Clinical trial NCT05965219: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Lead sponsor: Cerevel Therapeutics, LLC
Sponsor class: INDUSTRY
First posted: 2023-07-28
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

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

Primary outcomes:
measure: Part A: Maximum Observed Plasma Concentration (Cmax) of Emraclidine and its Metabolite CV-0000364
timeFrame: 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
measure: Part B: Cmax of Emraclidine and its Metabolite CV-0000364
timeFrame: 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
measure: Part C: Cmax of Metformin
timeFrame: 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
measure: 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
timeFrame: 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
measure: Part B: AUC0-t of Emraclidine and its Metabolite CV-0000364
timeFrame: 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
measure: Part C: AUC0-t of Metformin
timeFrame: 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
measure: Part A: Area Under the Plasma Concentration-time Curve from Time Zero to Infinity (AUCinf) of Emraclidine and its Metabolite CV-0000364
timeFrame: 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
measure: Part B: AUCinf of Emraclidine and its Metabolite CV-0000364
timeFrame: 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
measure: Part C: AUCinf of Metformin
timeFrame: 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 outcomes:
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) Based on Severity
timeFrame: From the first dose up to 1 month following last dose with investigational medicinal product (IMP) in each part of the study
measure: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Values
timeFrame: Up to end of treatment in each part of the study (up to an average of 15 days)
measure: Number of Participants With Clinically Significant Changes in Vital Sign Measurements
timeFrame: Up to end of treatment in each part of the study (up to an average of 15 days)
measure: Number of Participants With Clinically Significant Changes in Laboratory Assessments
timeFrame: Up to end of treatment in each part of the study (up to an average of 15 days)
measure: Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results
timeFrame: Up to end of treatment in each part of the study (up to an average of 15 days)
measure: Changes in Suicidality Assessed Using the Columbia Suicide Severity Rating Scale (C-SSRS) Score
timeFrame: Up to end of treatment in each part of the study (up to an average of 15 days)
Other outcomes:
Locations:
city: Overland Park
country: United States
facility: Overland Park, Kansas
state: Kansas
Study officials:
References: