A Trial to Evaluate the Effects of Itraconazole and Carbamazepine on the Pharmacokinetics of Emraclidine and of Emraclidine on the Pharmacokinetics of Metformin in Healthy Adult Participants

A Phase 1, Open-label, Three-Part, Fixed-Sequence Trial in Healthy Adult Participants to Evaluate the Effects of Itraconazole and Carbamazepine on the Single-Dose Pharmacokinetics of Emraclidine, and the Effect of Emraclidine on the Single-Dose Pharmacokinetics of Metformin

The primary purpose of the study is to evaluate the effect of itraconazole, a strong cytochrome P450 (CYP) 3A4 inhibitor, on the pharmacokinetics (PK) of emraclidine and metabolite CV-0000364 in Part A, the effect of carbamazepine, a strong CYP3A4 inducer, on the PK of emraclidine and metabolite CV-0000364 in Part B, and to evaluate the effect of emraclidine on the PK of metformin in Part C in healthy adult participants.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Metformin; Drug: Itraconazole; Drug: Emraclidine; Drug: Carbamazepine

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Overland Park, Kansas, United States, 66212
      • Overland Park, Kansas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria for All Participants:

• Healthy as determined by medical evaluation, including medical and psychiatric history, physical and neurological examinations, ECG, vital sign measurements, and laboratory test results, as evaluated by the investigator.
• Body mass index of 18.5 to 35.0 kilograms per square meter (kg/m^2), inclusive, and a total body weight ≥50 kilograms (kg) (110 pounds [lbs]).

Inclusion Criteria for Part A:

• Male and female (women of nonchildbearing potential only) participants, ages 18 to 55 years, inclusive, at the time of signing the informed consent form (ICF).

Inclusion Criteria for Part B:

• Male and female (women of nonchildbearing potential only) participants, ages 18 to 55 years, inclusive, at the time of signing the ICF.

Inclusion Criteria for Part C:

• Male and female (both women of childbearing and nonchildbearing potential) participants, ages 18 to 55 years, inclusive, at the time of signing the ICF.

• Sexually active women of childbearing potential must agree to use at least an acceptable birth control method during the trial and for 7 days after the last dose of IMP. Acceptable birth control methods that result in a failure rate of more than 1% per year include the following:

  • Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action
  • Male or female condom with or without spermicide
  • Cap, diaphragm, or sponge with spermicide

Exclusion Criteria for All Participants:

• Current or past history of significant cardiovascular, pulmonary, gastrointestinal, renal, hepatic, metabolic, genitourinary, endocrine (including diabetes mellitus, thyroid disorders), malignancy, 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.

• "Yes" responses for any of the following items on the C-SSRS (within the individual's lifetime):

  • Suicidal Ideation Item 3 (Active Suicidal Ideation With Any Methods [Not Plan] Without Intent to Act)
  • Suicidal Ideation Item 4 (Active Suicidal Ideation With Some Intent to Act, Without Specific Plan)
  • Suicidal Ideation Item 5 (Active Suicidal Ideation With Specific Plan and Intent)
  • Any of the Suicidal Behavior items (Actual Attempt, Interrupted Attempt, Aborted Attempt, or Preparatory Acts/Behavior)

• "Yes" responses for any of the following items on the C-SSRS (within past 12 months):

  • Suicidal Ideation Item 1 (Wish to be Dead)
  • Suicidal Ideation Item 2 (Non-Specific Active Suicidal Thoughts)
• Serious risk of suicide in the opinion of the investigator is also exclusionary.
• Any condition or surgery that could possibly affect drug absorption, including, but not limited to, bowel resections, bariatric weight loss surgery/procedures, gastrectomy, and cholecystectomy.
• Positive result for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen, hepatitis B total core antibody, or hepatitis C antibody with detectable viral ribonucleic acid (RNA) levels at Screening.
• Positive drug screen (including cotinine and tetrahydrocannabinol [THC]) or a positive test for alcohol.

