Clinical trial NCT04738123: A Study to Assess Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Adult Patients With Schizophrenia (EMERGENT-3)
Official title: A Phase 3, Randomized, Double-blind, Parallel-group, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Adults With DSM-5 Schizophrenia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Schizophrenia
Schizophrenia; Psychosis
Lead sponsor: Karuna Therapeutics
Sponsor class: INDUSTRY
First posted: 2021-02-04
Enrollment: 256
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase 3, randomized, double-blind, parallel-group, placebo-controlled, multicenter inpatient study to examine the efficacy and safety of KarXT in adult subjects who are acutely psychotic with a Diagnostic and Statistical Manual Fifth Edition (DSM-5) diagnosis of schizophrenia. The primary objective of the study is to assess the efficacy of KarXT (a fixed combination of xanomeline 125 mg and trospium chloride 30 mg twice daily \[BID\]) versus placebo in reducing Positive and Negative Syndrome Scale (PANSS) total scores in adult inpatients with a DSM-5 diagnosis of schizophrenia. The secondary objectives of the study are to evaluate improvement in disease severity and symptoms, safety and tolerability, and pharmacokinetics in adult inpatients with a DSM-5 diagnosis of schizophrenia.


Eligibility criteria: Inclusion Criteria:

1. Subject is aged 18 to 65 years, inclusive, at screening.
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 (oral and written) in English or local language to consent
3. Subject has a primary diagnosis of schizophrenia established by a comprehensive psychiatric evaluation based on the DSM-5 criteria and confirmed by Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorder Studies (MINI) version 7.0.2.
4. Subject is experiencing an acute exacerbation or relapse of psychotic symptoms, with onset less than 2 months before screening.

   1. The subject requires hospitalization for this acute exacerbation or relapse of psychotic symptoms.
   2. If already an inpatient at screening, has been hospitalized for less than 2 weeks for the current exacerbation at the time of screening.
5. Positive and Negative Syndrome Scale total score between 80 and 120, inclusive. Score of ≥4 (moderate or greater) for ≥2 of the following Positive Scale (P) items:

   1. Item 1 (P1; delusions)
   2. Item 2 (P2; conceptual disorganization)
   3. Item 3 (P3; hallucinatory behavior)
   4. Item 6 (P6; suspiciousness/persecution)
6. Subjects with no change (improvement) in PANSS total score between screening and baseline (Day -1) of more than 20%.
7. Subject has a CGI-S score of ≥4 at screening and baseline (Day -1) visits.
8. Subject will have been off lithium therapy for at least 2 weeks before baseline and free of all oral antipsychotic medications for at least 5 half-lives or 1 week, whichever is longer, before baseline (Day -1).
9. Subjects taking a long-acting injectable antipsychotic could not have received a dose of medication for at least 12 weeks (24 weeks for INVEGA TRINZA) before baseline visit (Day -1).
10. Subject is willing and able to be confined to an inpatient setting for the study duration, follow instructions, and comply with the protocol requirements.
11. BMI must be ≥18 and ≤40 kg/m2.
12. Subject resides in a stable living situation and is anticipated to return to that same stable living situation after discharge, in the opinion of the investigator.
13. Subject has an identified reliable informant/caregiver.
14. Women of childbearing potential, or men with sexual partners of childbearing potential, must be able and willing to use at least 1 highly effective method of contraception during the study and for 30 days after the last dose of study drug. Sperm donation is not allowed for 30 days after the final dose of study drug.

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). Symptoms of mild mood dysphoria or anxiety are allowed as long as these symptoms are not the primary focus of treatment. 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 they can be allowed into the study.
2. Subjects who are newly diagnosed or are experiencing their first treated episode of schizophrenia.
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. Subjects with 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 on the physical examination, medical history, ECG, or clinical laboratory results at screening.
9. Subjects cannot currently (within 5 half-lives or 1 week, whichever is longer, before baseline \[Day -1\]) be receiving oral antipsychotic medications; monoamine oxidase inhibitors; anticonvulsants (eg, lamotrigine, Depakote); tricyclic antidepressants (eg, imipramine, desipramine); selective serotonin reuptake inhibitors; or any other psychoactive medications except for as needed anxiolytics (eg, lorazepam, chloral hydrate).
10. Pregnant, lactating, or less than 3 months postpartum.
11. 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.
12. Positive test for coronavirus (COVID-19) within 2 weeks before screening and at screening.
13. Subjects with extreme concerns relating to global pandemics, such as COVID-19, that preclude study participation.
14. Subject has had psychiatric hospitalization(s) for more than 30 days (cumulative) during the 90 days before screening.
15. 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.
16. Subjects with prior exposure to KarXT.
17. Subjects who experienced any adverse effects due to xanomeline or trospium.
18. Participation in another clinical study in which the subject received an experimental or investigational drug agent within 3 months before screening.
19. Risk of violent or destructive behavior.
20. Current involuntary hospitalization or incarceration.

