Neoplasms

Musculoskeletal Diseases

All Conditions

Diseases and Abnormalities at or Before Birth

Skin and Connective Tissue Diseases

Nutritional and Metabolic Diseases

Symptoms and General Pathology

Rare Diseases

Osteochondroma

Exostoses, Multiple Hereditary

Osteochondromatosis

Exostoses

Osteophyte

Enchondromatosis

Hyperostosis

Bone Diseases

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Osteochondrodysplasias

Mucopolysaccharidosis IV

Bone Diseases, Developmental

Syndrome

Neoplastic Syndromes, Hereditary

Genetic Diseases, Inborn

Hereditary Multiple Osteochondromas

Ollier Disease

Mucopolysaccharidosis Type IV

Antineoplastic Agents

Dermatologic Agents

All Drugs and Chemicals

Tretinoin

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

Palovarotene 2.5 mg

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

Palovarotene 5.0 mg

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

Placebo

Ipsen Medical Director

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).

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.

Multicenter, randomized, double-blind, placebo-controlled

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

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

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).

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.

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.

The annualized rate of new or worsening deformities as assessed by radiographic imaging of both upper and lower limbs.

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.

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.

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.

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.

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.

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.

Clementia Pharmaceuticals Inc.

The Safety set included randomized participants who received at least 1 dose of study drug.

Participants were to receive placebo matching with palovarotene capsules orally once daily, for up to 24 months.

Participants were to receive weight-adjusted dose equivalent of palovarotene 2.5 mg capsules orally once daily, for up to 24 months.

Participants were to receive weight-adjusted dose equivalent of palovarotene 5.0 mg capsules orally once daily, for up to 24 months.

Total

Age, Continuous

Age, Customized

Sex: Female, Male

White

Black Or African American

Asian

American Indian Or Alaska Native

Multiple

Other

Missing

Race/Ethnicity, Customized

Hispanic or Latino

Not Hispanic or Latino

The Sponsor terminated the study early due to a partial clinical hold instituted by the Food and Drug Administration. Recruitment was stopped before full enrollment was reached, and study drug administration was discontinued.

Medical Director

Palovarotene 2.5 mg versus (vs) Palovarotene 5.0 mg: The annualized rate for number of new OCs was estimated using an unadjusted negative binomial regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.

Palovarotene 2.5 mg vs Placebo: The annualized rate for number of new OCs was estimated using an unadjusted negative binomial regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.

Palovarotene 5.0 mg vs Placebo: The annualized rate for number of new OCs was estimated using an unadjusted negative binomial regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.

The Full Analysis Set (FAS) included randomized participants who received at least 1 dose of study drug. Only data from the 56 participants for whom Month 12 efficacy imaging data were available were included in the analysis.

Annualized Rate of New Osteochondromas (OCs)

Palovarotene 2.5 mg vs Palovarotene 5.0 mg: The mean difference in the change from baseline for total OC volume was estimated using an unadjusted estimation equation model with independent working covariance matrix to address potential correlation within the same family members.

Palovarotene 2.5 mg vs Placebo: The mean difference in the change from baseline for total OC volume was estimated using an unadjusted estimation equation model with independent working covariance matrix to address potential correlation within the same family members.

Palovarotene 5.0 mg vs Placebo: The mean difference in the change from baseline for total OC volume was estimated using an unadjusted estimation equation model with independent working covariance matrix to address potential correlation within the same family members.

The FAS included randomized participants who received at least 1 dose of study drug. Only data from the 56 participants for whom Month 12 efficacy imaging data were available were included in the analysis.

Mean Change From Baseline in the Total Volume of New OCs at Month 12

Percentage of Participants With No New OCs

Palovarotene 2.5 mg vs Palovarotene 5.0 mg: The annualized rate for number of new or worsening deformities was estimated using an unadjusted negative binomial regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.

Palovarotene 2.5 mg vs Placebo: The annualized rate for number of new or worsening deformities was estimated using an unadjusted negative binomial regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.

Palovarotene 5.0 mg vs Placebo: The annualized rate for number of new or worsening deformities was estimated using an unadjusted negative binomial regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.

Annualized Rate of New or Worsening Deformities

Palovarotene 2.5 mg vs Palovarotene 5.0 mg: The annualized rate for number of MO-related surgeries was estimated using an unadjusted poisson regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.

Palovarotene 2.5 mg vs Placebo: The annualized rate for number of MO-related surgeries was estimated using an unadjusted poisson regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.

Palovarotene 5.0 mg vs Placebo: The annualized rate for number of MO-related surgeries was estimated using an unadjusted poisson regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.

The FAS included randomized participants who received at least 1 dose of study drug. Participants with planned surgeries within 6 months of enrollment to remove symptomatic OCs or to correct deformities present at baseline, and/or had surgical procedures that were a continuation of a previous procedure were excluded in the analysis.

Annualized Rate of MO-Related Surgeries

The Pharmacokinetic Set (PKS) included participants receiving treatment with palovarotene and with evaluable PK data.

Maximum Observed Plasma Drug Concentrations at Steady State (Cmax,ss) of Palovarotene

The PKS included participants receiving treatment with palovarotene and with evaluable PK data.

Minimum Observed Plasma Drug Concentrations at Steady State (Cmin,ss) of Palovarotene

Time to Maximum Observed Drug Concentration at Steady State (Tmax,ss) of Palovarotene

Area Under the Plasma Concentration-Time Curve at Steady State From Time 0 to 24 Hours After Dosing (AUC0-24,ss) of Palovarotene

Day 1

Month 1

The Safety set included randomized participants who received at least 1 dose of study drug. Only data from the participants analyzed at Day 1 and Month 1 were included in the analysis.

Number of Participants With Palatability of Sprinkled Palovarotene and Placebo

Overall Study

Behaviors and Mental Disorders

Quality of Life

Christine Alvarez, MD

The purpose of this study is to assess the health-related quality of life of subjects who have Hereditary Multiple Exostoses and to develop a disease specific quality of life survey. The investigators hypothesize that there are a wide range of quality of life experiences for patients with this syndrome.

At the time of recruitment, subjects will be asked to indicate whether they would like to participate in a one-time survey, or are willing to participate in the initial survey plus two additional questionnaire administrations, thereafter, which will be used to develop the disease-specific quality of life (QOL) score. All participants will complete either the SF-36 survey (for adult HME subjects) or the CHQ PF (for parents of children with HME), as applicable, in addition to a blank form with categorical subheadings (such as recreation, social function, etc.), which they will use to address any issues not covered in the standardized questionnaire. Standardized questionnaires will be scored and analyzed. The items listed on the second form will be compiled and reapplied to subjects that indicated interest in extended participation in survey completion. Subjects will be asked to determine which items apply to them and to rank these applicable items in order of importance. The results from this will be used to develop a 30 question, disease-specific questionnaire. The final step will be to readminister this survey, in conjunction with the SF-36 or CHQ PF, and follow up, in two weeks, with a second administration of the aforementioned surveys, in order to test the variability and validity of the disease-specific, health-related, quality of life score.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
An Efficacy and Safety Study of Palovarotene for the Treatment of MO	NCT03442985	Exostoses, Mult...	Palovarotene 2.... Palovarotene 5.... Placebo	2 Years - 14 Years	Ipsen
The Health-Related Quality of Life in Patients With Hereditary Multiple Exostoses	NCT00474448	Exostoses, Mult...		-	University of British Columbia

Spots Global Cancer Trial Database for hereditary multiple exostoses