Clinical trial NCT05145413: A Study to Assess Efficacy and Safety of Adjunctive KarXT in Subjects With Inadequately Controlled Symptoms of Schizophrenia
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Schizophrenia
Lead sponsor: Karuna Therapeutics
Sponsor class: INDUSTRY
First posted: 2021-12-06
Enrollment: 396
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, 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 6
timeFrame: Week 6
Secondary outcomes:
measure: Change from Baseline in Personal Social Performance (PSP) at Week 6
timeFrame: Week 6
measure: Change from Baseline in Clinical Global Impression-Severity (CGI-S) at Week 6
timeFrame: Week 6
measure: Change from Baseline in Positive and Negative Syndrome Scale (PANSS) Marder Positive symptom factor score at Week 6
timeFrame: Week 6
measure: Change from Baseline in Positive and Negative Syndrome Scale (PANSS) Marder Negative symptom factor score at Week 6
timeFrame: Week 6
measure: Categorical response defined as the proportion of subjects achieving a ≥ 30% improvement in PANSS total score at Week 6
timeFrame: Week 6
measure: Preference of Medication (POM) at Week 6
timeFrame: Week 6
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: IMA Clinical Research
state: Arizona
city: Phoenix
country: United States
facility: Local Institution - 147
state: Arizona
city: Little Rock
country: United States
facility: Pillar Clinical Research, LLC
state: Arkansas
city: Little Rock
country: United States
facility: Woodland International Research Group, LLC
state: Arkansas
city: Anaheim
country: United States
facility: Advanced Research Center, Inc.
state: California
city: Bellflower
country: United States
facility: CITrials - Bellflower
state: California
city: Cerritos
country: United States
facility: Synexus Clinical Research US, Inc.
state: California
city: Costa Mesa
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: CenExel Collaborative Neuroscience Research
state: California
city: La Habra
country: United States
facility: Omega Clinical Trials
state: California
city: Lafayette
country: United States
facility: Sunwise Clinical Research, LLC.
state: California
city: Lemon Grove
country: United States
facility: Synergy Clinical Research of Escondido
state: California
city: Los Angeles
country: United States
facility: Encino Hospital Medical Center
state: California
city: Oceanside
country: United States
facility: Excell Research, Inc.
state: California
city: Orange
country: United States
facility: Neuropsychiatric Research Center of Orange County
state: California
city: Pico Rivera
country: United States
facility: CNRI - Los Angeles, LLC
state: California
city: Riverside
country: United States
facility: CenExel Clinical Innovations, Inc.
state: California
city: San Diego
country: United States
facility: Cnri-San Diego
state: California
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Torrance
country: United States
facility: CenExel Collaborative Neuroscience Research
state: California
city: Coral Gables
country: United States
facility: Local Institution - 186
state: Florida
city: Hialeah
country: United States
facility: Reliable Clinical Research LLC
state: Florida
city: Hialeah
country: United States
facility: Galiz Research, LLC
state: Florida
city: Lauderhill
country: United States
facility: Adaptive Clinical Research, Inc
state: Florida
city: Miami Lakes
country: United States
facility: San Marcus Research Clinic, Inc.
state: Florida
city: Miami Lakes
country: United States
facility: Assertive Research Center
state: Florida
city: Miami Springs
country: United States
facility: Envision Trials LLC
state: Florida
city: Miami
country: United States
facility: Behavioral Clinical Research , Inc
state: Florida
city: Miami
country: United States
facility: Premier Clinical Research Institute, Inc.
state: Florida
city: Orange City
country: United States
facility: Local Institution - 124
state: Florida
city: Pembroke Pines
country: United States
facility: Pines Care Research Center, Inc.
state: Florida
city: Tampa
country: United States
facility: Interventional Psychiatry of Tampa Bay
state: Florida
city: Atlanta
country: United States
facility: Grady Memorial Hospital
state: Georgia
city: Atlanta
country: United States
facility: Synexus Clinical Research US, Inc.
state: Georgia
city: Atlanta
country: United States
facility: Local Institution - 192
state: Georgia
city: Augusta
country: United States
facility: Local Institution - 135
state: Georgia
city: Decatur
country: United States
facility: CenExel iResearch Atlanta
state: Georgia
city: Marietta
country: United States
facility: Psych Atlanta, P.C.
state: Georgia
city: Savannah
country: United States
facility: CenExel iResearch, LLC
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: American Medical Research, Inc.
state: Illinois
city: Chicago
country: United States
facility: Uptown Research Institute, LLC
state: Illinois
city: Prairie Village
country: United States
facility: Phoenix Medical Research, Inc.
