A Study to Assess Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Adult Patients With Schizophrenia (EMERGENT-3)

Schizophrenia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04738123
• Other study ID #: KAR-009
• Status: Completed
• Phase: Phase 3
• Start date: April 6, 2021
• Est. completion date: December 7, 2022

Study information

• Verified date: October 2023
• Source: Karuna Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 256
• Est. completion date: December 7, 2022
• Est. primary completion date: November 29, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Schizophrenia
• Schizophrenia; Psychosis

Intervention

Drug:
• Xanomeline and Trospium Chloride Capsules
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 8-35 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.
• Placebo
Placebo Capsules

Locations

Country	Name	City	State
Ukraine	Dnipropetrovsk Regional Clinical Hospital named after I.I. Mechnikov	Dnipro
Ukraine	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	Kharkiv
Ukraine	Regional Clinical Psychiatric Hospital No. 3, Psychiatric Department for First Episode Psychosis	Kharkiv
Ukraine	Kherson Regional Institution of Mental Care	Kherson
Ukraine	Kyiv City Psychoneurological Hospital #2	Kyiv
Ukraine	Kyiv Regional Medical Incorporation "Psychiatry", Center for Novel Treatment and Rehabilitation of Psychotic Disorders	Kyiv
Ukraine	Lviv Regional Clinical Psychiatric Hospital, Department #20	Lviv
Ukraine	Lviv Regional Clinical Psychiatric Hospital, Department #25	Lviv
Ukraine	Regional Institution of Mental Psychiatric Care of the Poltava Regional Council	Poltava
Ukraine	Cherkasy Regional Psychiatric Hospital of Cherkasy Regional Council	Smila
Ukraine	M.I. Pyrogov Vinnytsya National Medical University	Vinnytsya
United States	Advanced Research Center, Inc.	Anaheim	California
United States	Atlanta Center for Medical Research	Atlanta	Georgia
United States	Community Clinical Research, Inc.	Austin	Texas
United States	Clinical Innovations, Inc	Bellflower	California
United States	Pillar Clinical Research	Bentonville	Arkansas
United States	Hassman Research Institute	Berlin	New Jersey
United States	AMITA Health Center for Psychiatric Research	Chicago	Illinois
United States	Uptown Research Institute	Chicago	Illinois
United States	ProScience Research Group	Culver City	California
United States	iResearch Atlanta, LLC	Decatur	Georgia
United States	InSite Clinical Research, LLC	DeSoto	Texas
United States	Collaborative Neuroscience Research, LLC.	Garden Grove	California
United States	AMITA Health Center for Psychiatric Research	Hoffman Estates	Illinois
United States	Behavioral Clinical Research, Inc.	Hollywood	Florida
United States	Larkin Behavioral Health Services	Hollywood	Florida
United States	Woodland International Research Group	Little Rock	Arkansas
United States	CNS Network	Long Beach	California
United States	Hassman Research Institute	Marlton	New Jersey
United States	NRC Research Institute	Orange	California
United States	Artemis Institute for Clinical Research	San Diego	California

Sponsors (1)

Lead Sponsor	Collaborator
Karuna Therapeutics

Countries where clinical trial is conducted

United States,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 5	The PANSS is a medical scale used for measuring symptom severity of participants with schizophrenia. 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 total score is the sum of all scales with a minimum score of 30 and a maximum score of 210. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms.	Week 5
Secondary	Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Positive Score at Week 5	The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. For positive symptoms in schizophrenia, participants are rated from 1 to 7 on each symptom scale, with a minimum score of 7 and a maximum score of 49. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms.	Week 5
Secondary	Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Negative Score at Week 5	The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. For negative symptoms in schizophrenia, participants are rated from 1 to 7 on each symptom scale, with a minimum score of 7 and a maximum score of 49. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms.	Week 5
Secondary	Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Negative Marder Factor Score	The Negative Marder Factor score is derived from the PANSS and consists of the sum of 5 negative scales (N) and 2 general scales (G) (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), with a minimum score of 7 and a maximum score of 49.	Week 5
Secondary	Clinical Global Impression - Severity (CGI-S) Score at Week 5	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.	Week 5
Secondary	Percentage of Positive and Negative Syndrome Scale (PANSS) responders (a 30% change in PANSS total score) at Week 5	The PANSS is a medical scale used for measuring symptom severity of participants with schizophrenia. 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 total score is the sum of all scales with a minimum score of 30 and a maximum score of 210. A PANSS responder is defined as a participant with at least a 30% change in PANSS total score compared to baseline at Week 5.	Week 5