A Multiple Ascending Dose Trial of CVL-231 in Subjects With Schizophrenia

A Phase 1B Trial To Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Ascending Doses of CVL-231 in Subjects With Schizophrenia

The aim of this trial is to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of CVL-231 following multiple-dose oral administration in subjects with schizophrenia.

Inclusion Criteria:

1. Subjects with a primary diagnosis of schizophrenia per DSM-5, as confirmed by the MINI.
2. Subjects with the following scores on the PANSS at time of signing ICF and at Day -1: • Positive Subscale 7 (hostility) ≤3 (normal to moderate) • General Psychopathology Subscale 8 (uncooperativeness) ≤3 (normal to moderate)
3. Subjects with the following scores (normal to mild symptoms) at time of signing ICF and at Day -1: • All individual items of the Modified SAS (M-SAS) <2 • All individual items (Items 1-7) of the Abnormal Involuntary Movement Scale (AIMS) <2 • Clinical global assessment item of the Barnes Akathisia Rating Scale (BARS) <3
4. Body mass index of 17.5 to 38.0 kg/m2 and a total body weight >50 kg (110 lbs).

Cohorts 1 Through 5 (Part A):

Subjects are eligible to be included in trial (Cohorts 1 through 5) only if all of the following additional criteria apply:

1. Male and female subjects, ages 18 to 50 years, inclusive.
2. Subjects with a score on the CGI-S ≤4 (normal to moderately ill) at time of signing ICF and at Day -1.
3. Subjects with a PANSS total score of ≤80 at the time of signing ICF and at Day -1.

Cohort 6 (Part B):

Subjects are eligible to be included in trial (Cohort 6) only if all of the following additional criteria apply:

1. Male and female subjects, ages 18 to 55 years, inclusive.

2. Subjects with a score on the CGI-S ≥4 (moderately to severely ill) at time of signing ICF and at Day -1.

3. Subjects with a PANSS total score of ≥80 at the time of signing ICF and at Day -1. Additionally, subjects must meet a score of ≥4 (moderate or greater) for ≥2 of the following Positive Scale items at the time of signing ICF and at Day -1:

   • Positive Scale 1 (delusions)
   • Positive Scale 2 (conceptual disorganization)
   • Positive Scale 3 (hallucinatory behavior)
   • Positive Scale 6 (suspiciousness/persecution)

4. Subjects with a history of relapse and/or exacerbation of symptoms when not receiving antipsychotic treatment, excluding the current episode.

5. Subjects must be experiencing an acute exacerbation or relapse of symptoms, with onset less than 2 months prior to signing ICF.

Exclusion Criteria:

1. Subjects with a current DSM-5 diagnosis other than schizophrenia including, but not limited to, mental retardation; schizoaffective disorder; schizophreniform disorder; psychotic depression; major depressive disorder; bipolar disorder; post-traumatic stress disorder; generalized anxiety disorder, obsessive compulsive disorder, eating disorders (bulimia, anorexia), or other anxiety disorders as a primary diagnosis (subjects with anxiety symptoms secondary to schizophrenia are allowed); delirium, dementia, amnestic, or other cognitive disorders. Also, subjects with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder.
2. Subjects with schizophrenia who were considered resistant/refractory to antipsychotic treatment by history or who had a history of failure to respond to clozapine or response to clozapine treatment only.
3. Subjects with EPS being treated with a medication that required dose modification and/or new treatment within 6 months prior to signing ICF.
4. Subjects with a current history of significant pulmonary, gastrointestinal, renal, hepatic, metabolic, endocrine (including newly diagnosed diabetes mellitus or subjects with known diabetes mellitus with glycosylated hemoglobin (HbA1c)>7.5%), hematological, immunological, psychiatric (excluding schizophrenia), or neurological disease.
5. Subjects with a current or past history of significant cardiovascular disease.
6. Subjects who experienced acute depressive symptoms within the past 30 days.
7. Subjects with epilepsy or a history of seizures, except for a single seizure episode, eg, a childhood febrile seizure, or a seizure related to trauma or alcohol withdrawal.
8. An active central nervous system infection, demyelinating disease, degenerative neurological disease, mental retardation, or any central nervous system disease deemed to be progressive.
9. History of moderate to severe substance or alcohol-use disorder (excluding nicotine or caffeine) as per DSM-5 criteria within 12 months prior to signing ICF.
10. Subjects who answer "Yes" on the C-SSRS Suicidal Ideation Item 4 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan) and whose most recent episode meeting criteria for this C-SSRS Item 4 occurred within the last 6 months, OR Subjects who answer "Yes" on the C-SSRS Suicidal Ideation Item 5 (Active Suicidal Ideation with Specific Plan and Intent).
11. Human immunodeficiency virus seropositive status or acquired immunodeficiency syndrome, chronic hepatitis B or C.
12. Subject with a positive urine drug screen for illicit drugs or a positive breathalyzer test for alcohol.
13. Subjects with medically significant abnormal laboratory test results, vital sign results, or ECG findings.
14. Subjects who received transcranial magnetic stimulation or electroconvulsive therapy within 60 days of screening.
15. Any condition possibly affecting drug absorption, including bowel resections, bariatric weight loss surgery, or gastrectomy (this does not include gastric banding).
16. Subjects with difficulty swallowing.
17. Subjects with a history of neuroleptic malignant syndrome.
18. Subject who refuses to abstain from grapefruit-containing foods or beverages, or Seville orange-containing foods or beverages.

Cohorts 1 Through 5 (Part A) Subjects are excluded from the trial (Cohorts 1 through 5) if any of the following additional criteria apply:

1. Subjects who have experienced psychosis requiring hospitalization within the 6 months prior to signing ICF.

2. Subjects who experienced psychosis requiring a change in their antipsychotic medication (either drug type or dose) within the 3 months prior to signing ICF.

3. Subjects who fulfill any of the following dietary restrictions: • History of chronic consumption of >400 mg/day of caffeine-containing drinks or food • Refuses to abstain from caffeine-containing foods or caffeinated beverages for 48 hours prior to Day -1 through Follow up Visit • Refuses to abstain from alcohol from 7 days prior to Day -1 through Follow-up Visit

4. Subjects who have participated in any clinical trial within 60 days prior to signing ICF.

5. Subjects with a 12-lead ECG demonstrating any of the following:

   • Abnormal ST-T-wave morphologies that may interfere with QT analysis, such as flat or poorly defined end of the T wave or prominent U waves
   • Left ventricular hypertrophy
   • QT interval corrected for heart rate QTcF >450 msec
   • QRS interval >110 msec
   • Left or right bundle branch block
   • PR interval >240 msec
   • Heart rate <50 bpm or >90 bpm
   • Second- or third-degree atrioventricular block

6. Systolic blood pressure ≥130 mmHg and/or diastolic blood pressure ≥80 mmHg at Screening or Day -1, will be taken with subjects in the supine/semi-recumbent position, or symptomatic hypotension, or orthostatic hypotension, which is defined as a decrease of ≥20 mmHg in systolic blood pressure and/or a decrease of ≥10 mmHg in diastolic blood pressure after at least 3 minutes of standing compared with the immediately previous supine blood pressure. Subjects who are receiving chronic treatment with antihypertensive medications at Screening are also excluded.

Cohort 6 (Part B) Only Subjects are excluded from trial (Cohort 6 only) if any of the following additional criteria apply:

1. Subjects who have been hospitalized >14 days for the current episode of schizophrenia at the time of signing the ICF, excluding hospitalization for psychosocial reasons.
2. Subjects presenting with a first episode of schizophrenia, based on clinical judgment of the investigator.
3. Subjects with a 12-lead ECG exclusion as in Part A but will allow right bundle branch block in Part B.
4. Systolic blood pressure >130 mmHg and/or diastolic blood pressure >80 mmHg at Screening or Day -1 and subjects with orthostatic hypotension, defined as a decrease of ≥20 mmHg in systolic blood pressure and/or a decrease of ≥10 mmHg in diastolic blood pressure after at least 3 minutes of standing compared with the average resting supine/semi-recumbent blood pressure at Screening or Day -1, will be excluded. Subjects with a heart rate <50 bpm or >90 bpm. Subjects who are receiving chronic treatment with antihypertensive medications at Screening are also excluded.