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

Primary Purpose

Exostoses, Multiple Hereditary

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Palovarotene 2.5 mg
Palovarotene 5.0 mg
Placebo
Sponsored by
Clementia Pharmaceuticals Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Exostoses, Multiple Hereditary focused on measuring Multiple osteochondromas, Osteochondroma, Palovarotene, Hereditary multiple exostoses, HME, MO, Retinoic acid receptor gamma agonist, Retinoic acid receptor agonist

Eligibility Criteria

2 Years - 14 Years (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Children's Orthopaedic Center
  • Shriners Hospital for Children - Sacramento
  • University of California-San Francisco
  • Children's National Medical Center
  • The Paley Institute
  • Shriners Hospital for Children - Chicago
  • Johns Hopkins University
  • Boston Children's Hospital
  • Mayo Clinic - PPDS
  • Shriners Hospitals for Children - Portland
  • The Children's Hospital of Philadelphia (CHOP)
  • Shriners Hospital for Children - Philadelphia
  • Memorial Hermann Hospital
  • Westmead Children's Hospital
  • UZ Antwerpen
  • Hospital for Sick Children
  • Centre Hospitalier Universitaire Sainte-Justine
  • Shriners Hospital for Children - Canada
  • Hôpital universitaire Necker - Enfants Malades
  • Hôpital des Enfants, CHU de Toulouse
  • Istituti Ortopedici Rizzoli
  • Nagoya University Hospital
  • Osaka University Hospital
  • OLVG locatie Oost
  • Hospital Pediátrico de Coimbra
  • Hospital Universitario La Paz
  • Ege University Medical Faculty Hospital
  • Bezmialem Vakif University Medical Faculty Hospital
  • Evelina London Children's Hospital
  • Royal Manchester Childrens Hospital
  • Royal National Orthopaedic Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

Palovarotene 2.5 mg daily regimen

Palovarotene 5.0 mg daily regimen

Placebo regimen

Arm Description

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.
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.
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.
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.

Full Information

First Posted
October 11, 2017
Last Updated
July 7, 2022
Sponsor
Clementia Pharmaceuticals Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT03442985
Brief Title
An Efficacy and Safety Study of Palovarotene for the Treatment of MO
Acronym
MO-Ped
Official Title
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Palovarotene in Subjects With Multiple Osteochondromas
Study Type
Interventional

2. Study Status

Record Verification Date
July 2022
Overall Recruitment Status
Terminated
Why Stopped
Trial was terminated early to analyze the accumulated data and evaluate the efficacy, safety and future of palovarotene in MO.
Study Start Date
March 22, 2018 (Actual)
Primary Completion Date
March 24, 2020 (Actual)
Study Completion Date
October 30, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Clementia Pharmaceuticals Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Exostoses, Multiple Hereditary
Keywords
Multiple osteochondromas, Osteochondroma, Palovarotene, Hereditary multiple exostoses, HME, MO, Retinoic acid receptor gamma agonist, Retinoic acid receptor agonist

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Multicenter, randomized, double-blind, placebo-controlled
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
193 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Palovarotene 2.5 mg daily regimen
Arm Type
Experimental
Arm Title
Palovarotene 5.0 mg daily regimen
Arm Type
Experimental
Arm Title
Placebo regimen
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Palovarotene 2.5 mg
Intervention Description
Subjects received a weight-adjusted dose equivalent of 2.5 mg palovarotene, once daily, for up to 24 months.
Intervention Type
Drug
Intervention Name(s)
Palovarotene 5.0 mg
Intervention Description
Subjects received a weight-adjusted dose equivalent of 5.0 mg palovarotene, once daily, for up to 24 months.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Subjects received placebo, once daily, for up to 24 months.
Primary Outcome Measure Information:
Title
Annualized Rate of New Osteochondromas (OCs)
Description
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).
Time Frame
Month 12
Secondary Outcome Measure Information:
Title
Mean Change From Baseline in the Total Volume of New OCs at Month 12
Description
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.
Time Frame
Baseline (Day 1) and Month 12
Title
Percentage of Participants With No New OCs
Description
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.
Time Frame
Month 12
Title
Annualized Rate of New or Worsening Deformities
Description
The annualized rate of new or worsening deformities as assessed by radiographic imaging of both upper and lower limbs.
Time Frame
Month 12
Title
Annualized Rate of MO-Related Surgeries
Description
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.
Time Frame
Month 12
Title
Maximum Observed Plasma Drug Concentrations at Steady State (Cmax,ss) of Palovarotene
Description
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.
Time Frame
Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
Title
Minimum Observed Plasma Drug Concentrations at Steady State (Cmin,ss) of Palovarotene
Description
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 Frame
Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
Title
Time to Maximum Observed Drug Concentration at Steady State (Tmax,ss) of Palovarotene
Description
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.
Time Frame
Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
Title
Area Under the Plasma Concentration-Time Curve at Steady State From Time 0 to 24 Hours After Dosing (AUC0-24,ss) of Palovarotene
Description
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.
Time Frame
Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
Title
Number of Participants With Palatability of Sprinkled Palovarotene and Placebo
Description
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.
Time Frame
Day 1 and Month 1

