An Extension Study to Assess Long-term Safety, Tolerability, and Efficacy of KarXT in Adult Patients With Schizophrenia (EMERGENT-4)

An Open-label Extension Study to Assess the Long-term Safety, Tolerability, and Efficacy of KarXT in Subjects With DSM-5 Schizophrenia

This is a Phase 3, multicenter, 53-week, outpatient, open-label extension (OLE) study to evaluate the long-term safety, tolerability, and efficacy of KarXT in subjects with Diagnostic and Statistical Manual-Fifth Edition (DSM-5) schizophrenia who previously completed the treatment period of one of the two Phase 3 double-blind studies, KAR-007 or KAR-009. In this OLE 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 regardless of treatment assignment in the preceding Phase 3 acute study. 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 monitor trough concentrations of xanomeline and trospium after administration of KarXT.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Xanomeline and Trospium Chloride Capsules

• Study Type: Interventional
• Enrollment (Actual): 152
• Phase: Phase 3

Contacts and Locations

Study Locations

• Ukraine
  • Dnipro, Ukraine, 49005
    • Dnipropetrovsk Regional Clinical Hospital named after I.I. Mechnikov
  • Kharkiv, Ukraine, 61068
    • Institute of Neurology, Psychiatry and Narcology of the National Academy of Medical Sciences of Ukraine
  • Kharkiv, Ukraine
    • Regional Clinical Psychiatric Hospital No. 3, Adult Psychiatric Department No. 3
  • Kherson, Ukraine, 73488
    • Kherson Regional Insititution of Mental Care of Kherson Regional Council Male Psychiatric Department #3, Femail Psychiatric Department #10
  • Kyiv, Ukraine, 04080
    • Kyiv Regional Medical Incorporation "Psychiatry", Center for Novel Treatment and Rehabilitation of Psychotic Disorders
  • Lviv, Ukraine, 79021
    • Lviv Regional Clinical Psychiatric Hospital, Department #20
  • Lviv, Ukraine, 79021
    • Lviv Regional Clinical Psychiatric Hospital, Department #25
  • Poltava, Ukraine, 36013
    • Regional Facility for Psychiatric Care of Poltava Regional Council, 2-A acute general psychiatric male ward, 5-B acute, quiet, general psychiatric female ward, Poltava State Medical University, Academic Department of Psychiatry, Addictology and Medical
  • Vinnytsya, Ukraine, 21037
    • M.I. Pyrogov Vinnytsya National Medical University
  • Cherkasy Region
    • Smila, Cherkasy Region, Ukraine, 20708
      • Cherkasy Regional Psychiatric Hospital of Cherkasy Regional Council, Female Department #11, Male Department #12
• United States
  • Arkansas
    • Bentonville, Arkansas, United States, 72712
      • Pillar Clinical Research
    • Little Rock, Arkansas, United States, 72211
      • Woodland International Research Group
  • California
    • Anaheim, California, United States, 92805
      • Advanced Research Center, Inc.
    • Bellflower, California, United States, 90706
      • CiTrials
    • Bellflower, California, United States, 90706
      • Advanced Research Center Inc
    • Culver City, California, United States, 90230
      • ProScience Research Group
    • Garden Grove, California, United States, 92845
      • Collaborative Neuroscience Research, LLC
    • Glendale, California, United States, 91206
      • California Clinical Trial Medical Group
    • Lemon Grove, California, United States, 91945
      • Synergy San Diego
    • Long Beach, California, United States, 90806
      • CNS Network
    • Montclair, California, United States, 91763
      • Catalina Research Institute, LLC
    • Orange, California, United States, 92868
      • NRC Research Institute
    • Pico Rivera, California, United States, 90660
      • California Neuropsychopharmacology Clinical Research Institute
    • San Diego, California, United States, 92103
      • Artemis Institute for Clinical Research
    • San Diego, California, United States, 92102
      • California Neuropsychopharmacology Clinical Research Institute
    • Sherman Oaks, California, United States, 91403
      • Schuster Medical Research Institute
    • Torrance, California, United States, 90502
      • Collaborative Neuroscience Research, LLC.
  • Florida
    • Hollywood, Florida, United States, 33024
      • Research Centers of America
    • Hollywood, Florida, United States, 33021
      • Behavioral Clinical Research, Inc.
    • Miami Lakes, Florida, United States, 33016
      • Innovative Clinical Research, Inc.
  • Georgia
    • Atlanta, Georgia, United States, 30331
      • Atlanta Center for Medical Research
    • Decatur, Georgia, United States, 30030
      • iResearch Atlanta, LLC
  • Illinois
    • Chicago, Illinois, United States, 60640
      • Uptown Research Institute
    • Chicago, Illinois, United States, 60622
      • Mitchell L. Glaser
    • Hoffman Estates, Illinois, United States, 60169
      • AMITA Health Center for Psychiatric Research
    • Lincolnwood, Illinois, United States, 60712
      • Pillar Clinical Research
  • Missouri
    • Saint Louis, Missouri, United States, 63125
      • Arch Clinical Trials
  • Nevada
    • Las Vegas, Nevada, United States, 89102
      • Altea Research Institute
  • New Jersey
    • Berlin, New Jersey, United States, 08009
      • Hassman Research Institute
    • Marlton, New Jersey, United States, 08053
      • Hassman Research Institute
  • Ohio
    • North Canton, Ohio, United States, 44720
      • Neuro-Behavioral Clinical Research, Inc.
  • Texas
    • Austin, Texas, United States, 78754
      • Community Clinical Research
    • DeSoto, Texas, United States, 75115
      • InSite Clinical Research
    • Richardson, Texas, United States, 75080
      • Pillar Clinical Research, LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subject is aged 18 to 65 years, at time of enrollment into the preceding acute study (KAR-007/009).

