An Open-label Study to Assess the Long-term Safety, Tolerability, Effectiveness, and Durability of Effect of KarXT in Patients With DSM-5 Diagnosis of Schizophrenia

Study Overview
=================
Brief Summary
-----------------
This is a Phase 3b, 3-year, open-label, multi-center study in which patients with DSM-5 diagnosis of schizophrenia whose current medication(s) is not well tolerated and/or clinical symptoms are not well controlled will be switched to receive KarXT. The primary objectives of the study are to assess the long-term safety and tolerability of KarXT and assess effectiveness, persistence, and durability of effect of KarXT through the Investigator Assessment Questionnaire (IAQ) and Clinical Global Impression - Severity of Illness (CGI-S) scale in patients with a diagnosis of schizophrenia. The secondary objectives are to further assess the effectiveness using the Clinical Global Impression, Global Improvement (CGI-I), long-term safety and tolerability of KarXT, and evaluation of scores from multiple additional patient scales and assessments throughout the study.

Official Title
-----------------
A Multi-center, Open-label Study to Assess the Effectiveness, Long-term Safety, Tolerability, and Durability of Effect of KarXT in Patients With DSM-5 Diagnosis of Schizophrenia

Conditions
-----------------
Schizophrenia

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient is aged 18 to 65 years, inclusive, at screening. Patient can provide informed consent. A signed informed consent form (ICF) must be provided before any study assessments are performed. Patient must be fluent (oral and written) in the language of the ICF to consent. Patient has a primary diagnosis of schizophrenia established by a comprehensive psychiatric evaluation based on the DSM 5 (American Psychiatric Association, 2013) criteria and has been in the continuous care of the clinician or practice for at least 6 months prior to entering the study. The patient is dissatisfied with the side effects or general tolerability of their current antipsychotic medication, and for this reason, desires to change medications. Or, the patient is dissatisfied with the overall effectiveness or benefit of their current antipsychotic medication, and for this reason, desires to change medications. The patient has not required psychiatric hospitalization, acute crisis intervention, or other increase in their level of care due to symptom exacerbation within 4 weeks of screening, and in the opinion of the investigator, is psychiatrically stable to be managed in an outpatient setting. The patient has a CGI-S score of ≤4 (moderately severe or less) at screening and baseline visits. For at least 30 days prior to screening, the patient must have been prescribed and have taken an oral antipsychotic medication daily at a dose and frequency consistent with the drug label. Patient has an identified, reliable caregiver/informant that is willing (by informed consent) and able to respond to the ZBI 22 caregiver burden scale at specified visits. If the patient has been the patient of the investigator for ≥6 months and, in the opinion of the investigator, the patient is self-sufficient, then a caregiver/informant may not be necessary. Patient resides in a stable living situation and is anticipated to remain in a stable living situation for the duration of the study, in the opinion of the investigator. If a woman of childbearing potential (WOCBP) or a man whose sexual partner(s) is a WOCBP, the patient must be willing and able to adhere to the contraception guidelines as defined in Section 12.1 Appendix 1. Exclusion Criteria: Any primary DSM-5 disorder diagnosis other than schizophrenia within 12 months before screening. Exclusionary disorders include, but are not limited to, bipolar I or II disorder and schizoaffective disorder. Symptoms of mild mood dysphoria or anxiety are allowed, as long as these symptoms are not the primary focus of treatment. The patient has a history of or presence of a clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or oncologic disease or any other condition that, in the opinion of the investigator, is likely to jeopardize the safety of the patient or the validity of the study results. Patient has a history of or is at high risk of urinary retention, gastric retention, or narrow angle glaucoma. Patient has a history of irritable bowel syndrome (with or without constipation) or constipation requiring treatment for more than 30 days within the last 6 months. Clinically significant abnormal finding on the physical examination, medical history, electrocardiogram (ECG), or clinical laboratory results at screening. Patient is pregnant, lactating, or less than 3 months postpartum. Patient has tested positive for coronavirus disease 2019 (COVID-19) within 2 weeks of screening and/or baseline or patients who have prolonged symptoms of past infection, long COVID, that, in the opinion of the investigator, may interfere with the interpretation of safety during the study. Patient with extreme concerns relating to global pandemics, such as COVID-19, that precludes study participation. Patient is currently or recently (within 4 weeks of screening) involuntary hospitalization or incarceration. Patient participated in another clinical study in which they received an experimental or investigational drug agent within 30 days prior to screening.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KarXT<br> | Drug: Xanomeline and Trospium Chloride Capsules<br>* KarXT 50 mg/20 mg BID KarXT 100mg/20 mg BID KarXT 125mg/30 mg BID<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (TEAEs) leading to discontinuation |  | From initial dose to safety follow up visit (up to week 160) or early termination | 
| Persistence and durability of effect of KarXT via Investigator Assessment Questionnaire (IAQ) and Clinical Global Impression - Severity of Illness (CGI-S) scores at clinical visits throughout the study | Effectiveness of treatment is assessed by the IAQ total score, which is defined as the sum of 10 out of 12 items (positive symptoms, negative symptoms, somnolence, weight gain, signs and symptoms of prolactin elevation, akathisia, EPS, cognition, energy, and mood); each item is rated on a 5-point Likert scale (1 = Much better, 2 = Slightly better, 3 = About the same, 4 = Slightly worse, and 5 = Much worse). 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. | Through end of treatment (up to 156 weeks) or early termination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of serious TEAEs (TESAEs) | The number and percentage of participants with serious TEAEs will be determined | From initial dose to end of study visit (up to 160 weeks) or early termination | 
| Incidence of TEAEs of special interest | The number and percentage of participants with TEAEs of special interest will be determined | From initial dose to end of study visit (up to 160 weeks) or early termination | 
| Clinical Global Impression - Improvement (CGI-I) Score | The CGI-I asked the clinician question: Compared to the patient's condition at baseline, this patient's [average] condition has...? The clinician's answer rated on the following 7-point scale:1 = Very much improved; 2 = Much improved; 3 = Minimally improved; 4 = No change; 5 = Minimally worse; 6 = Much worse; 7 = Very much worse | Up to Week 24 | 
| Medication Satisfaction Questionnaire (MSQ) | Patient satisfaction with the treatment evaluated based on the question of overall how satisfied you are with your current antipsychotic therapy rated on the following 7-point scale: 1 = Extremely dissatisfied, 2=Very dissatisfied, 3=Somewhat dissatisfied, 4=Neither satisfied nor dissatisfied, 5=Somewhat satisfied, 6 = Very satisfied, 7 = Extremely satisfied. | Through end of treatment (up to 156 weeks) or early termination |