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

Clementia Pharmaceuticals

Status and phase: Completed; Phase 1

Conditions: Fibrodysplasia Ossificans Progressiva

Treatments: Drug: midazolam; Drug: Palovarotene

Study type: Interventional

Funder types: Industry

Identifiers

NCT04829773

PVO-1A-102

Details and patient eligibility

About

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.

Enrollment: 48 patients

Sex: All

Ages: 18 to 55 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

Key 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

Key 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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48 participants in 4 patient groups

PK Cohort 1

Experimental group

Description:

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.

Treatment:

Drug: Palovarotene

PK Cohort 2

Experimental group

Description:

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).

Treatment:

Drug: Palovarotene

PK Cohort 3

Experimental group

Description:

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.

Treatment:

Drug: Palovarotene

Drug-Drug interaction (DDI) Cohort

Experimental group

Description:

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.

Treatment:

Drug: midazolam

Drug: Palovarotene