An Open-label Study to Assess the Long-term Safety, Tolerability, and Efficacy of KarXT in Adult Patients With Schizophrenia (EMERGENT-5)

Phase 3CompletedNCT04820309

Karuna Therapeutics, Inc., a Bristol Myers Squibb company566 enrolled

Overview

This is a Phase 3, multicenter, 56-week, outpatient, open-label (OL) study to evaluate the long-term safety, tolerability, and efficacy of KarXT in de novo subjects with Diagnostic and Statistical Manual-Fifth Edition (DSM-5) schizophrenia. In this OL study, all subjects will receive KarXT (a fixed combination of xanomeline 125 mg and trospium chloride 30 mg twice daily \[BID\]) for up to 52 weeks. The primary objective of the study is to assess the long-term safety and tolerability of KarXT in subjects with a DSM-5 diagnosis of schizophrenia. The secondary objective of this study is to assess the long-term efficacy and characterize the pharmacokinetics of xanomeline and trospium after administration of KarXT.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

566

Conditions

Schizophrenia

Interventions

Oral 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 8-364 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. Re-escalation to 125/30 BID or re-titration in cases in which the subject has been off KarXT for a longer period of time (at least a week) is allowed and will require a discussion between the principal investigator and the medical monitor.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Subject is aged 18 to 65 years at screening. 2. Subject is capable of providing informed consent. 1. A signed informed consent form (ICF) must be provided before any study assessments are performed. 2. Subject must be fluent in (oral and written) the language of the ICGF 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 has not required psychiatric hospitalization, acute crisis intervention, or other increase in level of care due to symptom exacerbation within 8 weeks of screening and is psychiatrically stable in the opinion of the investigator. 5. PANSS total score ≤ 80 at screening and Baseline Visit B (Day 0). 6. Clinical Global Impression - Severity (CGI-S) score of ≤ 4 at screening and Baseline Visit B (Day 0). 7. At the time of screening, or at any time within the 30 days prior to screening, the subject must have received an oral antipsychotic medication daily at a dose and frequency consistent with the drug label. 8. In the opinion of the investigator, it is clinically appropriate for the subject to discontinue current antipsychotic therapy and initiate experimental treatment with KarXT. 9. Subject is willing and able, in the opinion of the investigator, to discontinue all antipsychotic medications prior to baseline visit. 10. Subject has an identified reliable informant willing to be able to address some questions related to certain study visits, if needed. An informant may not be necessary if the subject has been the patient of the investigator for ≥1 year. 11. At Day 0, subject will have been off lithium therapy for at least 2 weeks and must have discontinued all oral antipsychotic medications. 12. Subjects taking a long-acting injectable antipsychotic could not have received a dose of medication for at least 12 weeks (24 weeks for paliperidone palmitate) before Day 0. 13. Body mass index must be ≥ 18 and ≤ 40 kg/m2. 14. Subject resides in a stable living situation and is anticipated to remain in a stable living situation for the duration of study enrollment, in the opinion of the investigator. 15. Women of childbearing potential or men with sexual partners of childbearing potential must be willing and able to use at least 1 highly effective method of contraception during the study and for at least 30 days after the last dose of KarXT. Sperm donation is not allowed for 30 days after the final dose of KarXT. Exclusion Criteria: 1. Any primary DSM-5 disorder other than schizophrenia within 12 months before screening (confirmed using MINI version 7.0.2 at screening). 2. Subject has a history of moderate to severe alcohol use disorder or a substance (other than nicotine or caffeine) use disorder within the past 12 months or a positive urine drug screen (UDS) for a substance other than cannabis at screening or baseline. 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. Subject has human immunodeficiency virus (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 Columbia-Suicide Severity Rating Scale (C-SSRS). 8. Clinically significant abnormal finding from the physical examination, medical history, ECG, or clinical laboratory results at screening. 9. Subjects cannot currently (within 5 half-lives before Day 0) be receiving monoamine oxidase inhibitors, anticonvulsants, tricyclic antidepressants, centrally active anticholinergics, or any other psychoactive medications other than daily antipsychotic maintenance therapy. As-needed anxiolytics and/or sleep aids are permitted. Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors taken at stable dose may be permitted. 10. 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) within the past 12 months or having received clozapine within the past 3 years 11. Pregnant, lactating, or less than 3 months postpartum. 12. 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. 13. Subjects has tested positive for coronavirus disease 2019 (COVID-19) within 2 weeks of screening. 14. Subject has extreme concerns relating to global pandemics, such as COVID-19, that preclude study participation. 15. Subject has had psychiatric hospitalization(s) for more than 30 days (cumulative) within the 6 months before screening. 16. Subject has prior exposure to KarXT. 17. Risk of violent or destructive behavior. 18. Current involuntary hospitalization or incarceration.