2. Subject is capable of providing informed consent.

   1. A signed informed consent form must be provided before any study assessments are performed.
   2. Subject must be fluent in (oral and written) English (United States only) or local language (Ukraine only) to consent.
3. Subject has completed the treatment period on study drug (through Day 35 -2 days) of Studies KAR-007 or KAR-009.
4. Subject resides in a stable living situation, in the opinion of the investigator.
5. Subject has an identified, reliable informant/caregiver willing to be able to address some questions related to certain study visits, if needed. An informant/caregiver may not be necessary if the subject has been the patient of the investigator for ≥1 year.
6. Women of childbearing potential or men with sexual partners of childbearing potential must be sexually abstinent (in line with their preferred and usual lifestyle) or willing and able to use at least 1 highly effective method of contraception during the study and for at least 7 days after the last dose of KarXT. Sperm donation is not allowed for 7 days after the final dose of KarXT.

Exclusion Criteria:

1. Risk for suicidal behavior during the study as determined by the investigator's clinical assessment and Columbia-Suicide Severity Rating Scale (C-SSRS).
2. Any clinically significant abnormality, including any finding(s) from the physical examination, vital signs, ECG, or laboratory test at the end-of-treatment visit of Studies KAR-007 or KAR-009 that the investigator, in consultation with the medical monitor, would consider to jeopardize the safety of the subject.
3. Female subject is pregnant.
4. 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.
5. Subjects with extreme concerns relating to global pandemics such as coronavirus disease 2019 (COVID-19) that preclude study participation.
6. Risk of violent or destructive behavior.
7. Subjects participating in another investigational drug or device trial or planning on participating in another clinical trial during the course of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: KarXT

