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

NCT04136873 | Completed Phase 1 FDA Drug

• 1 other identifier: CVL-231-SCH-001
• Study Type: interventional
• Target: 130
• Locations: 1 country
• Sites: 5

Brief Summary

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.

Conditions

Schizophrenia

Outcome Measures

Primary Outcomes (5)

• Incidence of Treatment Emergent Adverse Events (TEAEs)

  Includes Incidence of Significant ECG Abnormalities Occurring Post-Baseline, significant changes in Vital signs (Systolic and Diastolic blood pressures, heart rate, respiratory rate and body temperature), and changes in laboratory measures (hematology, serum chemistry and urinalysis)

  Up to Day 72

• Incidence of suicidality as assessed by 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 Day 72

• 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.

  Up to Day 72

• 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).

  Up to Day 72

• 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.

  Up to Day 72

Secondary Outcomes (22)

• Single-dose: Area under the plasma concentration vs. time curve (AUC) for CVL-231 and Metabolite (PF-06892787)

  Day 1

• Single-dose: Peak Plasma Concentration (Cmax) for CVL-231 and Metabolite (PF-06892787)

  Day 1

• Single-dose: Time to Maximum Concentration (Tmax) for CVL-231 and Metabolite (PF-06892787)

  Day 1

• Single-dose: Metabolite to parent ratio for Cmax for CVL-231 and Metabolite (PF-06892787)

  Day 1

• Single-dose: Metabolite to parent ratio for AUC tau for CVL-231 and Metabolite (PF-06892787)

  Day 1

Study Arms (14)

Part A: 5 mg QD CVL-231

ACTIVE COMPARATOR

Oral Dose

Drug: CVL-231

Part A: 5 mg QD Placebo

PLACEBO COMPARATOR

Matching Placebo; Oral Dose

Drug: Matching Placebo

Part A: 10 mg QD CVL-231

ACTIVE COMPARATOR

Oral Dose

Drug: CVL-231

Part A: 10 mg QD Placebo

PLACEBO COMPARATOR

Matching Placebo; Oral Dose

Drug: Matching Placebo

Part A: 20 mg QD CVL-231

ACTIVE COMPARATOR

Oral Dose

Drug: CVL-231

Part A: 20 mg QD Placebo

PLACEBO COMPARATOR

Matching Placebo; Oral Dose

Drug: Matching Placebo

Part A: 5-10-20 mg BID CVL-231

ACTIVE COMPARATOR

Oral Dose

Drug: CVL-231

Part A: 5-10-20 mg BID Placebo

PLACEBO COMPARATOR

Matching Placebo; Oral Dose

Drug: Matching Placebo

Part A: 30 mg QD CVL-231

ACTIVE COMPARATOR

Oral Dose

Drug: CVL-231

Part A: 30 mg QD Placebo

PLACEBO COMPARATOR

Matching Placebo; Oral Dose

Drug: Matching Placebo

Part B 30 mg QD CVL-231

ACTIVE COMPARATOR

Oral Dose

Drug: CVL-231

Part B 30 mg QD Placebo

PLACEBO COMPARATOR

Matching Placebo; Oral Dose

Drug: Matching Placebo

Part B 20 mg BID CVL-231

ACTIVE COMPARATOR

Oral Dose

Drug: CVL-231

Part B 20 mg BID Placebo

PLACEBO COMPARATOR

Drug: Matching Placebo

Interventions

CVL-231 DRUG

CVL-231

Part A: 10 mg QD CVL-231; Part A: 20 mg QD CVL-231; Part A: 30 mg QD CVL-231; Part A: 5 mg QD CVL-231; Part A: 5-10-20 mg BID CVL-231; Part B 20 mg BID CVL-231; Part B 30 mg QD CVL-231

Matching Placebo DRUG

Placebo matching CVL-231

Part A: 10 mg QD Placebo; Part A: 20 mg QD Placebo; Part A: 30 mg QD Placebo; Part A: 5 mg QD Placebo; Part A: 5-10-20 mg BID Placebo; Part B 20 mg BID Placebo; Part B 30 mg QD Placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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).

Sponsors & Collaborators

• Cerevel Therapeutics, LLC: lead

Study Sites (5)

Pillar Clinical Research

Bentonville, Arkansas, 72712, United States

Location

Woodlands International Research Group

Little Rock, Arkansas, 72211, United States

Location

Synergy San Diego

Lemon Grove, California, 91945, United States

Location

Collaborative Neuroscience Network, LLC

Long Beach, California, 90806, United States

Location

Hassman Research Institute

Marlton, New Jersey, 08053, United States

Location

Related Publications (1)

• Krystal JH, Kane JM, Correll CU, Walling DP, Leoni M, Duvvuri S, Patel S, Chang I, Iredale P, Frohlich L, Versavel S, Perry P, Sanchez R, Renger J. Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial. Lancet. 2022 Dec 17;400(10369):2210-2220. doi: 10.1016/S0140-6736(22)01990-0.

  PMID: 36528376 DERIVED

MeSH Terms

Conditions

Schizophrenia

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Study Officials

• Matthew Leoni, MD

  Cerevel Therapeutics, LLC

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 16, 2019
• First Posted: October 23, 2019
• Study Start: October 15, 2019
• Primary Completion: May 7, 2021
• Study Completion: June 3, 2021
• Last Updated: July 2, 2021

Record last verified: 2021-07

Locations

US (5)