MINI) version 7.0.2. 
4. Subject is experiencing an acute exacerbation or relapse of psychotic symptoms, 
with onset less than 2 months before screening. 
a. The subject requires hospitalization for this acute exacerbation or relapse of psychotic 
symptoms. 
b. If already an inpatient at screening, has been hospitalized for less than 2 weeks for 
the current exacerbation at the time of screening. 
5. Positive and Negative Syndrome Scale total score between 80 and 120, inclusive. 
a. Score of ≥4 (moderate or greater) for ≥2 of the following Positive Scale (P) items: 
i. Item 1 (P1; delusions) 
ii. Item 2 (P2; conceptual disorganization) 
iii. Item 3 (P3; hallucinatory behavior) 
iv. Item 6 (P6; suspiciousness/persecution) 
6. Subjects with no change (improvement) in PANSS total score between screening and 
baseline (Day -1) of more than 20%. 
7. Subject has a CGI-S score of ≥4 at screening and baseline (Day -1) visits. 
8. Subject will have been off lithium therapy for at least 2 weeks before baseline and free 
of all oral antipsychotic medications for at least 5 half-lives or 1 week, whichever is 
longer, before baseline (Day -1). 
9. Subjects taking a long-acting injectable antipsychotic could not have received a dose of 
medication for at least 12 weeks (24 weeks for INVEGA TRINZA®) before baseline 
visit (Day -1). 
10. Subject is willing and able to be confined to an inpatient setting for the study duration, 
follow instructions, and comply with the protocol requirements. 


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11. BMI must be ≥18 and ≤40 kg/m2. 
12. Subject resides in a stable living situation and is anticipated to return to that same stable 
living situation after discharge, in the opinion of the investigator. 
13. Subject has an identified reliable informant. An informant is needed at the screening 
and baseline visits as well as at the end of the study for relevant assessments (site staff 
may act as informant while the subject is an inpatient). An informant may not be 
necessary if the subject has been the patient of the investigator for ≥1 year. 
14. Women of childbearing potential (WOCBP) , or men whose sexual partners are 
WOCBP, must willing and able to adhere to the contraception guidelines as defined in 
Section 8.4.1
 
8.2 
Exclusion Criteria 
Individuals meeting any of the following criteria at screening or baseline are ineligible to 
participate in this study: 
1. Any primary DSM-5 disorder other than schizophrenia within 12 months before 
screening (confirmed using MINI version 7.0.2 at screening). Exclusionary disorders 
include, but are not limited to, moderate to severe alcohol use disorder (within the past 
12 months), substance (other than nicotine or caffeine) use disorder within the past 
12 months (use of cannabis at screening will result in screen failure with the allowance 
to rescreen at a later date if no moderate to severe substance use disorder is determined), 
major depressive disorder, bipolar I or II disorder, schizoaffective disorder, obsessive 
compulsive disorder, and post-traumatic stress disorder. Symptoms of mild mood 
dysphoria or anxiety are allowed as long as these symptoms are not the primary focus of 
treatment. 
a. A screening subject with mild substance abuse disorder within the 12 months before 
screening must be discussed and agreed upon with the medical monitor before they 
can be allowed into the study. 
2. Subjects who are newly diagnosed or are experiencing their first treated episode of 
schizophrenia. 
3. History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, 
hematologic, GI, endocrine, immunologic, dermatologic, neurologic, or oncologic 
disease or any other condition that, in the opinion of the investigator, would jeopardize 
the safety of the subject or the validity of the study results. 
4. Subjects with HIV, cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma, and/or 
active hepatic viral infections based on either medical history or liver function test 
results. 
5. History or high risk of urinary retention, gastric retention, or narrow-angle glaucoma. 
6. History of irritable bowel syndrome (with or without constipation) or serious 
constipation requiring treatment within the last 6 months. 
7. Risk for suicidal behavior during the study as determined by the investigator’s clinical 
assessment and C-SSRS as confirmed by the following: 




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8.4 
Study Withdrawal, Removal, and Replacement of Subjects 
If a subject discontinues study treatment and is withdrawn from the study for any reason, the 
study site must immediately notify the medical monitor. The date and the reason for study 
discontinuation must be recorded on the electronic case report form (eCRF). Subjects who 
complete or discontinue early from the study will be discharged from the study site, if clinically 
warranted after completing all the Visit 10/early termination assessments as indicated in the 
Schedule of Assessments (Table 2). 
Note: A safety follow-up visit will be performed 1 week after the End of Treatment/Early 
Termination visit (Visit 10) for those subjects who do not roll over into the long-term open-label 
study KAR-008. 
In the event that a subject discontinues prematurely from the study because of a TEAE or serious 
TEAE, the TEAE or serious TEAE will be followed up until it resolves (returns to normal or 
baseline values) or stabilizes, or until it is judged by the investigator to no longer be clinically 
significant. 
Once a subject is withdrawn from the study, the subject will not re-enter the study. 
A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons 
including, but not limited to, the following: 
• progressive disease 
• unacceptable toxicity or AE 
• subject withdrawal of consent: at any time a subject’s participation in the study may be 
terminated at his/her request. The reason for subject withdrawal will be noted on the 
eCRF. 
• on the basis of the investigator’s clinical judgement 
• intercurrent illness: a condition, injury, or disease unrelated to the primary diagnosis that 
became apparent during treatment and necessitated the subject’s termination from the 
study 
• general or specific changes in the subject’s condition that renders him/her ineligible for 
further treatment according to the inclusion/exclusion criteria (eg, subject has need for a 
medication prohibited by the protocol) 
• subject fails to adhere to the protocol requirements (eg, drug noncompliance [if a study 
subject is off study drug for >5 days in a row]) 


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• violation of entry criteria; ie, subjects who are enrolled but are later discovered not to 
meet entry criteria 
• development of suicidal or assaultive behavior 
• alcohol or illegal drug use 
• pregnancy, as indicated in Section 12.7.8. Any study subject who becomes pregnant 
while participating in the study will be unblinded to study treatment randomization. If she 
is found to be on active treatment assignment, she will be followed until her pregnancy 
reaches term. 
• Sponsor’s decision to discontinue study. 
Subjects withdrawing from the study will be encouraged to complete the same final evaluations 
as subjects completing the study according to this protocol, particularly safety evaluations. The 
aim is to record data in the same way as for subjects who completed the study. 
Reasonable efforts will be made to contact subjects who leave the unit or are lost to follow-up. 
These efforts must be documented in the subject’s file. Subjects with AEs ongoing at end of 
study will be followed until the AE is resolved (regardless of whether they enroll in the 
long-term open-label study KAR-008) or the subject is considered to be in stable condition. 
The Sponsor has the right to terminate the study at any time in case of SAEs or if special 
circumstances concerning the study drug become known, making further treatment of subjects 
impossible. In this event, the investigator(s) will be informed of the reason for study termination. 
 Pregnancy 
No evidence of mutagenicity, or treatment effects on reproduction, fertility, or fetal parameters 
have been demonstrated in animals following administration of xanomeline, but there are no 
adequate and well-controlled studies in pregnant women (FDA Pregnancy Category B). Animal 
reproduction studies of trospium chloride have shown an adverse effect on the fetus, but 
potential benefits may warrant the use of the drug in pregnant women despite the risk (FDA 
Pregnancy Category C). 
Therefore, WOCBP in this study must be willing to use a highly effective method of birth 
control 
 
during the study and for 30 days after the last dose of study drug. WOCBP will have a serum 
pregnancy test at screening and a urine pregnancy test on Day -1 (before receiving KarXT) and 
thereafter, as designated at other scheduled visits (Table 2). In case of positive urine pregnancy 
test result, a serum sample should be sent to the central laboratory to confirm the result. 
Pregnant women are excluded from this study because the effects of KarXT on the developing 
human fetus are unknown with the potential for teratogenic or abortifacient effects. 
Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment 
of the mother with KarXT, women who are breastfeeding must not be enrolled in the study. 


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The effects of study drug on sperm are unknown. Men whose sexual partners are WOCBP must 
agree to use a highly effective method of birth control 
 
and must not impregnate a sexual partner during or 
for 30 days after the last dose of study drug. They must also agree to refrain from sperm donation 
for 30 days after the last dose of study drug. 
WOCBP will be instructed that known or suspected pregnancy occurring during the study should 
be confirmed and reported to the investigator. If a female subject becomes pregnant, the 
investigator must withdraw her from the study without delay. The subject must not receive any 
further doses of the study drug. Upon discontinuation from the study, only those procedures that 
would not expose the pregnant female subject to undue risk will be performed. See Section 
12.7.8 for further reporting and monitoring details. 
Full details of the pregnancy will be recorded on the withdrawal page (exit form) of the eCRF, or 
a pregnancy report will be completed if the subject has completed the study. Notification of the 
pregnancy should be submitted via the Pregnancy Reporting Form within 24 hours of knowledge 
of the pregnancy. Pregnancy is not to be considered an AE; however, it must be reported using 
the same procedure as described for reporting SAE (Section 12.7.4). 
8.5 
Completion of the Study or Lost to Follow-up 
The study will be completed when all subjects have completed their study-related procedures in 
accordance with the protocol. 
Every reasonable effort will be made to contact subjects who leave the facility and are lost to 
follow-up to obtain end of study information. Details regarding follow-up efforts are to be 
documented in the subject’s medical records/source documentation. 
8.6 
Study Termination 
The availability of any new adverse safety information related to KarXT may result in stopping 
the study. An investigator, Sponsor, or Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB) may take such actions. If the study is terminated for safety reasons, subjects 
will be notified immediately and assured that appropriate treatment and follow-up will be 
available. If an investigator terminates the study, the Sponsor, subjects, and IEC/IRB will be 
informed about the reason for such action. Similarly, if the Sponsor terminates the study, it will 
inform the investigators, the IEC/IRB, and the subjects of the reason for such an action. Similar 
notifications will be sent by the IEC/IRB if it takes such an action. 


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9 
TREATMENTS 
9.1 
Details of Study Treatments 
KarXT is formulated as hard hydroxypropyl methylcellulose oral capsules containing 2 distinct 
populations of drug beads, one of which is loaded with xanomeline tartrate and the other of 
which is loaded with trospium chloride. Each capsule contains the freebase equivalent of 
xanomeline and trospium according to the desired dose strength. In addition to the active 
ingredients, the drug beads contain microcrystalline cellulose (MCC). The beads are not coated 
and are formulated for immediate release of the active ingredients. 
 
Identity of Study Treatments 
Active study agents for treatment group will be size 0, Swedish-orange hydroxypropyl 
methylcellulose hard capsules. Placebo will be prepared in matching capsules; therefore, an 
unblinded pharmacist will be required to dispense study drug in a blinded fashion to personnel 
who will be responsible for administration of IP to the subject. For the 2-day lead-in period 
(Days 1 and 2), subjects randomized to active drug will receive capsule strength KarXT 50/20 
BID, followed by 2 capsules of KarXT 50/10 mg BID or a dosage of 100/20 BID for a total daily 
dosage of 200/40 mg xanomeline/trospium chloride for the remainder of Week 1 (Days 3 to 7). 
At the beginning of Week 2, dosing may be increased to 2 capsules of KarXT 62.5/15 mg or a 
dosage of 125/30 BID for a total daily dosage of 250/60 mg xanomeline/trospium chloride, 
depending on clinical response and tolerability. Investigators have the option to return a subject 
to KarXT 100/20 BID for the remainder of the treatment period, but dosing must not change 
after Visit 7 of the study. 
 
 
 
 
 
 
 
 
 
 
All investigational agents are to be stored according to requirements. 
 Packaging and Labelling 
The study packaging and labelling will be performed
 All 


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packaging and labelling operations will be performed according to Good Manufacturing Practice 
for Medicinal Products and the relevant regulatory requirements. 
Bulk supply bottles are labeled with the name of the drug, recommended storage conditions, the 
name and address of the manufacturer, and the Investigational Use Statement (“Caution: New 
Drug – Limited by Federal [US] Law to Investigational Use”). 
Further details on labelling of investigational products will be provided in the Pharmacy Manual. 
 Study Drug Storage 
KarXT and placebo must be stored at controlled room temperature 15 C-25 C in a secured 
location with no access to unauthorized personnel. 
 Study Drug Retention 
Study drug not used in KAR-007 may be used for the long-term extension study (KAR-008). 
Therefore, unused study drug for this particular study must be retained until completion or 
termination of the KarXT program, and written authorization from the Sponsor has been 
received. The unused study drug can be reassigned in the IWRS to subjects in the KAR-008 
study. All unused and used study drug must be destroyed at the site or returned, as specified by 
Sponsor. It is the investigator’s responsibility to ensure that the Sponsor has provided written 
authorization prior to return or destruction, and that appropriate records of the disposal are 
documented and maintained. No used or unused study drug may be disposed until fully 
accounted for by the study monitor. 
9.2 
Dose Schedule 
The first dose of the study drug will be administered in the morning of Day 1. The last dose will 
be administered in the morning of Visit 10 (Day 35 -2 days). The study drug should be 
administered daily BID on an empty stomach ie, at least 1 hour before a meal or 2 to 3 hours 
after a meal. Some considerations for dosing and PK blood withdrawals are provided in the 
subsections below. 
 Visit 2b/Day 1 Randomization and Dosing 
• The first dose will be administered in the morning, and the evening dose will be 
administered 12 ± 0.5 hours after the morning dose. 
• All subjects must be administered 4 dosages of the KarXT 50/20 or placebo before dose 
escalation to KarXT 100/20 or placebo BID. 
 Visit 3/Day 3 and/or Visits Occurring on Weekends/Holidays 
• If dose escalation to the KarXT 100/20 or placebo level is confirmed by investigator 
order on Visit 3/Day 3, that dose is to be administered in the morning. 
• When Day 3 occurs on a weekend, it is expected that the complete Visit 3 will be 
performed, and the subject’s dose will be escalated on Day 3. 


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• If completion of the visit is not possible on Day 3, the +1-day visit window may be used. 
In this instance, the dose will not be escalated until the study visit occurs. In all cases, the 
subject must have had at least 4 doses of KarXT 50/20 or placebo before escalating to 
KarXT 100/20 or placebo. 
• This may result in only 4 days of the KarXT 100/20 or placebo dose at Visit 5/Day 8, 
which is acceptable. 
• All subjects must be administered 8 doses of the KarXT 100/20 or placebo before dose 
escalation to KarXT 125/30 or placebo BID. 
 Visit 5/Day 8 Dosing and PK Considerations and Visit 8/Day 28 PK Considerations 
• If dose escalation to the KarXT 125/30 or placebo level is confirmed by investigator 
order on Visit 5/Day 8, that dose is to be administered in the morning (after the predose 
PK blood draw) to allow for serial postdose PK blood draws per protocol (Table 2, 
Footnote p). 
• Should the use of visit windows be necessary, serial PK sampling must accompany the 
actual day of dose escalation for Visit 5. 
• For Visit 8, serial PK sampling is meant to capture the PK profile of the subject’s final 
KarXT dose level (125/30 or 100/20) after multiple doses; therefore, there must be no 
changes in dose for at least 7 days prior to Visit 8. PK sampling must accompany the 
actual day of Visit 8 if a window is used. 
 Visit 10/Day 35 Dosing 
• All subjects will receive their final dose of KarXT or placebo on the morning of 
Visit 10/Day 35. 
9.3 
Measures to Minimize Bias: Study Treatment Assignment 
 Method of Study Treatment Assignment 
At Screening, the interactive web response system (IWRS) will assign a unique subject 
identification number to the subject known as the Subject Number. This number will be 
associated with the subject throughout the study. Every subject who signs an ICF must be 
entered into the IWRS regardless of eligibility in order to obtain a Subject Number. This 9-digit 
number will consist of a 3-digit study code and a 3-digit site identification followed by a 3-digit 
subject number assigned sequentially within each site, starting at 001. 
On Day -1, all eligible subjects will be randomly assigned in a 1:1 ratio to either KarXT or 
placebo groups. Subjects will be assigned a randomization number through the IWRS, in 
accordance with the randomization code generated by the authorized personnel at 
. 
At the study site, the randomization schedule will only be accessible to authorized unblinded 
pharmacy personnel or designee. Once a randomization number is allocated to one subject, it 
may not be assigned to another subject even if the former discontinued the study. 


