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

Exostoses, Multiple Hereditary Clinical Trial

— MO-Ped  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03442985
• Other study ID #: PVO-2A-201
• Secondary ID: 2017-002751-28
• Status: Terminated
• Phase: Phase 2
• Start date: March 22, 2018
• Est. completion date: October 30, 2020

Study information

• Verified date: July 2022
• Source: Ipsen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Terminated
• Enrollment: 193
• Est. completion date: October 30, 2020
• Est. primary completion date: March 24, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 14 Years

Eligibility

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.

Related Conditions & MeSH terms

• Exostoses, Multiple Hereditary

Intervention

Drug:
• Palovarotene 2.5 mg
Subjects received a weight-adjusted dose equivalent of 2.5 mg palovarotene, once daily, for up to 24 months.
• Palovarotene 5.0 mg
Subjects received a weight-adjusted dose equivalent of 5.0 mg palovarotene, once daily, for up to 24 months.

Other:
• Placebo
Subjects received placebo, once daily, for up to 24 months.

Locations

Country	Name	City	State
Australia	Westmead Children's Hospital	Westmead	New South Wales
Belgium	UZ Antwerpen	Edegem	Antwerp
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montréal	Quebec
Canada	Shriners Hospital for Children - Canada	Montréal	Quebec
Canada	Hospital for Sick Children	Toronto	Ontario
France	Hôpital universitaire Necker - Enfants Malades	Paris
France	Hôpital des Enfants, CHU de Toulouse	Toulouse
Italy	Istituti Ortopedici Rizzoli	Bologna	Emilia-Romagna
Japan	Nagoya University Hospital	Nagoya	Aiti
Japan	Osaka University Hospital	Suita	Osaka
Netherlands	OLVG locatie Oost	Amsterdam	Noord-Holland
Portugal	Hospital Pediátrico de Coimbra	Coimbra
Spain	Hospital Universitario La Paz	Madrid
Turkey	Ege University Medical Faculty Hospital	Bornova	Izmir
Turkey	Bezmialem Vakif University Medical Faculty Hospital	Istanbul
United Kingdom	Evelina London Children's Hospital	London
United Kingdom	Royal Manchester Childrens Hospital	Manchester
United Kingdom	Royal National Orthopaedic Hospital	Stanmore
United States	Johns Hopkins University	Baltimore	Maryland
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Shriners Hospital for Children - Chicago	Chicago	Illinois
United States	Memorial Hermann Hospital	Houston	Texas
United States	Children's Orthopaedic Center	Los Angeles	California
United States	Shriners Hospital for Children - Philadelphia	Philadelphia	Pennsylvania
United States	The Children's Hospital of Philadelphia (CHOP)	Philadelphia	Pennsylvania
United States	Shriners Hospitals for Children - Portland	Portland	Oregon
United States	Mayo Clinic - PPDS	Rochester	Minnesota
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	District of Columbia
United States	The Paley Institute	West Palm Beach	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Clementia Pharmaceuticals Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Italy,  Japan,  Netherlands,  Portugal,  Spain,  Turkey,  United Kingdom, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   MHE Coalition
•   MHE Research Foundation