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
14 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ipsen Medical Director
Organizational Affiliation
Ipsen
Official's Role
Study Director
Facility Information:
Facility Name
Children's Orthopaedic Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
Shriners Hospital for Children - Sacramento
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
University of California-San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94158
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
The Paley Institute
City
West Palm Beach
State/Province
Florida
ZIP/Postal Code
330407
Country
United States
Facility Name
Shriners Hospital for Children - Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60707
Country
United States
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205
Country
United States
Facility Name
Boston Children's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Mayo Clinic - PPDS
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Shriners Hospitals for Children - Portland
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
The Children's Hospital of Philadelphia (CHOP)
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Shriners Hospital for Children - Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19410-4160
Country
United States
Facility Name
Memorial Hermann Hospital
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Westmead Children's Hospital
City
Westmead
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
Facility Name
UZ Antwerpen
City
Edegem
State/Province
Antwerp
ZIP/Postal Code
2650
Country
Belgium
Facility Name
Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
Facility Name
Centre Hospitalier Universitaire Sainte-Justine
City
Montréal
State/Province
Quebec
ZIP/Postal Code
H3T 1C5
Country
Canada
Facility Name
Shriners Hospital for Children - Canada
City
Montréal
State/Province
Quebec
ZIP/Postal Code
H4A 0A9
Country
Canada
Facility Name
Hôpital universitaire Necker - Enfants Malades
City
Paris
ZIP/Postal Code
75015
Country
France
Facility Name
Hôpital des Enfants, CHU de Toulouse
City
Toulouse
ZIP/Postal Code
31059
Country
France
Facility Name
Istituti Ortopedici Rizzoli
City
Bologna
State/Province
Emilia-Romagna
ZIP/Postal Code
40136
Country
Italy
Facility Name
Nagoya University Hospital
City
Nagoya
State/Province
Aiti
ZIP/Postal Code
4668560
Country
Japan
Facility Name
Osaka University Hospital
City
Suita
State/Province
Osaka
ZIP/Postal Code
565-0871
Country
Japan
Facility Name
OLVG locatie Oost
City
Amsterdam
State/Province
Noord-Holland
ZIP/Postal Code
1091 AC
Country
Netherlands
Facility Name
Hospital Pediátrico de Coimbra
City
Coimbra
ZIP/Postal Code
3000-602
Country
Portugal
Facility Name
Hospital Universitario La Paz
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
Ege University Medical Faculty Hospital
City
Bornova
State/Province
Izmir
Country
Turkey
Facility Name
Bezmialem Vakif University Medical Faculty Hospital
City
Istanbul
ZIP/Postal Code
34093
Country
Turkey
Facility Name
Evelina London Children's Hospital
City
London
ZIP/Postal Code
SE1 7EH
Country
United Kingdom
Facility Name
Royal Manchester Childrens Hospital
City
Manchester
ZIP/Postal Code
M13 9WL
Country
United Kingdom
Facility Name
Royal National Orthopaedic Hospital
City
Stanmore
ZIP/Postal Code
HA7 4LP
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
29120519
Citation
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.
Results Reference
background
Links:
URL
http://www.mhecoalition.org/
Description
MHE Coalition
URL
http://www.mherf.org/
Description
MHE Research Foundation

Learn more about this trial

An Efficacy and Safety Study of Palovarotene for the Treatment of MO

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