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

An Open-Label 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

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.

Study Overview

• Status: Completed
• Conditions: Fibrodysplasia Ossificans Progressiva
• Intervention / Treatment: Drug: Palovarotene; Drug: midazolam

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Cambridge, Massachusetts, United States, 02142
      • Cambridge Ipsen US

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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.	Drug: Palovarotene; oral capsules
EXPERIMENTAL: 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).	Drug: Palovarotene; oral capsules
EXPERIMENTAL: 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.	Drug: Palovarotene; oral capsules
EXPERIMENTAL: 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.	Drug: Palovarotene; oral capsules; Drug: midazolam; oral syrup

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum (peak) observed plasma drug concentration		Days 1, 2, 3, 6, 7, 8, 11, 12, 13.
Time to reach maximum (peak) (t max) observed plasma concentration following drug administration		Days 1, 2, 3, 6, 7, 8, 11, 12, 13
Area under the plasma concentration time (AUC 0-last) curve from time zero to the last quantifiable time point, calculated by linear-log trapezoidal summation		Days 1, 2, 3, 6, 7, 8, 11, 12, 13
Area under the plasma concentration time curve from time zero to infinity (AUC 0-infinity)	calculated by linear-log trapezoidal summation and extrapolated to infinity by addition of the last quantifiable plasma concentration divided by the elimination rate constant	Days 1, 2, 3, 6, 7, 8, 11, 12, 13
Apparent terminal disposition rate constant/terminal rate constant yz	determined by linear regression of the terminal points of the log-linear plasma concentration-time curve	Days 1, 2, 3, 6, 7, 8, 11, 12, 13
Apparent terminal elimination half-life (t1/2)		Days 1, 2, 3, 6, 7, 8, 11, 12, 13
Apparent volume of distribution after oral administration (Vd/F)		Days 1, 2, 3, 6, 7, 8, 11, 12, 13
Apparent total clearance of the drug from plasma after oral administration (cLF)		Days 1, 2, 3, 6, 7, 8, 11, 12, 13
Area under the plasma concentration time curve from time zero to 24 hours only for DDI cohort		Days 1, 2, 15, 16
The last concentration before the next study drug administration at steady state for DDI cohort		Days 1, 2, 15, 16
Maximum (peak) observed plasma drug concentration at steady state for DDI cohort		Days 1, 2, 15, 16
Time to reach maximum (peak) observed plasma concentration following drug administration at steady state for DDI cohort		Days 1, 2, 15, 16
Minimum observed plasma concentration at steady state, taken as the lowest plasma concentration during dosing interval for DDI cohort		Days 1, 2, 15, 16
Accumulation ratio for DDI cohort		Days 1, 2, 15, 16

Secondary Outcome Measures

Outcome Measure	Time Frame
Occurrence of Adverse Events (AEs)	from baseline until the end of study (16 days)

Collaborators and Investigators

• Sponsor: Clementia Pharmaceuticals Inc.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 3, 2019
• Primary Completion (ACTUAL): March 29, 2019
• Study Completion (ACTUAL): March 29, 2019

Study Registration Dates

• First Submitted: April 1, 2021
• First Submitted That Met QC Criteria: April 1, 2021
• First Posted (ACTUAL): April 2, 2021

Study Record Updates

• Last Update Posted (ACTUAL): April 2, 2021
• Last Update Submitted That Met QC Criteria: April 1, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Muscular Diseases; Myositis; Myositis Ossificans; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: PVO-1A-102

Drug and device information, study documents

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