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 Blinding 
An IWRS will allocate treatment based on a prespecified randomization list generated by 
. Active and placebo study drug will be provided in bulk to each site participating in 
the study. For each dose, study drug and packaging will be identical in size, shape, color, and 
appearance (see Section 9.1.2). No other study site personnel (except the pharmacist or other 
designated unblinded individual), subjects, informants, Sponsor personnel, or Sponsor designees 
(eg, Sponsor’s Medical Monitor) will be unblinded to treatment assignment throughout the 
duration of the study unless unblinding is required. Both active study drug and placebo will be 
supplied as identical matching capsules. This prevents bias on the part of the study staff and the 
subject to influence the results of the study. 
If an investigator becomes unblinded to a given subject’s study treatment, that subject will be 
discontinued from the study unless there are ethical reasons for that subject not to be 
discontinued; approval from the Sponsor/medical monitor must be obtained in such instances. 
 will generate and maintain the security of the randomization code. In the event that 
emergency unblinding is required for a given subject because of AEs or concerns for the 
subject’s safety or wellbeing, the investigator may break the randomization code for just that 
subject via the IWRS, by which system the unblinding will be captured after consultation and 
agreement with the medical monitor/Sponsor. The unblinding and its cause will also be 
documented in the eCRF. Unblinding according to the protocol will occur only after completion 
of the study. 
If an AE is thought to be related to the study drug and poses a safety risk, the investigator must 
decide whether to stop investigational treatment and/or treat the subject. Subject withdrawal 
should be avoided, if possible. If discontinuation of treatment occurs, every attempt should be 
made to restart study drug if medically appropriate, whatever the duration of discontinuation. 
When a subject has an AE that requires that the investigator be unblinded, the investigator can 
obtain the treatment assignment from the IWRS system. The site is expected to notify the study 
medical monitor before breaking the study blind unless it is in the subject’s best interest if the 
blind is broken immediately. Note: In most circumstances, it is not necessary to unblind a 
subject, even if an SAE has occurred. For many drugs there is no specific therapy for AEs. The 
appropriate course of action is to stop the investigational drug and treat the signs and symptoms 
resulting from the AE. 
The members of the ISMC will be unblinded as they review the safety data from the study. 
9.4 
Dose Modification 
Subjects will be dosed as described in Section 7.1 and in accordance with the Schedule of 
Assessments (Table 2). The study drug doses were selected based on the previous preclinical and 
clinical studies (see Section 5.2). Per the protocol, subjects will be evaluated for dose 
adjustments at Visits 5, 6, and 7 and at unscheduled visits. No dose adjustments are allowed after 


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Visit 7. No other dose modifications are permissible in this study except those specified in this 
protocol. 
9.5 
Treatment Accountability and Compliance 
The pharmacist or other designated unblinded individual will maintain records of study treatment 
delivered to the study site, the inventory at the study site, the distribution to each subject, and the 
return of materials to the Sponsor or designee for storage or disposal. These records should 
include dates, quantities, batch/serial numbers, expiration dates, temperature log, and unique 
code numbers assigned to the product and study subjects. 
Administration of study drug will be supervised by study site personnel to ensure compliance. 
Investigators will maintain records that adequately document that the subjects were provided 
with the correct study treatment bulk supply and reconcile the products received from the drug 
dispensing center. Investigational product will not be returned to the Sponsor or designee until 
accountability has been fully monitored through the end of the study. Study drug accountability 
will be assessed periodically by the assigned unblinded study monitor. 
9.6 
Prior and Concomitant Therapy 
 Prior and Concomitant Medications 
Subjects will be asked for all prior medications they were taking up to 6 months before the study, 
up to the time of the first dose of study medication on Day 1. All prior medications will be 
recorded on the eCRF. 
Restricted prior therapies are provided in Section 8.2. 
All medications and other treatments taken by the subject during the study, including those 
treatments initiated before the start of the study, must be recorded on the eCRF. 
During the study (i.e., from the time of screening visit until study completion), subjects will 
refrain from the use of any new concomitant medications without the specific prior approval of 
the investigator. The administration of any other concomitant medications during the study 
period is prohibited without the prior approval of the investigator unless its use is deemed 
necessary in a medical emergency. Any medication or therapy that is taken by or administered to 
the subject during the course of the study must be recorded in the eCRF. The entry must include 
the dose, regimen, route, indication, dates of use, and time of use (only for concomitant 
medications used on an as needed basis [PRN] basis). 
After written informed consent is obtained from the subject, those subjects who are taking the 
following medications must have the minimum washout periods specified below and not take the 
medications for the duration of the study. 
• Within 5 half-lives or 1 week, whichever is longer, before baseline (Day -1), subjects 
could not have taken oral antipsychotic medications, MAO inhibitors, mood stabilizers 


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(ie, lithium), anticonvulsants (eg, lamotrigine, Depakote), tricyclic antidepressants (eg, 
imipramine, desipramine), selective serotonin reuptake inhibitors, or any other 
psychoactive medications except for anxiolytics that were taken on an as needed basis 
(eg, lorazepam, chloral hydrate). 
• Subjects taking a long acting injectable antipsychotic could not have received a dose of 
medication for at least 12 weeks (24 weeks for INVEGA TRINZA®). 
Note: Please direct questions relating to prohibited medications to the Medical Monitor. 
 Concomitant Medications for Anxiety and/or Sleep aid 
Subjects are allowed to take benzodiazepines (up to 6 mg lorazepam/day or equivalent) for 
anxiety, agitation, and insomnia on a PRN basis. Subjects may also use non-benzodiazepine 
medications (eg, zolpidem, zaleplon) as a sleep aid also on a PRN basis. Study sites must record 
the use of such medications in the eCRF on a per-administration basis and subject’s source 
document. 
 
 


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10 STUDY PROCEDURES 
Table 2 outlines the timing of procedures and assessments to be performed throughout the study. 
Section 12.6 specifies laboratory assessment samples to be obtained. See Sections 11, 12, and 13 
for additional details regarding efficacy, safety, and PK assessments, respectively. 
 


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Table 2. 
Schedule of Assessments 
PROCEDURE 
SCREENING 
PHASE 
TREATMENT PHASE 
SAFETY 
FOLLOW-UPv 
Unscheduled 
Visit(s)b 
VISIT 
1 
(Day -8 
to -2)a 
2a 
(Day 
-1) 
2b 
(Day 
1) 
3 
(Day 
3 +1 
day) 
4 
(Day 
7 ±2 
days) 
5 
(Day 
8  
-1/+2 
days) 
6 
(Day 
14 ±2 
days) 
7 
(Day 
21 ±2 
days) 
8 
(Day 
28 ±2 
days)u 
9 
(Day 
32 +1 
day) 
10/ET 
(Day 35  
-2 days) 
11 
(Day 42 
+5 days) 
WEEKS PAST 
RANDOMIZATION 
NA 
0 
 
 
1 
 
2 
3 
4 
 
5 
6 
 
Written informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Collect 
demographic 
information (date of 
birth, sex, race) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(females of 
childbearing 
potential only)c 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Urine test for 
drugs of abuse 
and alcohol 
testingd 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Review of 
inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Subject eligibility 
verification process 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, 
psychiatric, and 
medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examinatione 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 






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PROCEDURE 
SCREENING 
PHASE 
TREATMENT PHASE 
SAFETY 
FOLLOW-UPv 
Unscheduled 
Visit(s)b 
VISIT 
1 
(Day -8 
to -2)a 
2a 
(Day 
-1) 
2b 
(Day 
1) 
3 
(Day 
3 +1 
day) 
4 
(Day 
7 ±2 
days) 
5 
(Day 
8  
-1/+2 
days) 
6 
(Day 
14 ±2 
days) 
7 
(Day 
21 ±2 
days) 
8 
(Day 
28 ±2 
days)u 
9 
(Day 
32 +1 
day) 
10/ET 
(Day 35  
-2 days) 
11 
(Day 42 
+5 days) 
WEEKS PAST 
RANDOMIZATION 
NA 
0 
 
 
1 
 
2 
3 
4 
 
5 
6 
 
Rating Scale 
Barnes Rating Scale 
for Akathisia 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
X 
 
Abnormal Involuntary 
Movement Scale 
(AIMS) 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
X 
 
Discuss participation 
in KAR-008w 
 
 
 
 
 
 
 
X 
 
 
 
Abbreviations: AE = adverse event; BID = twice daily; BMI = body mass index; BP = blood pressure; CGI-S = Clinical Global Impression‒Severity scale; 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ET = early termination; ID = identification; MINI = Mini International 
Neuropsychiatric Interview; PK = pharmacokinetic; QTcF = QT interval corrected by Fridericia. 
a. 
Up to a 7-day extension of the screening phase is allowed, if needed. 
b. 
Other assessments as needed. 
c. 
A serum pregnancy test for females of childbearing potential should be done at screening, and urine pregnancy tests should be done at other visits. 
d. 
A National Institute on Drug Abuse-5 urine drug screen (cannabinoids or marijuana, phencyclidine, amphetamines, opiates, and cocaine) will be 
performed at screening and at Visit 2a (baseline). If a subject leaves the study site, they should have a urine drug screen and test for alcohol (breathalyzer 
or urine alcohol level) upon returning to the study site. 
e. 
A complete physical examination includes body temperature (°C), general appearance, head/eyes/ears/nose/throat, examination of thorax and 
abdomen, assessment of cardiac, musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited neurological 
examination. 
f. 
AEs as reported by subjects or observed by clinical staff and occurs from Day -1. One PK blood sample may be drawn if a relevant/significant AE 
(based on medical judgement) is reported during a scheduled visit or if there is a dose adjustment or a relevant/significant AE reported during an 
unscheduled visit (no multiple draws). 
g. 
Vital signs taken supine and standing after 2 minutes. BP includes systolic and diastolic BP and is to be taken in the same arm for the duration of the 
study. Heart rate is measured in beats/minute. During treatment, beginning with Day 1, orthostatic vital signs should occur 2 (±1) hours after morning 
dosing. Orthostatic vital signs are only required after the morning dose of the specified visit days, but additional orthostatic vital sign monitoring is 
allowed at the investigator’s discretion. It would be acceptable, for example, to do orthostatic vital signs BID after dosing increases for a day or 2 for 
subjects where it seems warranted, but this should not be done automatically. 




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KAR-008. 
w. Study staff should discuss KAR-008 protocol participation with potential subjects prior to the final day of participation in the acute study, via use of the 
provided recruitment materials. 


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10.1 Informed Consent 
Informed consent forms must be approved for use by the reviewing IEC/IRB. Before performing 
any study-related procedures, the investigator (or designee) will obtain written informed consent 
from the subject. 
10.2 Study Procedures 
Assessments and their timings are to be performed as outlined in the Schedule of Assessments 
(Table 2). Section 12.6 specifies laboratory assessment samples to be obtained. 
Assessments and procedures scheduled at a visit where study drug is administered should be 
performed before administration of treatment unless otherwise indicated in the Schedule of 
Assessments (Table 2). 
Efficacy assessments are described in Section 11 and include PANSS and CGI-S scores. 
Safety assessments are described in Section 12 and include spontaneous AEs; AESIs, 
procholinergic and anticholinergic symptoms; 
 SAS; BARS; 
AIMS; body weight; BMI; waist circumference; orthostatic vital signs; ECG; clinical laboratory 
assessments (hematology, clinical chemistry, coagulation, urinalysis, and drug screen); 
 
 physical examination; and C-SSRS. 
PK assessments are described in Section 13 and include estimation of AUC, Cmax, and Tmax. 
The investigator may, at his/her discretion, arrange for a subject to have an unscheduled 
assessment, especially in the case of AEs that require follow up or are considered by the 
investigator to be possibly related to the use of study drug. The unscheduled visit page in the 
eCRF must be completed. The assessments and procedures that may be performed during an 
unscheduled visit are outlined in the Schedule of Assessments (Table 2). Additional assessments 
can be performed as needed, at the discretion of the investigator, and after discussion with the 
medical monitor. 
Study discontinuation procedures are described in Sections 8.4 and 8.6. 


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11 EFFICACY ASSESSMENTS 
The Schedule of Assessments (Table 2) outlines the efficacy assessments to be performed 
throughout the study and their timing. 
11.1 Positive and Negative Syndrome Scale 
The PANSS is a clinician-administered scale used for measuring symptom severity of subjects 
with schizophrenia and is widely used in the study of antipsychotic therapy[22]. The PANSS 
rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general 
psychopathology symptom scales. Subjects are rated from 1 to 7 on each symptom scale. The 
positive symptoms in schizophrenia are the excess or distortion of normal function such as 
hallucinations, delusions, grandiosity, and hostility, and the negative symptoms in schizophrenia 
are the diminution or loss of normal functions. It takes approximately 45 to 50 minutes to 
administer. PANSS total score is the sum of all scales with a minimum score of 30 and a 
maximum score of 210. The PANSS assessment includes the Marder Factor. 
It is recommended, if at all possible, that the PANSS assessment should be performed before all 
the other scale assessments (except MINI at screening) for all visits at which it is performed. 
11.2 Clinical Global Impression‒Severity 
The CGI-S is a rating scale completed independently by a clinician that is used to measure illness 
and symptom severity in subjects with mental disorders. It is used to rate the severity of a 
subject’s illness at the time of assessment. The modified CGI-S asks the clinician 1 question: 
“Considering your total clinical experience, how mentally ill is the subject at this time?” The 
clinician’s answer is rated on the following 7-point scale: 1 = normal, not at all ill; 2 = borderline 
mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the 
most extremely ill subjects[23]. 
This rating is based upon observed and reported symptoms, behavior, and function in the past 
7 days. As symptoms and behavior can fluctuate over a week, the score should reflect the 
average severity level across the previous 7 days. 


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12 SAFETY ASSESSMENTS 
Safety assessments (spontaneous AEs; AESIs, procholinergic and anticholinergic symptoms; 
 SAS; BARS; AIMS; body weight; BMI; waist circumference; 
orthostatic vital signs; ECG; clinical laboratory assessments [hematology, clinical chemistry, 
coagulation, urinalysis, 
and drug screen]; physical examination; and C-SSRS) are to be 
performed at protocol-specified visits, as specified in the Schedule of Assessments (Table 2). 
12.1 Demographics, and Medical and Psychiatric History 
Demographic data will be collected for all subjects at Screening. The information to be captured 
includes date of birth (alternatively year of birth if full date of birth is not allowed to be collected 
for legal reasons), age, sex, race and ethnicity, which will be obtained from the subject and 
recorded in the eCRF. 
Medical and psychiatric history will be recorded at screening. Investigators should document the 
occurrence, signs, and symptoms of the subject’s preexisting conditions, including all baseline 
symptoms, ongoing illnesses, other chronic conditions, and surgical history at screening. Medical 
history will also include history of drug, substance, or alcohol abuse/dependence within 1 year 
before Screening. 
Illnesses first occurring or detected during the study and/or worsening of a concomitant illness 
during the study are to be documented as AEs on the eCRF in accordance with Section 12.7. All 
changes not present at baseline or described in the past medical history and identified as 
clinically noteworthy must be recorded as AEs. 
12.2 Vital Signs 
Orthostatic vital signs (systolic and diastolic BP and heart rate measurements) will be evaluated 
at the visits indicated in the Schedule of Assessments (Table 2). All vital signs will be measured 
supine and standing after 2 minutes. BP measurements are to be taken in the same arm for the 
duration of the study. During treatment, beginning with Day 1, orthostatic vital signs should 
occur 2 (±1) hours after morning dosing. Orthostatic vital signs are only required after the 
morning dose of the specified visit days, but additional orthostatic vital sign monitoring is 
allowed at the investigator’s discretion. 
Vital sign measurements will be repeated if clinically significant or machine/equipment errors 
occur. Out-of-range BP or heart rate measurements will be repeated at the investigator’s 
discretion. Any confirmed, clinically significant vital sign measurements must be recorded as 
AEs. 


