New combo pill shows promise for Tough-to-Treat schizophrenia

NCT ID NCT05145413

Disease control Sponsor: Karuna Therapeutics, Inc., a Bristol Myers Squibb company Source: ClinicalTrials.gov ↗

First seen Jun 27, 2026 · Last updated Jun 27, 2026

Summary

This phase 3 trial tested KarXT, a combination of two drugs, as an add-on treatment for 396 adults with schizophrenia whose symptoms were not well controlled by their current medication. Over 6 weeks, researchers measured changes in symptom severity using a standard rating scale. The goal was to see if adding KarXT could improve symptom control better than a placebo.

What this could mean

Our plain-language read of the trial. This is informational only, not medical advice or a prediction.

Active substance: KarXT (a combination of xanomeline and trospium chloride)
What this could lead to: If successful, KarXT could become a new add-on treatment to help control schizophrenia symptoms when current medications aren't enough.
What could go wrong: This is a 6-week study, so long-term safety and effectiveness are unknown. The improvement may be modest, and side effects like nausea or constipation are possible.

This is an AI summary of the original study and may miss details. Read our disclaimer.

Study facts

What this study's own registry entry says, in plain language.

Phase

Phase 3

Large-scale testing in a bigger group. Usually the last step before a treatment can be approved.

Participants

396 people

The number who actually took part.

Started

Nov 2021

Finished

Mar 2025

Lead sponsor

A company

The lead sponsor is a pharmaceutical, biotech, or medical-device company.

Who can take part

This study's own entry requirements. Only the study team can say for certain whether you qualify.

Ages

18 to 65 years

Sex

Anyone

Healthy volunteers

Not accepted

This study is not open to healthy volunteers. The entry requirements below say who it is open to.

Show the full entry requirements

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

Inclusion Criteria: 1. Subject is aged ≥18 to \<65 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 1. eGFR \< 60 mL/min 2. Alanine transaminase or aspartate transaminase (AST) \> 1.5 x upper limit of normal (ULN) 3. Total bilirubin \> 1.5 x ULN (Subjects with Gilbert's syndrome can be included as long as direct bilirubin is ≤ 1.5 x ULN) 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. Subjects who received investigational product as part of a clinical trial within 3 months of 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.

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Conditions

The condition(s) this trial relates to.

schizophrenia

As listed by the trial registrant

The condition terms exactly as the trial's registrant entered them.

Schizophrenia

Contacts and locations

Locations

"Special Hospital for Psychiatric Diseases ""Kovin"""

Kovin, 26220, Serbia
Adaptive Clinical Research, Inc

Lauderhill, Florida, 33319-4985, United States
Advanced Research Center, Inc.

Anaheim, California, 92805, United States
Altea Research Institute, Las Vegas

Las Vegas, Nevada, 89102, United States
Ambulatory for Individual Practice for Specialized Medical Care in Psychiatry - Dr Ivo Natsov

Cherven Bryag, 5980, Bulgaria
American Medical Research, Inc.

Chicago, Illinois, 60612-2307, United States
Arch Clinical Trials LLC

St Louis, Missouri, 63141, United States
Assertive Research Center

Miami Lakes, Florida, 33016, United States
At Health Texas

Richmond, Texas, 77407, United States
Behavioral Clinical Research , Inc

Miami, Florida, 33016, United States
Ben Taub Hospital

Houston, Texas, 77030, United States
CITrials - Bellflower

Bellflower, California, 90706-7079, United States
CNRI - Los Angeles, LLC

Pico Rivera, California, 90660, United States
CenExel Center for Behavioral Health

Gaithersburg, Maryland, 20877, United States
CenExel Clinical Innovations, Inc.

Riverside, California, 92506, United States
CenExel Collaborative Neuroscience Research

Garden Grove, California, 92845, United States
CenExel Collaborative Neuroscience Research

Torrance, California, 90504, United States
CenExel Hassman Research Institute

Berlin, New Jersey, 08009, United States
CenExel iResearch Atlanta

Decatur, Georgia, 30030, United States
CenExel iResearch, LLC

Savannah, Georgia, 31405, United States
Cherry Health

Grand Rapids, Michigan, 49548-6927, United States
Clinical Center ' Dr Dragisa Misovic Dedinje'

Belgrade, 11000, Serbia
Clinical Innovations Inc.

Costa Mesa, California, 92626, United States
Clinical Trial Network LLC

Houston, Texas, 77074, United States
Clinical Trials of America - Psychiatry

Hickory, North Carolina, 28601, United States
Cnri-San Diego

San Diego, California, 92123, United States
Community Clinical Research, Inc.

Austin, Texas, 78754, United States
DCC 'Sv. Vrach and Sv. Sv. Kuzma and Damyan', OOD

Sofia, 1408, Bulgaria
DCC Mladost M - Varna, OOD

Varna, 9020, Bulgaria
Encino Hospital Medical Center

Los Angeles, California, 91403, United States
Envision Trials LLC

Miami Springs, Florida, 33166, United States
Excell Research, Inc.

