A Study to Assess Safety and Efficacy of KarXT in Adult Patients With Schizophrenia

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

Official Title
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A Phase 2, Randomized, Double-blinded Study to Assess the Safety, Tolerability, and Efficacy of KarXT in Hospitalized Adults With DSM-5 Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Xanomeline and Trospium Chloride Capsules
* Drug: Placebo Capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is aged 18-60 years, inclusive, at screening 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. Subject is experiencing an acute exacerbation or relapse of symptoms, with onset less than 2 months before screening Positive and Negative Syndrome Scale total score between 80 and 120, inclusive, at screening Score of ≥ 4 (moderate or greater) for ≥ 2 of the following Positive Scale (P) items at screening: Item 1 (P1; delusions) Item 2 (P2; conceptual disorganization) Item 3 (P3; hallucinatory behavior) Item 6 (P6; suspiciousness/persecution) There should not be a change (improvement) in PANSS total score between screening and baseline of more than 20% Subjects taking a depot antipsychotic could not have received a dose of medication for at least 1 and a half injection cycles before baseline (eg, 3 or more weeks off for a 2-week cycle) Subject is capable of providing informed consent A signed ICF must be provided before any study assessments are performed Subject must be fluent (oral and written) in English in order to consent Subject must have CGI-S score of ≥ 4 at screening and baseline visits Body mass index must be ≥ 18 and ≤ 40 kg/m2 Both females of child bearing potential and males with partners of child bearing potential must be willing to use a double-barrier method of birth control (ie, any double combination of male or female condom with spermicidal gel, diaphragm, sponge, or cervical cap with spermicidal gel) during the study and for 7 days after the last dose of study drug. Subject has an identified reliable informant Exclusion Criteria: Any primary DSM-5 disorder other than schizophrenia within 12 months before screening (confirmed using MINI version 7.0.2 at screening) History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or oncologic disease or any other condition that, in the opinion of the investigator, would jeopardize the safety of the subject or the validity of the study results, to exclude patients with human immunodeficiency virus (HIV), cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma, and/or active hepatic viral infections based on the liver function test results. History of or high risk of urinary retention, gastric retention, or narrow-angle glaucoma History of irritable bowel syndrome (with or without constipation) or serious constipation requiring treatment within the last 6 months Has a DSM-5 diagnosis of moderate to severe substance abuse disorder (except tobacco use disorder) within the 12 months before screening (confirmed using MINI version 7.0.2 at screening), or current abuse as determined by urine toxicology screen or alcohol test. A screening subject with mild substance abuse disorder within the 12 months before screening must be discussed and agreed upon with the medical monitor before he/she can be allowed into the study. Clinically significant abnormal finding on the physical examination, medical history, ECG, or clinical laboratory results at screening Pregnant, lactating, or less than 3 months postpartum. Sperm donation is not allowed for 90 days after the final dose of study drug If, in the opinion of the investigator (and/or Sponsor), subject is unsuitable for enrollment in the study or subject has any finding that, in the view of the investigator (and/or Sponsor), may compromise the safety of the subject or affect their ability to adhere to the protocol visit schedule or fulfill visit requirements Subject has had psychiatric hospitalization(s) for more than 30 days (cumulative) during the 90 days before screening 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 Risk of violent or destructive behavior Current involuntary hospitalization or incarceration Participation in another clinical study in which the subject received an experimental or investigational drug agent within 3 months of screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KarXT<br> | Drug: Xanomeline and Trospium Chloride Capsules<br>* Xanomeline 50 mg/trospium 20 mg BID on days 1-2 followed by xanomeline 100 mg/trospium 20 mg BID on days 3-7. The dose is increased to xanomeline 125 mg/trospium 30 mg BID on days 8-34 unless the subject is experiencing adverse events from the xanomeline 100 mg/trospium 20 mg dose. Subjects who were increased to xanomeline 125 mg/trospium 30 mg will have the option to return to xanomeline 100 mg/trospium 20 mg depending on clinical response and tolerability. Dosing must not change after Visit 7 of the study (at 21 ± 2 days of dosing) and may be decreased for tolerability reasons no more than once during the study.<br>* Other names: KarXT;|
| Placebo Comparator: Placebo<br> | Drug: Placebo Capsules<br>* Placebo Capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 5 | The PANSS is a medical scale used for measuring symptom severity of participants with schizophrenia. The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. Participants were rated from 1 to 7 on each symptom scale. The total score is the sum of all scales with a minimum score of 30 and a maximum score of 210. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms. | Baseline and Week 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Positive Score at Week 5 | The PANSS is a medical scale used for measuring symptom severity of participants with schizophrenia. The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. The positive symptoms in schizophrenia are the excess or distortion of normal functions such as hallucinations, delusions, grandiosity, and hostility. Participants were rated from 1 to 7 on each symptom scale, with a minimum score of 7 and a maximum score of 49. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms. | Baseline and Week 5 | 
| Number of Participants With Each Clinical Global Impression - Severity (CGI-S) Score at Baseline and 5 Weeks | The CGI-S modified asked the clinician 1 question: Considering your total clinical experience, how mentally ill is the participant at this time? The clinician's answer 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 participants. | Baseline and Week 5 | 
| Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Negative Score at Week 5 | The PANSS is a medical scale used for measuring symptom severity of participants with schizophrenia. The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. The negative symptoms in schizophrenia are the diminution or loss of normal functions. Participants were rated from 1 to 7 on each symptom scale, with a minimum score of 7 and a maximum score of 49. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms. | Baseline and Week 5 | 
| Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Marder Factor Score | The Marder Negative Factor score is derived from the PANSS and consists of the sum of 5 negative scales (N) and 2 general scales (G) (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), with a minimum score of 7 and a maximum score of 49. | Baseline and Week 5 | 
| Percentage of Participants Who Were Clinical Global Impression - Severity of Illness (CGI-S) Responders | The CGI-S modified asks the clinician 1 question: Considering your total clinical experience, how mentally ill is the participant at this time? The clinician's answer was 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 participants. A CGI-S responder is defined as a participant with a CGI-S scale equal to 1 or 2. | Week 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Schizophrenia