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12.3 Physical Examination 
A complete physical examination (body temperature, general appearance, 
head/eyes/ears/nose/throat, examination of thorax and abdomen, assessment of cardiac, 
musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited 
neurological examination) will be performed at visits as specified in Table 2. Physical 
examinations will be performed by a physician or qualified designee. 
12.4 Weight, Height, Body Mass Index, Waist Circumference 
Height (screening only), weight, and waist circumference measurements will be obtained at visits 
as specified in Table 2. BMI should be calculated at these visits. All findings should be recorded 
in the eCRF. 
12.5 Electrocardiograms 
A 12-lead, resting ECG will be obtained at the visits indicated in the Schedule of Assessments 
(Table 2). During the ECG, ventricular rate (bpm), PR (msec), QRS (msec), QT (msec), and 
QTcF (msec) measurements will be obtained. ECG at Day 1 will be performed 2 hours 
(+ 15 minutes) post morning dose. ECGs at all other scheduled visits will be performed before 
blood withdrawal for any safety laboratory tests and/or PK analysis. 
All the ECGs obtained will be interpreted by experienced independent blinded reader(s) at the 
central reading facility. 
At screening, the investigator will examine the ECG traces for signs of cardiac disease that could 
exclude the subject from the study. An assessment of normal or abnormal will be recorded; if the 
ECG is considered abnormal, the abnormality will be documented on the eCRF. ECGs will be 
repeated if clinically significant abnormalities are observed or artifacts are present. 
12.6 Laboratory Assessments 
Laboratory assessment samples (Table 3) are to be obtained at designated visits as detailed in the 
Schedule of Assessments (Table 2). 






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eCRF during the rest of the study. Clinically significant vital signs and laboratory abnormalities 
should also be recorded as AEs. Surgical procedures that were planned before the subject 
enrolled in the study are not considered AEs if the conditions were known before study 
inclusion; the medical condition should be reported in the subject’s medical history. 
In accordance with the protocol, the investigator and/or study staff will elicit AEs and 
intercurrent illness during and at the end of the study period, and these will be recorded on the 
appropriate page of the eCRF. AEs will be elicited by asking the subject a nonleading question, 
for example, “Have you experienced any new or changed symptoms since we last asked?” The 
eCRF will be completed at the end of the study as soon as the results of the final laboratory tests 
are available. 
Each AE is to be documented on the eCRF with reference to date of onset, duration, frequency, 
severity, relationship to study drug, action taken with study drug, treatment of event, and 
outcome. Furthermore, each AE is to be classified as being serious or nonserious. Changes in 
AEs and resolution dates are to be documented on the eCRF. 
For the purposes of this study, the period of observation for collection of AEs extends from the 
time immediately after the administration of study drug on Day 1 until the End of Study 
 
 
or early termination. Follow up of the AE, even after the date of therapy discontinuation, 
is required if the AE persists until the event resolves or stabilizes at a level acceptable to the 
investigator. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the event should be noted. If the intensity category changes over a number of days, 
then those changes should be recorded separately (with distinct onset dates). 
The severity of AEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0 (Grades 1 through 5). 
Specific guidelines for classifying AEs by intensity and relationship to study drug are given in 
Table 4 and Table 5. 
Table 4. 
Classification of Adverse Events by Intensity 
MILD: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with 
everyday activities. 
MODERATE: An event that is sufficiently discomforting to interfere with normal everyday activities. 
SEVERE: An event that prevents normal everyday activities. 
 


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Table 5. 
Classification of Adverse Events by Relationship to Study Drug 
UNRELATED: This category applies to those AEs that are clearly and incontrovertibly due to extraneous 
causes (disease, environment, etc). 
UNLIKELY: This category applies to those AEs that are judged to be unrelated to the test drug but for which 
no extraneous cause may be found. An AE may be considered unlikely to be related to study drug if or when it 
meets 2 of the following criteria: (1) it does not follow a reasonable temporal sequence from administration of 
the test drug; (2) it could readily have been produced by the subject clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; (3) it does not follow a known pattern of 
response to the test drug; or (4) it does not reappear or worsen when the drug is readministered. 
POSSIBLY: This category applies to those AEs for which a connection with the test drug administration 
appears unlikely but cannot be ruled out with certainty. An AE may be considered possibly related if or when 
it meets 2 of the following criteria: (1) it follows a reasonable temporal sequence from administration of the 
drug; (2) it could not readily have been produced by the subject’s clinical state, environmental or toxic factors, 
or other modes of therapy administered to the subject; or (3) it follows a known pattern of response to the test 
drug. 
PROBABLY: This category applies to those AEs that the investigator feels with a high degree of certainty are 
related to the test drug. An AE may be considered probably related if or when it meets 3 of the following 
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
reasonably explained by the known characteristics of the subject clinical state, environmental or toxic factors, 
or other modes of therapy administered to the subject; (3) it disappears or decreases on cessation or reduction 
in dose (note that there are exceptions when an AE does not disappear upon discontinuation of the drug, yet 
drug-relatedness clearly exists; for example, as in bone marrow depression, fixed drug eruptions, or tardive 
dyskinesia); or (4) it follows a known pattern of response to the test drug. 
DEFINITELY: This category applies to those AEs that the investigator feels are incontrovertibly related to test 
drug. An AE may be assigned an attribution of definitely related if or when it meets all of the following 
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
reasonably explained by the known characteristics of the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; (3) it disappears or decreases on cessation or 
reduction in dose and recurs with reexposure to drug (if rechallenge occurs); and (4) it follows a known pattern 
of response to the test drug. 
Abbreviation: AE, adverse event. 
 
 Adverse Events of Special Interest 
The AEs of special interest will be monitored and include orthostasis and liver function test 
elevations inclusive of DILI. 
AEs of special interest should be recorded as AEs and reported as SAEs when appropriate. 
 Serious Adverse Events 
A, SAE is any untoward medical occurrence, in the view of either the investigator or Sponsor, 
that: 
• results in death, 
• is life-threatening, 
• results in inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization for elective treatment of a pre-existing, nonworsening condition is not, 


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however, considered an SAE; the details of such hospitalizations must be recorded on the 
medical history or physical examination page of the eCRF), 
• results in persistent or significant disability/incapacity, and/or 
• is a congenital anomaly/birth defect. 
Other important medical events that may not be immediately life-threatening or result in death or 
hospitalization, based upon appropriate medical judgment, are considered SAEs if they are 
thought to jeopardize the subject and/or require medical or surgical intervention to prevent one of 
the outcomes defining an SAE. SAEs are critically important for the identification of significant 
safety problems; therefore, it is important to take into account both the investigator’s and the 
Sponsor’s assessment. If either the Sponsor or the investigator believes that an event is serious, 
the event must be considered serious and evaluated by the Sponsor for expedited reporting. 
 Serious Adverse Event Reporting 
An SAE occurring from the time first dose of the study drug is administered, during the study, or 
within 1 week of stopping the treatment must be reported to the 
 
and will be communicated to the Sponsor. Any such SAE due to any 
cause, whether or not related to the study drug, must be reported within 24 hours of occurrence 
or when the investigator becomes aware of the event. Notification can be made using email. 
 email address is: 
 
The events must be recorded on the standard AE eCRF. Preliminary reports of SAEs must be 
followed up by detailed descriptions later on, including clear and anonymized photocopies of 
hospital case reports, consultant reports, autopsy reports, and other documents when requested 
and applicable. SAE reports must be made whether or not the investigator considers the event to 
be related to the investigational drug. 
Appropriate remedial measures should be taken to treat the SAE, and the response should be 
recorded. The investigator must report all additional follow-up evaluations to the 
 
within 24 hours of becoming aware of the additional 
information or as soon as is practicable. All SAEs will be followed up until the investigator and 
Sponsor agree the event is satisfactorily resolved. 
Any SAE that is not resolved by the end of the study or upon discontinuation of the subject’s 
participation in the study is to be followed up until it either resolves, stabilizes, returns to 
baseline values (if a baseline value is available), or is shown to not be attributable to the study 
drug or procedures. 
 Drug-Induced Liver Injury 
The sponsor has incorporated the following for monitoring of the drug induced liver injury: 
• An increase of serum ALT or AST to >3 × upper limit of normal (ULN) should be 
followed by repeat testing within 48 to 72 hours of all 4 of the usual serum measures 


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(ALT, AST, ALP, and total bilirubin) to confirm the abnormalities and to determine if 
they are increasing or decreasing. An inquiry should be made about the symptoms 
(fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, and rash). 
• Close observation should be initiated with ALT or AST >3 × ULN: 
o Repeat liver enzyme and serum bilirubin tests 2 or 3 times weekly. Frequency of 
retesting can decrease to once per week or less if abnormalities stabilize or the trial 
drug has been discontinued, and the subject is asymptomatic. 
o Obtain a more detailed history of symptoms and prior or concurrent diseases. 
o Obtain a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug 
use, and special diets. 
o Rule out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy; and biliary 
tract disease. 
o Obtain a history of exposure to environmental chemical agents. 
o Obtain additional tests to evaluate liver function, as appropriate (eg, international 
normalized ratio, direct bilirubin). 
o Consider gastroenterology or hepatology consultations. 
• Discontinuation of treatment should be considered if: 
o ALT or AST >8 × ULN 
o ALT or AST >5 × ULN for more than 2 weeks 
o ALT or AST >3 × ULN and (total bilirubin >2 × ULN or international normalized 
ratio >1.5) 
o ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or eosinophilia (>5%) 
• Hepatic adjudication of cases should include an evaluation for alternative causes such as 
viral, autoimmune, alcohol, hepatobiliary disorders, nonalcoholic steatohepatitis, 
concomitant medications, etc. 
• Follow up to resolution of elevated liver enzymes. 
• Gamma-glutamyl transpeptidase elevations alone should not prompt drug 
discontinuation. 
 Trial Discontinuation Criteria Other than DILI and Pregnancy 
12.7.6.1 
Individual Stopping Criteria 
Based on NCI CTCAE v5.0, study drug will be discontinued in any subject who has a ≥ Grade 4 
AE. Discontinuation or reduction in the dosage of the study drug for Grade 3 AEs other than 
DILI AEs (see Section 12.7.5) will be at the discretion of the investigator. 
12.7.6.2 
Trial Stopping Rules 
The safety and tolerability aspects of KarXT will be overseen by an ISMC. The ISMC will meet 
periodically and review the unblinded data and will be responsible for advising the sponsor on 


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ways to safeguard the interests of the clinical study subjects. The committee is expected to 
recommend sponsor whether to: 
a. Continue the clinical study without modification; or 
b. Continue the clinical study with modification (listing the specific modifications 
recommended); or 
c. Terminate the study. 




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 Pregnancy 
WOCBP must have a negative pregnancy test at screening. The investigator must notify the 
Sponsor (or designee) of any female subject or female partner of a male subject that becomes 
pregnant while participating in the study. Any known cases of pregnancy in female subjects will 
be reported until the subject completes or withdraws from the study. The pregnancy will be 
reported immediately by faxing/emailing a completed pregnancy report to the Sponsor (or 
designee) within 24 hours of knowledge of the event. The pregnancy will not be processed as an 
SAE; however, the investigator will follow-up with the subject until completion of the pregnancy 
and must assess the outcome in the shortest possible time but not more than 30 days after 
completion of the pregnancy. 
If a female subject becomes pregnant, the investigator must withdraw her from the study without 
delay. The subject must not receive any further doses of the study drug. Upon discontinuation 
from the study, only those procedures that would not expose the subject to undue risk will be 
performed. 
If the female subject or the female partner of the male subject is willing and able to consent to 
pregnancy follow-up, she will be followed until her pregnancy reaches term. Information 
regarding the pregnancy must only be submitted after obtaining written consent from the 
pregnant partner. The investigator will arrange counseling for the pregnant partner by a specialist 
to discuss the risks of continuing with the pregnancy and the possible effects on the fetus. 
The investigator should notify the Sponsor (or designee) of the pregnancy outcome by 
submitting a follow-up pregnancy report. If the outcome of the pregnancy involved spontaneous 
or therapeutic abortion (any congenital anomaly detected in an aborted fetus is to be 
documented), stillbirth, neonatal death, or congenital anomaly, the investigator will report the 
event by faxing/emailing a completed pregnancy report form to the Sponsor (or designee) within 
24 hours of knowledge of the event. This event is considered an SAE. 
The investigator should also be notified of pregnancy occurring during the study but confirmed 
after completion of the study. In the event that a subject is subsequently found to be pregnant 
after inclusion in the study, any pregnancy will be followed to term, and the status of mother and 
child will be reported to the Sponsor after delivery. 
 Overdose 
The investigator must immediately notify the Sponsor of any occurrence of overdose with study 
drug. Overdose should be managed with symptomatic and supportive care. 


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12.9 Simpson-Angus Scale 
The SAS is an established instrument to measure drug-related extrapyramidal syndromes. It is a 
10-item testing instrument used to assess gait, arm dropping, shoulder shaking, elbow rigidity, 
wrist rigidity, leg pendulousness, head dropping, glabella tap, tremor, and salivation. The range 
of scores is from 0 to 40 with increased scores indicating increased severity. 
12.10 Barnes Akathisia Rating Scale 
The BARS is a rating scale used to assess the severity of drug-induced akathisia, or restlessness, 
involuntary movements and inability to sit still. The range of scores is 0 to 14, with higher scores 
indicating greater severity[25]. 


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12.11 Abnormal Involuntary Movement Scale 
The AIMS is a rating scale that is used to measure involuntary movements know as tardive 
dyskinesia, which can sometimes develop as a side effect of long-term treatment with 
antipsychotic medications. It is a 12-item scale to assess orofacial, extremity, and truncal 
movements as well as the overall severity, incapacitation, and the subject’s level of awareness of 
the movements. Items are scored from 0 (none) to 4 (severe). A higher score indicates more 
severe dyskinesia. 
12.12 Columbia-Suicide Severity Rating Scale 
The C-SSRS is a tool designed to systematically assess and track suicidal AEs (suicidal behavior 
and suicidal ideation) throughout the study[26]. The strength of this suicide classification system 
is in its ability to comprehensively identify suicidal events while limiting the over identification 
of suicidal behavior. The scale takes approximately 5 minutes to administer. The C-SSRS will be 
administered by a trained rater at the site. 
This study will utilize 2 versions of the C-SSRS. At the screening visit, the “lifetime” version 
will be completed; for all subsequent visits the “Since Last Visit” version of the C-SSRS will be 
administered. 


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12.14 Mini International Neuropsychiatric Interview Version 7.0.2 
The MINI is a short structured diagnostic interview developed for DSM-5 psychiatric disorders. 
With an administration time of approximately 15 minutes, it was designed to meet the need for a 
short but accurate structured psychiatric interview for multicenter clinical studies and 
epidemiology. 


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14 STATISTICAL ANALYSIS 
A SAP will be prepared after the protocol is approved. This document will provide further details 
regarding the definition of analysis variables and analysis methodology to address all study 
objectives. The SAP will serve as a compliment to the protocol and supersedes it in case of 
differences. 
14.1 Determination of Sample Size 
Assuming treatment difference of change from baseline in PANSS total score at Week 5 is 
8 points between drug and placebo (standard deviation 16), a sample size of approximately 
172 (86 evaluable subjects per arm) will result in a power of 90.3% for a 2-sided alpha of 0.05 
(P ≤ 0.05). With a dropout rate of 30%, a total of 246 subjects are estimated to be enrolled. 
14.2 Analysis Populations 
Intent-to-Treat Population 
All subjects who are randomized to the study will be included in the intent-to-treat (ITT) 
population. 
Modified ITT Population 
All subjects who are randomized, received at least 1 dose of study drug, have a baseline PANSS 
assessment, and at least 1 post-baseline PANSS assessment will be included in the mITT 
population and will be used in the efficacy analysis. 
Safety Population 
All subjects who received at least 1 dose of study drug will be included in the safety population 
and will be used in the safety analysis. 
PK Population 
All subjects who have an evaluable PK profile will be included in the PK population and will be 
used in the PK analysis. Subjects must have received at least 1 dose of active study drug and 
have at least 1 measurable plasma concentration of study drug. 


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14.4 Efficacy Analysis 
 Primary Estimand 
The population of the primary estimand is among adult inpatients (aged 18-65 years) with a 
DSM-5 diagnosis of schizophrenia, confirmed by MINI for schizophrenia, who are acutely 
psychotic and hospitalized with PANSS score of 80 to 120 at time of enrollment, defined 
according to the inclusion/exclusion criteria. Subjects will receive flexible dose KarXT, whereby 
a subject receiving 100/20 (xanomeline 100 mg/trospium 20 mg) may be titrated upwards to 
KarXT 125/30 on Day 8. All subjects who are increased to 125/30 BID will have the option to 
return to KarXT 100/20, but may not change their dose after Visit 7 (Day 21) or decrease their 
dose for tolerability reasons more than once. The primary analysis will be executed on the mITT 
population, including all subjects with a baseline and at least 1 post-baseline PANSS 
measurement, grouped as randomized. 
The variable is the change from baseline in PANSS total score at Week 5. 
Intercurrent events: 


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• Discontinuation from study treatment prior to the completion of the 5 weeks of efficacy 
assessments: While on treatment strategy where efficacy results recorded prior to subject 
discontinuation from the study will be included in the analysis 
• Use of concomitant medication for anxiety and/or sleep aid: Treatment policy strategy 
where results will be used regardless of concomitant medications for anxiety and/or sleep 
aid 
The population level summary is the difference between treatment groups (KarXT vs placebo) in 
mean change from baseline in PANSS at Week 5, obtained from a mixed model repeated 
measures (MMRM). 
 
 
 
 Analysis of the Primary Efficacy Endpoint 
The primary efficacy endpoint of the study is the change from baseline in PANSS total score at 
Week 5. The difference between KarXT and placebo at Week 5 will be estimated using an 
MMRM. The model will include the change from baseline PANSS total scores at Week 2, Week 
3, Week 4, and Week 5 as the response. Within-subject correlation will be accounted for using 
an unstructured covariance matrix. Fixed effects will include the treatment group (KarXT or 
placebo), visit, and the interaction between the treatment group and visit, site, age, sex, and 
baseline PANSS total score. Low-enrolling sites may be pooled, if necessary, for modeling 
purposes. The algorithm for pooling sites will be specified in the SAP. 
Sensitivity analyses of the primary efficacy endpoint may be performed on an observed case 
basis, using multiple imputation techniques, and classifying treatment dropouts as treatment 
failures. Alternative time-varying parameterizations of dose level and use of concomitant 
medication for anxiety and/or sleep aid may also be included in sensitivity analyses. In addition, 
alternative covariance matrices for the MMRM may be investigated. The sensitivity analyses of 
the primary endpoint will be specified in the SAP. 
 Analysis of Secondary Efficacy Endpoints 
The continuous secondary endpoints (change from baseline to Week 5 in PANSS positive score, 
PANSS negative score, PANSS Negative Marder Factor score, and CGI-S) will be analyzed in 
the same manner as the primary efficacy analysis (ie, using MMRM). 
The categorical secondary endpoint (percentage of PANSS responders at Week 5) will be 
compared between the treatment groups (KarXT and placebo) using the Cochran-Mantel-
Haenszel test. 
The statistical analysis of the primary and key secondary efficacy variables will account for 
multiplicity by using a fixed sequence testing procedure. This testing procedure will control the 
overall Type 1 error rate across all hypotheses/endpoints being tested. 


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14.5 Safety Analysis 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities version 
22.1 or higher. The incidence of TEAEs (events with onset dates on or after the start of the study 
drug) will be summarized for each treatment group separately by System Organ Class and 
Preferred Term. All AEs will be listed by subject, along with information regarding onset, 
duration, relationship and severity to study drug, action taken with study drug, treatment of 
event, and outcome. 
Orthostatic vital signs, clinical laboratory data, 
 ECG parameters, and physical 
examinations will be summarized using descriptive statistics, including observed and change 
from baseline values, as well as numbers of subjects with values outside limits of the normal 
range at each time point by treatment group. Similar descriptive summaries will be provided for 
SAS, BARS, 
 AIMS, body weight, BMI, and waist 
circumference. 
14.6 Pharmacokinetic Analysis 
PK results will be listed for all subjects who received active treatment. The profiles or time 
points obtained with protocol deviations affecting PK results will be flagged and may be 
excluded from summaries and analyses. 
The data will be presented graphically via individual plots and mean plots summarized by actual 
treatment, visit, and time point. 
PK parameters for xanomeline and trospium will be derived from plasma concentration data 
using noncompartmental methods. Actual time elapsed from dosing will be used to estimate all 
individual PK parameters. The primary PK parameters of interest will include Cmax, Tmax, and 
AUC from 0 to 12 hours (or from 0 to the last measurable concentration). Additional parameters 
(not limited to the following) such as the elimination half-life, clearance, and volume of 
distribution will be determined if the data permit. 
The effect of dose on PK and other inferential analyses for exposure-response relationship may 
be performed. The details of the PK analysis will be described in the SAP. The 
noncompartmental analysis will be described as a part of final clinical study report. 
14.7 Interim Analysis 
No interim analysis is planned for this study. 
14.8 Handling of Missing Data 
Several different methods to handle the missing data in the primary efficacy endpoint analysis 
may be used. 


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• For the primary efficacy analysis, likelihood-based modeling approach will be used to 
handle incomplete data. For this purpose, an MMRM will be applied. 
• Sensitivity analysis for the primary efficacy endpoint will be conducted using the last 
observation carried forward approach. In this analysis, the missing values will be 
replaced by the previous visit PANSS total score carried forward. 
• Sensitivity analysis for the primary efficacy endpoint will be conducted using the 
Multiple Imputation approach (ie, by replacing each missing value with a set of plausible 
values that represent the uncertainty about the right value to impute). 




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15.2 Data Handling 
Any data to be recorded directly on the eCRFs (to be considered as source data) will be 
identified at the start of the study. Data reported on the eCRF that are derived from source 
documents should be consistent with the source documents, or the discrepancies must be 
explained. See also Section 15.3. 
Clinical data will be entered by site personnel on eCRFs for transmission to the Sponsor. Data on 
eCRFs transmitted via the web-based data system must correspond to and be supported by source 
documentation maintained at the study site, unless the study site makes direct data entry to the 
databases for which no other original or source documentation is maintained. In such cases, the 
study site should document which eCRFs are subject to direct data entry and should have in 
place procedures to obtain and retain copies of the information submitted by direct data entry. 
All study forms and records transmitted to the Sponsor must only include coded identifiers such 
that directly identifying personal information is not transmitted. The primary method of data 
transmittal is via the secure, internet-based electronic data capture (EDC) system 
 
Access to the EDC system is available to only authorized users via the study’s 
secured internet web site, where a user unique assigned username and password are required for 
access. 
Any changes made to data after collection will be made through the use of the EDC system. 
Electronic CRFs will be considered complete when all missing and/or incorrect data have been 
resolved. 
15.3 Source Documents 
Source documents are considered to be all information in original records and certified copies of 
original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. The investigator will provide direct 
access to source documents and/or source data in the facilitation of trial-related monitoring, 
audits, review by IECs/IRBs, and regulatory inspections. 
The investigator/institution should maintain adequate and accurate source documents and trial 
records that include all pertinent observations on each of the site’s trial subjects. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, not obscure the original entry, and be explained if necessary. 


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Data recorded on source documents will be transcribed onto eCRFs. Copies of completed eCRFs 
will be provided to the Sponsor and the sites at the end of the study. The completed eCRFs will 
be retained by the investigator. 
15.4 Record Retention 
Study records and source documents must be preserved for at least 15 years after the completion 
or discontinuation of/withdrawal from the study, at least 2 years after the drug being studied has 
received its last approval for sale, or at least 2 years after the drug development has stopped, and 
in accordance with the applicable local privacy laws, whichever is the longer time period. 
The investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subject health information, including, but not limited to, the 
Standards for Individually Identifiable Health Information, 45 CFR, Parts 160 and 164 (the 
Health Insurance Portability Accountability Act of 1996 [HIPAA] Privacy Regulation). The 
investigator shall ensure that study subjects authorize the use and disclosure of protected health 
information in accordance with HIPAA Privacy Regulation and in a form satisfactory to the 
Sponsor. 
15.5 Monitoring 
The study will be monitored according to the KAR-007 monitoring plan to ensure that it is 
conducted and documented properly according to the protocol, GCP, and all applicable 
regulatory requirements. 
Monitoring visits, on-site and remote (telephone) or a combination and contacts will be made at 
appropriate times during the study. The Principal Investigator will assure him/her and adequate 
site personnel are available throughout the study to collaborate with clinical monitors. Clinical 
monitors must have direct access to source documentation in order to check the completeness, 
clarity, and consistency of the data recorded in the eCRFs for each subject. 
The investigator will make available to the clinical monitor all source documents and medical 
records necessary to review protocol adherence and eCRFs. In addition, the investigator will 
work closely with the clinical monitor and, as needed, provide them appropriate evidence that the 
study is being conducted in accordance with the protocol, applicable regulations, and GCP 
guidelines. 
15.6 Quality Control and Quality Assurance 
The Sponsor or its designee will perform the quality assurance and quality control activities of 
this study; however, responsibility for the accuracy, completeness, security, and reliability of the 
study data presented to the Sponsor lies with the investigator generating the data. 
The Sponsor will arrange audits as part of the implementation of quality assurance to ensure that 
the study is being conducted in compliance with the protocol, standard operating procedures, 


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GCP, and all applicable regulatory requirements. Audits will be independent of and separate 
from the routine monitoring and quality control functions. Quality assurance procedures will be 
performed at study sites and during data management to assure that safety and efficacy data are 
adequate and well documented. 
15.7 Protocol Amendment and Protocol Deviation 
 Protocol Amendment 
Amendments to the protocol that entail corrections of typographical errors, clarifications of 
confusing wording, changes in study personnel, and minor modifications that have no effect on 
the safety of subjects or the conduct of the study will be classed as administrative amendments 
and will be submitted to the IEC/IRB for information only.
 will ensure that 
acknowledgement is received and filed. Amendments that are classed as substantial amendments 
must be submitted to the appropriate regulatory authorities and the IECs/IRBs for approval and 
will not be implemented at sites until such approvals are received other than in the case of an 
urgent safety measure. 
 Protocol Deviations 
Should a protocol deviation occur, the Sponsor must be informed as soon as possible. Protocol 
deviations and/or violations and the reasons they occurred will be included in the clinical study 
report. Reporting of protocol deviations to the IEC/IRB and in accordance with applicable 
regulatory authority mandates is an investigator’s responsibility. 
All protocol deviations will be tracked in the Clinical Trial Management System. Deviations 
considered major will be identified as such before study unblinding during medical monitor 
periodic review. 
Major protocol deviations will be tabulated including the frequency and percentage of subjects 
with each type of deviation by treatment group. 
15.8 Ethical Considerations 
This study will be conducted in accordance with this protocol, the accepted version of the 
Declaration of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, 
Subpart D, of Title 21 of the CFR; and in compliance with GCP guidelines. 
IECs/IRBs will review and approve this protocol and the ICF. All subjects are required to give 
written informed consent before participation in the study. 
15.9 Financing and Insurance 
Before the study commences, the Sponsor (or its designee) and the investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study. This agreement will 
be documented in a financial agreement that will be signed by the investigator (or the institution 
signatory) and the Sponsor (or its designee). 


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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. 
15.10 Publication Policy/Disclosure of Data 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Intellectual property rights (and related matters) generated by the investigator and others 
performing the clinical study will be subject to the terms of a clinical study agreement that will 
be agreed between the institution and the Sponsor or their designee. With respect to such rights, 
the Sponsor or its designee will solely own all rights and interests in any materials, data, and 
intellectual property rights developed by investigators and others performing the clinical study 
described in this protocol, subject to the terms of any such agreement. In order to facilitate such 
ownership, investigators will be required to assign all such inventions either to their institution or 
directly to the Sponsor or its designee, as will be set forth in the clinical study agreement. 


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16 REFERENCES 
 
Patel KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: overview and treatment options. 
P T. 2014;Sep 39(9):638-645. 
 
van Os J, Kapur S. Schizophrenia. Lancet. 2009 Aug 22;374(9690):635-645. 
 
Wu EQ, Shi L, Birnbaum H, Hudson T, Kessler R. Annual prevalence of diagnosed 
schizophrenia in the USA: a claims data analysis approach. Psychol Med. 2006 
Nov;36(11):1535-1540. 
 
Crismon L, Argo TR, Buckley PF. Schizophrenia. In: DiPiro JT, Talbert RL, Yee GC, et 
al., editors. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, New 
York: McGraw-Hill; 2014:1019–1046. 
 
Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome 
in schizophrenia: implications for MATRICS. Schizophr Res. 2004;72(1):41-51. 
 
Huhn M, Nikolakopoulou A, Schnider-Thoma J, et al. Comparative efficacy and 
tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode 
schizophrenia: a systematic review and network meta-analysis. Lancet. 
2019;394(10202):939-951. 
 
Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in 
patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223. 
 
Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 
15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 
2013;382(9896):951-962. 
 
Emsley R, Chiliza B, Asmal L, Harvey BH. The nature of relapse in schizophrenia. BMC 
Psychiatry. 2013;13:50. 
 
Kahn RS, Sommer IE, Murray RM, et al. Schizophrenia. Nat Rev Dis Primers. 
2015;1:15067. 
 
Sellin AK, Shad M, Tamminga, C. Muscarinic agonists for the treatment of cognition in 
schizophrenia. CNS Spectr. 2008 Nov;13(11):985-996. 
 
Wess J, Eglen RM, Gautam D. Muscarinic acetylcholine receptors: mutant mice provide 
new insights for drug development. Nat Rev Drug Discov. 2007 Sep;6:(9):721-733. 
 
Mirza NR, Peters D, Sparks RG. Xanomeline and the antipsychotic potential of muscarinic 
receptor subtype selective agonists. CNS Drug Rev. 2003 Summer;9(2):159-186. 
 
Thorn CA, Moon J, Bourbonais CA, et al. Striatal, hippocampal, and cortical networks are 
differentially responsive to the M4- and M1-muscarinic acetylcholine receptor mediated 
effects of xanomeline. ACS Chem Neurosci. 2019;10(8):3910. 
 
Farde L, Suhara T, Halldin C, et al. PET study of the M1-agonists [11C]xanomeline and 
[11C]butylthio-TZTP in monkey and man. Dementia. 1996;7(4):187-195. 
 
Bodick NC, Offen WW, Levey AI, et al. Effect of xanomeline, a selective muscarinic 
receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. 
Arch Neurol. 1997;54(4):465-473. 


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Bodick NC, Offen WW, Shannon HE, et al. The selective muscarinic agonist xaqnomeline 
improves both the cognitive deficits and behavioral symptoms of Alzheimer’s disease. 
Alzheimer Dis Assoc Disord. 1997; 11 Suppl 4:S16-22. 
 
Shekhar A, Potter WZ, Lightfoot J, et al. Selective muscarinic receptor agonist xanomeline 
as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008 Aug;165(8):1033-
1039. 
 
Staskin D, Sand P, Zinner N, Dmochowski R, Trospium Study Group. Once daily trospium 
chloride is effective and well tolerated for the treatment of overactive bladder; results from 
a multicenter phase III trial. J Urol. 2007;178(3 Pt 1):978-983; discussion 983-984. 
 
Scheife R, Takeda M. Central nervous system safety of anticholinergic drugs for the 
treatment of overactive bladder in the elderly. Clin Ther. 2005;27(2):144-153. 
 
Brannan SK, Paul SM and Breier A. Xanomeline plus trospium: A novel strategy to 
enhance pro-muscarinic efficacy and mitigate peripheral side effects. Proceedings of the 
ASCP annual meeting 2019. 
 
Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr Bull. 1987;13(2):261-276. 
 
Guy W. EDCEU Assessment Manual for Psychopharmacology – Revised. Rockville, MD, 
US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug 
Abuse, and Mental Health Administration, NIMH Psychopharmacology Research Branch, 
Division of Extramural Research Programs, 1976:534-7. DHEW Publication No ADM 
76-338. 
 
Buchanan RW, Davis M, Goff D, et al. A summary of the FDA-NIMH-MATRICS 
workshop on clinical trial design for neurocognitive drugs for schizophrenia. 
Schizophrenia Bulletin. 2005 Jan;31(1):5-19. 
 
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989 
May;154 (5):672–676. 
 
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s 
pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007 
Jul;164(7):1035-1043. 
 
Chatoor D, Emmanuel A. Constipation and evacuation disorders. Best Pract Res Clin 
Gastroenterol. 2009;23(4):517–530. 
 
Constipation. National Institute of Diabetes and Digestive and Kidney Diseases. 
https://www.niddk.nih.gov/health-information/digestive-diseases/constipation/all-content. 
February 2015. Accessed 28 Mar 2020. 
 
American Gastroenterological Association, Bharucha AE, Dorn SD, Lembo A, Pressman 
A. American Gastroenterological Association medical position statement on constipation. 
Gastroenterology. 2013 Jan;144(1):211–217. 
 
Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. 
Functional bowel disorders. Gastroenterology. 2006 Apr;130(5):1480–1491. 


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Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol. 1997 Sep;32(9):920–924. 
 
Locke GR III, Pemberton JH, Phillips SF. American Gastroenterological Association 
Medical Position Statement: guidelines on constipation. Gastroenterology. 2000 
Dec;119(6):1761–1766. 
 
[HMA] Heads of Medicines Agencies. Clinical Trial Facilitation Group page. 
Recommendations related to contraception and pregnancy testing in clinical trials. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
September 15, 2014. Accessed 27 Mar 2020. 
 









SAP_001.pdf: 




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TABLE OF CONTENTS
Section
Page
1.
Information From the Study Protocol.........................................................................9
1.1. 
Introduction and Objectives.............................................................................9
1.1.1. 
Introduction..........................................................................................9
1.1.2. 
Study Objectives ..................................................................................9
1.1.2.1. Primary Objective .................................................................9
1.1.2.2. Secondary Objectives............................................................9
1.2. 
Study Design ....................................................................................................10
1.2.1. 
Synopsis of Study Design ..................................................................10
1.2.2. 
Randomization Methodology.............................................................13
1.2.3. 
Stopping Rules and Unblinding.........................................................13
1.2.4. 
Study Procedures ...............................................................................14
1.2.5. 
Efficacy, Pharmacokinetic, and Safety Endpoints.............................21
1.2.5.1. Efficacy Endpoints..............................................................21
1.2.5.2. Pharmacokinetic Endpoints.................................................21
1.2.5.3. Safety Endpoints .................................................................21
2. 
Analysis Populations ...................................................................................................23
2.1. 
Population Definitions ....................................................................................23
2.2. 
Protocol Violations..........................................................................................23
3. 
General Statistical Methods .......................................................................................25
3.1. 
Sample Size Justification................................................................................25
3.2. 
General Methods.............................................................................................25
3.3. 
Computing Environment................................................................................25
3.4. 
Baseline Definitions.........................................................................................25
3.5. 
Methods of Pooling Data ................................................................................26
3.6. 
Adjustments for Covariates ...........................................................................26
3.7. 
Multiple Comparisons/Multiplicity...............................................................26
 


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Section
Page
3.9.
Withdrawals, Dropouts, Loss to Follow-up..................................................27
3.10. Missing, Unused, and Spurious Data ............................................................27
3.11. Visit Windows..................................................................................................29
3.12. Interim Analyses .............................................................................................29
4. 
Study Analyses .............................................................................................................30
4.1. 
Subject Disposition..........................................................................................30
4.2. 
Demographics and Baseline Characteristics ................................................30
4.3. 
Efficacy Evaluation.........................................................................................30
4.3.1. 
Primary Estimand...............................................................................30
4.3.2. 
Analysis of the Primary Efficacy Endpoint .......................................31
4.3.3. 
Analysis of Secondary Efficacy Endpoints........................................32
4.3.3.1. Change from Baseline in PANSS Positive Score at Week 
5 ..........................................................................................33
4.3.3.2. Change from Baseline in PANSS Negative Score at Week 
5 ..........................................................................................33
4.3.3.3. Change from Baseline in PANSS Negative Marder Factor 
Score at Week 5 ..................................................................34
4.3.3.4. Change from Baseline in CGI-S Score at Week 5..............35
4.3.3.5. Percentage of PANSS Responders at Week 5.....................35
4.3.4. 
Sensitivity Analyses...........................................................................35
 
 
 
 
 
 
4.5. 
Pharmacokinetic Evaluations ........................................................................38
4.6. 
Safety Analyses................................................................................................38
4.6.1. 
Study Drug Exposure and Treatment Compliance ............................38
4.6.2. 
Spontaneous Adverse Events.............................................................38
4.6.3. 
Simpson-Angus Scale ........................................................................39
4.6.4. 
Barnes Rating Scale for Akathisia .....................................................39


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Section
Page
4.6.5. 
Abnormal Involuntary Movement Scale (AIMS) ..............................40
4.6.6. 
Body Weight, Body Mass Index, Waist Circumference....................40
4.6.7. 
Orthostatic Vital Signs.......................................................................40
4.6.8. 
Laboratory Data .................................................................................40
4.6.9. 
Electrocardiograms ............................................................................42
4.6.10. 
Physical Examination.........................................................................42
4.6.11. 
Columbia-Suicide Severity Rating Scale...........................................42
4.6.12. 
Prior and Concomitant Medications ..................................................42
 
4.6.14. 
Mini International Neuropsychiatric Interview (MINI) Version 
7.0.2....................................................................................................43
 
 
 
7. 
References ....................................................................................................................48


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TABLES INCLUDED IN THE TEXT
Page
Table 1 
Study Design ...................................................................................................................12 
Table 2 
Schedule of Assessments.................................................................................................16 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AIMS 
Abnormal Involuntary Movement Scale 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomic therapeutic chemical class 
AUC 
Area under the concentration versus time curve 
BARS 
Barnes Akathisia Rating Scale 
BID 
Twice daily 
BMI 
Body Mass Index 
 
 
C-SSRS 
Columbia Suicide Severity Rating Scale 
Cmax 
Maximum plasma concentration 
CGI-S 
Clinical Global Impression‒Severity 
CI 
Confidence interval 
CRF 
Case report form 
CSR 
Clinical study report 
DILI 
Drug induced liver injury 
DSM-5 
Diagnostic and Statistical Manual‒Fifth Edition 
ECG 
12-lead electrocardiogram 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISMC 
Independent Safety Monitoring Committee 
ITT 
Intent-to-treat 
IWRS 
Interactive web response system 
LOCF 
Last observation carried forward 
LS 
Least Squares 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
MMRM 
Mixed Model Repeated Measures 
mITT 
Modified Intent-to-Treat 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
PANSS 
Positive and negative syndrome scale 
PK 
Pharmacokinetic 
PMM 
Pattern Mixture Models 


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Abbreviation
Definition
PP
Per-Protocol
PT
Preferred term
SAP
Statistical analysis plan
SD
Standard deviation
SE
Standard error
SNP
Single nucleotide polymorphism
SOC
System organ class
TEAE
Treatment-emergent adverse event
Tmax
Time to maximum plasma concentration
WBC
White blood cell (count)


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1.
INFORMATION FROM THE STUDY PROTOCOL 
1.1.
Introduction and Objectives
1.1.1.
Introduction
This document presents the statistical analysis plan (SAP) for Study KAR-007, A Phase 3, 
Randomized, Double-blind, Parallel-group, Placebo-controlled, Multicenter Study to Evaluate 
the Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Adults with Diagnostic and 
DSM-5) Schizophrenia. This SAP is based upon protocol 
version 1.4 dated 09 August 2021.
This SAP is designed to outline the methods to be used in the analysis of study data in order to 
answer the study objectives. Populations for analysis, data handling rules, statistical methods, 
and formats for data presentation are provided. The statistical analyses and summary tabulations 
described in this SAP will provide the basis for the results sections of the clinical study report 
(CSR) for this study.
In addition, the SAP is intended to clarify many of the details of the more limited discussion in 
the statistical section of the protocol. Therefore, the SAP will expand on and may modify the 
plans outlined in the study protocol. If changes are made to the plans outlined in the protocol, 
the SAP will supersede the relevant contents of the protocol.
1.1.2.
Study Objectives
1.1.2.1.
Primary Objective
The primary objective of the study is to evaluate the efficacy of KarXT 125/30 (125 mg
xanomeline, 30 mg trospium) twice daily (BID) versus placebo in reducing Positive and 
Negative Syndrome Scale (PANSS) total scores in adult inpatients with a DSM-5 diagnosis of 
schizophrenia.
1.1.2.2.
Secondary Objectives
The secondary objectives of the study are:
To evaluate the reduction of PANSS positive score in subjects treated with KarXT 
versus placebo
To evaluate the reduction of PANSS negative score in subjects treated with KarXT 
versus placebo
To evaluate the reduction of PANSS Marder Factor negative symptoms score in subjects 
treated with KarXT versus placebo
To evaluate the improvement in 
(CGI-S) results in
subjects treated with KarXT versus placebo


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To evaluate the percentage of subjects seeing a 30% reduction in PANSS total score in 
subjects treated with KarXT versus placebo
To evaluate the safety and tolerability of KarXT
To assess the pharmacokinetics (PK) of xanomeline and trospium after administration of 
KarXT in adults who are acutely psychotic with a DSM-5 diagnosis of schizophrenia
 
 
 
1.2.
Study Design
1.2.1.
Synopsis of Study Design
This is a Phase 3, randomized, double-blind, parallel-group, placebo-controlled, multicenter, 
inpatient clinical study in adults who are acutely psychotic with a DSM-5 diagnosis of 
schizophrenia, designed to test the hypothesis that treatment with KarXT will result in
significantly greater reduction (ie, improvement) in PANSS total score at Week 5 from baseline 
compared with placebo. Total study duration is up to 8 weeks, including a 7-day screening 
phase (up to a 7-day extension of the screening phase is allowed, if necessary), a 5 week 
treatment period, and a  7-day follow-up period (only for subjects who do not rollover to KAR-
008 study). Subjects completing this study will have the option of rolling over into a long-term 
open-label study (KAR-008) in which every subject will receive KarXT.
Screening Period:
Screening of subjects will take place in 7 days or less before Day -1 (Days -8 to -2). Up to a 7-
day extension of the screening time is allowed, if necessary.
Treatment Period:
In the treatment period, all subjects assigned to KarXT will start on a lead-in dose of KarXT 
50/20 (xanomeline 50 mg/trospium 20 mg) BID for the first 2 days (Days 1 and 2) followed by 
KarXT 100/20 (xanomeline 100 mg/trospium 20 mg) BID for the remainder of Week 1 (Days 3 
to 7). On Day 8, dosing will be titrated upwards to KarXT 125/30 BID unless the subject is 
continuing to experience adverse events (AEs) from the previous dose of KarXT 100/20 BID. 


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All subjects who are increased to KarXT 125/30 BID, depending on clinical response and 
tolerability, will have the option to return to KarXT 100/20 BID for the remainder of the 
treatment period. Dosing must not change after Visit 7 (Day 21) of the study and may be 
decreased for tolerability reasons no more than once during the study. In addition, dose 
escalation to KarXT 125/30 BID may not occur outside of the permitted visit window for Visit 
5/Day 8.
Safety Follow-up Period:
A safety follow-up visit (Visit 11/Day 42 + 5 days) will be performed for all those subjects who 
do not rollover into the long-term open label study KAR-008.
Table 1 presents the study design.




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The last dose of study drug will be administered the morning of Visit 10.


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1.2.2.
Randomization Methodology
On Day -1, all eligible subjects will be randomly assigned in a 1:1 ratio to either KarXT or 
placebo groups. Up to 246 subjects are planned to be randomized (123 per group).
Randomization will be stratified by site. Although the randomization will target balance by site, 
this does not guarantee balance overall; however, with sufficient sample size within each site, 
balance should be maintained.
Subjects will be assigned a randomization number through the interactive web response system 
(IWRS) in accordance with the randomization code generated by the authorized personnel at 
At the study site, the randomization schedule will only be accessible to authorized 
unblinded pharmacy personnel or designee. Once a randomization number is allocated to one 
subject, it may not be assigned to another subject even if the former discontinued the study.
 will generate and maintain the security of the randomization code.
1.2.3.
Stopping Rules and Unblinding
The availability of any new adverse safety information related to KarXT may result in stopping 
of the study. An Independent Ethics Committee (IEC) / Institutional Review Board (IRB) or the 
Sponsor either on its own or on the recommendation of the Independent Safety Monitoring 
Committee (ISMC), may take such actions. An investigator may take such actions at their own 
site.
The safety and tolerability aspects of KarXT will be overseen by an Independent Safety 
Monitoring Committee (ISMC). The ISMC will meet periodically and review the unblinded data 
and will be responsible for advising the sponsor on ways to safeguard the interests of the clinical 
study subjects. The committee may recommend to the Sponsor whether to:
a.
Continue the clinical study without modification
b. Continue the clinical study with modification
c.
Terminate the study
At a subject level, based on National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI-CTCAE]
Grade 4 AE. 
 
In the event that emergency unblinding is required for a given subject because of AEs or 
code for just that subject via the IWRS, by which system the unblinding will be captured after 
consultation and agreement with the medical monitor/Sponsor. The unblinding and its cause will 


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also be documented in the electronic case report form (CRF). Otherwise, unblinding according 
to the protocol will occur only after completion of the study.
1.2.4.
Study Procedures
The schedule of assessments, as outlined in the study protocol, is provided in Table 2.










