Study Evaluating the Effect of Food on the Pharmacokinetics of Palovarotene and the Effect of Palovarotene on the Pharmacokinetics of the CYP3A4 Substrate Midazolam in Two Cohorts of Healthy Adult Subjects

NCT ID: NCT04829773

Last Updated: 2021-04-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 48 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-01-03
• Study Completion Date: 2019-03-29

Brief Summary

Study to evaluate the effect of food and the effect of swallowing capsule whole versus sprinkling on apple sauce on the pharmacokinetics (PK)/bioavailability of palovarotene, and evaluate the effect of palovarotene on the PK of the CYP3A4 substrate midazolam.

Conditions

Fibrodysplasia Ossificans Progressiva

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

PK Cohort 1

Subjects received three single oral doses of palovarotene on Days 1, 6, and 11, separated by 5-day washout periods.

Sequence A-B-C: Subjects received a single oral dose of palovarotene whole capsule under fasting conditions (at least a 10-hour overnight fast); followed by a single oral dose of palovarotene whole capsule 30 minutes after the start of a standardized high-fat, high-caloric breakfast; and then followed by a single oral dose of palovarotene sprinkled on 1 teaspoon of apple sauce, administered 30 minutes after the start of a standardized high-fat, high-caloric breakfast.

Group Type: EXPERIMENTAL

Palovarotene

Intervention Type: DRUG

oral capsules

PK Cohort 2

Subjects received three single oral doses of palovarotene on Days 1, 6, and 11, separated by 5-day washout periods.

Sequence B-C-A: Subjects received a single oral dose of palovarotene whole capsule 30 minutes after the start of a standardized high-fat, high-caloric breakfast; followed by a single oral dose of palovarotene sprinkled on 1 teaspoon of apple sauce, administered 30 minutes after the start of a standardized high-fat, high-caloric breakfast; and then followed by a single oral dose of palovarotene whole capsule under fasting conditions (at least a 10-hour overnight fast).

Group Type: EXPERIMENTAL

Palovarotene

Intervention Type: DRUG

oral capsules

PK Cohort 3

Subjects received three single oral doses of palovarotene on Days 1, 6, and 11, separated by 5-day washout periods.

Sequence C-A-B: Subjects received a single oral dose of palovarotene sprinkled on 1 teaspoon of apple sauce, administered 30 minutes after the start of a standardized high-fat, high-caloric breakfast; followed by a single oral dose of palovarotene whole capsule under fasting conditions (at least a 10-hour overnight fast); and then followed by a single oral dose of palovarotene whole capsule 30 minutes after the start of a standardized high-fat, high-caloric breakfast.

Group Type: EXPERIMENTAL

Palovarotene

Intervention Type: DRUG

oral capsules

Drug-Drug interaction (DDI) Cohort

On the morning of Day 1, subjects received a single dose of midazolam 30 minutes after the start of a standardized breakfast. On Day 2 (after the 24-hour midazolam blood draw) through Day 15, subjects received a daily, single dose of palovarotene in the morning 30 minutes after the start of a standardized breakfast. A second dose of midazolam was administered on Day 15 in the morning (immediately following the palovarotene dose) 30 minutes after the start of a standardized breakfast.

Group Type: EXPERIMENTAL

Palovarotene

Intervention Type: DRUG

oral capsules

midazolam

Intervention Type: DRUG

oral syrup

Interventions

Palovarotene

oral capsules

Intervention Type: DRUG

midazolam

oral syrup

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Generally healthy male or female aged 18 to 55 years, inclusive; body mass index (BMI) of 18 to 30 kg/m2 and a body weight of >50 kg; resting pulse of >45 bpm and <100 bpm; systolic and diastolic blood pressure of <140/90 mmHg

Exclusion Criteria

• a history or current evidence of a clinically significant or uncontrolled disease, disease or condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs
• exposure to synthetic oral retinoids or creams containing retinoids in the past 30 days prior to the signature of the informed consent.
• history or presence of silent infections, including positive tests for human immunodeficiency virus type 1 (HIV-1), human immunodeficiency virus type 2 (HIV-2), hepatitis B virus (HBV), or hepatitis C virus (HCV)
• history of allergy or hypersensitivity to retinoids, gelatin, or lactose
• For the DDI component only, the subject had a history of allergy or hypersensitivity to benzodiazepines, midazolam, cherries, or midazolam formulation excipients

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Clementia Pharmaceuticals Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ipsen Medical Director

Role: STUDY_DIRECTOR

Ipsen

Locations

Cambridge Ipsen US

Cambridge, Massachusetts, United States

Countries

United States

References

Marino R, Dube L, Ogier J, Le Quan Sang KH. The Pharmacokinetic Profile of Palovarotene: An Open-Label Phase I Trial Investigating the Effect of Food and Potential for Drug-Drug Interaction in Healthy Participants. Eur J Drug Metab Pharmacokinet. 2023 Nov;48(6):691-707. doi: 10.1007/s13318-023-00856-2. Epub 2023 Oct 7.

Reference Type: DERIVED

PMID: 37804430 (View on PubMed)

Other Identifiers

PVO-1A-102

Identifier Type: -

Identifier Source: org_study_id