Oceanside, California, 92056, United States
Galiz Research, LLC

Hialeah, Florida, 33016-1814, United States
Grady Memorial Hospital

Atlanta, Georgia, 30303, United States
Green Mountain Research Institute

Rutland, Vermont, 05701, United States
IMA Clinical Research

Phoenix, Arizona, 85012, United States
IMA Clinical Research

Monroe, Louisiana, 71201-2986, United States
InSite Clinical Research; LLC

DeSoto, Texas, 75115, United States
Insight Clinical Trials LLC

Independence, Ohio, 44131, United States
Institute of Mental Health

Belgrade, 11000, Serbia
Interventional Psychiatry of Tampa Bay

Tampa, Florida, 33629, United States
JPS Health Network

Fort Worth, Texas, 76104, United States
Local Institution - 124

Orange City, Florida, 32763, United States
Local Institution - 129

St Louis, Missouri, 63128, United States
Local Institution - 135

Augusta, Georgia, 30912, United States
Local Institution - 147

Phoenix, Arizona, 85012, United States
Local Institution - 158

Boston, Massachusetts, 02114, United States
Local Institution - 168

Garfield Heights, Ohio, 44125, United States
Local Institution - 185

Worcester, Massachusetts, 01655, United States
Local Institution - 186

Coral Gables, Florida, 33134, United States
Local Institution - 187

Boston, Massachusetts, 02118, United States
Local Institution - 192

Atlanta, Georgia, 30331, United States
Local Institution - 250

Toyoake-shi, Aichi-ken, 470-1168, Japan
Local Institution - 254

Karatsu-shi, Saga-ken, 847-0031, Japan
Local Institution - 255

Fukuoka, 819-0037, Japan
Local Institution - 256

Tokyo, 162-0843, Japan
Local Institution - 257

Shirakawa, Fukushima, 961-0021, Japan
Local Institution - 258

Kōnan, Aichi-ken, 483-8248, Japan
Local Institution - 313

Razgrad, 7200, Bulgaria
Local Institution - 320

Sofia, 1407, Bulgaria
Local Institution - 321

Plovdiv, 4004, Bulgaria
Local Institution - 413

Belgrade, 11000, Serbia
Local Institution - 417

Belgrade, 11000, Serbia
Local Institution - 501

Kielce, 25-411, Poland
Local Institution - 502

Siemianowice Śląskie, 41-100, Poland
Local Institution - 503

Lodz, 90-227, Poland
Local Institution - 504

Tuszyn, 95-080, Poland
Local Institution - 505

Lublin, 20-109, Poland
Local Institution - 506

Bialystok, 15-404, Poland
Local Institution - 507

Gdansk, 80-546, Poland
Local Institution - 508

Suchy Las, 62-002, Poland
Local Institution - 509

Grudziądz, 86-300, Poland
Local Institution - 601

Mysore, Karnataka, 570001, India
Local Institution - 602

Mangalore, Karnataka, 575018, India
Local Institution - 603

Nagpur, Maharashtra, 440010, India
Local Institution - 604

Ahmedabad, Gujarat, 380013, India
Local Institution - 605

Nashik, Maharashtra, 422005, India
Local Institution - 606

Rajkot, Rajasthan, 360001, India
Local Institution - 607

Ahmedabad, Gujarat, 380008, India
Local Institution - 608

Nashik, Maharashtra, 422001, India
Local Institution - 609

Surat, Gujarat, 395001, India
Local Institution - 610

Aurangabad, Maharashtra, 431005, India
Local Institution - 611

Kozhikode, Kerala, 673009, India
Local Institution - 612

Lucknow, Uttar Pradesh, 226003, India
Local Institution - 613

Vadodara, Gujarat, 390021, India
Local Institution - 614

Mangalore, Karnataka, 575003, India
Local Institution - 615

Ajmer, Rajasthan, 305001, India
Local Institution - 616

Guwahati, Assam, 781032, India
Local Institution - 617

Belgavi, Karnataka, 590001, India
Local Institution - 618

Bikaner, Rajasthan, 334003, India
Local Institution - 619

Mumbai, Maharashtra, 400008, India
Local Institution - 701

London, Greater London, SE5 8AF, United Kingdom
Local Institution - 702

Chertsey, Surrey, KT16 9AU, United Kingdom
Local Institution - 703

Birmingham, West Midlands, B4 6NH, United Kingdom
Local Institution - 704

Glasgow, Strathclyde, G51 4TF, United Kingdom
Local Institution - 705

Brighton, East Sussex, BN1 9RY, United Kingdom
Local Institution - 706

Ashton-under-Lyne, Greater Manchester, OL6 7SR, United Kingdom
Local Institution - 707