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screening and at Visit 2a (baseline). If a subject leaves the study site, they should have a urine drug screen and test for alcohol (breathalyzer or urine alcohol level) 
upon returning to thestudy site.
A complete physical examination includes body temperature (°C), general appearance, head/eyes/ears/nose/throat, examination of thorax and abdomen, 
assessment of cardiac, musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited neurological examination.
AEs as reported by subjects or observed by clinical staff and occurs from Day -1. One PK blood sample may be drawn if a relevant/significant AE (based on 
medical judgement) is reported during a scheduled visit or if there is a dose adjustment or a relevant/significant AE reported during an unscheduled visit (no
multiple draws).
Vital signs taken supine and standing after 2 minutes. BP includes systolic and diastolic BP and is to be taken in the same arm for the duration of the study. Heart 
rate is measured in beats/minute. During treatment, beginning with Day 1, orthostatic vital signs should occur 2 (±1) hours after morning dosing. Orthostatic vital 
signs are only required after the morning dose of the specified visit days, but additional orthostatic vital sign monitoring 
It would be acceptable, for example, to do orthostatic vital signs BID after dosing increases for a day or 2 for subjects where it seems warranted, but this should 
not be done automatically.
ECG on Day 1 will be done at 2 hours + 15 minutes post morning dose. ECGs at all other scheduled visits will be performed before blood withdrawal for any safety 
laboratory tests and/or PK analysis. During the ECG, ventricular rate (bpm), PR (msec), QRS (msec), QT (msec), and QTcF (msec) measurements should be 
obtained.
Refer to protocol Table 3 for individual laboratory tests. For urinalysis, a urine dipstick will be performed at the site and the sample will be sent to central lab in case 
of abnormalities.
Optional COVID-
antibody, and HIV-2 antibody. If the subject tests positive for anti-HCV antibody, then HCV RNA via polymerase chain reaction should be performed to 
confirm or rule out active infection.
If an eligible subject is not already an inpatient, the subject should be admitted to the inpatient unit.
Starting on Day 1, study drug is administered daily BID (first dose of study will be administered in the morning of Day 1, and evening dose will be administered 
12 ± 0.5 hours after the morning dose and after last PK sampling [for Visits 5 and 8] is completed), on an empty stomach ie, at least 1 hour before a meal or 2 to 3 
hours after a meal by the study staff, with the last dose administered on the morning of Visit 10. All subjects must receive at least 4 dosages of the 50/20 BID 
before dose escalation to KarXT 100/20 BID.
For Visit 5/Day 8 and Visit 8/Day 28, 7 PK blood draws are required: before the morning dose, and at 0.5 hour ± 5 minutes, 1 hour ± 5 minutes, 2 hours ± 10 
minutes, 4 hours ± 10 minutes, 8 hours ± 10 minutes, and 12 hours ± 10 minutes after the morning dose (Note: The 12-hour samples must be collected before 
administration of the evening dose). PK blood draws at Visit 5 must be drawn in relation to the first dose of KarXT 125/30 for subjects who are escalated in the 


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morning of Visit 5/Day 8 -1/+2 days. PK blood must also be drawn in relation to the morning dose for subjects who are not escalated at Visit 5/Day 8 -1/+2 days. 
For Visit 10/ET, a single PK blood sample should be drawn before discharge (preferably in the morning after the last dose of the study drug). One PK blood 
sample may also be drawn if a relevant/ significant AE is reported during a scheduled visit or if there is a dose adjustment or a relevant/significant AE reported 
during an unscheduled visit (no multiple draws). For an ET Visit that is related to an AE, the collection of a PK blood sample is not optional and should be drawn 
before discharge.
MINI should be performed before PANSS assessment.
It is recommended, if at all possible, that the PANSS assessment should be performed before all the other scale assessments (except MINI) for all visits at 
which it is performed. The PANSS assessment includes the Marder Factor.
C-SSRS first time use lifetime, other times use
Last
version. At the Unscheduled visit, the C-SSRS should be performed to monitor subjects for
suicidality.
There must be no changes in dose for at least 7 days leading up to Visit 8.
Safety follow-up visit will be performed 1 week (Day 42 +5 days) after Visit 10/ET for subjects who do not rollover in to the long-term open-label study 
KAR-008.
Study staff should discuss KAR-008 protocol participation with potential subjects prior to the final day of participation in the acute study, via use of the provided 
recruitment materials.


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1.2.5.
Efficacy, Pharmacokinetic, and Safety Endpoints
1.2.5.1.
Efficacy Endpoints
The primary efficacy endpoint is change from baseline in PANSS total score at Week 5.
The secondary efficacy endpoints are:
Change from baseline in PANSS positive score at Week 5
Change from baseline in PANSS negative score at Week 5
Change from baseline in PANSS Negative Marder Factor score at Week 5
Change from baseline in CGI-S score at Week 5
Percentage of PANSS responders (at least 30% reduction in PANSS total score) at 
Week 5
1.2.5.2.
Pharmacokinetic Endpoints
The pharmacokinetic endpoints are:
Area under the plasma concentration-time curve (AUC)
Maximum observed plasma concentration (Cmax)
Time to maximum observed plasma concentration (Tmax)
Blood samples for PK analysis of KarXT levels will be collected at the time points indicated in 
the Schedule of Assessments (Table 2). Pharmacokinetic parameters to be determined include 
Cmax, Tmax, and AUC from 0 to 12 hours (or from 0 to the last measurable concentration). 
Additional parameters (not limited to the following) such as the elimination half-life, clearance, 
and volume of distribution will be determined if the data permit.
1.2.5.3.
Safety Endpoints
The safety endpoints are:
Spontaneously reported AEs including adverse events of special interest (AESIs)
Spontaneously reported procholinergic and anticholinergic symptoms
Simpson-Angus Scale
Barnes Akathisia Rating Scale (BARS)


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Abnormal Involuntary Movement Scale (AIMS)
Body weight, body mass index (BMI), waist circumference
Orthostatic vital signs (supine and standing after 2 minutes): blood pressure (systolic and 
diastolic) and heart rate
Clinical laboratory evaluations: hematology, clinical chemistry, coagulation, urinalysis, 
and drug screen
12-lead electrocardiogram (ECG)
Physical examination
Suicidal ideation scale with the use of the Columbia Suicide Severity Rating Scale 
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2.
ANALYSIS POPULATIONS 
2.1.
Population Definitions
The following analysis populations will be evaluated and used for presentation and analysis of 
the data:
Intent-to-Treat (ITT) Population: All subjects who are randomized to the study will be 
included in the ITT population.
Modified ITT (mITT) Population: All subjects who are randomized, received at least 1 dose 
of study drug, have a baseline PANSS assessment, and at least 1 post-baseline PANSS 
assessment will be included in the mITT population and will be used in the efficacy 
analysis.
Completer Population: All mITT subjects who have a valid PANSS total score at Week 5. 
The Completer population will be used for a sensitivity analysis of the primary efficacy 
endpoint.
Per-Protocol Population (PP): All subjects who were randomized, received at least one dose 
of study medication, have a baseline and at least one post-baseline PANSS assessment, and 
have no major protocol deviations. The PP population will be used for a sensitivity analysis 
of the primary efficacy endpoint.
Safety Population: All subjects who received at least 1 dose of study drug will be included 
in the safety population and will be used in the safety analysis.
PK Population: All subjects who have an evaluable PK profile will be included in the PK 
population and will be used in the PK analysis. Subjects must have received at least 1 dose 
of active study drug and have at least 1 measurable plasma concentration of study drug.
The mITT population is the primary population for the analysis of efficacy parameters. The PK
population is the primary population for the analysis of PK parameters. The Safety population is 
the primary population for the analysis of safety parameters. Efficacy analyses will be 
conducted based on treatment as randomized while safety analyses will be conducted based on 
treatment received.
2.2.
Protocol Violations
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 CSR.
Reporting of protocol deviations to the IEC/IRB and in accordance with applicable regulatory 
All protocol deviations will be tracked in the Clinical Trial Management System. Deviations 
considered major will be identified as such before study unblinding during medical monitor 
periodic review. Major protocol deviations will be tabulated including the frequency and 


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percentage of subjects with each type of deviation by treatment group for the ITT population.
All protocol violations will be presented in a data listing.


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3.
GENERAL STATISTICAL METHODS 
3.1.
Sample Size Justification
Assuming treatment difference of change from baseline in PANSS total score at Week 5 is 8 
points between KarXT and placebo (standard deviation 16), a sample size of approximately 172 
(86 evaluable subjects per arm) will result in a power of 90.3% for a 2-
0.05). With a dropout rate of 30%, a total of 246 subjects are estimated to be enrolled.
3.2.
General Methods
All data listings that contain an evaluation date will contain a relative study day (Rel Day).  Pre-
treatment and on-treatment study days are numbered relative to the day of the first dose of study 
medication which is designated as Day 1.  The preceding day is Day -1, the day before that is 
Day -2, etc.  
All output will be incorporated into Microsoft Word or Excel files, or Adobe Acrobat PDF files, 
sorted and labeled according to the International Council for Harmonisation (ICH) 
recommendations, and formatted to the appropriate page size(s).
Tabulations will be produced for appropriate demographic, baseline, efficacy, pharmacokinetic, 
and safety parameters.  For categorical variables, summary tabulations of the number and 
percentage of subjects within each category of the parameter will be presented.  For continuous 
variables, the number of subjects, mean, median, standard deviation (SD), minimum, and 
maximum values will be presented.  
Formal statistical hypothesis testing will be performed on the primary and secondary efficacy 
endpoints with all tests conducted at the 2-sided, 0.05 level of significance. Summary statistics 
will be presented, as well as the confidence intervals (CIs) on selected parameters, as described 
in sections below.
3.3.
Computing Environment
Unless otherwise noted, all descriptive statistical analyses will be performed using 
 
. Medical history 
and AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA)
Version 23.1 or higher. Concomitant medications will be coded using the World Health 
Organization Drug Dictionary version March 2018 or newer. CDISC database will conform to 
SDTM Implementation Guide 3.2 and ADaM Implementation Guide 1.1
3.4.
Baseline Definitions
For all analyses, baseline will be defined as the most recent measurement prior to the first 
administration of study drug. If multiple values are present for the same date, the values from 
the last assessment will be used as the baseline unless otherwise specified.


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3.5.
Methods of Pooling Data
For analyses not stratified by site, data from all study centers will be combined. For analyses 
stratified by site, study centers with two or fewer subjects of any treatment group will be pooled
3.6.
Adjustments for Covariates
The analysis of the primary and continuous secondary efficacy endpoints will be adjusted for 
site, age, and gender (male versus female). Sites may be pooled as noted in the previous section. 
Details are provided in the relevant efficacy analysis section. 
3.7.
Multiple Comparisons/Multiplicity
In order to account for multiplicity, the Sponsor has pre-specified a step-down procedure 
(hierarchical order of testing) to control the overall Type-1 error rate across all primary and 
secondary efficacy endpoints. The secondary endpoints are presented according to the Sponsor-
specified hierarchical order in Section 4.3.3.


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3.9.
Withdrawals, Dropouts, Loss to Follow-up
Subjects who are withdrawn or discontinue from the study will not be replaced.
3.10.
Missing, Unused, and Spurious Data
Several different methods to handle the missing data in the primary efficacy endpoint 
analysis may be used.
For the primary efficacy analysis, a likelihood-based modeling approach will be 
used to handle incomplete data. For this purpose an MMRM will be applied.


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Sensitivity analysis for the primary efficacy endpoint will be conducted using the 
last observation carried forward approach (LOCF). In this analysis, the missing 
values will be replaced by the last available PANSS total score carried forward.
Sensitivity analysis for the primary efficacy endpoint will be conducted using the 
Multiple Imputation approach (ie, by replacing each missing value with a set of 
plausible values that represent the uncertainty about the right value to impute).
When tabulating AE data, partial dates will be handled to more accurately determine 
whether an event was treatment-emergent.
AE start dates that are missing or incomplete will be handled as follows:
(1) Missing Day Only
If the month and year are the same as the month and year of the first dose 
date, the first dose date will be used.
If the month and year are before the month and year of the first dose date, 
the last day of the month will be assigned to the missing day.
If the month and year are after the month and year of the first dose date, the 
first day of the month will be assigned to the missing day.
(2) Missing Day and Month
If the year is the same as the year of the first dose date, the first dose date 
will be used.
If the year is prior to the year of the first dose date, December 31 will be 
assigned to the missing fields.
If the year is after the year of first dose date, January 1 will be assigned to 
the missing fields.
(3) Missing Day, Month, and Year
The first dose date will be used.
If the stop date is non-missing and the imputed start date is after the reported stop date, the 
stop date will be used as the start date. If the stop date is missing and the imputed start date 
ontinuation will be used.
AE stop dates that are missing or incomplete will be handled as follows:
(1) Missing Day Only
The last day of the month will be assigned as the missing day.


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(2) Missing Day and Month
December 31 will be assigned to missing fields. 
(3) Missing Day, Month, and Year
The event will be regarded as ongoing.
If the start date is non-missing and the imputed stop date is before the start date, the start 
date will be used. If the death date is available and the imputed stop date is after the death 
date, the death date will be used.
3.11.
Visit Windows
All data will be tabulated per the evaluation visit as recorded on the CRF, even if the assessment 
is outside of the visit window. If the evaluation visit is missing in the database but there is data 
from an unscheduled or additional visit that is inside the visit window, the data from the 
unscheduled or additional visit will be used in data summaries. Note, if the circumstance arises 
where an unscheduled or additional visit falls within two separate nominal visit windows (see 
for Example Day 7 and Day 8 in the Schedule of Assessments), the unscheduled or additional 
visit will be considered for the earlier of the two nominal visits.
3.12.
Interim Analyses
No interim analysis is planned for this study.


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4.
STUDY ANALYSES 
4.1.
Subject Disposition
Subject disposition will be tabulated and will include the number screened, the number 
randomized, the number treated in total, the number dosed with KarXT, the number dosed with 
placebo, the number in each analysis population, the number of subjects who completed 
treatment, and the number who withdrew prior to completing treatment and reason(s) for 
withdrawal. Subject disposition will be summarized by treatment and overall.
A by-subject data listing of study completion information including the reason for premature 
study withdrawal, if applicable, will be presented. Subject disposition will include all patients 
screened.
4.2.
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized and presented by treatment 
group and overall.  Age, height, weight, and BMI at baseline will be summarized using 
descriptive statistics (number of subjects, mean, SD, median, minimum, and maximum).  The 
number and percentage of subjects in each gender, ethnicity, race category, and child-bearing 
potential status will also be presented. Subject demographics and baseline characteristics will be 
summarized for each of the ITT, mITT, and Safety populations. Subject demographics and 
baseline characteristics will also be presented in by-patient listings.
Medical history will be summarized in a table by MedDRA System Organ Class (SOC) and 
Preferred Term (PT) by treatment group and overall for the ITT population. A by-patient listing 
of medical history will also be provided.
4.3.
Efficacy Evaluation
4.3.1.
Primary Estimand
The primary clinical question of interest is: What is the treatment effect of KarXT vs 
placebo at Week 5 on the change from baseline in PANSS total score in qualified 
subjects as defined in entry criteria, regardless of treatment discontinuations for any 
reason?
The population of the primary estimand is among adult inpatients (aged 18-65 years) with a 
DSM-5 diagnosis of schizophrenia, confirmed by MINI for schizophrenia, who are acutely 
psychotic and hospitalized with PANSS score of 80 to 120 at time of enrollment, defined 
according to the inclusion/exclusion criteria. Subjects will receive flexible dose KarXT, 
whereby a subject receiving 100/20 (xanomeline 100mg/trospium 20 mg) may be titrated 
upwards to KarXT 125/30 on Day 8. All subjects who are increased to 125/30 BID will have the 
option to return to KarXT 100/20, but may not change their dose after Visit 7 (Day 21) nor 
decrease their dose for tolerability reasons more than once. The primary analysis will be 


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executed on the mITT population, including all subjects with a baseline and at least one post-
baseline PANSS measurement, grouped as randomized.
The variable is the change from baseline in PANSS total score at Week 5.  
Intercurrent events:
Discontinuation from study treatment prior to the completion of the 5 weeks of efficacy 
assessments: Hypothetical strategy assuming subjects that discontinue study treatment 
prior to study discontinuation would follow the same trend as subjects who continued 
and remained in the study for the full 5 weeks. Data collected up to the point of
treatment discontinuation will be included in the analysis.
Use of concomitant medication for anxiety and/or sleep aid: Treatment policy strategy 
where results will be used regardless of concomitant medications for anxiety and/or 
sleep aid as is customary in trials of acute Schizophrenia.
The population level summary is the difference between treatment groups (KarXT vs placebo) 
in mean change from baseline in PANSS at Week 5, obtained from a mixed model with repeated 
measures (MMRM).
Robustness of the estimand will be assessed through sensitivity analyses using alternative 
methods for handling of missing data and accounting for use of concomitant medications for 
anxiety and/or sleep aid (e.g. subgroup by use of concomitant medication).
4.3.2.
Analysis of the Primary Efficacy Endpoint
The PANSS is a medical scale used for measuring symptom severity of subjects with 
schizophrenia and is widely used in the study of antipsychotic therapy. The PANSS rating form 
contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology 
symptom scales. Subjects are rated from 1 to 7 on each symptom scale. The positive symptoms 
in schizophrenia are the excess or distortion of normal function such as hallucinations, 
delusions, grandiosity, and hostility, and the negative symptoms in schizophrenia are the 
diminution or loss of normal functions. PANSS total score is the sum of all 30 items with a 
minimum score of 30 and a maximum score of 210. Higher scores indicate more severe 
symptoms. If a patient has a PANSS assessment recorded, but any of the 30 items are missing,
that value will be imputed with the average of the non-missing items with a given domain as 
follows:
If no more than 2 items are missing from the PANSS positive scales, then the PANSS Positive 
Score will be calculated as the average of the non-missing items multiplied by 7.
Similarly, if no more than 2 items are missing from the PANSS negative scales, then the PANSS 
Negative Score will be calculated as the average of the non-missing items multiplied by 7.
If no more than 4 items are missing from the general psychopathology symptom scales, then the 
score will be calculated as the average of the non-missing items multiplied by 16.


