An Efficacy and Safety Study of Palovarotene for the Treatment of MO
- Conditions
- Exostoses, Multiple Hereditary
- Interventions
- Registration Number
- NCT03442985
- Lead Sponsor
- Clementia Pharmaceuticals Inc.
- Brief Summary
This is a randomized, double-blind, placebo-controlled study comparing the safety and efficacy of 2 dosage regimens of palovarotene versus placebo in preventing disease progression in pediatric subjects with multiple osteochondromas (MO).
- Detailed Description
Multiple osteochondromas is a rare condition where children develop multiple benign cartilage-capped bony tumors called osteochondromas on bones throughout the body, resulting in pain, deformity, limb length discrepancy, disability, and eventually arthritis and possible malignancy. The primary objective is to compare the efficacy of two dosage regimens of palovarotene with placebo to prevent the formation of new osteochondromas in pediatric MO subjects with exostosin 1 or exostosin 2 gene mutations. Osteochondroma formation was assessed by whole body magnetic resonance imaging (MRI). Secondary efficacy objectives were to compare the effects of palovarotene with placebo on the volume of osteochondromas as assessed by MRI; the proportion of subjects with no new osteochondromas as assessed by whole-body MRI; the annualized rate of new or worsening deformities; the annualized rate of MO-related surgeries; and palatability. The overall safety and pharmacokinetics of palovarotene and the effects of palovarotene on linear growth, bone growth plates, bone mineral density, quality of life, and pain due to osteochondromas was also studied.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 193
- Written, signed, and dated informed subject/parent consent and age-appropriate assent (performed according to local regulations).
- A clinical diagnosis of MO with disease-causing exostosin 1 or 2 gene mutations.
- Male or female from 2 to 14 years of age.
- Female subjects must be premenarchal at screening.
- A bone age at screening of 14 years or less.
- Symptomatic MO, defined as five or more clinically evident osteochondromas and a new or enlarged osteochondroma that occurred in the preceding 12 months, five or more clinically evident osteochondromas and the presence of a painful osteochondroma, a skeletal deformity, a joint limitation, or prior surgery for a MO-related complication.
- The ability to undergo whole body MRI with or without sedation/general anesthesia.
- Use of two effective methods of birth control during treatment, and for 1 month after treatment discontinuation, unless committed to true abstinence from heterosexual sex. Sexually active females of child-bearing potential must also agree to start effective methods of birth control at screening.
Key
- Weight under 10 kg.
- Other syndromic conditions such as Langer-Giedion or Potocki-Shaffer.
- Any subject with neurologic signs suggestive of spinal cord impingement.
- Concomitant medications that are strong inhibitors or inducers of cytochrome P450 3A4 activity.
- Amylase or lipase >2 times the above the upper limit of normal (>2×ULN) or with a history of chronic pancreatitis.
- Elevated aspartate aminotransferase or alanine aminotransferase above 2.5×ULN.
- Any surgical implant that is contraindicated for MRI.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo regimen Placebo - Palovarotene 2.5 mg daily regimen Palovarotene 2.5 mg - Palovarotene 5.0 mg daily regimen Palovarotene 5.0 mg -
- Primary Outcome Measures
Name Time Method Annualized Rate of New Osteochondromas (OCs) Month 12 The annualized rate of new OCs was assessed by whole-body magnetic resonance imaging (MRI) (that is, the total number of new OCs divided by the time in years between the baseline and latest post-baseline MRI).
- Secondary Outcome Measures
Name Time Method Mean Change From Baseline in the Total Volume of New OCs at Month 12 Baseline (Day 1) and Month 12 The change from baseline in the total volume of OCs was assessed by whole-body MRI. Baseline was defined as the last available value prior to first administration of study drug.
Percentage of Participants With No New OCs Month 12 The percentage of participants with no new OCs as assessed by whole-body MRI. Participants with new OCs not identified by MRI due to surgical resection during the treatment period were categorized as having new OCs for this analysis.
Annualized Rate of New or Worsening Deformities Month 12 The annualized rate of new or worsening deformities as assessed by radiographic imaging of both upper and lower limbs.
Annualized Rate of MO-Related Surgeries Month 12 The MO-related surgeries included any procedure indicated for the treatment of MO, such as an excision of a symptomatic OC or correction of a limb deformity.
Maximum Observed Plasma Drug Concentrations at Steady State (Cmax,ss) of Palovarotene Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose The Cmax,ss of palovarotene was evaluated. The pharmacokinetic (PK) sampling was performed at Month 1. If samples could not be obtained at Month 1, then one additional attempt was made at a subsequent visit.
Minimum Observed Plasma Drug Concentrations at Steady State (Cmin,ss) of Palovarotene Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose The Cmin,ss of palovarotene was evaluated. The PK sampling was performed at Month 1. If samples could not be obtained at Month 1, then one additional attempt was made at a subsequent visit.
Time to Maximum Observed Drug Concentration at Steady State (Tmax,ss) of Palovarotene Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose The Tmax,ss of palovarotene was evaluated. The PK sampling was performed at Month 1. If samples could not be obtained at Month 1, then one additional attempt was made at a subsequent visit.
Area Under the Plasma Concentration-Time Curve at Steady State From Time 0 to 24 Hours After Dosing (AUC0-24,ss) of Palovarotene Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose The AUC0-24,ss of palovarotene was evaluated. The PK sampling was performed at Month 1. If samples could not be obtained at Month 1, then one additional attempt was made at a subsequent visit.
Number of Participants With Palatability of Sprinkled Palovarotene and Placebo Day 1 and Month 1 Palatability of palovarotene and placebo when sprinkled on specific foods as assessed with a 5-point hedonic face scale at the first dose (Day 1) and at Month 1 in all participants (including \<4 years old) who sprinkled the palovarotene or placebo onto a spoonful of specific foods. The hedonic face scale ranges from 1 to 5 where, 1= dislike very much, 2= dislike slightly, 3= neither like nor dislike, 4= like slightly, 5= like very much. Higher scores indicate positive outcome.
Trial Locations
- Locations (31)
Osaka University Hospital
🇯🇵Suita, Osaka, Japan
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Nagoya University Hospital
🇯🇵Nagoya, Aiti, Japan
OLVG locatie Oost
🇳🇱Amsterdam, Noord-Holland, Netherlands
Boston Children's Hospital
🇺🇸Boston, Massachusetts, United States
University of California-San Francisco
🇺🇸San Francisco, California, United States
Memorial Hermann Hospital
🇺🇸Houston, Texas, United States
UZ Antwerpen
🇧🇪Edegem, Antwerp, Belgium
The Paley Institute
🇺🇸West Palm Beach, Florida, United States
Children's Orthopaedic Center
🇺🇸Los Angeles, California, United States
Shriners Hospital for Children - Chicago
🇺🇸Chicago, Illinois, United States
Johns Hopkins University
🇺🇸Baltimore, Maryland, United States
Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
The Children's Hospital of Philadelphia (CHOP)
🇺🇸Philadelphia, Pennsylvania, United States
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦Montréal, Quebec, Canada
Shriners Hospital for Children - Canada
🇨🇦Montréal, Quebec, Canada
Hôpital universitaire Necker - Enfants Malades
🇫🇷Paris, France
Hôpital des Enfants, CHU de Toulouse
🇫🇷Toulouse, France
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Evelina London Children's Hospital
🇬🇧London, United Kingdom
Royal Manchester Childrens Hospital
🇬🇧Manchester, United Kingdom
Hospital Pediátrico de Coimbra
🇵🇹Coimbra, Portugal
Ege University Medical Faculty Hospital
🇹🇷Bornova, Izmir, Turkey
Bezmialem Vakif University Medical Faculty Hospital
🇹🇷Istanbul, Turkey
Royal National Orthopaedic Hospital
🇬🇧Stanmore, United Kingdom
Shriners Hospital for Children - Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Shriners Hospital for Children - Sacramento
🇺🇸Sacramento, California, United States
Shriners Hospitals for Children - Portland
🇺🇸Portland, Oregon, United States
Mayo Clinic - PPDS
🇺🇸Rochester, Minnesota, United States
Westmead Children's Hospital
🇦🇺Westmead, New South Wales, Australia
Istituti Ortopedici Rizzoli
🇮🇹Bologna, Emilia-Romagna, Italy