A Study to Assess Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Adult Patients With Schizophrenia (EMERGENT-3)

Karuna Therapeutics, Inc., a Bristol Myers Squibb company256 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

256

Conditions

Schizophrenia Schizophrenia; Psychosis

Interventions

Oral 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 8-35 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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

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 or local language 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/caregiver. 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.

Locations (32)

Pillar Clinical Research

Bentonville, Arkansas, United States

Woodland International Research Group

Little Rock, Arkansas, United States

Advanced Research Center, Inc.

Anaheim, California, United States

Clinical Innovations, Inc

Bellflower, California, United States

ProScience Research Group

Culver City, California, United States

Outcomes

Primary Outcomes

Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 5

The Positive and Negative Syndrome Scale (PANSS) is a medical scale used for measuring symptom severity of participants with schizophrenia and is widely used in the study of antipsychotic therapy. 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 positive symptoms in schizophrenia are the excess or distortion of normal function such as hallucinations, delusions, grandiosity, and hostility, and the negative symptoms in schizophrenia are the diminution or loss of normal functions. PANSS total score is the sum of all 30 items with a minimum score of 30 and a maximum score of 210. Higher scores indicate more severe symptoms. The PANSS Total Score is then the sum of the positive, negative, and general psychopathology symptom scores. Baseline is defined as the PANSS score at screening.

Time frame: From baseline up to Week 5

Secondary Outcomes

Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Positive Score at Week 5

PANSS positive score is the sum of all PANSS 7 positive symptom scales with a minimum score of 7 and a maximum score of 49. Higher scores indicate more severe symptoms. Participants are rated from 1 to 7 on each symptom scale. The positive symptoms in schizophrenia are the excess or distortion of normal function such as hallucinations, delusions, grandiosity, and hostility. If a patient has a PANSS assessment recorded and no more than 2 items are missing from the PANSS positive scales, then the PANSS Positive Score will be calculated as the average of the non-missing items multiplied by 7. If 3 or more items are missing (\> 30%) at a particular visit, the respective positive score at the visit will not be calculated and will be treated as missing data. Baseline is defined as the PANSS score at screening.

Time frame: From baseline up to Week 5

Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Negative Score at Week 5

PANSS negative score is the sum of all PANSS 7 negative symptom scales with a minimum score of 7 and a maximum score of 49. Higher scores indicate more severe symptoms. Participants are rated from 1 to 7 on each symptom scale. The negative symptoms in schizophrenia are the diminution or loss of normal functions. If a participant has a PANSS assessment recorded, and no more than 2 items are missing from the PANSS negative scales, then the PANSS Negative Score will be calculated as the average of the non-missing items multiplied by 7. If 3 or more items are missing (\> 30%) at a particular visit, the respective negative score at the visit will not be calculated and will be treated as missing data. Baseline is defined as the PANSS score at screening.

Time frame: From baseline up to Week 5

Positive and Negative Syndrome Scale (PANSS) Negative Marder Factor Score Change From Baseline at Week 5

PANSS Marder factor score is the sum of 5 negative scales and 2 general scales (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). Participants are rated from 1 to 7 on each symptom scale. Higher score indicates more severe symptoms. The negative symptoms in schizophrenia are the diminution or loss of normal functions. Baseline is defined as the PANSS score at screening.

Time frame: From baseline up to Week 5

Clinical Global Impression-Severity (CGI-S) Score Change From Baseline at Week 5

Clinical Global Impression-Severity (CGI-S) Score is a measurement to evaluate severity and treatment response in schizophrenia. Completed independently by a clinician, the CGI-S assesses extremely ill patients, by asking 1 question and providing a rating based upon observed and reported symptoms, behavior, and function in the past 7 days to reflect the average severity level across the 7 days. Higher score indicates more severe illness. The CGI-S categorizes the severity of the illness as: 1 = Normal, not at all ill; 2 = Borderline mentally ill; 3 = Mildly ill; 4 = Moderately ill; 5 = Markedly ill; 6 = Severely ill; and 7 = Among the most extremely ill patients. This scale reflects the total score. Baseline is defined as CGI-S score at screening. The change from baseline in total score is reported.

Time frame: From baseline up to Week 5

Number of Participants Who Achieve >=30% Reduction in Positive and Negative Symptoms Scale (PANSS) Total Score From Baseline to Week 5

Positive and Negative Syndrome Scale (PANSS) is a scale used for measuring symptom severity of subjects with schizophrenia and is widely used in the study of antipsychotic therapy. The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. Subjects are rated from 1 to 7 on each symptom scale. The positive symptoms in schizophrenia are the excess or distortion of normal function such as hallucinations, delusions, grandiosity, and hostility, and the negative symptoms in schizophrenia are the diminution or loss of normal functions. PANSS total score is the sum of all 30 items with a minimum score of 30 and a maximum score of 210. Higher scores indicate more severe symptoms. The PANSS Total Score is then the sum of the positive, negative, and general psychopathology symptom scores. Baseline is defined as screening. Note: Floor adjusted data were used for this analysis. Floor adjusted total score = total score - 30.

Time frame: From baseline up to Week 5

Number of Participants Experiencing Adverse Events (AEs)

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Adverse events are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal.

Time frame: From first dose up to Day 42

Number of Participants Experiencing Cholinergic Symptom Adverse Event

The number of participants experiencing adverse events related to procholinergic symptoms (believed to be associated with xanomeline) and anticholinergic symptoms (believed to be associated with trospium) symptoms. Examples of procholinergic symptoms include vomiting, nausea, diarrhea, sweating and hyper-salivation. Examples of anticholinergic include dizziness, confusion, hallucinations, and somnolence.

