A Study to Assess Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Adult Patients With Schizophrenia (EMERGENT-2)
Condition: Schizophrenia; Schizophrenia; Psychosis
MeSH terms: Schizophrenia
Intervention: Xanomeline and Trospium Chloride Capsules; Placebo
Intervention description: Oral xanomeline 50 mg/trospium chloride 20 mg BID (twice a day) for the first 2 days (Days 1 and 2) followed by xanomeline 100 mg/trospium chloride 20 mg BID for the remainder of Week 1 (Days 3 to 7). At Visit 5 (Day 8), dosing was to be titrated upwards to xanomeline 125 mg/trospium chloride 30 mg BID unless the subject was continuing to experience adverse events (AEs) from the previous dose of KarXT 100/20 BID. All subjects who were increased to KarXT 125/30 BID, depending on clinical response and tolerability, had the option to return to KarXT 100/20 BID for the remainder of the treatment period.; Placebo Capsules twice a day (BID)
Intervention MeSH terms: Xanomeline; Trospium chloride
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 252.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        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 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.

         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.