A Study to Assess Efficacy and Safety of Adjunctive KarXT in Subjects With Inadequately Controlled Symptoms of Schizophrenia

Schizophrenia Clinical Trial

— ARISE  

Official title:

A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of Adjunctive KarXT in Subjects With Inadequately Controlled Symptoms of Schizophrenia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05145413
• Other study ID #: CN012-0008
• Secondary ID: CN012-0008KAR-01
• Status: Recruiting
• Phase: Phase 3
• Start date: November 12, 2021
• Est. completion date: February 28, 2025

Study information

• Verified date: June 2024
• Source: Karuna Therapeutics
• Contact: BMS Clinical Trials Contact Center www.BMSClinicalTrials.com
• Phone: 855-907-3286
• Email: Clinical.Trials[@]bms.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase 3, 6-week, randomized, double-blind, placebo-controlled, multicenter, outpatient study in subjects with schizophrenia with an inadequate response to their current atypical antipsychotic treatment. The primary objective of the study is to assess the efficacy of adjunctive KarXT (a fixed dose combination of xanomeline and trospium chloride twice daily [BID]) versus placebo in the treatment of subjects with inadequately controlled symptoms of schizophrenia as measured by the Positive and Negative Syndrome Scale (PANSS) Total Score.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: February 28, 2025
• Est. primary completion date: February 28, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 59 Years

Eligibility

Inclusion Criteria:

1. Subject is aged =18 to <60 years at the time of randomization

2. Subject is capable of providing signed Informed Consent Form before any study assessments will be performed

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 currently being treated with stable dosing of monotherapy risperidone, paliperidone, aripiprazole, or their LAIs ziprasidone, lurasidone, or cariprazine and has been taking this treatment with the same dosing regimen for at least 8 weeks at the time of Day 1 (Visit 3)

5. The subject has had at least 1 previous inadequate response to above antipsychotics that was dosed appropriately (within the label) for at least 6 weeks

6. The subject has not required psychiatric hospitalization, incarceration in prison, acute crisis intervention, or other increase in the level of care due to symptom exacerbation within 8 weeks of Screening and is psychiatrically stable in the opinion of the Investigator

7. To be eligible for randomization, subjects need to have detectable levels of background antipsychotic medication (measured at Visit 1)

8. Positive and Negative Syndrome Scale (PANSS) total score = 70 at Screening and randomization

9. Clinical Global Impression-Severity (CGI-S) scale with a score = 4 (moderate) at Screening and randomization

10. PANSS Marder Positive symptom factor = 4 on 2 (or more) items (PANSS items, delusions, hallucinations, grandiosity, suspiciousness and persecution, stereotyped thinking, somatic concern, unusual thought content or lack of judgment and insight), at Screening and randomization

11. Subjects with = 20-point decrease in PANSS Total score between Visit 1 and Visit 3

12. Subject is willing and able to visit the clinic in an outpatient setting for the study duration, follow instructions, and comply with the protocol requirements

13. Body Mass Index (BMI) must be within 18 to 40 kg/m2 (inclusive of both values)

14. Subject resides in a stable living situation in the opinion of the Investigator

15. Subject has identified a reliable informant/ caregiver willing and able to assist with study activities as needed throughout the subject's participation in the study. The informant needs to be physically present at the Baseline visit, but can complete the remaining study visits assessments via phone (as needed and as per local regulations). In Bulgaria, the informant needs to physically present at the Baseline visit and should be physically present at all study visits where the Investigator determines that his/her input would be beneficial.

16. Women of childbearing potential (WOCP), or men whose sexual partners are WOCP, must be able and willing to use at least 1 highly effective method of contraception during the study and for at least 1 menstrual cycle (e.g., 30 days) after the last dose of study drug. Sperm donation is not allowed for 30 days after the final dose of the study drug. A female subject is considered to be a WOCP after menarche and until she is in a postmenopausal state for 12 months or otherwise permanently sterile (for which acceptable methods include hysterectomy, bilateral salpingectomy, or bilateral oophorectomy)

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. The subject has a history of moderate to severe substance use disorder (other than nicotine) within the past 12 months

1. A Screening subject with mild substance use disorder within the 12 months before Screening must be discussed with the Medical Monitor before being allowed into the study

2. Subjects who test positive for cannabis at Screening may be permitted to enroll in consultation with the Medical Monitor if the subject's pattern of use is not indicative of a moderate to severe substance use disorder

3. Subject has a history of treatment-resistant schizophrenia defined as:

a. Failure to minimally respond to 2 adequate courses of antipsychotic drug (APD) pharmacotherapy Note: Failure to minimally respond is defined as persistence symptoms of moderate severity in 2 or more psychotic symptom domains or persistence of severe symptoms in 1 or more psychotic symptom domains despite adequate dose and duration (6 weeks or longer) of APD treatment.

4. History of symptom instability a. > 3 psychiatric hospitalizations over the last 12 months or 2 over the last 6 months

5. Current APD is other than aripiprazole, risperidone, paliperidone, or their LAI versions, ziprasidone, lurasidone, or cariprazine

6. Subjects who are diagnosed with schizophreniform disorder or are experiencing their first treated episode of schizophrenia

7. Significant or severe medical conditions including pulmonary, cardiovascular, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or oncologic disease or any other condition that, in the opinion of the Investigator, could jeopardize the safety of the subject or the validity of the study results

8. Subjects with human immunodeficiency virus (HIV), cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma, and/or active hepatic viral infections as indicated by medical history, serologies or LFT results

9. History or high risk of urinary retention, gastric retention, or narrow-angle glaucoma as evaluated by the Investigator

10. History of irritable bowel syndrome (with or without constipation) or any serious constipation requiring treatment within the last 6 months

11. Risk for suicidal behavior during the study as determined by the Investigator's

clinical assessment and/or C-SSRS as confirmed by the following:

1. Answers "Yes" on items 4 or 5 (C-SSRS - ideation) with the most recent episode occurring within the 2 months before Screening or,

2. Answers "Yes" to any of the 5 items (C-SSRS behavior) with an episode occurring within the 12 months before Screening

12. Clinically significant abnormal finding on the physical examination, medical history, ECG, or clinical laboratory results at Screening

13. Urine toxicology screen is positive for phencyclidine, amphetamines, opiates, cocaine, or alcohol (clinically significant alcohol use in the opinion of the Investigator)

14. Subject is currently taking, or plans to take while in the study, any prohibited concomitant medication.

15. Pregnant, lactating, or less than 3 months postpartum

16. If, in the opinion of the Investigator and/or Sponsor/Medical Monitor subject is unsuitable for enrollment in the study or subject has any finding that, in the view of the Investigator and/or Sponsor/Medical Monitor, may compromise the safety of the subject or affect his/her ability to adhere to the protocol visit schedule or fulfill visit requirements

17. Positive test for coronavirus (COVID-19) within 2 weeks or at Screening

18. Subjects with extreme concerns relating to global pandemics, such as COVID-19, that would obscure ratings or be expected to disrupt adherence to trial procedures

19. Unable to taper and discontinue a concomitant medication that would preclude participation in the double-blind adjunctive treatment (e.g., cannot stop anticholinergic)

20. Subjects with prior exposure to KarXT

21. Subjects who experienced any adverse effects due to xanomeline or trospium

22. Participation in another clinical study in which the subject was enrolled within 3 months before Screening

23. Risk of violent or destructive behavior as per Investigator's judgment that would interfere with subject's participation

24. Current involuntary hospitalization or incarcerationor on parole/probation

25. For all male subjects only, any one of the following:

1. History of bladder stones

2. History of recurrent urinary tract infections

3. Serum prostate specific antigen (PSA) >10 ng/mL

4. An International Prostate Symptom Score (IPSS) of 5 (almost always) on either item 1, 3, 5, or 6

5. A sum of scores on IPSS items 1, 3, 5, and 6 of =9 Note: IPSS will be required only for male subjects = 45 years of age. Subjects already enrolled in the study will have these assessments at their next clinic visit planned after re-consenting to determine current eligibility.

