An Efficacy and Safety Study of Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva.
- Registration Number
- NCT03312634
- Lead Sponsor
- Clementia Pharmaceuticals Inc.
- Brief Summary
Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by heterotopic ossification (HO) often associated with painful, recurrent episodes of soft tissue swelling (flare-ups) that lead to ankyloses of major joints with cumulative and irreversible loss of movement and disability.
- Detailed Description
One of the primary objectives was to evaluate the efficacy of palovarotene in decreasing new HO in participants with FOP as assessed by low-dose, whole body computed tomography (WBCT), excluding head, compared to untreated participants from Clementia's FOP natural history study (Study PVO-1A-001, NHS). The other primary objective was to evaluate the safety of palovarotene in participants with FOP.
This study was conducted in three parts. Part A was the main part of the study, Part B, the 2-year (24-month) extension and Part C was an up-to-2-year post last dose of study treatment follow-up for skeletally immature participants.
Participants in Part A and B received a chronic/flare-up dosing regimen of palovarotene for up to 4 years (48 months) as follows:
* Chronic treatment: orally administered 5 mg palovarotene once daily.
* Flare-up treatment: orally administered 20 mg palovarotene once daily for 4 weeks (28 days) followed by orally administered 10 mg palovarotene once daily for 8 weeks (56 days). Flare-up treatment may be extended until the Investigator determines that the flare-up has resolved.
Note that all dosing was weight-adjusted in skeletally immature participants (those under the age of 18 years with less than 90% skeletal maturity on hand/wrist x-rays performed at Screening).
In part C, participants who were enrolled in Parts A or B who discontinued the study and were skeletally immature were invited back to participate in the off-treatment safety follow-up. No new participants were enrolled into Part C.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 107
- Written, signed, and dated informed subject/parent consent; and for subjects who are minors, age-appropriate assent (performed according to local regulations).
- Males or females at least 4 years of age.
- No flare-up symptoms within the past 4 weeks, including at the time of enrollment.
- Abstinent or using two highly effective forms of birth control.
- Accessible for treatment and follow-up; able to undergo all study procedures including low-dose WBCT (excluding head) without sedation.
Key
- Weight <10 kg.
- Concomitant medications that are strong inhibitors or inducers of cytochrome P450 (CYP450) 3A4 activity; or kinase inhibitors such as imatinib.
- Amylase or lipase >2x above the upper limit of normal (ULN) or with a history of chronic pancreatitis.
- Elevated aspartate aminotransferase or alanine aminotransferase >2.5x ULN.
- Fasting triglycerides >400 mg/dL with or without therapy.
- Female subjects who are breastfeeding.
- Subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant disease.
- Simultaneous participation in another clinical research study (other than palovarotene studies) within 4 weeks prior to Screening; or within five half-lives of the investigational agent, whichever is longer.
- Any reason that, in the opinion of the Investigator, would lead to the inability of the subject and/or family to comply with the protocol.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Palovarotene Chronic/Flare-Up Regimen Palovarotene Participants received 5 mg palovarotene once daily for up to 48 months; and 20 mg palovarotene once daily for 28 days, followed by 10 mg for 56 days for flareups. (Dosing was adjusted for weight in skeletally immature subjects.)
- Primary Outcome Measures
Name Time Method Annualized New Heterotopic Ossification (HO) Baseline (within one month of screening/Day 1) and up to 24 months The annualized new HO was assessed by low-dose, whole body computed tomography (WBCT), excluding head. The weighted linear mixed effect method without square-root transformation and negatives included was used for annualized new HO analysis.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Any New HO From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months) The new HO was assessed by WBCT scan. The percentage of participants with any new HO (volume \> 0 mm\^3) were analyzed using the Bayesian distribution. Results are presented for overall ITT period.
Number of Body Regions With New HO From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months) All participants were analyzed for number of body regions with any new HO (new HO \> 0 mm\^3). The presence of HO across various body regions was analyzed using WBCT scan. Results are presented for overall ITT period
Percentage of Participants With Flare-Ups Month 12 Flare-up as an event with one or more flare-up symptoms, and regardless of flare-up symptom onset. Flare-up was evaluated remotely, or by telephone or video-conferencing, unless the Investigator deemed that a site visit was necessary.
Ratio of Flare-Up Per Participant-Month of Exposure From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months) Flare-up as an event with one or more flare-up symptoms, and regardless of flare-up symptom onset. Flare-up was evaluated remotely, or by telephone or video-conferencing, unless the Investigator deemed that a site visit was necessary. The flare-up rate per participant-month exposure was analyzed using a negative binomial regression. Results are presented for overall ITT period.
Trial Locations
- Locations (16)
Hospital Italiano de Buenos Aires, Tte General Juan Domingo Peron 4190
🇦🇷Buenos Aires, Argentina
Royal National Orthopaedic Hospital, Brockely Hill
🇬🇧Stanmore, United Kingdom
Royal North Shore Hospital
🇦🇺Saint Leonards, New South Wales, Australia
Norrlands Universitetssjukhus
🇸🇪Umeå, Sweden
Hospital Israelita Albert Einstein
🇧🇷Sao Paulo, SP, Brazil
The University of Tokyo Hospital
🇯🇵Tokyo, Bunkyo-ku, Japan
Groupe Hospitalier Necker Enfants Malades
🇫🇷Paris, France
University of California San Francisco, Division of Endocrinology and Metabolism
🇺🇸San Francisco, California, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
University of Pennsylvania, Internal Medicine
🇺🇸Philadelphia, Pennsylvania, United States
Hospital for Sick Children, 555 University Avenue
🇨🇦Toronto, Ontario, Canada
Toronto General Hospital
🇨🇦Toronto, Ontario, Canada
Istituto Giannina Gaslini
🇮🇹Genoa, Liguria, Italy
Hospital Universitari i Politècnic La Fe, Unidad de ReumatologÃa Pediatrica
🇪🇸Valencia, Avinguda De Fernando Abril Martorell, Nº 106, Spain
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Queensland University of Technology
🇦🇺Woolloongabba, Queensland, Australia