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

NCT ID: NCT03442985

Last Updated: 2022-08-01

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 193 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-03-22
• Study Completion Date: 2020-10-30

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.

Conditions

Exostoses, Multiple Hereditary

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Palovarotene 2.5 mg daily regimen

Group Type: EXPERIMENTAL

Palovarotene 2.5 mg

Intervention Type: DRUG

Subjects received a weight-adjusted dose equivalent of 2.5 mg palovarotene, once daily, for up to 24 months.

Palovarotene 5.0 mg daily regimen

Group Type: EXPERIMENTAL

Palovarotene 5.0 mg

Intervention Type: DRUG

Subjects received a weight-adjusted dose equivalent of 5.0 mg palovarotene, once daily, for up to 24 months.

Placebo regimen

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Subjects received placebo, once daily, for up to 24 months.

Interventions

Palovarotene 2.5 mg

Subjects received a weight-adjusted dose equivalent of 2.5 mg palovarotene, once daily, for up to 24 months.

Intervention Type: DRUG

Palovarotene 5.0 mg

Subjects received a weight-adjusted dose equivalent of 5.0 mg palovarotene, once daily, for up to 24 months.

Intervention Type: DRUG

Placebo

Subjects received placebo, once daily, for up to 24 months.

Intervention Type: OTHER

Eligibility Criteria

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.

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.

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 14 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Clementia Pharmaceuticals Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ipsen Medical Director

Role: STUDY_DIRECTOR

Ipsen

Locations

Children's Orthopaedic Center

Los Angeles, California, United States

Shriners Hospital for Children - Sacramento

Sacramento, California, United States

University of California-San Francisco

San Francisco, California, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

The Paley Institute

West Palm Beach, Florida, United States

Shriners Hospital for Children - Chicago

Chicago, Illinois, United States

Johns Hopkins University

Baltimore, Maryland, United States

Boston Children's Hospital

Boston, Massachusetts, United States

Mayo Clinic - PPDS

Rochester, Minnesota, United States

Shriners Hospitals for Children - Portland

Portland, Oregon, United States

The Children's Hospital of Philadelphia (CHOP)

Philadelphia, Pennsylvania, United States

Shriners Hospital for Children - Philadelphia

Philadelphia, Pennsylvania, United States

Memorial Hermann Hospital

Houston, Texas, United States

Westmead Children's Hospital

Westmead, New South Wales, Australia

UZ Antwerpen

Edegem, Antwerp, Belgium

Hospital for Sick Children

Toronto, Ontario, Canada

Centre Hospitalier Universitaire Sainte-Justine

Montreal, Quebec, Canada

Shriners Hospital for Children - Canada

Montreal, Quebec, Canada

Hôpital universitaire Necker - Enfants Malades

Paris, , France

Hôpital des Enfants, CHU de Toulouse

Toulouse, , France

Istituti Ortopedici Rizzoli

Bologna, Emilia-Romagna, Italy

Nagoya University Hospital

Nagoya, Aiti, Japan

Osaka University Hospital

Suita, Osaka, Japan

OLVG locatie Oost

Amsterdam, North Holland, Netherlands

Hospital Pediátrico de Coimbra

Coimbra, , Portugal

Hospital Universitario La Paz

Madrid, , Spain

Ege University Medical Faculty Hospital

Bornova, İzmir, Turkey (Türkiye)

Bezmialem Vakif University Medical Faculty Hospital

Istanbul, , Turkey (Türkiye)

Evelina London Children's Hospital

London, , United Kingdom

Royal Manchester Childrens Hospital

Manchester, , United Kingdom

Royal National Orthopaedic Hospital

Stanmore, , United Kingdom

Countries

United States; Australia; Belgium; Canada; France; Italy; Japan; Netherlands; Portugal; Spain; Turkey (Türkiye); United Kingdom

References

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.

Reference Type: BACKGROUND

PMID: 29120519 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://www.mhecoalition.org/

MHE Coalition

http://www.mherf.org/

MHE Research Foundation

Other Identifiers

2017-002751-28

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PVO-2A-201

Identifier Type: -

Identifier Source: org_study_id