Related Conditions & MeSH terms

• Schizophrenia

Intervention

Drug:
• Xanomeline and Trospium Chloride Capsules
KarXT 50 mg/20 mg BID KarXT 75mg/20 mg BID KarXT 100mg/20 mg BID KarXT 125mg/30 mg BID
• Placebo
Placebo Capsules

Locations

Country	Name	City	State
Bulgaria	Ambulatory for Individual Practice for Specialized Medical Care in Psychiatry - Dr Ivo Natsov	Cherven Bryag
Bulgaria	Medical Centre Asklepii, OOD	Dupnitsa
Bulgaria	Medical Center Lifemed	Kardzhali
Bulgaria	State Psychiatric Hospital Sv. Ivan Rilski, Novi Iskar	Novi Iskar
Bulgaria	Medical Center Medconsult Pleven OOD	Pleven
Bulgaria	UMHAT 'Dr. Georgi Stranski', EAD	Pleven
Bulgaria	Local Institution - 321	Plovdiv
Bulgaria	UMHAT Sv. Georgi, EAD	Plovdiv
Bulgaria	Local Institution - 313	Razgrad
Bulgaria	MHAT Dr Ivan Seliminski AD	Sliven
Bulgaria	"Medical Center ""Sv.Naum"""	Sofia
Bulgaria	DCC Sv. Vrach and Sv. Sv. Kuzma and Damyan, OOD	Sofia
Bulgaria	Local Institution - 320	Sofia
Bulgaria	Medical Center Akademika EOOD	Sofia
Bulgaria	Medical Center Hera EOOD	Sofia
Bulgaria	Medical Center Intermedica, OOD	Sofia
Bulgaria	MHC - Sofia, EOOD	Sofia
Bulgaria	Medical Center VAS OOD	Targovishte
Bulgaria	DCC Mladost M - Varna, OOD	Varna
Bulgaria	Mental Health Center-Vratsa EOOD	Vratsa
India	Local Institution - 604	Ahmedabad	Gujarat
India	Local Institution - 607	Ahmedabad	Gujarat
India	Local Institution - 615	Ajmer	Rajasthan
India	Local Institution - 610	Aurangabad	Maharashtra
India	Local Institution - 617	Belgavi	Karnataka
India	Local Institution - 618	Bikaner	Rajasthan
India	Local Institution - 616	Guwahati	Assam
India	Local Institution - 611	Kozhikode	Kerala
India	Local Institution - 612	Lucknow	Uttar Pradesh
India	Local Institution - 602	Mangalore	Karnataka
India	Local Institution - 614	Mangalore	Karnataka
India	Local Institution - 619	Mumbai	Maharashtra
India	Local Institution - 601	Mysore	Karnataka
India	Local Institution - 603	Nagpur	Maharashtra
India	Local Institution - 605	Nashik	Maharashtra
India	Local Institution - 608	Nashik	Maharashtra
India	Local Institution - 606	Rajkot	Rajasthan
India	Local Institution - 609	Surat	Gujarat
India	Local Institution - 613	Vadodara	Gujarat
Poland	Local Institution - 506	Bialystok
Poland	Local Institution - 507	Gdansk
Poland	Local Institution - 509	Grudziadz
Poland	Local Institution - 501	Kielce
Poland	Local Institution - 503	Lodz
Poland	Local Institution - 505	Lublin
Poland	Local Institution - 502	Siemianowice Slaskie
Poland	Local Institution - 508	Suchy Las
Poland	Local Institution - 504	Tuszyn
Romania	Local Institution - 803	Brasov
Romania	Local Institution - 802	Bucuresti
Romania	Local Institution - 804	Bucuresti
Romania	Local Institution - 807	Bucuresti
Romania	Local Institution - 809	Bucuresti
Romania	Local Institution - 810	Bucuresti
Romania	Local Institution - 808	Craiova
Romania	Local Institution - 801	Galati
Romania	Local Institution - 806	Iasi
Romania	Local Institution - 805	Sibiu
Serbia	"Clinical Center "" Dr Dragisa Misovic Dedinje"""	Belgrade
Serbia	Institute of Mental Health	Belgrade
Serbia	Local Institution - 413	Belgrade
Serbia	Local Institution - 417	Belgrade
Serbia	University Clinical Center of Serbia	Belgrade
Serbia	"Special Hospital for Psychiatric Diseases ""Kovin"""	Kovin
Serbia	Local Institution - 414	Kovin
Serbia	University Clinical Center Kragujevac	Kragujevac
Serbia	University Clinical Center Kragujevac	Kragujevac
Serbia	University Clinical Center Kragujevac	Kragujevac
Serbia	University Clinical Center Kragujevac	Kragujevac
Serbia	"Special Hospital for Psychiatric Diseases ""Gornja Toponica"""	Nis
Serbia	Local Institution - 415	Nis
Serbia	"Special Hospital for Psychiatric Diseases ""Sveti Vracevi"""	Novi Knezevac
Serbia	Local Institution - 416	Novi Knezevac
Serbia	"Special Hospital for Psychiatric Disease ""Dr Slavoljub Bakalovic"""	Vrsac
United Kingdom	Local Institution - 706	Ashton Under Lyne	Greater Manchester
United Kingdom	Local Institution - 703	Birmingham	West Midlands
United Kingdom	Local Institution - 705	Brighton	East Sussex
United Kingdom	Local Institution - 702	Chertsey	Surrey
United Kingdom	Local Institution - 704	Glasgow	Strathclyde
United Kingdom	Local Institution - 701	London	Greater London
United Kingdom	Local Institution - 709	Maidstone	Kent
United Kingdom	Local Institution - 710	Manchester	Greater Manchester
United Kingdom	Local Institution - 708	Oxford	Oxfordshire
United Kingdom	Local Institution - 707	Pool, Reruth	Cornwall
United States	Advanced Research Center, Inc.	Anaheim	California
United States	Local Institution - 184	Ann Arbor	Michigan
