A Trial of 15 and 30 mg Doses of CVL-231 (Emraclidine) in Participants With Schizophrenia

Study Overview
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Brief Summary
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This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group, 6-week trial to evaluate the efficacy, safety, and tolerability of 2 fixed doses of CVL-231 (Emraclidine) (15 mg QD and 30 mg QD) in male and female participants who have schizophrenia and are experiencing an acute exacerbation of psychosis.

Official Title
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A Phase 2, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of Two Fixed Doses (15 mg and 30 mg QD) of CVL-231 (Emraclidine) in Participants With Schizophrenia Experiencing an Acute Exacerbation of Psychosis

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: CVL-231 15 mg
* Drug: Required CVL-231 30 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary diagnosis of schizophrenia per DSM-5, as confirmed by the MINI for Psychotic Disorders. CGI-S ≥4 (moderately to severely ill) at the time of signing the ICF and Baseline. PANSS Total Score between 85 and 120, inclusive, at the time of signing the ICF and at Baseline. Experiencing an acute exacerbation or relapse of psychotic symptoms, with onset less than 60 days prior to signing the ICF. Willing to discontinue all prohibited medications to meet protocol-required washouts prior to and during the trial period. Body mass index of 18.0 to 40.0 kg/m2 and a total body weight ≥50 kg (110 lbs). Ability, in the opinion of the investigator, to understand the nature of the trial, participate in trial visits, and comply with protocol requirements. Exclusion Criteria: Current DSM-5 diagnosis other than schizophrenia (note: anxiety symptoms secondary to schizophrenia are allowed); Acute depressive symptoms within 30 days prior to signing the ICF that require treatment with an antidepressant are exclusory. Acute manic symptoms within 30 days prior to signing the ICF that require treatment with a mood stabilizer are exclusory. Any of the following: Schizophrenia considered resistant/refractory to antipsychotic treatment by history (failure to respond to 2 or more courses of adequate pharmacological treatment defined as an adequate dose per label and a treatment duration of at least 4 weeks) History of response to clozapine treatment only or failure to respond to clozapine treatment Any of the following regarding history of schizophrenia: Time from initial onset of schizophrenia <2 years based on prior records or participant self-report Presenting with an initial diagnosis of schizophrenia Presenting for the first time with an acute psychotic episode requiring treatment Reduction (improvement) in PANSS total score of ≥20% between Screening and Baseline. Current or past history of significant cardiovascular, pulmonary, gastrointestinal, renal, hepatic, metabolic, genitourinary, endocrine (including diabetes mellitus), malignancy (except for basal cell carcinoma of the skin and cervical carcinoma in situ, at the discretion of the investigator), hematological, immunological, neurological, or psychiatric disease that, in the opinion of the investigator or medical monitor, could compromise either participant safety or the results of the trial. Active central nervous system infection, demyelinating disease, degenerative neurological disease, brain tumor, prior hospitalization for severe head trauma, seizures (excluding febrile seizures in childhood), or any central nervous system disease deemed to be progressive during the course of the trial that may confound the interpretation of the trial results Diagnosis of moderate to severe substance or alcohol-use disorder (excluding nicotine or caffeine) as per DSM-5 criteria within 12 months prior to signing the ICF. Risk for suicidal behavior as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) and investigator's clinical assessment. Any condition that could possibly affect drug absorption. Use of prohibited medications prior to randomization within the required wash-out period or likely to require prohibited concomitant therapy during the trial. Clinically significant abnormal findings on the physical examination, medical history review, ECG, or clinical laboratory results at screening. Positive pregnancy test result prior to receiving IMP. Note: female participants who are pregnant, breastfeeding, or planning to become pregnant during IMP treatment or within 7 days after the last dose of IMP are also excluded.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Placebo-controlled
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CVL-231 15 mg, once daily (QD)<br>Oral Dose | Drug: CVL-231 15 mg<br>* CVL-231 15 mg, oral (tablet), once per day for 6 weeks<br>|
| Experimental: CVL-231 30 mg, once daily (QD)<br>Oral Dose | Drug: Required CVL-231 30 mg<br>* CVL-231 30 mg, oral (tablet), once per day for 6 weeks<br>|
| Placebo Comparator: Placebo, once daily (QD)<br>Oral Dose | Drug: Placebo<br>* Matching placebo, oral (tablet), once per day for 6 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline at Week 6 in the Positive and Negative Syndrome Scale (PANSS) total score | The PANSS measures symptom severity of participants with schizophrenia and 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 with a total minimum score of 30 and a maximum score of 210. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms. | Baseline through Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline at Week 6 in the Clinical Global Impression - Severity (CGI-S score) | The CGI-S captures clinician's response to: 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. | Baseline through Week 6 | 
| Change from Baseline at all time points in Positive and Negative Syndrome Scale (PANSS) total score | The PANSS measures symptom severity of participants with schizophrenia and 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 with a total minimum score of 30 and a maximum score of 210. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms. | Baseline through Week 6 | 
| Change from Baseline at all time points in the Clinical Global Impression - Severity (CGI-S) score | The CGI-S captures clinician's response to: 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. | Baseline through Week 6 | 
| Percentage of responders at Week 6 (responders defined as ≥30% reduction from Baseline in PANSS total score) | A PANSS responder is defined as a participant with at least a 30% change in PANSS total score compared to baseline at Week 6. | Baseline through Week 6 | 
| Incidence and Severity of Treatment Emergent Adverse Events (TEAEs) | Any AE occurring following the start of treatment or occurring before treatment but increasing in severity afterward will be counted as treatment-emergent AE (TEAE) | Up to Week 10 | 
| Incidence of clinically significant changes in electrocardiogram (ECG) results | Assessment of clinically significant changes in electrocardiogram measures measured by 12-lead ECG recording after the participant has been supine and at rest for at least 3 minutes | Up to Week 6 | 
| Incidence of clinically significant changes in clinical laboratory results |  | Up to Week 6 | 
| Incidence of clinically significant changes in vital sign measurements | Assessment of clinically significant changes in vital signs including temperature, systolic and diastolic blood pressure, and heart rate. | Up to Week 6 | 
| Incidence of clinically significant changes in physical and neurological examination results |  | Up to Week 6 | 
| Clinically significant findings in suicidality assessed using the Columbia Suicide-Severity Rating Scale (C-SSRS) | The C-SSRS rates an individual's degree of suicidal ideation (SI) on a scale, ranging from wish to be dead to active suicidal ideation with specific plan and intent. The scale identifies SI severity and intensity, which may be indicative of an individual's intent to commit suicide. C-SSRS SI severity subscale ranges from 0 (no SI) to 5 (active SI with plan and intent). | Up to Week 6 | 
| Frequency of clinically significant findings in extrapyramidal symptoms evaluated using the Simpson Angus Scale (SAS) | The SAS consists of a list of 10 symptoms of parkinsonism. Each item is rated on a 5-point scale, with a score of 0 representing absence of symptoms and a score of 4 representing a severe condition. The SAS total score is the sum of the scores for all 10 items. | Up to Week 6 | 
| Frequency of clinically significant findings in extrapyramidal symptoms evaluated using the Barnes Akathisia Rating Scale (BARS) | The BARS consists of 4 items related to akathisia: The first 3 items are rated on a 4-point scale, with a score of 0 representing absence of symptoms and a score of 3 representing a severe condition. The global clinical evaluation is made on a 6-point scale, with a score of 0 representing absence of symptom and a score of 5 representing severe akathisia. | Up to Week 6 | 
| Frequency of clinically significant findings in extrapyramidal symptoms evaluated using the Abnormal Involuntary Movement Scale (AIMS) | The AIMS assessment consists of 10 items describing symptoms of dyskinesia. Each item is rated on a 5-point scale, with a score of 0 representing absence of symptoms (for item 10, no awareness), and a score of 4 indicating a severe condition (for item 10, awareness, severe distress). In addition, the AIMS includes 2 yes/no questions that address the subject's dental status. | Up to Week 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Schizophrenia, Schizophrenia Spectrum and Other Psychotic Disorders, Mental Disorders