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The PANSS Total Score is then the sum of the positive, negative and general psychopathology 
symptom scores.
If any of the above thresholds for calculating the PANSS Positive Score, PANSS Negative 
Score, or the general psychopathology symptom scales (> 30% of the items missing in a given 
domain at a particular visit), the respective total score at the visit will not be calculated and will 
be treated as missing data.
The primary efficacy endpoint of the study is the change from baseline in PANSS total score at 
Week 5. The difference between KarXT and placebo at Week 5 will be estimated using 
MMRM. The model will include the change from baseline PANSS total scores at Week 2, Week 
3, Week 4, and Week 5 as the response. The treatment difference at Week 5 will be estimated 
using contrasts. The MMRM will include the treatment group (KarXT or placebo), visit, and the 
interaction between the treatment group and visit as fixed factors. Site, age, gender, and baseline 
PANSS total score will be used as covariates in the model. Low enrolling sites will be pooled as 
outlined in Section 3.5.
An unstructured covariance structure will be utilized for the MMRM analysis. The denominator 
degrees of freedom will be computed using the Kenward-Roger method. In the event that the
model does not converge with the unstructured covariance structure, the sandwich variance 
estimator in combination with the following covariance structures will be attempted in the 
following, pre-specified order: heterogeneous Toeplitz structure (TOEPH), heterogeneous 
compound symmetry (CSH). 
The least squares (LS) mean, standard error (SE), and LS mean difference between KarXT and 
placebo group at Week 5 along with the 95% CI will be provided. The p-value for the 
hypothesis testing will also be provided. Treatment difference will be assessed with a 2-sided
alpha level of 0.05.  
Observed values and change from baseline in PANSS total score will also be summarized by 
visit. LS mean, SE, 95% CI, and p-value for LS mean difference from the primary MMRM will
also be provided for Week 2, Week 3, and Week 4.
The mITT population will be used for the primary efficacy analysis. Observed and change from 
baseline PANSS total score will also be summarized by treatment group and visit for the mITT 
population using descriptive statistics. 
Estimated mean change from baseline PANSS total score will be graphed by treatment group 
and visit. The x-axis will include the week (Week 2, Week 3, Week 4, Week 5) and the y-axis 
will represent change from baseline. LS means estimates and associated standard error bars 
from the primary MMRM will be used for the display.
Sensitivity analyses will be performed as outlined in Section 4.3.4.
A by-patient listing will also be provided.


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4.3.3.
Analysis of Secondary Efficacy Endpoints
Statistical testing will be performed on the secondary efficacy endpoints according to the 
following hierarchical order:
1) Change from baseline in PANSS positive score at Week 5
2) Change from baseline in PANSS negative score at Week 5
3) Change from baseline in PANSS Negative Marder Factor score at Week 5
4) Change from baseline in CGI-S score at Week 5
5) Percentage of PANSS responders (at least 30% reduction in PANSS total score) at Week 
5
The efficacy tests will stop if the previous test shows no statistical significance in favor of 
KarXT at the alpha level of 0.05.
4.3.3.1.
Change from Baseline in PANSS Positive Score at Week 5
PANSS positive score is the sum of all PANSS 7 positive symptom scales with a minimum 
score of 7 and a maximum score of 49. If a patient has a PANSS assessment recorded and no
more than 2 items are missing from the PANSS positive scales, then the PANSS Positive Score 
will be calculated as the average of the non-missing items multiplied by 7. If 3 or more items are
missing (> 30%) at a particular visit, the respective positive score at the visit will not be 
calculated and will be treated as missing data.
The PANSS positive score will be analyzed using a model similar to the MMRM used for the 
primary endpoint. 
The model will include the observed change from baseline PANSS positive score at Week 2, 
Week 3, Week 4, and Week 5 as the response. The MMRM will include the treatment group 
(KarXT or placebo), visit, and the interaction between the treatment group and visit as fixed 
factors. Baseline PANSS positive score, site, age, and gender will be used as covariates in the 
model.
Observed and change from baseline PANSS positive scores will be summarized descriptively by 
treatment group and visit for the mITT population.
Estimated mean change from baseline PANSS positive score will be graphed by treatment group 
and visit. The x-axis will include the week (Week 2, Week 3, Week 4, Week 5) and the y-axis 
will represent the change from baseline. LS means estimates from the MMRM will be used for 
the display.


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4.3.3.2.
Change from Baseline in PANSS Negative Score at Week 5
PANSS negative score is the sum of all PANSS 7 negative symptom scales with a minimum 
score of 7 and a maximum score of 49. If a patient has a PANSS assessment recorded, and no
more than 2 items are missing from the PANSS negative scales, then the PANSS Negative 
Score will be calculated as the average of the non-missing items multiplied by 7. If 3 or more 
items are missing (> 30%) at a particular visit, the respective negative score at the visit will not 
be calculated and will be treated as missing data. 
The PANSS negative score will be analyzed using a model similar to the MMRM used for the 
primary endpoint. 
The model will include the observed change from baseline PANSS negative score at Week 2, 
Week 3, Week 4, and Week 5 as the response. The MMRM will include the treatment group 
(KarXT or placebo), visit, and the interaction between the treatment group and visit as fixed 
factors. Baseline PANSS negative score, site, age, and gender will be used as covariates in the 
model.
Observed and change from baseline PANSS negative scores will be summarized descriptively 
by treatment group and visit for the mITT population. 
Estimated mean change from baseline PANSS negative score will be graphed by treatment 
group and visit. The x-axis will include the week (Week 2, Week 3, Week 4, Week 5) and the y-
axis will represent the change from baseline. LS means estimates from the MMRM will be used 
for the display.
4.3.3.3.
Change from Baseline in PANSS Negative Marder Factor Score at Week 5
PANSS Marder factor score is the sum of 5 negative scales and 2 general scales (N1. Blunted 
affect; N2. Emotional withdrawal; N3. Poor rapport; N4. Passive/apathetic social withdrawal; 
N6. Lack of spontaneity; G7. Motor retardation; and G16. Active social avoidance).  If a patient 
has a PANSS assessment recorded, but any of the 7 items are missing, that value will be 
imputed with the average of the non-missing items with a given domain as follows:
If no more than 1 item is missing from the considered PANSS negative scales, then the 
sum of the considered PANSS negative scales will be calculated as the average of the 
non-missing items multiplied by 5. 
If 2 or more items are missing (> 30%) from the considered PANSS negative scales or 1 or 
more items are missing (> 30%) from considered general scales at a particular visit, the 
respective PANSS Negative Marder Factor at the visit will not be calculated and will be treated 
as missing data.
The PANSS Marder Factor score will be analyzed using a model similar to the MMRM used for 
the primary endpoint.  


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The model will include the observed change from baseline PANSS negative marder factor score 
at Week 2, Week 3, Week 4, and Week 5 as the response. The MMRM will include the 
treatment group (KarXT or placebo), visit, and the interaction between the treatment group and 
visit as fixed factors. Baseline PANSS negative marder factor score, site, age, and gender will 
be used as covariates in the model.
Observed and change from baseline PANSS Marder factor scores will be summarized 
descriptively by treatment group and visit for the mITT population.
Estimated mean change from baseline PANSS negative marder factor score will be graphed by 
treatment group and visit. The x-axis will include the week (Week 2, Week 3, Week 4, Week 5) 
and the y-axis will represent the change from baseline. LS means estimates from the MMRM 
will be used for the display.
4.3.3.4.
Change from Baseline in CGI-S Score at Week 5
The CGI-S categorizes the severity of the illness as: 1 = Normal, not at all ill; 2 = Borderline 
mentally ill; 3 = Mildly ill; 4 = Moderately ill; 5 = Markedly ill; 6 = Severely ill; and 7 = 
Among the most extremely ill patients. 
CGI-S will be analyzed using a model similar to the MMRM used for the primary endpoint.  
The model will include the observed change from baseline CGI-S score at Week 1, Week 2, 
Week 3, Week 4, and Week 5 as the response. The MMRM will include the treatment group 
(KarXT or placebo), visit, and the interaction between the treatment group and visit as fixed 
factors. Baseline CGI-S score, site, age, and gender will be used as covariates in the model.  
CGI-S scores at Week 5 will also be compared using the Mann-Whitney U (Wilcoxon Rank 
Sum) Test. The results of the Mann-Whitney U (Wilcoxon Rank Sum) Test will not be 
considered for hierarchical testing purposes.
Observed and change from baseline CGI-S scores will be summarized descriptively by 
treatment group and visit for the mITT population.
Estimated mean change from baseline CGI-S score will be graphed by treatment group and visit. 
The x-axis will include the week (Week 2, Week 3, Week 4, Week 5) and the y-axis will 
represent the change from baseline. LS means estimates from the MMRM will be used for the 
display.
CGI-S scores will also be summarized by visit using frequency counts for the mITT population.
In addition, shift tables from Baseline to worst value and at each scheduled post-Baseline visit
will be provided by treatment group. A by-patient listing will also be provided.


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4.3.3.5.
Percentage of PANSS Responders at Week 5
A PANSS responder is defined as a subject with reduction from baseline of at least 30% (at least 
a 30% improvement) at Week 5 in the PANSS total score.
The percent of PANSS responders at each visit will be compared between the treatment groups 
(KarXT and placebo) using the Cochran-Mantel-Haenszel test stratified by site.
Percentage of PANSS responders at each visit will also be graphed by treatment group and visit.
The x-axis will include the visit and the y-axis will represent the percentage of responders.
Since the minimum baseline PANSS total score is not 0 (30 when PANSS rated as 1-7 for each 
item), the response rate based on this score tends to be underestimated. Thus, a floor adjusted 
PANSS total score, defined as the original total score minus 30, will also be used to derive the 
responders. The PANSS responders based on floor adjusted PANSS total score will be analyzed 
and presented using the same methods as described above.
4.3.4.
Sensitivity Analyses
Completer Analysis: 
The primary efficacy analysis will be repeated for the Completer population.  
Per Protocol Analysis: 
The primary efficacy analysis will be repeated for the PP population.
Last Observation Carried Forward (LOCF):
In this analysis, the missing PANSS total scores will be replaced by the most-recent post-
baseline visit assessment values. The values at Week 5 generated via LOCF will be compared 
using an Analysis of Covariance (ANCOVA) model with treatment group as a fixed factor and 
baseline PANSS total score and site will be used as a covariate in the model. This analysis will 
be performed in the mITT population.
Multiple Imputation (MI) Analysis with Missing At Random Assumption:
Multiple Imputation is a broadly applicable technique for handling missing data. Missing data 
are imputed multiple times using a regression method. Each imputed data set is analyzed by the
MMRM model, and the point estimates and standard errors are combined to provide inferences 
that reflect the uncertainty about the missing values. MI will assume that data are missing at 
random (MAR). 
Primary endpoint data that are missing will be multiply imputed separately for each treatment 
arm using a regression procedure within SAS PROC MI, with baseline value, Week 2, Week 3, 
and Week 4 as explanatory variables, and Week 5 as the dependent variable. The regression method 
assumes monotone missingness, such that if a given visit has a missing value, all subsequent 


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visits are missing as well. For non-monotone missing data, the Monte Carlo Markov Chain 
(MCMC) method in PROC MI will be used to impute intermittent missing data so that each 
imputed dataset has a monotone missing pattern. The proportion of non-monotone missing data 
is expected to be very small. One hundred imputed datasets (per treatment arm) will be 
generated from the MCMC method. The regression method is then used to impute missing 
values having a monotone missingness pattern.
Each of the imputed datasets will then be analyzed via the MMRM and the resulting estimates 
(LS means and standard errors) combined using SAS PROC MIANALZYE to produce 
inferential results (difference in LS means, 95% CI for the difference, and the pvalue from the 
test that the difference is zero). Point estimates (LS means and differences) will be calculated as 
the average of the 100 complete-data estimates. A total variance estimate will be calculated as a 
weighted sum of within-imputation variance, which is the average of the complete-data variance 
estimates, and a between-imputation variance term. Complete details may be found in the SAS 
documentation for the MIANALYZE procedure (see Combining Inferences from Imputed Data 
Sets under Details).
http://support.sas.com/documentation/onlinedoc/stat/143/mianalyze.pdf.
Analyses will be conducted using PROC MI and PROC MIANALYZE in SAS 9.4 (or later). 
MI analysis with Missing Not At Random assumption (Placebo group based imputation):  
Another MI analysis will be performed with the assumption that the data is not missing at 
random. Methods similar to the procedure described above will be used in the mITT population. 
However, the missing values will be imputed using Placebo based imputation. Placebo based 
imputation assumes that the trajectories of all subjects are assumed to follow the trajectory of 
those subjects in placebo group.
MI analysis with Missing Not At Random assumption (Tipping point based imputation):
If the primary analysis significantly favors KarXT, another MI analysis may be performed in the 
mITT population with the assumption that the data in the KarXT group is not missing at 
random. A tipping point based assumption will be used, i.e. the trajectories of the subjects in the 
KarXT group after withdrawal are assumed to be worse by a certain amount, delta. After the MI 
using the MAR assumption, as defined above, has been done, the amount, delta, will be added to 
each imputed value in the KarXT group. Successively harsher deltas will be imposed on the 
imputed values in the KarXT group, starting with a PANSS total score increment (worsening) of 
0.5 points. The delta is further increased in subsequent steps of
the statistical significance is lost, i.e. until the p-value becomes >0.05. For the placebo group, 
the MI using MAR assumption will be used.


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4.5.
Pharmacokinetic Evaluations
PK analysis will be conducted by the Sponsor designee and analysis will be specified in another 
document. However, PK results will be listed for all subjects who received active treatment and 
the data will be presented graphically via individual plots and mean plots summarized by actual 
treatment, visit, and timepoint. The profiles or time points obtained with protocol deviations 
affecting PK results will be flagged and may be excluded from summary figures.
4.6.
Safety Analyses
Safety analyses will be conducted using the Safety population.


