Clinical trial NCT04829773: 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
Official title: 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Fibrodysplasia Ossificans Progressiva
Lead sponsor: Ipsen
Sponsor class: INDUSTRY
First posted: 2021-04-02
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This study had two components. One component evaluated the effect of food and the effect of swallowing capsule whole versus sprinkling on apple sauce on the PK/bioavailability of palovarotene, and the other component evaluated the effect of palovarotene on the PK of the CYP3A4 substrate midazolam. The PK of palovarotene after single and multiple doses was also evaluated as part of the DDI component. Two cohorts of healthy adult subjects were enrolled, one for each component.
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Maximum (peak) observed plasma drug concentration
timeFrame: Days 1, 2, 3, 6, 7, 8, 11, 12, 13.
measure: Time to reach maximum (peak) (t max) observed plasma concentration following drug administration
timeFrame: Days 1, 2, 3, 6, 7, 8, 11, 12, 13
measure: 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
timeFrame: Days 1, 2, 3, 6, 7, 8, 11, 12, 13
measure: Area under the plasma concentration time curve from time zero to infinity (AUC 0-infinity)
timeFrame: Days 1, 2, 3, 6, 7, 8, 11, 12, 13
measure: Apparent terminal disposition rate constant/terminal rate constant yz
timeFrame: Days 1, 2, 3, 6, 7, 8, 11, 12, 13
measure: Apparent terminal elimination half-life (t1/2)
timeFrame: Days 1, 2, 3, 6, 7, 8, 11, 12, 13
measure: Apparent volume of distribution after oral administration (Vd/F)
timeFrame: Days 1, 2, 3, 6, 7, 8, 11, 12, 13
measure: Apparent total clearance of the drug from plasma after oral administration (cLF)
timeFrame: Days 1, 2, 3, 6, 7, 8, 11, 12, 13
measure: Area under the plasma concentration time curve from time zero to 24 hours only for DDI cohort
timeFrame: Days 1, 2, 15, 16
measure: The last concentration before the next study drug administration at steady state for DDI cohort
timeFrame: Days 1, 2, 15, 16
measure: Maximum (peak) observed plasma drug concentration at steady state for DDI cohort
timeFrame: Days 1, 2, 15, 16
measure: Time to reach maximum (peak) observed plasma concentration following drug administration at steady state for DDI cohort
timeFrame: Days 1, 2, 15, 16
measure: Minimum observed plasma concentration at steady state, taken as the lowest plasma concentration during dosing interval for DDI cohort
timeFrame: Days 1, 2, 15, 16
measure: Accumulation ratio for DDI cohort
timeFrame: Days 1, 2, 15, 16
Secondary outcomes:
measure: Occurrence of Adverse Events (AEs)
timeFrame: from baseline until the end of study (16 days)
Other outcomes:
Locations:
city: Cambridge
country: United States
facility: Cambridge Ipsen US
state: Massachusetts
Study officials:
affiliation: Ipsen
name: Ipsen Medical Director
role: STUDY_DIRECTOR
References: