An Efficacy and Safety Study of Palovarotene for the Treatment of MO (MO-Ped)

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Palovarotene in Subjects With Multiple Osteochondromas

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).

Study Overview

• Status: Terminated
• Conditions: Exostoses, Multiple Hereditary
• Intervention / Treatment: Drug: Palovarotene 2.5 mg; Drug: Palovarotene 5.0 mg; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 193
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Westmead Children's Hospital
• Belgium
  • Antwerp
    • Edegem, Antwerp, Belgium, 2650
      • UZ Antwerpen
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montréal, Quebec, Canada, H3T 1C5
      • Centre Hospitalier Universitaire Sainte-Justine
    • Montréal, Quebec, Canada, H4A 0A9
      • Shriners Hospital for Children - Canada
• France
  • Paris, France, 75015
    • Hôpital Universitaire Necker - Enfants Malades
  • Toulouse, France, 31059
    • Hôpital des Enfants, CHU de Toulouse
• Italy
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40136
      • Istituti Ortopedici Rizzoli
• Japan
  • Aiti
    • Nagoya, Aiti, Japan, 4668560
      • Nagoya University Hospital
  • Osaka
    • Suita, Osaka, Japan, 565-0871
      • Osaka University Hospital
• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1091 AC
      • OLVG locatie Oost
• Portugal
  • Coimbra, Portugal, 3000-602
    • Hospital Pediatrico de Coimbra
• Spain
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
• Turkey
  • Istanbul, Turkey, 34093
    • Bezmialem Vakif University Medical Faculty Hospital
  • Izmir
    • Bornova, Izmir, Turkey
      • Ege University Medical Faculty Hospital
• United Kingdom
  • London, United Kingdom, SE1 7EH
    • Evelina London Children's Hospital
  • Manchester, United Kingdom, M13 9WL
    • Royal Manchester Childrens Hospital
  • Stanmore, United Kingdom, HA7 4LP
    • Royal National Orthopaedic Hospital
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Orthopaedic Center
    • Sacramento, California, United States, 95817
      • Shriners Hospital for Children - Sacramento
    • San Francisco, California, United States, 94158
      • University of California-San Francisco
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • West Palm Beach, Florida, United States, 330407
      • The Paley Institute
  • Illinois
    • Chicago, Illinois, United States, 60707
      • Shriners Hospital for Children - Chicago
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - PPDS
  • Oregon
    • Portland, Oregon, United States, 97239
      • Shriners Hospitals for Children - Portland
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia (CHOP)
    • Philadelphia, Pennsylvania, United States, 19410-4160
      • Shriners Hospital for Children - Philadelphia
  • Texas
    • Houston, Texas, United States, 77030
      • Memorial Hermann Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 months to 12 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• 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 Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Palovarotene 2.5 mg daily regimen	Drug: Palovarotene 2.5 mg; Subjects received a weight-adjusted dose equivalent of 2.5 mg palovarotene, once daily, for up to 24 months.
Experimental: Palovarotene 5.0 mg daily regimen	Drug: Palovarotene 5.0 mg; Subjects received a weight-adjusted dose equivalent of 5.0 mg palovarotene, once daily, for up to 24 months.
Placebo Comparator: Placebo regimen	Other: Placebo; Subjects received placebo, once daily, for up to 24 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized Rate of New Osteochondromas (OCs)	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).	Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline in the Total Volume of New OCs at 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.	Baseline (Day 1) and Month 12
Percentage of Participants With No New OCs	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.	Month 12
Annualized Rate of New or Worsening Deformities	The annualized rate of new or worsening deformities as assessed by radiographic imaging of both upper and lower limbs.	Month 12
Annualized Rate of MO-Related Surgeries	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.	Month 12
Maximum Observed Plasma Drug Concentrations at Steady State (Cmax,ss) of Palovarotene	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.	Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
Minimum Observed Plasma Drug Concentrations at Steady State (Cmin,ss) of Palovarotene	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.	Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
Time to Maximum Observed Drug Concentration at Steady State (Tmax,ss) of Palovarotene	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.	Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
Area Under the Plasma Concentration-Time Curve at Steady State From Time 0 to 24 Hours After Dosing (AUC0-24,ss) of Palovarotene	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.	Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
Number of Participants With Palatability of Sprinkled Palovarotene and Placebo	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.	Day 1 and Month 1

Collaborators and Investigators

• Sponsor: Clementia Pharmaceuticals Inc.

Publications and helpful links

General Publications

• Inubushi T, Lemire I, Irie F, Yamaguchi Y. Palovarotene Inhibits Osteochondroma Formation in a Mouse Model of Multiple Hereditary Exostoses. J Bone Miner Res. 2018 Apr;33(4):658-666. doi: 10.1002/jbmr.3341. Epub 2017 Nov 30.

Helpful Links

• MHE Coalition
• MHE Research Foundation

Study record dates

Study Major Dates

• Study Start (Actual): March 22, 2018
• Primary Completion (Actual): March 24, 2020
• Study Completion (Actual): October 30, 2020

Study Registration Dates

• First Submitted: October 11, 2017
• First Submitted That Met QC Criteria: February 21, 2018
• First Posted (Actual): February 22, 2018

Study Record Updates

• Last Update Posted (Actual): August 1, 2022
• Last Update Submitted That Met QC Criteria: July 7, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Palovarotene; Retinoic acid receptor agonist; Retinoic acid receptor gamma agonist; Osteochondroma; Multiple osteochondromas; Hereditary multiple exostoses; HME; MO
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Genetic Diseases, Inborn; Musculoskeletal Diseases; Bone Diseases; Neoplastic Syndromes, Hereditary; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Bone Diseases, Developmental; Osteochondrodysplasias; Hyperostosis; Osteochondroma; Exostoses, Multiple Hereditary; Osteochondromatosis; Exostoses; Osteophyte
• Other Study ID Numbers: PVO-2A-201; 2017-002751-28 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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