Locations (117)

Local Institution - 011-238

Little Rock, Arkansas, United States

Woodland International Research Group

Little Rock, Arkansas, United States

Local Institution - 011-201

Rogers, Arkansas, United States

Woodland Research Northwest

Rogers, Arkansas, United States

Local Institution - 011-240

Anaheim, California, United States

Outcomes

Primary Outcomes

Number of Participants With Treatment Emergent Adverse Events (TEAEs)

TEAEs are defined as events with an onset date on or after the first dose of KarXT. An Adverse Event is any symptom, physical sign, syndrome, or disease that either emerges during the study or, if present at baseline, worsens during the study, regardless of the suspected cause of the event using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0.

Time frame: From time of consent to end of study (approximately 400 days)

Secondary Outcomes

Number of Participants With Serious Treatment Emergent Adverse Events (STEAEs)

An 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; results in persistent or significant disability/incapacity, and/or; is a congenital anomaly/birth defect using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0.

Time frame: From time of consent to end of study (approximately 400 days)

Number of Participants With TEAE Leading to Study Drug Discontinuation

Time frame: From time of consent to end of study (approximately 400 days)

Change From Baseline in PANSS Total Score at Week 52

The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. Participants are rated from 1 to 7 on each symptom scale. The positive symptoms in schizophrenia are the excess or distortion of normal function and the negative symptoms 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.

Time frame: At baseline and week 52

Change From Baseline in PANSS Positive Score at Week 52

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. Higher scores indicate more severe symptoms. Participants 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.

Time frame: At baseline and week 52

Change From Baseline in PANSS Negative Score at Week 52

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. Higher scores indicate more severe symptoms. Participants are rated from 1 to 7 on each symptom scale. The negative symptoms in schizophrenia are the diminution or loss of normal functions.

Time frame: At baseline and week 52

Change From Baseline in PANSS Marder Factor Negative Score at Week 52

PANSS Marder factor score is a subscale of the PANSS; 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). Participants are rated from 1 to 7 on each symptom subscale. Higher score indicates more severe symptoms. The negative symptoms in schizophrenia are the diminution or loss of normal functions.

Time frame: At baseline and week 52

Change From Baseline in Clinical Global Impressions-severity (CGI-S) Score Week 52

Completed independently by a clinician, 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, by asking the clinical 1 question and providing a rating based upon observed and reported symptoms, behavior, and function in the past 7 days to reflect the average severity level across the 7 days. Higher score indicates more severe illness.

Time frame: At baseline and week 52

Percentage of Participants With a ≥30% Reduction in PANSS Total Score at Week 52

A PANSS responder is defined as a participant with a reduction from baseline of at least a 30% improvement at Week 52 in the PANSS total score. The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. Participants are rated from 1 to 7 on each symptom scale. 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.

Time frame: At baseline and week 52

Number of Participants With Adverse Events of Special Interest (AESI)

LFT elevations, inclusive of drug-induced liver injury (DILI) and symptomatic orthostasis including syncope (a transient loss of consciousness or fainting) is to be captured as an AESI and reported as such. Non symptomatic orthostasis will not be reported as an AESI. Any such AESI due to any cause, whether or not related to KarXT, must be reported within 24 hours of occurrence or when the investigator becomes aware of the event.

Time frame: From time of consent to end of study (approximately 400 days)

Number of Participants With Anticholinergic and Procholinergic Symptoms

The number of participants experiencing adverse events related to procholinergic symptoms (believed to be associated with xanomeline) and anticholinergic symptoms (believed to be associated with trospium) symptoms. Examples of procholinergic symptoms include vomiting, nausea, diarrhea, sweating and hyper-salivation. Examples of anticholinergic include dizziness, confusion, hallucinations, and somnolence.