Exclusion Criteria for Part A:

• History of presence of any of the following and deemed clinically significant by the investigator or designee and confirmed by the medical monitor:

  • Ventricular dysfunction or risk factors for torsades de pointes (e.g., heart failure, cardiomyopathy, family history of long-QT syndrome)

• Any of the following clinical laboratory test results at the Screening Visit or Check-in (Day -1), which can be confirmed by a single repeat measurement, if deemed necessary:

  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > upper limit of normal (ULN).
  • Total bilirubin >ULN. If Gilbert's syndrome is suspected, total bilirubin >ULN is acceptable if the conjugated or direct bilirubin fraction is <20% of total bilirubin.
  • Hypokalemia (potassium levels < lower limit of normal [LLN] millimoles per liter [mmol/L]), and/or hypomagnesemia (magnesium levels <1.2 milligrams per deciliter [mg/dL]; <0.5 mmol/L), and/or hypocalcemia (corrected serum calcium <8.0 mg/dL or ionized calcium <1.0 mmol/L).

Exclusion Criteria for Part B:

• Participants positive for human leukocyte antigen (HLA)-B*1502 or HLA-A*3101.
• Family history of drug reaction with eosinophilia and systemic symptoms (DRESS).
• Family history of porphyria.
• History of cardiac conduction disturbance including second- and third-degree atrioventricular heart block.

• Any of the following clinical laboratory test results at the Screening Visit or Check-in (Day -1), which can be confirmed by a single repeat measurement:

  • Platelets, white blood cell count, absolute neutrophil count, or hemoglobin <LLN.
  • Serum sodium <LLN.

• Any of the following clinical laboratory test results at the Screening Visit or Check-in (Day -1), which can be confirmed by a single repeat measurement, if deemed necessary:

  • AST or ALT >ULN.
  • Total bilirubin >ULN. If Gilbert's syndrome is suspected, total bilirubin >ULN is acceptable if the conjugated or direct bilirubin fraction is <20% of total bilirubin.

Exclusion Criteria for Part C:

• Any of the following clinical laboratory test results at the Screening Visit or Check-in (Day -1), as assessed by the central laboratory and confirmed by a single repeat measurement, if deemed necessary:

  • AST or ALT ≥2 × ULN.
  • Total bilirubin >1.5 × ULN. If Gilbert's syndrome is suspected, total bilirubin >1.5 × ULN is acceptable if the conjugated or direct bilirubin fraction is <20% of total bilirubin.
• Female participants who are pregnant, breastfeeding, or planning to become pregnant during IMP treatment or within 7 days after the last dose of IMP. Women of childbearing potential must have a negative serum pregnancy test result at the Screening Visit and a negative urine pregnancy test result at Check-in.

[Note: Other inclusion and exclusion criteria as per protocol may apply.]

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: Emraclidine Followed by Itraconazole + Emraclidine; Participants will receive a single oral dose of emraclidine 10 milligrams (mg) on Day 1 in Treatment Period (TP) 1 followed by itraconazole 200 mg, orally, twice daily (BID) on Day 1 and once daily (QD) from Days 2 to 14, with a single oral dose of emraclidine 10 mg co-administered on Day 5 in TP 2.	Drug: Itraconazole; Itraconazole oral solution.; Other Names: Sporanox; Drug: Emraclidine; Emraclidine tablets.
Experimental: Part B: Emraclidine Followed by Carbamazepine + Emraclidine; Participants will receive a single oral dose of emraclidine 30 mg on Day 1 in TP 1 followed by carbamazepine 100 mg BID from Days 1 to 3, 200 mg BID from Days 4 to 6, and 300 mg BID from Days 7 to 19, orally, with a single oral dose of emraclidine 30 mg on Day 16 in TP 2.	Drug: Emraclidine; Emraclidine tablets.; Drug: Carbamazepine; Carbamazepine tablets.; Other Names: Tegretol-XR
Experimental: Part C: Metformin Followed by Emraclidine + Metformin; Participants will receive a single oral dose of metformin 850 mg on Day 1 in TP 1 followed by emraclidine 30 mg, orally, QD for Days 1 to 10, with a single oral dose of metformin 850 mg co-administered on Day 8 in TP 2.	Drug: Metformin; Metformin tablets.; Other Names: Glucophage; Drug: Emraclidine; Emraclidine tablets.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Part A: Maximum Observed Plasma Concentration (Cmax) of Emraclidine and its Metabolite CV-0000364	Pre-dose and at multiple time points post-dose from Day 1 in TP 1 up to Day 15 in TP 2 of Part A
Part B: Cmax of Emraclidine and its Metabolite CV-0000364	Pre-dose and at multiple time points post-dose from Day 1 in TP 1 up to Day 20 in TP 2 of Part B
Part C: Cmax of Metformin	Pre-dose and at multiple time points post-dose from Day 1 in TP 1 up to Day 11 in TP 2 of Part C
Part A: Area Under the Plasma Concentration-time Curve from Time Zero to Last Specified Sampling Time (AUC0-t) of Emraclidine and its Metabolite CV-0000364	Pre-dose and at multiple time points post-dose from Day 1 in TP 1 up to Day 15 in TP 2 of Part A
Part B: AUC0-t of Emraclidine and its Metabolite CV-0000364	Pre-dose and at multiple time points post-dose from Day 1 in TP 1 up to Day 20 in TP 2 of Part B
Part C: AUC0-t of Metformin	Pre-dose and at multiple time points post-dose from Day 1 in TP 1 up to Day 11 in TP 2 of Part C
Part A: Area Under the Plasma Concentration-time Curve from Time Zero to Infinity (AUCinf) of Emraclidine and its Metabolite CV-0000364	Pre-dose and at multiple time points post-dose from Day 1 in TP 1 up to Day 15 in TP 2 of Part A
Part B: AUCinf of Emraclidine and its Metabolite CV-0000364	Pre-dose and at multiple time points post-dose from Day 1 in TP 1 up to Day 20 in TP 2 of Part B
Part C: AUCinf of Metformin	Pre-dose and at multiple time points post-dose from Day 1 in TP 1 up to Day 11 in TP 2 of Part C

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Based on Severity		From the first dose up to 1 month following last dose with investigational medicinal product (IMP) in each part of the study
Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Values		Up to end of treatment in each part of the study (up to an average of 15 days)
Number of Participants With Clinically Significant Changes in Vital Sign Measurements		Up to end of treatment in each part of the study (up to an average of 15 days)
Number of Participants With Clinically Significant Changes in Laboratory Assessments		Up to end of treatment in each part of the study (up to an average of 15 days)
Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results		Up to end of treatment in each part of the study (up to an average of 15 days)
Changes in Suicidality Assessed Using the Columbia Suicide Severity Rating Scale (C-SSRS) Score	The C-SSRS includes 'yes' or 'no' responses for assessment of suicidal ideation and behavior as well as numeric ratings for the severity of ideation, if present (from 1 to 5, with 5 being the most severe). Greater lethality or potential lethality of suicidal behaviors (endorsed on the behavior subscale) indicates increased risk.	Up to end of treatment in each part of the study (up to an average of 15 days)

Collaborators and Investigators

• Sponsor: Cerevel Therapeutics, LLC

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2023
• Primary Completion (Actual): November 10, 2023
• Study Completion (Actual): November 10, 2023

Study Registration Dates

• First Submitted: July 20, 2023
• First Submitted That Met QC Criteria: July 20, 2023
• First Posted (Actual): July 28, 2023

Study Record Updates

• Last Update Posted (Actual): April 2, 2024
• Last Update Submitted That Met QC Criteria: April 1, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Hormones, Hormone Substitutes, and Hormone Antagonists; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Anticonvulsants; Sodium Channel Blockers; Antimanic Agents; Hormone Antagonists; Cytochrome P-450 Enzyme Inducers; Antifungal Agents; Steroid Synthesis Inhibitors; Cytochrome P-450 CYP3A Inducers; 14-alpha Demethylase Inhibitors; Metformin; Itraconazole; Carbamazepine
• Other Study ID Numbers: CVL-231-HV-1010

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No