A Study to Assess Safety and Efficacy of KarXT in Adult Patients With Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia
Intervention: Xanomeline and Trospium Chloride Capsules; Placebo Capsules
Intervention description: 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 8-34 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. Dosing must not change after Visit 7 of the study (at 21 ± 2 days of dosing) and may be decreased for tolerability reasons no more than once during the study.; Placebo Capsules
Intervention MeSH terms: Xanomeline; Trospium chloride
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 182.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: Schizophrenia

Summary:

      This is a Phase 2, randomized, double-blinded, placebo-controlled, inpatient study to examine
      the efficacy, safety, and tolerability profile of KarXT in adult subjects diagnosed with
      DSM-5 schizophrenia who are in an acute exacerbation phase. The primary objective of the
      study is to assess the efficacy of KarXT (a fixed combination of xanomeline and trospium
      chloride) (xanomeline 125 mg/trospium 30 mg twice daily [BID]) versus placebo in reducing
      Positive and Negative Syndrome Scale (PANSS) total scores in adult inpatients with a
      Diagnostic and Statistical Manual-Fifth Edition (DSM-5) diagnosis of schizophrenia. The
      secondary objectives of the study are to assess overall safety and tolerability of KarXT in
      adult inpatients with a DSM-5 diagnosis of schizophrenia.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Subject is aged 18-60 years, inclusive, at screening

          2. Subject has a primary diagnosis of schizophrenia established by a comprehensive
             psychiatric evaluation based on the DSM-5 (American Psychiatric Association 2013)
             criteria and confirmed by Mini International Neuropsychiatric Interview for
             Schizophrenia and Psychotic Disorder Studies (MINI) version 7.0.2.

          3. Subject is experiencing an acute exacerbation or relapse of symptoms, with onset less
             than 2 months before screening

          4. Positive and Negative Syndrome Scale total score between 80 and 120, inclusive, at
             screening

               1. Score of ≥ 4 (moderate or greater) for ≥ 2 of the following Positive Scale (P)
                  items at screening:

               2. Item 1 (P1; delusions)

               3. Item 2 (P2; conceptual disorganization)

               4. Item 3 (P3; hallucinatory behavior)

               5. Item 6 (P6; suspiciousness/persecution)

          5. There should not be a change (improvement) in PANSS total score between screening and
             baseline of more than 20%

          6. Subjects taking a depot antipsychotic could not have received a dose of medication for
             at least 1 and a half injection cycles before baseline (eg, 3 or more weeks off for a
             2-week cycle)

          7. Subject is capable of providing informed consent

               1. A signed ICF must be provided before any study assessments are performed

               2. Subject must be fluent (oral and written) in English in order to consent

          8. Subject must have CGI-S score of ≥ 4 at screening and baseline visits

          9. Body mass index must be ≥ 18 and ≤ 40 kg/m2

         10. Both females of child bearing potential and males with partners of child bearing
             potential must be willing to use a double-barrier method of birth control (ie, any
             double combination of male or female condom with spermicidal gel, diaphragm, sponge,
             or cervical cap with spermicidal gel) during the study and for 7 days after the last
             dose of study drug.

         11. Subject has an identified reliable informant

        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. 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, to exclude patients with human immunodeficiency virus (HIV), cirrhosis,
             biliary duct abnormalities, hepatobiliary carcinoma, and/or active hepatic viral
             infections based on the liver function test results.

          3. History of or high risk of urinary retention, gastric retention, or narrow-angle
             glaucoma

          4. History of irritable bowel syndrome (with or without constipation) or serious
             constipation requiring treatment within the last 6 months

          5. Has a DSM-5 diagnosis of moderate to severe substance abuse disorder (except tobacco
             use disorder) within the 12 months before screening (confirmed using MINI version
             7.0.2 at screening), or current abuse as determined by urine toxicology screen or
             alcohol test. 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 he/she can be allowed into the study.

          6. Clinically significant abnormal finding on the physical examination, medical history,
             ECG, or clinical laboratory results at screening

          7. Pregnant, lactating, or less than 3 months postpartum. Sperm donation is not allowed
             for 90 days after the final dose of study drug

          8. 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
             their ability to adhere to the protocol visit schedule or fulfill visit requirements

          9. Subject has had psychiatric hospitalization(s) for more than 30 days (cumulative)
             during the 90 days before screening

         10. 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

         11. Risk of violent or destructive behavior

         12. Current involuntary hospitalization or incarceration

         13. Participation in another clinical study in which the subject received an experimental
             or investigational drug agent within 3 months of screening