Time frame: From time of consent to end of study (approximately 400 days)

Change From Baseline in Simpson-Angus Rating Scale (SAS)

The Simpson-Angus Rating Scale (SAS) is a clinical tool used to assess the severity of extrapyramidal symptoms (EPS), which are drug-induced movement disorders often associated with antipsychotic medications. The scale consists of 10 items, each rated from 0 (none) to 4 (severe), with a total score range of 0 to 40. Higher scores indicate more severe symptoms. The SAS helps clinicians monitor and manage EPS in patients, guiding treatment decisions to minimize these side effects.

Time frame: From time of consent to end of study (approximately 400 days)

Change From Baseline in Barnes Akathisia Rating Scale (BARS)

The BARS 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.

Time frame: From time of consent to end of study (approximately 400 days)

Change From Baseline in Total Abnormal Involuntary Movement Scale (AIMS)

The Abnormal Involuntary Movement Scale (AIMS) is a tool used to assess the severity of tardive dyskinesia and other involuntary movements, often caused by antipsychotic medications. It includes 12 items, with the first 10 focusing on specific body areas and movement severity, rated from 0 (none) to 4 (severe). The total score ranges from 0 to 28, with higher scores indicating more severe symptoms. AIMS helps clinicians monitor and manage these movement disorders, guiding treatment adjustments to reduce side effects.

Time frame: From time of consent to end of study (approximately 400 days)

Change From Baseline in Body Mass Index (BMI)

BMI is a person's weight in kilograms divided by the square of height in meters. Baseline is defined as measurements taken at screening.

Time frame: From time of consent to end of study (approximately 400 days)

Change From Baseline in Waist Circumference

The change in waist circumference in centimeters from baseline. Baseline is defined as measurements taken at screening.

Time frame: From time of consent to end of study (approximately 400 days)

Change From Baseline in Blood Pressure Values

The change from baseline in orthostatic diastolic and systolic blood pressure measured while supine and standing after 2 minutes. Baseline is defined as measurements taken at screening.

Time frame: From time of consent to end of study (approximately 400 days)

Change From Baseline in Heart Rate

The change from baseline in orthostatic heart rate measured while supine and standing after 2 minutes. Baseline is defined as measurements taken at screening.

Time frame: From time of consent to end of study (approximately 400 days)

Number of Participants With Clinically Significant Changes in Clinical Laboratory Assessments

Laboratory assessments include: * Hematology * Serum chemistry * Urinalysis * HbA1c * Prolactin levels * Coagulation studies * Viral Serology * Pregnancy test

Time frame: From time of consent to end of study (approximately 400 days)

Number of Participants With Clinically Significant Changes in 12 Lead Electrocardiogram

An electrocardiogram (ECG) measures electrical activity of the heart to detect cardiac problems.

Time frame: From time of consent to end of study (approximately 400 days)

Number of Participants With Clinically Significant Changes in Physical Examination

A complete physical examination (body temperature, general appearance, head/eyes/ears/nose/throat \[HEENT\], examination of thorax and abdomen, assessment of cardiac, musculoskeletal, and circulatory systems, palpations for lymphadenopathy, and limited neurological examination) will be performed. A targeted physical examination includes at a minimum body temperature, a check of general appearance, as well as examination of organ systems that are relevant to the investigator based on review of the participant's reported AEs, review of systems, or concomitant medication use. These also include symptom-driven physical examinations which will be performed as clinically indicated at any study visit.

Time frame: From time of consent to end of study (approximately 400 days)

Number of Participants With Suicidal Ideation Based on the Columbia Suicide Severity Rating Scale (C-SSRS)

The Columbia Suicide Severity Rating Scale (C-SSRS) is a tool used to assess the severity and immediacy of suicidal ideation and behavior. It covers suicidal thoughts, plans, and actions, including the frequency, intensity, and context of these behaviors. The C-SSRS does not use a numerical scoring system like some other assessment tools. Instead, it categorizes the severity of suicidal ideation and behavior based on specific criteria. The scale helps clinicians identify individuals at risk of suicide and monitor changes over time, guiding treatment decisions and ensuring safety. It is quick and easy to administer, making it useful in various clinical and research settings.

Time frame: From time of consent to end of study (approximately 400 days)