Clinical trial NCT04820309: An Open-label Study to Assess the Long-term Safety, Tolerability, and Efficacy of KarXT in Adult Patients With Schizophrenia (EMERGENT-5)
Official title: An Open-label Study to Assess the Long-term Safety, Tolerability, and Efficacy of KarXT in De Novo Subjects With DSM-5 Schizophrenia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Schizophrenia
Lead sponsor: Karuna Therapeutics
Sponsor class: INDUSTRY
First posted: 2021-03-29
Enrollment: 568
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of treatment-emergent adverse events (TEAEs)
timeFrame: From initial dose through 7 days after the final dose (up to 53 weeks)
Secondary outcomes:
measure: Incidence of serious TEAEs
timeFrame: From initial dose through 7 days after the final dose (up to 53 weeks)
measure: Incidence of TEAEs leading to withdrawal
timeFrame: From initial dose through 7 days after the final dose (up to 53 weeks)
measure: Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 52
timeFrame: Week 52
measure: Change From Baseline in PANSS Positive Score at Week 52
timeFrame: Week 52
measure: Change From Baseline in PANSS Negative Score at Week 52
timeFrame: Week 52
measure: Change From Baseline in PANSS Negative Marder Factor Score
timeFrame: Week 52
measure: Change From Baseline in Clinical Global Impression - Severity (CGI-S) Score at Week 52
timeFrame: Week 52
measure: Percentage of PANSS responders (a 30% change in PANSS total score) at Week 52
timeFrame: Week 52
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Local Institution - 011-238
state: Arkansas
city: Rogers
country: United States
facility: Local Institution - 011-201
state: Arkansas
city: Anaheim
country: United States
facility: Local Institution - 011-240
state: California
city: Bellflower
country: United States
facility: Local Institution - 011-222
state: California
city: Bellflower
country: United States
facility: Local Institution - 011-263
state: California
city: Cerritos
country: United States
facility: Local Institution - 011-257
state: California
city: Costa Mesa
country: United States
facility: ATP Clinical Research Inc
state: California
city: Culver City
country: United States
facility: Local Institution - 011-206
state: California
city: Garden Grove
country: United States
facility: Local Institution - 011-253
state: California
city: Glendale
country: United States
facility: Local Institution - 011-202
state: California
city: La Habra
country: United States
facility: Omega Clinical Trials
state: California
city: Long Beach
country: United States
facility: Alliance for Wellness dba Alliance for Research
state: California
city: Oceanside
country: United States
facility: North County Clinical Research (NCCR)
state: California
city: Oceanside
country: United States
facility: Local Institution - 011-229
state: California
city: Orange
country: United States
facility: Local Institution - 011-242
state: California
city: Pico Rivera
country: United States
facility: Local Institution - 011-244
state: California
city: Riverside
country: United States
facility: Local Institution - 011-233
state: California
city: Santa Rosa
country: United States
facility: Local Institution - 011-251
state: California
city: Sherman Oaks
country: United States
facility: Local Institution - 011-246
state: California
city: Torrance
country: United States
facility: Local Institution - 011-252
state: California
city: Hallandale Beach
country: United States
facility: Local Institution - 011-224
state: Florida
city: Hollywood
country: United States
facility: Local Institution - 011-261
state: Florida
city: Homestead
country: United States
facility: Local Institution - 011-231
state: Florida
city: Miami Lakes
country: United States
facility: Local Institution - 011-234
state: Florida
city: Miami
country: United States
facility: Local Institution - 011-203
state: Florida
city: Miami
country: United States
facility: Local Institution - 011-215
state: Florida
city: Miami
country: United States
facility: Local Institution - 011-220
state: Florida
city: Okeechobee
country: United States
facility: Local Institution - 011-216
state: Florida
city: Pembroke Pines
country: United States
facility: Local Institution - 011-219
state: Florida
city: West Palm Beach
country: United States
facility: Local Institution - 011-262
state: Florida
city: Atlanta
country: United States
facility: Local Institution - 011-259
state: Georgia
city: Atlanta
country: United States
facility: Local Institution - 011-237
state: Georgia
city: Decatur
country: United States
facility: Local Institution - 011-235
state: Georgia
city: Chicago
country: United States
facility: Local Institution - 011-204
state: Illinois
city: Wichita
country: United States
facility: Local Institution - 011-223
state: Kansas
city: Shreveport
country: United States
facility: Local Institution - 011-205
state: Louisiana
city: Gaithersburg
country: United States
facility: Local Institution - 011-211
state: Maryland
city: Ann Arbor
country: United States
facility: Local Institution - 011-232
state: Michigan
city: Flowood
country: United States
facility: Local Institution - 011-226
state: Mississippi
city: Saint Charles
country: United States
facility: Local Institution - 011-227
state: Missouri
city: Saint Louis
country: United States
facility: Local Institution - 011-241
state: Missouri
city: Las Vegas
country: United States
facility: Local Institution - 011-239
state: Nevada
city: Berlin
country: United States
facility: Local Institution - 011-230
state: New Jersey
city: Marlton
country: United States
facility: Local Institution - 011-249
state: New Jersey
city: New York
country: United States
facility: Local Institution - 011-256
state: New York
city: New York
country: United States
facility: Local Institution - 011-210
state: New York
city: Rochester
country: United States
facility: Local Institution - 011-250
state: New York
city: Hickory
country: United States
facility: Clinical Trials of America
state: North Carolina
city: Dayton
country: United States
facility: Local Institution - 011-218
state: Ohio
city: North Canton
country: United States
facility: Local Institution - 011-248
state: Ohio
city: West Chester
country: United States
facility: Local Institution - 011-221
state: Ohio
city: Oklahoma City
country: United States
facility: SP Research PLLC
state: Oklahoma
city: Moosic
country: United States
facility: Global Medical Institutes LLC Scranton Medical Institute
state: Pennsylvania
city: West Chester
country: United States
facility: Local Institution - 011-207
state: Pennsylvania
city: Franklin
country: United States
facility: Psychiatric Consultants
state: Tennessee
city: Austin
country: United States
facility: Local Institution - 011-243
state: Texas
city: Austin
country: United States
facility: BioBehavioral Research of Austin P.C.
state: Texas
city: DeSoto
country: United States
facility: Local Institution - 011-236
state: Texas
city: Fort Worth
country: United States
facility: Local Institution - 011-258
state: Texas
city: Richmond
country: United States
facility: healthTx
state: Texas
city: Draper
country: United States
facility: Cedar Clinical Research
state: Utah
city: Bellevue
country: United States
facility: Local Institution - 011-209
state: Washington
city: Everett
country: United States
facility: Local Institution - 011-260
state: Washington
city: San Juan
country: Puerto Rico
facility: INSPIRA Clinical Research
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: