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

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

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

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. The secondary objectives of the study are to evaluate the efficacy of adjunctive KarXT compared with placebo on the Personal and Social Performance Scale (PSP), improvement in disease severity and symptoms, safety and tolerability, and pharmacokinetics.

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.

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

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.

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).

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.

Categorical response defined as the proportion of subjects achieving a ≥ 30% improvement in PANSS total score 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.'

Inclusion Criteria: Subject is aged ≥18 to <60 years at the time of randomization Subject is capable of providing signed Informed Consent Form before any study assessments will be performed 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 Subject is currently being treated with monotherapy risperidone, paliperidone, aripiprazole, ziprasidone, lurasidone, or cariprazine and has been taking this treatment with the same dosing regimen for at least 8 weeks at the time of Screening (supported by documentation) 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 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 To be eligible for randomization, subjects need to have detectable levels of background antipsychotic medication (measured at Visit 1) Positive and Negative Syndrome Scale (PANSS) total score ≥ 70 at Screening and randomization Clinical Global Impression-Severity (CGI-S) scale with a score ≥ 4 (moderate) at Screening and randomization 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 Subjects with ≤ 20-point decrease in PANSS Total score between Visit 1 and Visit 3 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 Body Mass Index (BMI) must be within 18 to 40 kg/m2 (inclusive of both values) Subject resides in a stable living situation in the opinion of the Investigator 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 must be physically present at all study visits 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: Any primary DSM-5 disorder other than schizophrenia within 12 months before screening (confirmed using MINI version 7.0.2 at screening) The subject has a history of moderate to severe substance use disorder (other than nicotine) within the past 12 months 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 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 Subject has a history of inadequate response to schizophrenia medications defined as: Failure to minimally respond to 2 adequate courses of pharmacotherapy (a minimum of 6 weeks at an adequate dose per the label) Having received any trial of clozapine regardless of dose, duration, or indication History of symptom instability a. > 3 psychiatric hospitalizations over the last 12 months or 2 over the last 6 months Current APD is other than aripiprazole, risperidone, paliperidone, or their LAI versions, ziprasidone, lurasidone, or cariprazine a. olanzapine, quetiapine, or haloperidol is not permitted Subjects who are diagnosed with schizophreniform disorder or are experiencing their first treated episode of schizophrenia 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 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 History or high risk of urinary retention, gastric retention, or narrow-angle glaucoma as evaluated by the Investigator History of irritable bowel syndrome (with or without constipation) or any serious constipation requiring treatment within the last 6 months Risk for suicidal behavior during the study as determined by the Investigator's clinical assessment and/or C-SSRS as confirmed by the following: Answers "Yes" on items 4 or 5 (C-SSRS - ideation) with the most recent episode occurring within the 2 months before Screening or, Answers "Yes" to any of the 5 items (C-SSRS behavior) with an episode occurring within the 12 months before Screening Clinically significant abnormal finding on the physical examination, medical history, ECG, or clinical laboratory results at Screening Urine toxicology screen is positive for non-cannabis or non-benzodiazepine substances Recent history of receiving monoamine oxidase inhibitors, anticonvulsants (eg, lamotrigine, divalproex), lithium, tricyclic antidepressants (eg, imipramine, desipramine), or any other psychoactive medications except for as-needed anxiolytics (eg, lorazepam, chloral hydrate) Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors taken at a stable dose for at least 8 weeks prior to Screening may be permitted Mirtazapine may be used as a hypnotic if started at least 8 weeks prior to Screening and at a stable dose Pregnant, lactating, or less than 3 months postpartum 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 Positive test for coronavirus (COVID-19) within 2 weeks or at Screening 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 Unable to taper and discontinue a concomitant medication that would preclude participation in the double-blind adjunctive treatment (e.g., cannot stop anticholinergic) Subjects with prior exposure to KarXT Subjects who experienced any adverse effects due to xanomeline or trospium Participation in another clinical study in which the subject received an experimental or investigational drug agent within 3 months before Screening or has participated in more than 2 clinical studies in the past year Risk of violent or destructive behavior as per Investigator's judgment that would interfere with subject's participation Current involuntary hospitalization or incarceration