Time frame: From first dose up to Day 42

Change From Baseline in Simpson-Angus Scale Total Score (SAS)

The Simpson-Angus Scale (SAS) is an established instrument to measure drug-related extrapyramidal syndromes. It is a 10-item testing instrument used to assess gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, leg pendulousness, head dropping, glabella tap, tremor, and salivation. The range of scores is from 0 to 40 with increased scores indicating increased severity. Baseline is defined as the Simpson-Angus Scale score recorded on Day -1.

Time frame: From baseline up to week 5

Change From Baseline in Barnes Akathisia Rating Scale (BARS) Total Score

The BARS for akathisia is a rating scale used to assess the severity of drug-induced akathisia, or restlessness, involuntary movements and inability to sit still. The range of scores is 0 to 14, with higher scores indicating greater severity. Baseline is defined as the BARS score recorded on Day -1.

Time frame: From baseline up to week 5

Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score

The AIMS is a rating scale that is used to measure involuntary movements known as tardive dyskinesia, which can sometimes develop as a side effect of long-term treatment with antipsychotic medications. This measurement was a 12-item scale to assess orofacial, extremity, and truncal movements as well as the overall severity, incapacitation, and the participant's level of awareness of the movements. Items are scored from 0 (none) to 4 (severe). A higher score indicates more severe dyskinesia. Baseline is defined as the AIMS score recorded on Day -1. The total score is the sum of sub scores for items 1-7. The first 7 items are used to measure the severity of abnormal movements in the orofacial region (4 items: facial muscles, lips, jaw, tongue), upper extremities (1 item), lower extremities (1 item), and trunk (1 item). Change from baseline for the total scores are reported.

Time frame: From baseline up to week 5

Number of Participants Who Experienced Weight Change

The number of participants who lost weight, maintained their weight, or gained weight between baseline and week 5. Baseline is defined as measurements taken at screening.

Time frame: From baseline up to week 5

Change From Baseline in Body Mass Index (BMI)

The change in Body Mass Index (BMI) from baseline up to week 5. BMI is a person's weight in kilograms divided by the square of height in meters. Baseline is defined as measurements taken at screening.

Time frame: From baseline up to week 5

Change From Baseline in Waist Circumference

The change in waist circumference in centimeters from baseline up to week 5. Baseline is defined as measurements taken at screening.

Time frame: From baseline up to week 5

Change From Baseline in Orthostatic Vital Signs - Blood Pressure

The change from baseline in orthostatic diastolic and systolic blood pressure measured while supine and standing after 2 minutes. Baseline is defined as measurements taken at screening.

Time frame: From baseline up to week 5

Change From Baseline in Orthostatic Vital Signs - Heart Rate

The change from baseline in orthostatic heart rate measured while supine and standing after 2 minutes. Baseline is defined as measurements taken at screening.

Time frame: From baseline up to week 5

Change From Baseline in Electrocardiogram (ECG) Mean Heart Rate

The change from baseline up to Day 35 or early termination in ECG mean heart rate. Baseline is defined as measurements taken at screening.

Time frame: From baseline up to Day 35 or early termination

Number of Participants Experiencing Clinically Significant Abnormal Physical Examination Results

The number of participants experiencing clinically significant abnormal physical examination results. Baseline is defined as measurements taken at screening.

Time frame: From baseline up to week 5

Number of Participants Experiencing Each Suicidal Ideation Scale Category as Per Columbia Suicide Severity Rating Scale (C-SSRS)

C-SSRS assesses suicidal behavior and ideation on a scale with 4 general categories: suicidal ideation, intensity of ideation, suicidal behavior, and actual attempts. C-SSRS comprehensively identifies suicidal events while limiting the over identification of suicidal behavior. The C-SSRS was administered by a trained rater at the site. This study used 2 versions of the C-SSRS. At the Screening Visit, the "Lifetime" version was completed; for all subsequent visits, the "Since Last Visit" version of the C-SSRS was administered. Risk for suicidal behavior during the study was determined by the investigator's clinical assessment and C-SSRS as confirmed by the following: * Answering "Yes" on items 4 or 5 (C-SSRS - ideation) with the most recent episode occurring within the 2 months before screening, or * Answering "Yes" to any of the 5 items (C-SSRS behavior) with an episode occurring within the 12 months before screening. Non-suicidal, self-injurious behavior is not exclusionary.

Time frame: From screening up to Day 42

Area Under the Plasma Concentration-Time Curve (AUC)

AUC is the total area under the plasma drug concentration-time curve from time zero to 12 hours after drug administration. Dose level 125/30 BID at Week 4 (Visit 8 \[Day 28\]) is reported.

Time frame: At days 8 and 28

Maximum Concentration (Cmax)

Cmax is the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered and before the administration of a second dose. Dose level 125/30 BID at Week 4 (Visit 8 \[Day 28\]) is reported.

Time frame: At days 8 and 28

Time to Maximum Concentration (Tmax)

Tmax is defined as the time it takes for a drug to reach the maximum concentration (Cmax) after administration of a drug. Dose level 125/30 BID at Week 4 (Visit 8 \[Day 28\]) is reported.

Time frame: At days 8 and 28

Mean Observed Hemoglobin Levels

The mean observed Hemoglobin levels are displayed as measured at the specified timepoints. Baseline is defined as first dose. Reference Range: Male: 138 - 172 g/L Female: 121 - 151 g/L