United States	Grady Memorial Hospital	Atlanta	Georgia
United States	Synexus Clinical Research US, Inc.	Atlanta	Georgia
United States	Local Institution - 135	Augusta	Georgia
United States	Community Clinical Research, Inc.	Austin	Texas
United States	Insight Clinical Trials LLC	Beachwood	Ohio
United States	Northwest Clinical Research Center	Bellevue	Washington
United States	CITrials - Bellflower	Bellflower	California
United States	Local Institution - 158	Boston	Massachusetts
United States	Local Institution - 187	Boston	Massachusetts
United States	Synexus Clinical Research US, Inc.	Cerritos	California
United States	American Medical Research, Inc.	Chicago	Illinois
United States	Northwestern University	Chicago	Illinois
United States	Uptown Research Institute, LLC	Chicago	Illinois
United States	University of Cincinnati Medical Center	Cincinnati	Ohio
United States	Clinical Innovations Inc.	Costa Mesa	California
United States	Arch Clinical Trials LLC	Creve Coeur	Missouri
United States	Proscience Research Group	Culver City	California
United States	CenExel iResearch Atlanta	Decatur	Georgia
United States	Local Institution - 179	Eugene	Oregon
United States	CenExel Center for Behavioral Health	Gaithersburg	Maryland
United States	Local Institution - 168	Garfield Heights	Ohio
United States	Galiz Research, LLC	Hialeah	Florida
United States	Reliable Clinical Research LLC	Hialeah	Florida
United States	IMA Clinical Research Hickory	Hickory	North Carolina
United States	Larkin Community Hospital Behavioral Health Services	Hollywood	Florida
United States	Local Institution - 180	Houston	Texas
United States	Local Institution - 183	Houston	Texas
United States	University Hills Clinical Research - Irving	Irving	Texas
United States	Western Michigan University Homer Stryker M.D. School of Medicine	Kalamazoo	Michigan
United States	Omega Clinical Trials	La Habra	California
United States	Sunwise Clinical Research, LLC.	Lafayette	California
United States	Michigan State University	Lansing	Michigan
United States	Altea Research Institute, Las Vegas	Las Vegas	Nevada
United States	Synergy Clinical Research of Escondido	Lemon Grove	California
United States	Pillar Clinical Research, LLC	Little Rock	Arkansas
United States	Woodland International Research Group, LLC	Little Rock	Arkansas
United States	Encino Hospital Medical Center	Los Angeles	California
United States	Psych Atlanta, P.C.	Marietta	Georgia
United States	Local Institution - 188	Marlton	New Jersey
United States	Local Institution - 120	Miami	Florida
United States	Premier Clinical Research Institute, Inc.	Miami	Florida
United States	Assertive Research Center	Miami Lakes	Florida
United States	San Marcus Research Clinic, Inc.	Miami Lakes	Florida
United States	South Florida Research Phase I-IV, Inc.	Miami Springs	Florida
United States	St. Francis Medical Center	Monroe	Louisiana
United States	Manhattan Behavioral Medicine, PLLC	New York	New York
United States	Manhattan Psychiatric Center	New York	New York
United States	Synexus Clinical Research US, Inc.	New York	New York
United States	Excell Research, Inc.	Oceanside	California
United States	Omaha Insomnia and Psychiatric Services LLC	Omaha	Nebraska
United States	Neuropsychiatric Research Center of Orange County	Orange	California
United States	Local Institution - 124	Orange City	Florida
United States	Pines Care Research Center, Inc.	Pembroke Pines	Florida
United States	Local Institution - 147	Phoenix	Arizona
United States	Local Institution - 161	Phoenix	Arizona
United States	CNRI - Los Angeles, LLC	Pico Rivera	California
United States	Phoenix Medical Research, Inc.	Prairie Village	Kansas
United States	Pillar Clinical Research, LLC	Richardson	Texas
United States	At Health Texas	Richmond	Texas
United States	CenExel Clinical Innovations, Inc.	Riverside	California
United States	Psychiatry and Alzheimer's Care of Rochester. PLLC	Rochester	New York
United States	Green Mountain Research Institute	Rutland	Vermont
United States	PsychCare Consultants Research	Saint Louis	Missouri
United States	Local Institution - 164	Stanford	California
United States	Richmond Behavioral Associates ERG Clinical Research - New York PLLC	Staten Island	New York
United States	Interventional Psychiatry of Tampa Bay	Tampa	Florida
United States	Local Institution - 186	Tampa	Florida
United States	CenExel Collaborative Neuroscience Research	Torrance	California
United States	CenExel Collaborative Neuroscience Research	Torrance	California
United States	Local Institution - 185	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Karuna Therapeutics

Countries where clinical trial is conducted

United States,  Bulgaria,  India,  Poland,  Romania,  Serbia,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 6	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 6
Secondary	Change from Baseline in Personal Social Performance (PSP) at Week 6	The PSP scale assesses functioning using a structured clinical interview across four dimensions: socially useful activities, personal and social relationships, self-care, and disturbing and aggressive behaviors. The PSP provides a score between 1 and 100 using a 6-point severity scale	Week 6
Secondary	Change from Baseline in Clinical Global Impression-Severity (CGI-S) at Week 6	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 6
Secondary	Change from Baseline in Positive and Negative Syndrome Scale (PANSS) Marder Positive symptom factor score at Week 6	The Positive Marder Factor score is derived from the PANSS and consists of the sum of 4 positive symptom items (P), one negative symptom item (N) and 3 general symptom items (G) (P1. Delusions; P3. Hallucinations; P5. Grandiosity; P6. Suspiciousness and persecution; N7. Stereotyped thinking; G1. Somatic concern; G9. Unusual thought content; G12. Lack of judgment and insight).	Week 6
Secondary	Change from Baseline in Positive and Negative Syndrome Scale (PANSS) Marder Negative symptom factor score at Week 6	The Negative Marder Factor score is derived from the PANSS and consists of the sum of 5 negative symptom items (N) and 2 general symptom items (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 6
Secondary	Categorical response defined as the proportion of subjects achieving a = 30% improvement in PANSS total score at Week 6		Week 6
Secondary	Preference of Medication (POM) at Week 6	The POM is a two-item questionnaire assessing the patient's and informant's preference, respectively, for the current antipsychotic as compared with the most recent pre-study antipsychotic. The POM is scored on the following scale: 1 = 'much better, I prefer this medication,' 2 = 'slightly better,' 3 = 'about the same,' 4 = 'slightly worse,' and 5 = 'much worse, I much prefer my previous medication.'	Week 6

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