state: Kansas
city: Monroe
country: United States
facility: IMA Clinical Research
state: Louisiana
city: Gaithersburg
country: United States
facility: CenExel Center for Behavioral Health
state: Maryland
city: Boston
country: United States
facility: Local Institution - 158
state: Massachusetts
city: Boston
country: United States
facility: Local Institution - 187
state: Massachusetts
city: Worcester
country: United States
facility: Local Institution - 185
state: Massachusetts
city: Ann Arbor
country: United States
facility: Michigan Clinical Research Institute PC
state: Michigan
city: Grand Rapids
country: United States
facility: Cherry Health
state: Michigan
city: Kalamazoo
country: United States
facility: Western Michigan University Homer Stryker M.D. School of Medicine
state: Michigan
city: Saint Louis
country: United States
facility: Local Institution - 129
state: Missouri
city: Saint Louis
country: United States
facility: Arch Clinical Trials LLC
state: Missouri
city: Omaha
country: United States
facility: Omaha Insomnia and Psychiatric Services LLC
state: Nebraska
city: Las Vegas
country: United States
facility: Altea Research Institute, Las Vegas
state: Nevada
city: Berlin
country: United States
facility: CenExel Hassman Research Institute
state: New Jersey
city: New York
country: United States
facility: Synexus Clinical Research US, Inc.
state: New York
city: New York
country: United States
facility: Manhattan Psychiatric Center
state: New York
city: New York
country: United States
facility: Manhattan Behavioral Medicine, PLLC
state: New York
city: Rochester
country: United States
facility: Psychiatry and Alzheimer's Care of Rochester. PLLC
state: New York
city: Staten Island
country: United States
facility: Richmond Behavioral Associates ERG Clinical Research - New York PLLC
state: New York
city: Hickory
country: United States
facility: Clinical Trials of America - Psychiatry
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Garfield Heights
country: United States
facility: Local Institution - 168
state: Ohio
city: Independence
country: United States
facility: Insight Clinical Trials LLC
state: Ohio
city: Oklahoma City
country: United States
facility: The Rivus Wellness & Research Institute
state: Oklahoma
city: Eugene
country: United States
facility: Prevention Science Institute
state: Oregon
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: Fort Worth
country: United States
facility: JPS Health Network
state: Texas
city: Houston
country: United States
facility: Ben Taub Hospital
state: Texas
city: Houston
country: United States
facility: Clinical Trial Network LLC
state: Texas
city: Irving
country: United States
facility: University Hills Clinical Research - Irving
state: Texas
city: Richardson
country: United States
facility: Pillar Clinical Research, LLC
state: Texas
city: Richmond
country: United States
facility: At Health Texas
state: Texas
city: Richmond
country: United States
facility: Perceptive Pharma Research
state: Texas
city: Rutland
country: United States
facility: Green Mountain Research Institute
state: Vermont
city: Bellevue
country: United States
facility: Northwest Clinical Research Center
state: Washington
city: Kazanlak
country: Bulgaria
facility: MHAT Dr. Hristo Stambolski, EOOD
state: Stara Zagora
city: Cherven Bryag
country: Bulgaria
facility: Ambulatory for Individual Practice for Specialized Medical Care in Psychiatry - Dr Ivo Natsov
city: Dupnitsa
country: Bulgaria
facility: Medical Centre 'Asklepii', OOD
city: Kardzhali
country: Bulgaria
facility: Medical Center Lifemed
city: Novi Iskar
country: Bulgaria
facility: State Psychiatric Hospital 'Sv. Ivan Rilski', Novi Iskar
city: Pleven
country: Bulgaria
facility: Medical Center Medconsult Pleven OOD
city: Pleven
country: Bulgaria
facility: UMHAT 'Dr. Georgi Stranski', EAD
city: Plovdiv
country: Bulgaria
facility: UMHAT Sv. Georgi, EAD
city: Plovdiv
country: Bulgaria
facility: Local Institution - 321
city: Razgrad
country: Bulgaria
facility: Local Institution - 313
city: Sliven
country: Bulgaria
facility: MHAT Dr Ivan Seliminski AD
city: Sofia
country: Bulgaria
facility: Medical Center 'Sv.Naum'
city: Sofia
country: Bulgaria
facility: MHC - Sofia, EOOD
city: Sofia
country: Bulgaria
facility: Local Institution - 320
city: Sofia
country: Bulgaria
facility: DCC 'Sv. Vrach and Sv. Sv. Kuzma and Damyan', OOD
city: Sofia
country: Bulgaria
facility: Medical Center Akademika EOOD
city: Sofia
country: Bulgaria
facility: Medical Center Hera EOOD
city: Sofia
country: Bulgaria
facility: Medical Center Intermedica, OOD
city: Targovishte
country: Bulgaria
facility: Medical Center VAS OOD
city: Varna
country: Bulgaria
facility: DCC Mladost M - Varna, OOD
city: Vratsa
country: Bulgaria
facility: Mental Health Center-Vratsa EOOD
city: Guwahati
country: India
facility: Local Institution - 616
state: Assam
city: Ahmedabad
country: India
facility: Local Institution - 607
state: Gujarat
city: Ahmedabad
country: India
facility: Local Institution - 604
state: Gujarat
city: Surat
country: India
facility: Local Institution - 609
state: Gujarat
city: Vadodara
country: India
facility: Local Institution - 613
state: Gujarat
city: Belgavi
country: India
facility: Local Institution - 617
state: Karnataka
city: Mangalore
country: India
facility: Local Institution - 614
state: Karnataka
city: Mangalore
country: India
facility: Local Institution - 602
state: Karnataka
city: Mysore
country: India
facility: Local Institution - 601
state: Karnataka
city: Kozhikode
country: India
facility: Local Institution - 611
state: Kerala
city: Aurangabad
country: India
facility: Local Institution - 610
state: Maharashtra
city: Mumbai
country: India
facility: Local Institution - 619
state: Maharashtra
city: Nagpur
country: India
facility: Local Institution - 603
state: Maharashtra
city: Nashik
country: India
facility: Local Institution - 608
state: Maharashtra
city: Nashik
country: India
facility: Local Institution - 605
state: Maharashtra
city: Ajmer
country: India
facility: Local Institution - 615
state: Rajasthan
city: Bikaner
country: India
facility: Local Institution - 618
state: Rajasthan
city: Rajkot
country: India
facility: Local Institution - 606
state: Rajasthan
city: Lucknow
country: India
facility: Local Institution - 612
state: Uttar Pradesh
city: Toyoake-shi
country: Japan
facility: Local Institution - 250
state: Aichi-ken
city: Konan
country: Japan
facility: Local Institution - 258
state: Aichi
city: Shirakawa
country: Japan
facility: Local Institution - 257
state: Fukushima
city: Karatsu-shi
country: Japan
facility: Local Institution - 254
state: Saga-Ken
city: Fukuoka
country: Japan
facility: Local Institution - 255
city: Tokyo
country: Japan
facility: Local Institution - 256
city: Bialystok
country: Poland
facility: Local Institution - 506
city: Gdansk
country: Poland
facility: Local Institution - 507
city: Grudziadz
country: Poland
facility: Local Institution - 509
city: Kielce
country: Poland
facility: Local Institution - 501
city: Lodz
country: Poland
facility: Local Institution - 503
city: Lublin
country: Poland
facility: Local Institution - 505
city: Siemianowice Śląskie
country: Poland
facility: Local Institution - 502
city: Suchy Las
country: Poland
facility: Local Institution - 508
city: Tuszyn
country: Poland
facility: Local Institution - 504
city: Brasov
country: Romania
facility: Local Institution - 803
city: Bucuresti
country: Romania
facility: Local Institution - 809
city: Bucuresti
country: Romania
facility: Local Institution - 804
city: Bucuresti
country: Romania
facility: Local Institution - 810
city: Bucuresti
country: Romania
facility: Local Institution - 802
city: Bucuresti
country: Romania
facility: Local Institution - 807
city: Craiova
country: Romania
facility: Local Institution - 808
city: Galati
country: Romania
facility: Local Institution - 801
city: Iasi
country: Romania
facility: Local Institution - 806
city: Sibiu
country: Romania
facility: Local Institution - 805
city: Belgrade
country: Serbia
facility: Clinical Center ' Dr Dragisa Misovic Dedinje'
city: Belgrade
country: Serbia
facility: Institute of Mental Health
city: Belgrade
country: Serbia
facility: Local Institution - 413
city: Belgrade
country: Serbia
facility: Local Institution - 417
city: Belgrade
country: Serbia
facility: University Clinical Center of Serbia
city: Kovin
country: Serbia
facility: Special Hospital for Psychiatric Diseases "Kovin"
city: Kovin
country: Serbia
facility: Special Hospital for Psychiatric Diseases 'Kovin'
city: Kragujevac
country: Serbia
facility: University Clinical Center Kragujevac
city: Nis
country: Serbia
facility: University Clinical Center Nis
city: Nis
country: Serbia
facility: Special Hospital for Psychiatric Diseases 'Gornja Toponica'
city: Novi Knezevac
country: Serbia
facility: Special Hospital for Psychiatric Diseases 'Sveti Vracevi'
city: Vrsac
country: Serbia
facility: Special Hospital for Psychiatric Disease 'Dr Slavoljub Bakalovic'
city: Pool, Reruth
country: United Kingdom
facility: Local Institution - 707
state: Cornwall
city: Brighton
country: United Kingdom
facility: Local Institution - 705
state: East Sussex
city: London
country: United Kingdom
facility: Local Institution - 701
state: Greater London
city: Ashton Under Lyne
country: United Kingdom
facility: Local Institution - 706
state: Greater Manchester
city: Manchester
country: United Kingdom
facility: Local Institution - 710
state: Greater Manchester
city: Maidstone
country: United Kingdom
facility: Local Institution - 709
state: Kent
city: Oxford
country: United Kingdom
facility: Local Institution - 708
state: Oxfordshire
city: Glasgow
country: United Kingdom
facility: Local Institution - 704
state: Strathclyde
city: Chertsey
country: United Kingdom
facility: Local Institution - 702
state: Surrey
city: Birmingham
country: United Kingdom
facility: Local Institution - 703
state: West Midlands
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: