Clinical trial NCT02190747: An Efficacy and Safety Study of Palovarotene to Treat Preosseous Flare-ups in FOP Subjects
Official title: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of a RARγ-Specific Agonist (Palovarotene) in the Treatment of Preosseous Flare-ups in Subjects With Fibrodysplasia Ossificans Progressiva (FOP)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Fibrodysplasia Ossificans Progressiva
Keywords: Intervention study
Clinical trial Phase 2
Efficacy and safety
Heterotopic ossification
Flare-up
Palovarotene
Retinoic acid receptor agonist
Retinoic acid receptor gamma agonist
Clementia
Myositis Ossificans Progressiva
Munchmeyer's Disease
FOP
Lead sponsor: Ipsen
Sponsor class: INDUSTRY
First posted: 2014-07-15
Enrollment: 40
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Fibrodysplasia ossificans progressiva (FOP) is a rare, severely disabling disease characterized by painful, recurrent episodes of soft tissue swelling (flare-ups) that result in abnormal bone formation in muscles, tendons, and ligaments. Flare-ups begin early in life and may occur spontaneously or after soft tissue trauma, vaccinations, or influenza infections. Recurrent flare-ups progressively restrict movement by locking joints leading to cumulative loss of function and disability. Mouse models of FOP have demonstrated the ability of retinoic acid receptor (RAR) gamma agonists to prevent heterotopic ossification (HO) following injury. The purpose of the study is to evaluate whether palovarotene, an RAR gamma agonist, will prevent HO during and following a flare-up in subjects with FOP.

Detailed description: The primary objective is to evaluate the ability of different doses of palovarotene to prevent HO at the flare-up site in subjects with FOP as assessed by plain radiographs.

This is a Phase 2, multi-center, randomized, double-blind, sponsor-unblinded, placebo-controlled study. Two cohorts of subjects will be randomized into different dosing regimens of palovarotene for a 6-week (42 days) treatment period. The study will consist of three periods:

1. A Screening period to occur within 7 days of a distinct flare-up. The first dose of study drug will be taken within 7 days of the flare-up initiation.
2. A double-blind treatment period of 6 weeks (42 days) duration.
3. A follow-up period of 6 weeks (42 days) duration.

An initial cohort (Cohort 1) of subjects will be randomly assigned 3:1 to either palovarotene or placebo daily for 42 days. Subjects randomized to palovarotene in Cohort 1 will receive an initial daily dose of 10 mg for 14 days followed by 5 mg daily for 28 days.

In Cohort 2, new FOP subjects meeting all inclusion/exclusion criteria will be randomly assigned 3:3:2 to two dose regimens of palovarotene (10 mg for 14 days and 5 mg for 28 days; 5 mg for 14 days and 2.5 mg for 28 days) or placebo daily for 42 days. Doses will be weight-adjusted and subjects randomized within three weight-range categories (20 to \<40 kg, 40 to \<60 kg, and ≥60 kg).

Subjects completing the study and still meeting eligibility requirements will be given the opportunity to enroll into an open-label extension study.

Eligibility criteria: Inclusion Criteria:

* Written, signed, and dated informed subject/parent consent or age-appropriate assent.
* Subjects clinically diagnosed with classic Fibrodysplasia Ossificans Progressiva (FOP).
* Symptomatic onset of a distinct flare-up within 7 days of Study Day 1 (start of study drug) and defined by the presence of at least two of six of the following symptoms: pain, soft tissue swelling, decreased range of motion, stiffness, redness, and warmth. Flare-up must be confirmed by the physician at the Screening visit.
* Flare-up is at an appendicular area (upper or lower extremity), abdomen, or chest; and subject has received, is receiving, or is willing to receive treatment per standard of care, which may or may not include oral prednisone (2 mg/kg PO to a maximum dose of 100 mg daily) for 4 days.
* Abstinent or using two highly effective forms of birth control.
* Subjects must be accessible for treatment and follow-up. Subjects living at distant locations from the investigational site must be able and willing to travel to a site for the initial and all follow-up visits.

Exclusion Criteria:

* Weight \<20 kg.
* Intercurrent non-healed fracture at any location.
* Complete immobilization of joint at site of flare-up.
* The inability of the subject to undergo imaging assessments using plain radiographs.
* If currently using vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, or herbal preparations, fish oil, and unable or unwilling to discontinue use of these products for the duration of the study.
* Exposure to synthetic oral retinoids in the past 30 days prior to Screening (signature of the informed consent).
* Concurrent treatment with tetracycline due to the potential increased risk of pseudotumor cerebri.
* History of allergy or hypersensitivity to retinoids or lactose.
* Concomitant medications that are inhibitors or inducers of CYP450 3A4 activity.
* Amylase or lipase \>1.5x above the upper limit of normal or with a history of chronic pancreatitis.
* Elevated aspartate aminotransferase or alanine aminotransferase \>2.5x the upper limit of normal.
* Fasting triglycerides \>400 mg/dL with or without therapy.

Primary outcomes:
measure: Percentage of Responders at Week 6
timeFrame: Baseline (Day 1) and Week 6 (Day 42)
Secondary outcomes:
measure: Percentage of Subjects With New HO at Weeks 6 and 12
timeFrame: Weeks 6 and 12 (Day 84)
measure: Change From Baseline in Amount (Area) of New HO Formed at the Flare-up Site at Weeks 6 and 12
timeFrame: Baseline, Weeks 6 and 12
measure: Percentage of Responders at Week 12
timeFrame: Baseline and Week 12
measure: Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12
timeFrame: Baseline, Weeks 2, 4, 6 and 12
measure: Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12
timeFrame: Baseline, Weeks 2, 4, 6 and 12
measure: Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12
timeFrame: Baseline, Weeks 2, 4, 6 and 12
measure: Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12
timeFrame: Baseline, Weeks 2, 4, 6 and 12
measure: Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12
timeFrame: Baseline, Weeks 2, 4, 6 and 12
measure: Change From Baseline in Amount of Bone Formation (Volume) at Weeks 6 and 12
timeFrame: Baseline, Weeks 6 and 12
measure: Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12
timeFrame: Weeks 6 and 12
measure: Change From Baseline in Percent of Normal Arc of Motion at the Primary Joint (Flare-up Site) at Weeks 6 and 12
timeFrame: Baseline, Weeks 6 and 12
measure: Subject and Investigator Global Assessment of Movement at Weeks 6 and 12
timeFrame: Weeks 6 and 12
measure: Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12
timeFrame: Baseline, Weeks 2, 4, 6, 9 and 12
measure: Percentage of Subjects Who Used Any Assistive Devices and Adaptations for Daily Living at Weeks 6 and 12
timeFrame: Weeks 6 and 12
measure: Duration of Active Symptomatic Flare-up
timeFrame: From Day 1 to Day 84
measure: Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12
timeFrame: Baseline, Weeks 2, 4, 6, 9 and 12
measure: Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12
timeFrame: Baseline, Weeks 2, 4, 6, 9 and 12
measure: Maximum Measured Plasma Concentration (Cmax) of Palovarotene
timeFrame: Pre-dose and 3, 6, 10, and 24 hours (hrs) post-dose at Week 2, and at Week 4 or 6
measure: Minimum Measured Plasma Concentration (Cmin) of Palovarotene
timeFrame: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
measure: Time of Maximum Measured Plasma Concentration (Tmax) of Palovarotene
timeFrame: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
measure: Apparent Terminal Elimination Half-life (t1/2) of Palovarotene
timeFrame: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
measure: Area Under the Plasma Concentration Versus Time Curve Over the 24-hr Dosing Interval (AUC[0-24hr]) of Palovarotene
timeFrame: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
measure: Apparent Clearance of Palovarotene (CL/F)
timeFrame: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco, Division of Endocrinology and Metabolism
state: California
city: Philadelphia
country: United States
facility: University of Pennsylvania, Center for Research in FOP & Related Disorders
state: Pennsylvania
city: Paris
country: France
facility: Hôpital Necker-Enfants Malades, Department of Genetics
city: Stanmore
country: United Kingdom
facility: The Royal National Orthopaedic Hospital, Brockley Hill
state: Middlesex
Study officials:
affiliation: Ipsen
name: Ipsen Medical Director
role: STUDY_DIRECTOR
References:
citation: Shimono K, Tung WE, Macolino C, Chi AH, Didizian JH, Mundy C, Chandraratna RA, Mishina Y, Enomoto-Iwamoto M, Pacifici M, Iwamoto M. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-gamma agonists. Nat Med. 2011 Apr;17(4):454-60. doi: 10.1038/nm.2334. Epub 2011 Apr 3.
citation: Pignolo RJ, Baujat G, Hsiao EC, Keen R, Wilson A, Packman J, Strahs AL, Grogan DR, Kaplan FS. Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP): Results of a Randomized, Placebo-Controlled, Double-Blind Phase 2 Trial. J Bone Miner Res. 2022 Oct;37(10):1891-1902. doi: 10.1002/jbmr.4655. Epub 2022 Aug 17.