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

Inclusion criteria

• Subjects with a primary diagnosis of schizophrenia per DSM-5, as confirmed by the MINI.
• 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)
• 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
• 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:

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

• Male and female subjects, ages 18 to 55 years, inclusive.
• Subjects with a score on the CGI-S ≥4 (moderately to severely ill) at time of signing ICF and at Day -1.
• 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)
• Subjects with a history of relapse and/or exacerbation of symptoms when not receiving antipsychotic treatment, excluding the current episode.
• Subjects must be experiencing an acute exacerbation or relapse of symptoms, with onset less than 2 months prior to signing ICF.

Exclusion criteria

• 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.
• 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.
• Subjects with EPS being treated with a medication that required dose modification and/or new treatment within 6 months prior to signing ICF.
• 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.
• Subjects with a current or past history of significant cardiovascular disease.
• Subjects who experienced acute depressive symptoms within the past 30 days.
• 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.
• An active central nervous system infection, demyelinating disease, degenerative neurological disease, mental retardation, or any central nervous system disease deemed to be progressive.
• 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.
• 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).
• Human immunodeficiency virus seropositive status or acquired immunodeficiency syndrome, chronic hepatitis B or C.
• Subject with a positive urine drug screen for illicit drugs or a positive breathalyzer test for alcohol.
• Subjects with medically significant abnormal laboratory test results, vital sign results, or ECG findings.
• Subjects who received transcranial magnetic stimulation or electroconvulsive therapy within 60 days of screening.
• Any condition possibly affecting drug absorption, including bowel resections, bariatric weight loss surgery, or gastrectomy (this does not include gastric banding).
• Subjects with difficulty swallowing.
• Subjects with a history of neuroleptic malignant syndrome.
• 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:

• Subjects who have experienced psychosis requiring hospitalization within the 6 months prior to signing ICF.
• Subjects who experienced psychosis requiring a change in their antipsychotic medication (either drug type or dose) within the 3 months prior to signing ICF.
• 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
• Subjects who have participated in any clinical trial within 60 days prior to signing ICF.
• 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
• 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:

• 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.
• Subjects presenting with a first episode of schizophrenia, based on clinical judgment of the investigator.
• Subjects with a 12-lead ECG exclusion as in Part A but will allow right bundle branch block in Part B.
• 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.