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4.6.1. 
Study Drug Exposure and Treatment Compliance 
Drug exposure and treatment compliance have previously been seen to have an influence on the 
total PANSS score.  
To get a better understanding of drug exposure, treatment duration in days, cumulative dose 
taken in mg, and the number of subjects experiencing a dose reduction will be summarized by 
treatment group. By-patient listings will also be provided. 
Treatment duration in days will be calculated as the number of days subjects were administered 
study drug as determined below: 
Treatment duration (days) = last treatment date – first treatment date + 1 
To get a better understanding of treatment compliance, the number of planned doses, the 
number of doses actually taken, compliance (%), and the number of doses missed will be 
summarized by treatment group. By-patient listings will also be provided. 
Treatment compliance (%) will be calculated as determined below: 
Compliance (%) = (number of doses taken/number of planned doses)*100 
4.6.2. 
Spontaneous Adverse Events 
All AEs will be coded using the MedDRA coding system and displayed in tables by treatment 
received and in data listings using SOC and PT. AE grade assessment will be based on 
investigator reporting using NCI-CTCAE, version 5.0. 
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
where treatment-emergent is defined as any AE with onset after the administration of study 
medication through the end of the study (28 days after last dose administered), or any event that 
was subsequently considered drug-related by the Investigator through the end of the study. 
The number and percentage of subjects with any treatment-emergent adverse event (TEAE), 
with any TEAE event assessed by the Investigator as related to treatment (definite, probable, or 
possible relationship), with any serious TEAE, with any serious related TEAE, with any TEAE 
leading to study drug withdrawal with any TEAEs, with a NCI-CTCAE grade of 3 or higher, 
with a TEAE leading to dose reduction, and with any TEAE leading to death will be 
summarized by treatment group and overall.   
AESIs will be monitored and will include orthostasis and liver function test elevations inclusive 
of DILI. The number and percentage of subjects with an AESI, with a related AESI, with a 
serious AESI, and with an AESI of NCI-CTCAE grade 3 or higher will be summarized by 
treatment group and overall.  
Procholinergic symptoms (believed to be associated with xanomeline) and anticholinergic 
symptoms (believed to be associated with trospium) will also be identified. The number and 


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percentage of subjects with treatment-emergent procholinergic and anticholinergic symptoms 
will also be summarized by treatment group and overall. 
In these tabulations, each subject will contribute only once (i.e., the most related occurrence or
the most intense occurrence) to each of the incidence rates in the descriptive analysis, regardless 
of the number of episodes.
All AEs occurring on-study will be listed in by-patient listings. Listings will also be provided 
for the following: drug product related TEAEs, Serious TEAEs, drug product related serious 
TEAEs, TEAEs leading to study drug withdrawal, events of special interest, procholinergic 
symptoms, anticholinergic symptoms, and deaths.
4.6.3.
Simpson-Angus Scale
The Simpson-Angus Scale is an established instrument to measure drug-related extrapyramidal 
syndromes. It is a 10-item testing instrument used to assess gait, arm dropping, shoulder 
shaking, elbow rigidity, wrist rigidity, leg pendulousness, head dropping, glabella tap, tremor, 
and salivation. The range of scores is from 0 to 40 with increased scores indicating increased 
severity.
Observed and change from baseline Simpson-Angus Rating Scale total score, subscale score 
[Simpson-Angus Rating Scale Total Score (Excluding Item 10)], and individual item scores will 
be summarized by treatment group and visit for the Safety population. A by-patient listing will 
be provided.
4.6.4.
Barnes Rating Scale for Akathisia
The Barnes Rating Scale for akathisia is a rating scale used to assess the severity of drug-
induced akathisia, or restlessness, involuntary movements and inability to sit still. The range of 
scores is 0 to 14, with higher scores indicating greater severity. 
Observed and change from baseline BARS and the four individual scores will be summarized 
by treatment group and visit for the Safety population. A by-patient listing will be provided.
4.6.5.
Abnormal Involuntary Movement Scale (AIMS)
The AIMS is a rating scale that is used to measure involuntary movements known as tardive 
dyskinesia, which can sometimes develop as a side effect of long-term treatment with 
antipsychotic medications. It is a 12-item scale to assess orofacial, extremity, and truncal 
movements as well as the overall severity, incapacitati
of the movements. Items are scored from 0 (none) to 4 (severe). A higher score indicates more 
severe dyskinesia. 
Observed and change from baseline for AIMS total score (items 1-7, observed movements),
Item 8 (overall severity index), Item 9 (incapacitation), and Item 10 (awareness) will be 
summarized by treatment group and visit for the Safety population. A by-patient listing for all 
items will be provided.


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4.6.6.
Body Weight, Body Mass Index, Waist Circumference
Observed, change from baseline, and percentage change from baseline in body weight as well as 
the percentage of subjects who have gained or lost weight (+/- 7 percent from baseline body 
weight) will be summarized by treatment group and visit.
BMI, and waist circumference will be summarized by treatment group and visit. Male subjects 
with a waist circumference of greater than 102 cm and female subjects with a waist 
circumference of greater than 88 cm will also be summarized by treatment group and visit. 
By-subject listings will be provided.
4.6.7.
Orthostatic Vital Signs
Observed and change from baseline in orthostatic vital signs (systolic blood pressure, diastolic 
blood pressure, and heart rate) will be summarized by treatment group, position (supine, 
standing) and visit. The difference between supine and standing measurements will also be 
summarized. A by-subject listing will be provided.
4.6.8.
Laboratory Data
Clinical laboratory values will be presented using the International System of Units (SI). Values 
will be normalized against normal ranges from a common source (US National Library of 
Medicine [NLM], MedlinePlus) as outlined in Section 6 according to the following Scale Model 
formula (Karvanen):
where s = the individual laboratory value normalized against the laboratory normal range from 
the common source; x = the original individual laboratory value; Ux is the upper limit of the 
normal range for an individual laboratory parameter; Us is the upper limit of the laboratory 
normal range for that laboratory parameter from the common source. If NLM ranges are 
unavailable as a common source for a given parameter, official 
 reference ranges will be 
utilized. 
Clinical laboratory parameters include:
Hematology
Full and differential blood count, hematocrit, hemoglobin, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, mean corpuscular volume, platelet count, red blood cell
count, white blood cell (WBC) count with differential


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Serum Chemistry
Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, uric acid, blood
urea nitrogen or urea, carbon dioxide, creatinine, creatine kinase and subtypes, electrolytes 
(sodium, potassium, chloride, calcium, phosphorous), gamma-glutamyl transferase, glucose,
lactate dehydrogenase, total bilirubin, direct bilirubin, total cholesterol, triglycerides, total
protein
Coagulation
Prothrombin time, activated partial thromboplastin time, fibrinogen
Urine Analysis (Dipstick)
Appearance, pH, protein, glucose, ketone bodies, indicators of blood and WBCs, specific 
gravity, urobilinogen, occult blood, WBCs
Serology
HBV, HCV, HIV
Other
COVID-19
The observed and change from baseline to each visit will be summarized for each clinical 
laboratory parameter by treatment received, if applicable. In the event of repeat values, the last 
non-missing value will be used.
The frequency of patients with abnormal safety laboratory parameters (Hematology, Chemistry, 
Coagulation) will be tabulated by treatment received.
Shift tables of change in NCI-CTCAE grade of laboratory parameters from baseline to worst on-
study values will be presented for hematology, chemistry, and coagulation by treatment 
received, if applicable. If multiple values are equal and qualify for the worst on-study value for 
a given laboratory parameter, the earliest of the values will be considered. Shift tables of 
urinalysis results will be provided.
The number and percentage of subjects in each treatment group with an elevated alanine 
aminotransferase level (>3 x ULN, >5 x ULN, >8 x ULN, >10 x ULN, >20 x ULN), an elevated 
aspartate aminotransferase (>3 x ULN, >5 x ULN, >8 x ULN, >10 x ULN, >20 x ULN), an 
elevated alkaline phosphatase (>1.5 x ULN, > 2 x ULN), an elevated total bilirubin (>1.5 x 
ULN, >2 x ULN), or an elevated gamma-glutamyl transferase (>2 x ULN) will be presented by 
study visit and treatment received
ULN) or an elevated aspartate aminotransferase (>3 x ULN) in combination with alkaline 
phosphatase <2 x ULN and elevated total bilirubin (>2 x ULN).


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The number and percentage of subjects in each treatment group with an elevated glucose level ( 
> 100 mg/dL), an abnormal shift in glucose level (thresholds of 10.0%, 25.0%, and 50.0% in 
either direction), an elevated total cholesterol ( > 200 mg/dL), an abnormal shift in total 
cholesterol (thresholds of 10.0%, 25.0%, and 50.0% in either direction), an elevated 
triglycerides (> 150 mg/dL), or an abnormal shift in triglycerides (thresholds of 10.0%, 25.0%, 
and 50.0% in either direction) will be presented by study visit and treatment received. A listing 
presenting the all of the laboratory values for aforementioned parameters for all subjects 
meeting at least one of the aforementioned criteria will be provided.
In the event of lab disruptions due to COVID-19, additional analyses may be conducted to 
investigate any impact in an ad-hoc fashion if deemed appropriate. 
All laboratory data, including pregnancy tests, urine drug screens, and alcohol test results, will
be provided in by-patient listings.
4.6.9.
Electrocardiograms
ECG results for ventricular rate, PR, QRS, QT, and QTcF will be summarized descriptively by 
visit and treatment received and the number and percentage of subjects with normal, abnormal, 
and clinically significant abnormal results will be provided. The overall interpretation will also 
be summarized by visit and treatment received. A by-patient listing will be provided.
4.6.10.
Physical Examination
Results of the physical examination will be presented by visit and treatment received. A by-
patient listing will also be provided.
4.6.11.
Columbia-Suicide Severity Rating Scale
The C-SSRS is a measure of suicidal ideation and behavior. The rating scale has 4 general 
categories: suicidal ideation, intensity of ideation, suicidal behavior, and actual attempts. The 
frequency and percentage of subjects with each response for suicidal ideation, intensity of 
ideation, and suicidal behavior items will be summarized as appropriate by visit and treatment 
received. A by-patient listing will also be provided.
4.6.12.
Prior and Concomitant Medications
Prior medications are defined as any medications with a start date prior to first dose date. 
Prior medication use will be summarized using the Anatomical Therapeutic Chemical Class 
level 2 (ATC2) and preferred term by treatment received. 
Concomitant medications are defined as medications either ongoing at the time of first dose date 
or which start on or after the first dose date but before drug discontinuation. A medication may 
be considered both prior and concomitant.


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Concomitant medication use will be summarized using ATC2 and preferred term by treatment 
received. 
The use of prior and concomitant medications will be presented in a by-patient listing.
.
4.6.14.
Mini International Neuropsychiatric Interview (MINI) Version 7.0.2
The MINI is a short structured diagnostic interview developed for DSM-5 psychiatric disorders. 
With an administration time of approximately 15 minutes, it was designed to meet the need for a 
short but accurate structured psychiatric interview for multicenter clinical studies and 
epidemiology.
Available results from the MINI will be presented in by-patient listings.










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Protocol KAR-007
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7.
REFERENCES 
A.D.A.M. Medical Encyclopedia [Internet]. Atlanta (GA): A.D.A.M., Inc.; ©1997-2021.
Alanine transaminase (ALT) blood test; [updated 2019 Jan 26; cited 2021 Jan 15]; 
[about 3 p.]. Available from: https://medlineplus.gov/ency/article/003473.htm
Albumin blood (serum) test; [updated 2019 Jan 26; cited 2021 Jan 15]; [about 3 p.]. 
Available from: https://medlineplus.gov/ency/article/003480.htm
ALP blood test; [updated 2019 Apr 29; cited 2021 Jan 15]; [about 3 p.]. Available 
from: https://medlineplus.gov/ency/article/003470.htm
Aspartate aminotransferase (AST) blood test; [updated 2019 Jan 26; cited 2021 Jan 15]; 
[about 3 p.]. Available from: https://medlineplus.gov/ency/article/003472.htm
Bilirubin blood test; [updated 2019 Jan 26; cited 2021 Jan 15]; [about 4 p.]. Available 
from: https://medlineplus.gov/ency/article/003479.htm
Blood differential test; [updated 2019 Jan 29; cited 2021 Jan 15]; [about 5 p.]. Available 
from: https://medlineplus.gov/ency/article/003657.htm
Blood sugar test; [updated 2020 Jan 26; cited 2021 Jan 15]; [about 3 p.]. Available from: 
https://medlineplus.gov/ency/article/003482.htm
BUN - blood test; [updated 2019 Apr 29; cited 2021 Jan 15]; [about 3 p.]. Available 
from: https://medlineplus.gov/ency/article/003474.htm
Calcium blood test; [updated 2019 Sep 29; cited 2021 Jan 15]; [about 3 p.]. Available 
from: https://medlineplus.gov/ency/article/003477.htm
CBC blood test; [updated 2018 Oct 24; cited 2021 Jan 15]; [about 6 p.]. Available from: 
https://medlineplus.gov/ency/article/003642.htm
Chloride test blood; [updated 2019 Apr 29; cited 2021 Jan 15]; [about 3 p.]. Available 
from: https://medlineplus.gov/ency/article/003485.htm
CO2 blood test; [updated 2019 Apr 29; cited 2021 Jan 15]; [about 3 p.]. Available from: 
https://medlineplus.gov/ency/article/003469.htm
Creatinine blood test; [updated 2019 Jul 04; cited 2021 Jan 15]; [about 3 p.]. Available 
from: https://medlineplus.gov/ency/article/003475.htm
Fibrinogen blood test; [updated 2019 Jan 29; cited 2021 Jan 15]; [about 3 p.]. Available 
from: https://medlineplus.gov/ency/article/003650.htm


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Protocol KAR-007
Statistical Analysis Plan; 28 June 2022, Version 3.0
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Gamma-glutamyl transferase (GGT) blood test; [updated 2019 Jan 26; cited 2021 Jan 
15]; [about 3 p.]. Available from: https://medlineplus.gov/ency/article/003458.htm
High blood cholesterol levels; [updated 2021 Jan 05; cited 2021 Jan 18]; [about 11 a.]. 
Available from https://medlineplus.gov/ency/article/000403.htm
Lactate dehydrogenase test; [updated 2020 Feb 06; cited 2021 Jan 15]; [about 3 p.]. 
Available from: https://medlineplus.gov/ency/article/003471.htm
Partial thromboplastin time (PTT); [updated 2019 Jan 29; cited 2021 Jan 15]; [about 4 
p.]. Available from: https://medlineplus.gov/ency/article/003653.htm
Phosphorus blood test; [updated 2019 Sep 29; cited 2021 Jan 15]; [about 3 p.]. Available 
from: https://medlineplus.gov/ency/article/003478.htm
Potassium test; [updated 2019 Apr 29; cited 2021 Jan 15]; [about 5 p.]. Available from: 
https://medlineplus.gov/ency/article/003484.htm
Prothrombin time (PT); [updated 2019 Jan 29; cited 2021 Jan 15]; [about 4 p.]. 
Available from: https://medlineplus.gov/ency/article/003652.htm
Sodium blood test; [updated 2019 Sep 29; cited 2021 Jan 15]; [about 4 p.]. Available 
from: https://medlineplus.gov/ency/article/003481.htm
Total protein; [updated 2019 Apr 29; cited 2021 Jan 15]; [about 3 p.]. Available from: 
https://medlineplus.gov/ency/article/003483.htm
Triglycerides Test; [updated 2020 Jul 31; cited 2021 Jan 15]; [about 4 p.]. Available 
from: https://medlineplus.gov/lab-tests/triglycerides-test/
Uric acid blood; [updated 2019 Apr 29; cited 2021 Jan 15]; [about 3 p.]. Available 
from: https://medlineplus.gov/ency/article/003476.htm
Complete Blood Count (CBC). Labcorp. https://www.labcorp.com/help/patient-test
info/complete-blood-count-cbc. Published 2021. Accessed 2021 Jan 28.
Creatine Kinase (CK), Total Plus Isoenzymes. Labcorp. 
https://www.labcorp.com/tests/002154/creatine-kinase-ck-total-plus-isoenzymes.
Published 2020 April 15. Accessed 2021 Jan 28. 
Karvanen J. The Statistical Basis of Laboratory Data Normalization. Drug Information Journal, 
Vol. 37, pp. 101 107, 2003.