Schizophrenia, Schizophrenia; Psychosis
Conditions
Brief 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.
Interventions
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.
DRUGPlacebo
Placebo Capsules twice a day (BID)
Sponsors
Karuna Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 5 | Baseline and Week 5 | 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. It takes approximately 45 to 50 minutes to administer. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Positive Score at Week 5 | Baseline and Week 5 | 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. For positive symptoms in schizophrenia, participants are rated from 1 to 7 on each symptom scale, with a minimum score of 7 and a maximum score of 49. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms. |
| Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Negative Score at Week 5 | Baseline and Week 5 | The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. For negative symptoms in schizophrenia, participants are rated from 1 to 7 on each symptom scale, with a minimum score of 7 and a maximum score of 49. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms. |
| Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Marder Factor Negative Score | Baseline and Week 5 | The Marder Factor Negative Score is derived from the Positive and Negative Syndrome Scale (PANSS) and consists of the sum of 5 negative scales (N) and 2 general scales (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. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms. |
| Change From Baseline Clinical Global Impression - Severity (CGI-S) Score at Week 5 | Baseline and Week 5 | 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. |
| Percentage of Positive and Negative Syndrome Scale (PANSS) Responders (>=30% Change in PANSS Total Score) at Week 5 | Baseline and Week 5 | 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 PANSS responder is defined as a participant with at least a 30% change in PANSS total score compared to baseline at Week 5. |
Countries
United States
Participant flow
Recruitment details
The study was conducted in 21 study centers in the United States.
Pre-assignment details
A total of 407 participants were screened, 252 were randomized, and 251 participants were treated.
Participants by arm
| Arm | Count |
|---|---|
| KarXT Participants received oral capsule KarXT (xanomeline/trospium chloride BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium chloride 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium chloride 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium chloride 30 mg BID unless the Participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium chloride 20 mg BID. All Participants who were increased to xanomeline 125 mg/trospium chloride 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium chloride 20 mg BID for the remainder of the treatment period. | 126 |
| Placebo Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks. | 126 |
| Total | 252 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 6 |
| Overall Study | Other | 9 | 8 |
| Overall Study | Withdrawal by Subject | 13 | 12 |
Baseline characteristics
| Characteristic | KarXT | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 45.6 years STANDARD_DEVIATION 10.42 | 45.9 years STANDARD_DEVIATION 10.58 | 46.2 years STANDARD_DEVIATION 10.78 |
| Baseline PANSS General Psychopathology Score | 48.6 units on a scale STANDARD_DEVIATION 5.79 | 48.5 units on a scale STANDARD_DEVIATION 5.88 | 48.4 units on a scale STANDARD_DEVIATION 5.99 |
| Baseline PANSS Marder Factor Negative Score | 22.9 units on a scale STANDARD_DEVIATION 4.97 | 22.7 units on a scale STANDARD_DEVIATION 4.85 | 22.5 units on a scale STANDARD_DEVIATION 4.73 |
| Baseline PANSS Negative Score | 22.9 units on a scale STANDARD_DEVIATION 4 | 22.9 units on a scale STANDARD_DEVIATION 3.9 | 22.9 units on a scale STANDARD_DEVIATION 3.82 |
| Baseline PANSS Positive Score | 26.8 units on a scale STANDARD_DEVIATION 3.74 | 26.7 units on a scale STANDARD_DEVIATION 3.85 | 26.7 units on a scale STANDARD_DEVIATION 3.97 |
| Baseline PANSS Total Score | 98.3 units on a scale STANDARD_DEVIATION 8.93 | 98.1 units on a scale STANDARD_DEVIATION 9.31 | 97.9 units on a scale STANDARD_DEVIATION 9.71 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 25 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 111 Participants | 225 Participants | 114 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 97 Participants | 189 Participants | 92 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 26 Participants | 57 Participants | 31 Participants |
| Region of Enrollment United States | 126 participants | 252 participants | 126 participants |
| Sex: Female, Male Female | 31 Participants | 62 Participants | 31 Participants |
| Sex: Female, Male Male | 95 Participants | 190 Participants | 95 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 126 | 0 / 125 |
| other Total, other adverse events | 95 / 126 | 73 / 125 |
| serious Total, serious adverse events | 2 / 126 | 2 / 125 |
Outcome results
Primary
Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 5
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. It takes approximately 45 to 50 minutes to administer. 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.
Time frame: Baseline and Week 5
Population: The Modified Intent-to-Treat (MITT) population included all participants who were randomized, received at least one dose of study medication, and had a baseline and at least one post-baseline PANSS assessment. Here, the number of participants analyzed indicates participants who were evaluable for this measure at given time points for each group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| KarXT | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 5 | -21.2 score on a scale | Standard Deviation 1.652 |
| Placebo | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 5 | -11.6 score on a scale | Standard Deviation 1.6 |
p-value: <0.000195% CI: [-13.9, -5.2]Mixed Model for Repeated Measures
Secondary
Change From Baseline Clinical Global Impression - Severity (CGI-S) Score at Week 5
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.
Time frame: Baseline and Week 5
Population: The Modified Intent-to-Treat (MITT) population included all participants who were randomized, received at least one dose of study medication, and had a baseline and at least one post-baseline PANSS assessment. Here, the number of participants analyzed indicates participants who were evaluable for this measure at given time points for each group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| KarXT | Change From Baseline Clinical Global Impression - Severity (CGI-S) Score at Week 5 | -1.2 score on a scale | Standard Error 0.103 |
| Placebo | Change From Baseline Clinical Global Impression - Severity (CGI-S) Score at Week 5 | -0.7 score on a scale | Standard Error 0.099 |
p-value: <0.0001Mixed Model for Repeated Measures
Secondary
Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Marder Factor Negative Score
The Marder Factor Negative Score is derived from the Positive and Negative Syndrome Scale (PANSS) and consists of the sum of 5 negative scales (N) and 2 general scales (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. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms.
Time frame: Baseline and Week 5
Population: The Modified Intent-to-Treat (MITT) population included all participants who were randomized, received at least one dose of study medication, and had a baseline and at least one post-baseline PANSS assessment. Here, the number of participants analyzed indicates participants who were evaluable for this measure at given time points for each group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| KarXT | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Marder Factor Negative Score | -4.2 score on a scale | Standard Error 0.53 |
| Placebo | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Marder Factor Negative Score | -2.0 score on a scale | Standard Error 0.517 |
p-value: 0.0022Mixed Model for Repeated Measures
Secondary
Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Negative Score at Week 5
The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. For negative symptoms in schizophrenia, participants are rated from 1 to 7 on each symptom scale, with a minimum score of 7 and a maximum score of 49. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms.
Time frame: Baseline and Week 5
Population: The Modified Intent-to-Treat (MITT) population included all participants who were randomized, received at least one dose of study medication, and had a baseline and at least one post-baseline PANSS assessment. Here, the number of participants analyzed indicates participants who were evaluable for this measure at given time points for each group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| KarXT | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Negative Score at Week 5 | -3.4 score on a scale | Standard Deviation 0.479 |
| Placebo | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Negative Score at Week 5 | -1.6 score on a scale | Standard Deviation 0.466 |
p-value: 0.0055Mixed Model Repeated Measures
Secondary
Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Positive Score at Week 5
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. For positive symptoms in schizophrenia, participants are rated from 1 to 7 on each symptom scale, with a minimum score of 7 and a maximum score of 49. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms.
Time frame: Baseline and Week 5
Population: The Modified Intent-to-Treat (MITT) population included all participants who were randomized, received at least one dose of study medication, and had a baseline and at least one post-baseline PANSS assessment. Here, the number of participants analyzed indicates participants who were evaluable for this measure at given time points for each group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| KarXT | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Positive Score at Week 5 | -6.8 score on a scale | Standard Deviation 0.526 |
| Placebo | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Positive Score at Week 5 | -3.9 score on a scale | Standard Deviation 0.512 |
p-value: <0.0001Mixed Model for Repeated Measures
Secondary
Percentage of Positive and Negative Syndrome Scale (PANSS) Responders (>=30% Change in PANSS Total Score) at Week 5
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 PANSS responder is defined as a participant with at least a 30% change in PANSS total score compared to baseline at Week 5.
Time frame: Baseline and Week 5
Population: The Modified Intent-to-Treat (MITT) population included all participants who were randomized, received at least one dose of study medication, and had a baseline and at least one post-baseline PANSS assessment. Here, the number of participants analyzed indicates participants who were evaluable for this measure at given time points for each group. The overall number of participants was analyzed (N) = number of subjects with Week 5 score.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KarXT | Percentage of Positive and Negative Syndrome Scale (PANSS) Responders (>=30% Change in PANSS Total Score) at Week 5 | 51 Participants |
| Placebo | Percentage of Positive and Negative Syndrome Scale (PANSS) Responders (>=30% Change in PANSS Total Score) at Week 5 | 28 Participants |
p-value: <0.0001Mixed Model for Repeated Measures