Pool, Reruth, Cornwall, TR15 3QE, United Kingdom
Local Institution - 708

Oxford, Oxfordshire, OX3 7JX, United Kingdom
Local Institution - 709

Maidstone, Kent, ME16 9PH, United Kingdom
Local Institution - 710

Manchester, Greater Manchester, M8 5RB, United Kingdom
Local Institution - 801

Galati, 800179, Romania
Local Institution - 802

Bucharest, 41914, Romania
Local Institution - 803

Brasov, 500123, Romania
Local Institution - 804

Bucharest, 10825, Romania
Local Institution - 805

Sibiu, 550281, Romania
Local Institution - 806

Iași, 700282, Romania
Local Institution - 807

Bucharest, 60222, Romania
Local Institution - 808

Craiova, 200157, Romania
Local Institution - 809

Bucharest, 041914, Romania
Local Institution - 810

Bucharest, 40874, Romania
MHAT Dr Ivan Seliminski AD

Sliven, 8800, Bulgaria
MHAT Dr. Hristo Stambolski, EOOD

Kazanlak, Stara Zagora, 6100, Bulgaria
MHC - Sofia, EOOD

Sofia, 1202, Bulgaria
Manhattan Behavioral Medicine, PLLC

New York, New York, 10036, United States
Manhattan Psychiatric Center

New York, New York, 10027, United States
Medical Center 'Sv.Naum'

Sofia, 1113, Bulgaria
Medical Center Akademika EOOD

Sofia, 1431, Bulgaria
Medical Center Hera EOOD

Sofia, 1510, Bulgaria
Medical Center Intermedica, OOD

Sofia, 1680, Bulgaria
Medical Center Lifemed

Kardzhali, 6600, Bulgaria
Medical Center Medconsult Pleven OOD

Pleven, 5800, Bulgaria
Medical Center VAS OOD

Targovishte, 7700, Bulgaria
Medical Centre 'Asklepii', OOD

Dupnitsa, 2600, Bulgaria
Mental Health Center-Vratsa EOOD

Vratsa, 3000, Bulgaria
Michigan Clinical Research Institute PC

Ann Arbor, Michigan, 48105, United States
Neuropsychiatric Research Center of Orange County

Orange, California, 92868, United States
Northwest Clinical Research Center

Bellevue, Washington, 98007, United States
Northwestern University

Chicago, Illinois, 60611, United States
Omaha Insomnia and Psychiatric Services LLC

Omaha, Nebraska, 68144, United States
Omega Clinical Trials

La Habra, California, 90631, United States
Perceptive Pharma Research

Richmond, Texas, 77407, United States
Phoenix Medical Research, Inc.

Prairie Village, Kansas, 66208, United States
Pillar Clinical Research, LLC

Little Rock, Arkansas, 72204, United States
Pillar Clinical Research, LLC

Richardson, Texas, 75080, United States
Pines Care Research Center, Inc.

Pembroke Pines, Florida, 33024, United States
Premier Clinical Research Institute, Inc.

Miami, Florida, 33122, United States
Prevention Science Institute

Eugene, Oregon, 97403, United States
Proscience Research Group

Culver City, California, 90230, United States
Psych Atlanta, P.C.

Marietta, Georgia, 30060, United States
Psychiatry and Alzheimer's Care of Rochester. PLLC

Rochester, New York, 14623, United States
Reliable Clinical Research LLC

Hialeah, Florida, 33012, United States
Richmond Behavioral Associates ERG Clinical Research - New York PLLC

Staten Island, New York, 10314, United States
San Marcus Research Clinic, Inc.

Miami Lakes, Florida, 33014, United States
Special Hospital for Psychiatric Disease 'Dr Slavoljub Bakalovic'

Vršac, 26300, Serbia
Special Hospital for Psychiatric Diseases 'Gornja Toponica'

Niš, 18202, Serbia
Special Hospital for Psychiatric Diseases 'Kovin'

Kovin, 26220, Serbia
Special Hospital for Psychiatric Diseases 'Sveti Vracevi'

Novi Kneževac, 23330, Serbia
Stanford University School of Medicine

Stanford, California, 94305, United States
State Psychiatric Hospital 'Sv. Ivan Rilski', Novi Iskar

Novi Iskar, 1282, Bulgaria
Sunwise Clinical Research, LLC.

Lafayette, California, 94549, United States
Synergy Clinical Research of Escondido

Lemon Grove, California, 91945, United States
Synexus Clinical Research US, Inc.

Cerritos, California, 90703, United States
Synexus Clinical Research US, Inc.

Atlanta, Georgia, 30328, United States
Synexus Clinical Research US, Inc.

New York, New York, 10017, United States
The Rivus Wellness & Research Institute

Oklahoma City, Oklahoma, 73112, United States
UMHAT 'Dr. Georgi Stranski', EAD

Pleven, 5800, Bulgaria
UMHAT Sv. Georgi, EAD

Plovdiv, 4002, Bulgaria
University Clinical Center Kragujevac

Kragujevac, 34000, Serbia
University Clinical Center Nis

Niš, 18000, Serbia
University Clinical Center of Serbia

Belgrade, 11000, Serbia
University Hills Clinical Research - Irving

Irving, Texas, 75062, United States
University of Cincinnati Medical Center

Cincinnati, Ohio, 45219, United States
Uptown Research Institute, LLC

Chicago, Illinois, 60640, United States
Western Michigan University Homer Stryker M.D. School of Medicine

Kalamazoo, Michigan, 49001, United States
Woodland International Research Group, LLC

Little Rock, Arkansas, 72211, United States

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