Primary outcomes:
measure: Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 5
timeFrame: From baseline up to Week 5
Secondary outcomes:
measure: Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Positive Score at Week 5
timeFrame: From baseline up to Week 5
measure: Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Negative Score at Week 5
timeFrame: From baseline up to Week 5
measure: Positive and Negative Syndrome Scale (PANSS) Negative Marder Factor Score Change From Baseline at Week 5
timeFrame: From baseline up to Week 5
measure: Clinical Global Impression-Severity (CGI-S) Score Change From Baseline at Week 5
timeFrame: From baseline up to Week 5
measure: Number of Participants Who Achieve >=30% Reduction in Positive and Negative Symptoms Scale (PANSS) Total Score From Baseline to Week 5
timeFrame: From baseline up to Week 5
measure: Number of Participants Experiencing Adverse Events (AEs)
timeFrame: From first dose up to Day 42
measure: Number of Participants Experiencing Cholinergic Symptom Adverse Event
timeFrame: From first dose up to Day 42
measure: Change From Baseline in Simpson-Angus Scale Total Score (SAS)
timeFrame: From baseline up to week 5
measure: Change From Baseline in Barnes Akathisia Rating Scale (BARS) Total Score
timeFrame: From baseline up to week 5
measure: Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score
timeFrame: From baseline up to week 5
measure: Number of Participants Who Experienced Weight Change
timeFrame: From baseline up to week 5
measure: Change From Baseline in Body Mass Index (BMI)
timeFrame: From baseline up to week 5
measure: Change From Baseline in Waist Circumference
timeFrame: From baseline up to week 5
measure: Change From Baseline in Orthostatic Vital Signs - Blood Pressure
timeFrame: From baseline up to week 5
measure: Change From Baseline in Orthostatic Vital Signs - Heart Rate
timeFrame: From baseline up to week 5
measure: Change From Baseline in Electrocardiogram (ECG) Mean Heart Rate
timeFrame: From baseline up to Day 35 or early termination
measure: Number of Participants Experiencing Clinically Significant Abnormal Physical Examination Results
timeFrame: From baseline up to week 5
measure: Number of Participants Experiencing Each Suicidal Ideation Scale Category as Per Columbia Suicide Severity Rating Scale (C-SSRS)
timeFrame: From screening up to Day 42
measure: Area Under the Plasma Concentration-Time Curve (AUC)
timeFrame: At days 8 and 28
measure: Maximum Concentration (Cmax)
timeFrame: At days 8 and 28
measure: Time to Maximum Concentration (Tmax)
timeFrame: At days 8 and 28
measure: Mean Observed Hemoglobin Levels
timeFrame: From baseline up to Days 21, 35, or early temination
measure: Mean Observed Hematocrit Levels
timeFrame: From baseline up to Days 21, 35, or early temination
measure: Mean Observed Erythrocyte Levels
timeFrame: From baseline up to Days 21, 35, or early temination
measure: Mean Observed Platelets Levels
timeFrame: From baseline up to Days 21, 35, or early temination
measure: Mean Observed Leukocytes Levels
timeFrame: From baseline up to Days 21, 35, or early temination
measure: Mean Observed Lymphocytes Levels
timeFrame: From baseline up to Days 21, 35, or early temination
measure: Mean Observed Activated Partial Thromboplastin Time
timeFrame: From baseline up to Days 21, 35, or early temination
measure: Mean Observed Prothrombin Time
timeFrame: From baseline up to Days 21, 35, or early temination
measure: Mean Observed Urinalysis - pH
timeFrame: From baseline up to Days 21, 35, or early temination
measure: Mean Observed Urinalysis - Prolactin
timeFrame: From baseline up to Days 21, 35, or early temination
measure: The Number of Participants With Positive Drug Screen Results
timeFrame: At screening, at Dat -1, and upon return from departure from study site at any time up to Day 42
measure: The Number of Participants With Elevated Liver Function Test Results
timeFrame: From screening up to Day 42
Other outcomes:
Locations:
city: Bentonville
country: United States
facility: Pillar Clinical Research
state: Arkansas
city: Little Rock
country: United States
facility: Woodland International Research Group
state: Arkansas
city: Anaheim
country: United States
facility: Advanced Research Center, Inc.
state: California
city: Bellflower
country: United States
facility: Clinical Innovations, Inc
state: California
city: Culver City
country: United States
facility: ProScience Research Group
state: California
city: Garden Grove
country: United States
facility: Collaborative Neuroscience Research, LLC.
state: California
city: Long Beach
country: United States
facility: CNS Network
state: California
city: Orange
country: United States
facility: NRC Research Institute
state: California
city: San Diego
country: United States
facility: Artemis Institute for Clinical Research
state: California
city: Hollywood
country: United States
facility: Behavioral Clinical Research, Inc.
state: Florida
city: Hollywood
country: United States
facility: Larkin Behavioral Health Services
state: Florida
city: Atlanta
country: United States
facility: Atlanta Center for Medical Research
state: Georgia
city: Decatur
country: United States
facility: iResearch Atlanta, LLC
state: Georgia
city: Chicago
country: United States
facility: AMITA Health Center for Psychiatric Research
state: Illinois
city: Chicago
country: United States
facility: Uptown Research Institute
state: Illinois
city: Hoffman Estates
country: United States
facility: AMITA Health Center for Psychiatric Research
state: Illinois
city: Berlin
country: United States
facility: Hassman Research Institute
state: New Jersey
city: Marlton
country: United States
facility: Hassman Research Institute
state: New Jersey
city: Austin
country: United States
facility: Community Clinical Research, Inc.
state: Texas
city: DeSoto
country: United States
facility: InSite Clinical Research, LLC
state: Texas
city: Dnipro
country: Ukraine
facility: Dnipropetrovsk Regional Clinical Hospital named after I.I. Mechnikov
city: Kharkiv
country: Ukraine
facility: Institute of Neurology, Psychiatry and Narcology of the National Academy of Medical Sciences of Ukraine
city: Kharkiv
country: Ukraine
facility: Regional Clinical Psychiatric Hospital No. 3, Adult Psychiatric Department No. 3
city: Kharkiv
country: Ukraine
facility: Regional Clinical Psychiatric Hospital No. 3, Psychiatric Department for First Episode Psychosis
city: Kherson
country: Ukraine
facility: Kherson Regional Institution of Mental Care
city: Kyiv
country: Ukraine
facility: Kyiv City Psychoneurological Hospital #2
city: Kyiv
country: Ukraine
facility: Kyiv Regional Medical Incorporation "Psychiatry", Center for Novel Treatment and Rehabilitation of Psychotic Disorders
city: Lviv
country: Ukraine
facility: Lviv Regional Clinical Psychiatric Hospital, Department #20
city: Lviv
country: Ukraine
facility: Lviv Regional Clinical Psychiatric Hospital, Department #25
city: Poltava
country: Ukraine
facility: Regional Institution of Mental Psychiatric Care of the Poltava Regional Council
city: Smila
country: Ukraine
facility: Cherkasy Regional Psychiatric Hospital of Cherkasy Regional Council
city: Vinnytsya
country: Ukraine
facility: M.I. Pyrogov Vinnytsya National Medical University
Study officials:
affiliation: Karuna Therapeutics
name: Inder Kaul, MD
role: STUDY_DIRECTOR
References: