A Single Ascending Dose Trial of CVL-936 in Healthy Subjects

Study Overview
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Brief Summary
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The aim of this trial is to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of CVL-936 following single ascending oral doses in healthy subjects.

Official Title
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A Phase 1, Double-Blind, Sponsor-Open, Placebo-Controlled, First-In-Human Trial To Evaluate The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Single Ascending Doses of CVL-936 In Healthy Subjects

Conditions
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Substance Use Disorders (SUD)

Intervention / Treatment
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* Drug: CVL-936
* Drug: Matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Healthy male subjects and female subjects of nonchildbearing potential, ages 18 to 50 years Exclusion Criteria: Subjects with a current history of significant pulmonary, gastrointestinal, renal, hepatic, metabolic, endocrine, hematological, immunological, psychiatric, or neurological disease that, in the opinion of the investigator or medical monitor, could compromise either subject safety or the results of the trial. Subjects with epilepsy or a history of seizures Systolic supine blood pressure ≥130 mmHg and/or supine diastolic blood pressure ≥80 mmHg at Screening or Day -1, or orthostatic hypotension at Screening or Day -1. Subjects with a history of hypersensitivity to any dopamine-blocker medication.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: A sample size of 9 subjects per cohort has been chosen based on the need to minimize exposure of humans to CVL-936 and PF-06815106 and the requirement to provide adequate safety, tolerability, and PK information at each dose. Each cohort will be conducted as a crossover design with 3 periods and each cohort will have up to 6 subjects receiving CVL-936 and 3 subjects receiving placebo within each period, with a total of approximately 18 subjects if 2 cohorts complete or a total of approximately 27 subjects if 3 cohorts complete.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Comparator: Group 1 Period 1: 0.5mg CVL-936<br>Oral suspension/solution | Drug: CVL-936<br>* CVL-936<br>|
| Placebo Comparator: Placebo Comparator: Group 1 Period 1: 0.5mg Matching Placebo<br>Matching Placebo; Oral suspension/solution | Drug: Matching Placebo<br>* Placebo matching CVL-936<br>|
| Active Comparator: Active Comparator: Group 1 Period 2:TBD mg CVL-936<br>Oral suspension/solution | Drug: CVL-936<br>* CVL-936<br>|
| Placebo Comparator: Placebo Comparator: Group 1 Period 2:TBD mg Matching Placebo<br>Matching Placebo; Oral suspension/solution | Drug: Matching Placebo<br>* Placebo matching CVL-936<br>|
| Active Comparator: Active Comparator: Group 1 Period 3:TBD mg CVL-936<br>Oral suspension/solution | Drug: CVL-936<br>* CVL-936<br>|
| Placebo Comparator: Placebo Comparator: Group 1 Period 3:TBD mg Matching Placebo<br>Matching Placebo; Oral suspension/solution | Drug: Matching Placebo<br>* Placebo matching CVL-936<br>|
| Active Comparator: Active Comparator: Group 2 Period 1:TBD mg CVL-936<br>Oral suspension/solution | Drug: CVL-936<br>* CVL-936<br>|
| Placebo Comparator: Placebo Comparator: Group 2 Period 1:TBD mg Matching Placebo<br>Matching Placebo; Oral suspension/solution | Drug: Matching Placebo<br>* Placebo matching CVL-936<br>|
| Active Comparator: Active Comparator: Group 2 Period 2:TBD mg CVL-936<br>Oral suspension/solution | Drug: CVL-936<br>* CVL-936<br>|
| Placebo Comparator: Placebo Comparator: Group 2 Period 2:TBD mg Matching Placebo<br>Matching Placebo; Oral suspension/solution | Drug: Matching Placebo<br>* Placebo matching CVL-936<br>|
| Active Comparator: Active Comparator: Group 2 Period 3:TBD mg CVL-936<br>Oral suspension/solution | Drug: CVL-936<br>* CVL-936<br>|
| Placebo Comparator: Placebo Comparator: Group 2 Period 3:TBD mg Matching Placebo<br>Matching Placebo; Oral suspension/solution | Drug: Matching Placebo<br>* Placebo matching CVL-936<br>|
| Active Comparator: Active Comparator: Group 3: TBD mg CVL-936<br>Oral suspension/solution | Drug: CVL-936<br>* CVL-936<br>|
| Placebo Comparator: Placebo Comparator: Group 3: TBD mg Matching Placebo<br>Matching Placebo; Oral suspension/solution | Drug: Matching Placebo<br>* Placebo matching CVL-936<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects with reported Treatment Emergent Adverse Events (TEAEs) |  | At the end of Period 3 (30 Days) | 
| Number of Subjects with Clinically significant changes in Electrocardiogram measures (PR, RR, QT and QTcF) |  | At the end of Period 3 (30 Days) | 
| Number of Subjects with Clinically meaningful changes in Vital signs (Systolic and Diastolic blood pressures, heart rate, respiratory rate and body temperature) |  | At the end of Period 3 (30 Days) | 
| Number of Subjects with Clinically significant changes in laboratory measures | Number of subjects with clinically significant changes in hematology, serum chemistry and urinalysis will be reported | At the end of Period 3 (30 Days) | 
| Change from baseline of 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). | At the end of Period 3 (30 Days) | 
| Change from Baseline of Simpson-Angus Scale (SAS) Results | Evaluating Extrapyramidal symptoms using the SAS. The SAS consists of a list of 10 symptoms of parkinsonism (gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, salivation, and akathisia). 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. | At the end of Period 3 (30 Days) | 
| Change from Baseline of Abnormal Involuntary Movement Scale (AIMS) Results | The AIMS assessment consists of 10 items describing symptoms of dyskinesia. Facial and oral movements (items 1 through 4), extremity movements (items 5 and 6), and trunk movements (item 7) are observed unobtrusively while the subject is at rest, and the investigator also makes global judgments on the subject's dyskinesias (items 8 through 10). 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. The AIMS Movement Rating Score is defined as the sum of items 1 through 7 (ie, items 1 through 4, facial and oral movements; items 5 and 6, extremity movements; and item 7, trunk movements). | At the end of Period 3 (30 Days) | 
| Change from Baseline of Barnes Akathisia Rating Scale (BARS) Results | Evaluating Extrapyramidal symptoms using the BARS. The BARS consists of 4 items related to akathisia: objective observation of akathisia by the investigator, subjective feelings of restlessness by the subject, subjective distress due to akathisia, and global clinical assessment of 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. | At the end of Period 3 (30 Days) |