Drug: Xanomeline and Trospium Chloride Capsules; Oral xanomeline 50 mg/trospium chloride 20 mg BID on days 1-2 followed by xanomeline 100 mg/trospium chloride 20 mg BID on days 3-7. The dosage is increased to xanomeline 125 mg/trospium chloride 30 mg BID on days 8-364 unless the subject is experiencing adverse events from the xanomeline 100 mg/ trospium chloride 20 mg dose. Subjects who were increased to xanomeline 125 mg/trospium chloride 30 mg will have the option to return to xanomeline 100 mg/ trospium chloride 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.; Other Names: KarXT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From first dose to end of study (Up to approximately 53 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Serious Adverse Events (SAEs)	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.	From first dose to end of study (Up to approximately 53 weeks)
Number of Participants With Treatment-Emergent Adverse Events (TEAE) Leading to Study Drug Discontinuation	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.	From first dose to end of study (Up to approximately 53 weeks)
Change From Baseline in Positive and Negative Syndrome Scale (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. Open-label Extension Baseline (OLEB) is defined as the most recent measurement prior to the first administration of study drug in KAR-008. The assessments performed on Visit 10 (Day 35) of studies KAR-007 or KAR-009 will be considered for OLEB baseline along with any additional procedures that will be performed on Day 0 of KAR-008.	Open-label extension baseline, week 52
Change From Baseline in Positive and Negative Syndrome Scale (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. Open-label Extension Baseline (OLEB) is defined as the most recent measurement prior to the first administration of study drug in KAR-008. The assessments performed on Visit 10 (Day 35) of studies KAR-007 or KAR-009 will be considered for OLEB baseline along with any additional procedures that will be performed on Day 0 of KAR-008.	Open-labe extension baseline, week 52
Change From Baseline in Positive and Negative Syndrome Scale (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. Open-label Extension Baseline (OLEB) is defined as the most recent measurement prior to the first administration of study drug in KAR-008. The assessments performed on Visit 10 (Day 35) of studies KAR-007 or KAR-009 will be considered for OLEB baseline along with any additional procedures that will be performed on Day 0 of KAR-008.	Open-label extension baseline, week 52
Change From Baseline in PANSS Negative Marder Factor Score at Week 52	PANSS Negative 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). Participants are rated from 1 to 7 on each symptom scale. Higher score indicates more severe symptoms. The negative symptoms in schizophrenia are the diminution or loss of normal functions. Open-label Extension Baseline (OLEB) is defined as the most recent measurement prior to the first administration of study drug in KAR-008. The assessments performed on Visit 10 (Day 35) of studies KAR-007 or KAR-009 will be considered for OLEB baseline along with any additional procedures that will be performed on Day 0 of KAR-008.	Open-label extension baseline, week 52
Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at 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. Open-label Extension Baseline (OLEB) is defined as the most recent measurement prior to the first administration of study drug in KAR-008. The assessments performed on Visit 10 (Day 35) of studies KAR-007 or KAR-009 will be considered for OLEB baseline along with any additional procedures that will be performed on Day 0 of KAR-008.	Open-label extension baseline, week 52
Percentage of PANSS Responders With >=30% Reduction in PANSS Total Score at Week 52	A PANSS responder is defined as a participant with reduction from open-label extension baseline (OLEB) 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. OLEB is defined as the most recent measurement prior to the first administration of study drug in KAR-008. The assessments performed on Visit 10 (Day 35) of studies KAR-007 or KAR-009 will be considered for OLEB baseline along with any additional procedures that will be performed on Day 0 of KAR-008.	At week 52

Collaborators and Investigators

• Sponsor: Karuna Therapeutics
• Investigators: Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2021
• Primary Completion (Actual): October 3, 2023
• Study Completion (Actual): October 3, 2023

Study Registration Dates

• First Submitted: December 2, 2020
• First Submitted That Met QC Criteria: December 2, 2020
• First Posted (Actual): December 9, 2020

Study Record Updates

• Last Update Posted (Actual): October 28, 2024
• Last Update Submitted That Met QC Criteria: October 2, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Schizophrenia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Psychotropic Drugs; Urological Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Cholinergic Agonists; Parasympatholytics; Parasympathomimetics; Muscarinic Agonists; Xanomeline; Trospium chloride
• Other Study ID Numbers: KAR-008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No