Clinical trial NCT03442985: An Efficacy and Safety Study of Palovarotene for the Treatment of MO
Official title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Palovarotene in Subjects With Multiple Osteochondromas
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Exostoses, Multiple Hereditary
Keywords: Multiple osteochondromas
Osteochondroma
Palovarotene
Hereditary multiple exostoses
HME
MO
Retinoic acid receptor gamma agonist
Retinoic acid receptor agonist
Lead sponsor: Ipsen
Sponsor class: INDUSTRY
First posted: 2018-02-22
Enrollment: 193
Sex: ALL
Minimum age (years): 2
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter, randomized, double-blind, placebo-controlled
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Annualized Rate of New Osteochondromas (OCs)
timeFrame: Month 12
Secondary outcomes:
measure: Mean Change From Baseline in the Total Volume of New OCs at Month 12
timeFrame: Baseline (Day 1) and Month 12
measure: Percentage of Participants With No New OCs
timeFrame: Month 12
measure: Annualized Rate of New or Worsening Deformities
timeFrame: Month 12
measure: Annualized Rate of MO-Related Surgeries
timeFrame: Month 12
measure: Maximum Observed Plasma Drug Concentrations at Steady State (Cmax,ss) of Palovarotene
timeFrame: Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
measure: Minimum Observed Plasma Drug Concentrations at Steady State (Cmin,ss) of Palovarotene
timeFrame: Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
measure: Time to Maximum Observed Drug Concentration at Steady State (Tmax,ss) of Palovarotene
timeFrame: Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
measure: Area Under the Plasma Concentration-Time Curve at Steady State From Time 0 to 24 Hours After Dosing (AUC0-24,ss) of Palovarotene
timeFrame: Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
measure: Number of Participants With Palatability of Sprinkled Palovarotene and Placebo
timeFrame: Day 1 and Month 1
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Orthopaedic Center
state: California
city: Sacramento
country: United States
facility: Shriners Hospital for Children - Sacramento
state: California
city: San Francisco
country: United States
facility: University of California-San Francisco
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: West Palm Beach
country: United States
facility: The Paley Institute
state: Florida
city: Chicago
country: United States
facility: Shriners Hospital for Children - Chicago
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic - PPDS
state: Minnesota
city: Portland
country: United States
facility: Shriners Hospitals for Children - Portland
state: Oregon
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia (CHOP)
state: Pennsylvania
city: Philadelphia
country: United States
facility: Shriners Hospital for Children - Philadelphia
state: Pennsylvania
city: Houston
country: United States
facility: Memorial Hermann Hospital
state: Texas
city: Westmead
country: Australia
facility: Westmead Children's Hospital
state: New South Wales
city: Edegem
country: Belgium
facility: UZ Antwerpen
state: Antwerp
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montréal
country: Canada
facility: Centre Hospitalier Universitaire Sainte-Justine
state: Quebec
city: Montréal
country: Canada
facility: Shriners Hospital for Children - Canada
state: Quebec
city: Paris
country: France
facility: Hôpital universitaire Necker - Enfants Malades
city: Toulouse
country: France
facility: Hôpital des Enfants, CHU de Toulouse
city: Bologna
country: Italy
facility: Istituti Ortopedici Rizzoli
state: Emilia-Romagna
city: Nagoya
country: Japan
facility: Nagoya University Hospital
state: Aiti
city: Suita
country: Japan
facility: Osaka University Hospital
state: Osaka
city: Amsterdam
country: Netherlands
facility: OLVG locatie Oost
state: Noord-Holland
city: Coimbra
country: Portugal
facility: Hospital Pediátrico de Coimbra
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Bornova
country: Turkey
facility: Ege University Medical Faculty Hospital
state: Izmir
city: Istanbul
country: Turkey
facility: Bezmialem Vakif University Medical Faculty Hospital
city: London
country: United Kingdom
facility: Evelina London Children's Hospital
city: Manchester
country: United Kingdom
facility: Royal Manchester Childrens Hospital
city: Stanmore
country: United Kingdom
facility: Royal National Orthopaedic Hospital
Study officials:
affiliation: Ipsen
name: Ipsen Medical Director
role: STUDY_DIRECTOR
References:
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.