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

Christine Alvarez, MD

The purpose of this study is to establish the genetic profile of families in British Columbia with HME.

The purpose of this study is to establish the genetic make-up of families and patients with HME. This will occur as the patient presents to a regular clinic visit. Dr. Alvarez will be introduced to interested patients and their parent(s) and a brief discussion about the project will occur. If the patient and their direct family are interested they will be entered into the study. This will involve interviewing the patients and their direct family. This interview will take about 1 hour. We are interested in identifying all affected family members as far up the family tree as possible. We ask that the idea of the study be introduced to extended family members by the participating family members and then have them call Dr. Alvarez to set up an appointment. Each available member will be interviewed and a physical exam done to determine the location of osteochondromas. In addition, Xrays will be done to determine the location of all osteochondromas. All Xrays will be reviewed. No new ones will be taken unless it is part of the patient's routine care.

To complete the genetic work up DNA analysis will be done on all available family members. This will entail obtaining a blood sample from each family member willing to partake in the study. These blood samples will be used only for the purpose of identifying abnormalities in the genes related to osteochondromas. The blood samples will be taken at British Columbia's Children's Hospital and processed there. DNA samples will be kept confidential.

Establishing the Genetic Profile of Multiple Hereditary Exostoses (HME) in Families of BC

Circle of Care

Vancouver Foundation

Children's & Women's Health Centre of British Columbia

University of British Columbia

Dr. Christine Alvarez

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

The investigator's goal for this project is to examine the causes of the wide variability of the expression of Hereditary Multiple Exostoses (HME). Previous work completed by our group shows that there exists a correlation between genotype and phenotype such that certain mutations or affected genes cause certain patterns of presentation, symptoms, and signs. The investigators intend to achieve this goal by increasing our study sample size to build upon the results generated from the pilot project of this study, in order to obtain statistical significance. This will be achieved by performing genotype-phenotype analysis on new families presenting with HME in British Columbia.

Subject Recruitment:

New patients presenting with HME will be identified through the offices and clinics of British Columbia Children's Hospital Orthopaedic Department. All potential participants will be educated about the study's rationale, purpose, and procedures and informed consent will be obtained.

Demographics:

All probands (affected patient), their first degree family members and extended family members willing to participate in the study will be interviewed. Information including age, gender, ethnic origin, family history, symptoms, complications and previous surgery will be elucidated.

Phenotype:

Affected patients will have their osteochondroma(s) mapped for location, size, morphology, and symptoms. A total of seventy-five phenotypic parameters divided into four major data categories will be collected. The first two categories are accumulated from physical examinations and include stature and limb segment lengths (15 (x2 for left and right). The other two categories, lesion quality (19 parameters) and limb alignment and deformity (26 parameters) will be drawn from radiographic examinations which are part of the patient's current care. All available xrays will be reviewed and the exostoses characterized radiographically. This will establish the patient's genotype.

Genotype:

Each participant whose genotype is unknown will have a 10 cc. blood sample collected at BC Children's Hospital. This sample will be processed for mutation analysis (DNA extraction from blood samples, mutation analysis) at the Clinical Molecular Diagnostic Laboratory at BC Children's Hospital. The techniques used in the pilot study will be implemented with the exception that microsatellite markers will not be used in order to save cost.

Using EXT 1 and EXT 2 primers (Appendix 1) both strands of a DNA segment are sequenced using ABI Big Dye chemistry Version 2. The resulting sequencing reaction products are then run on an ABI 3100 Avant genetic analyzer. Once a sequence is obtained it is analyzed with SeqScape version 2 software which allows comparison with reference sequence.

Data Analysis:

All information resulting from this research study will be kept strictly confidential. All documents will be identified by an ID number and kept in locked filing cabinets. Participants will not be identified by name in any reports of the completed study. Databases will be stored on project-dedicated laptop computer which is locked in the research office.

The phenotypic data collected will be used to describe family degrees (designed using Cyrillic software), phenotypes of affected individuals and mutations in the exostoses genes of interest (site and type of mutation). Subject heights and segment lengths will be converted to percentile figures to standardize for age and gender to allow for comparison amongst groups.

Genotypic data from the mutation analysis of blood samples will include location of the mutation (early in the gene versus late in the gene), type of mutation (alteration of gene as missense, frameshift, nonsense or splice site), and the amino acid change that was caused by the mutation. The data will be analyzed as follows:

Preliminary Analysis

1. EXT 1 versus EXT 2
2. Males versus Females
3. EXT 1 males versus EXT 1 females versus EXT 2 males versus EXT 2 females

   Secondary Analysis
4. Types of mutations (Missense versus Nonsense versus Splice site versus Frameshift)
5. Early or late mutation (less than 1700 base pairs versus greater than 1700 base pairs)

With 2-way analyses, an unpaired t-test will be calculated and with greater than 2-way analyses, an ANOVA will be calculated. Power will be calculated for every comparison due to the huge variation in sample size. Statistical significance will be set to prior at 0.05 and power of 0.8.

Gene Mutations and Orthopaedic Symptoms Correlation of Multiple Hereditary Exostoses: Multicentre Project

Genotype-Phenotype Correlation of Multiple Hereditary Exostoses: Multicentre Project

Principle Investigator

Behaviors and Mental Disorders

Quality of Life

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.

The Health-Related Quality of Life in Patients With Hereditary Multiple Exostoses

MHE Coalition

204 children and adult patients with HME, admitted to our Hospital for diagnosis and treatment.

the patients will be stratified by age in four subgroups:

* subgroup I (0-7 Years)
* subgroup II (8-12 Years)
* subgroup III (13-18 Years)
* subgroup IV (\>18 Years)

204 children and adult voluntary healty controls will be stratified in the same manner and matched with the population in study in order to assess normal and pathologic growth.

blood samples and buccal swabs will be obtained from patients with HME in order to analyze the genotype (EXT1 or EXT2 mutations) and correlate the genotypic pattern with the phenotypic presentation

blood and buccal swab genetic test

measurement of ulnar length with anthropometer and patient's height

measurement of range of motion of elbow, forearm and wrist

Range of motion

Giovanni Luigi Di Gennaro, MD

the purpose of the present registry is to describe the epidemiology of forearm deformities in patients with Hereditary Multiple Exostoses and to identify, independent predictors of severity of the disease and potential association with genotypic patterns

Hereditary Multiple Exostoses (HME) is a rare pediatric autosomal dominant disorder caused by loss-of-function mutations in the genes encoding the heparan sulfate (HS)-synthesizing enzymes EXT1 or EXT2. HME affects 1 in 50,000 people and has 100% penetrance but great variability in phenotypic expression. HME is characterized by formation of cartilaginous outgrowths, called osteochondromas or exostoses, next to the growth plates of many axial and appendicular skeletal elements, causing multiple, painful disfiguring and disabling skeletal deformities, and potential malignant transformation into peripherral chondrosarcoma.

The involvement of upper-limb bones by HME is associated with greater loss of function than elsewhere in the body, but even here the loss of function may be limited. Moreover, the constant relationship between height and ulnar length has long been recognized in forensic medicine and has been recently analyzed also in HME, in order to predict the clinical and functional outcomes of the upper limb.

the present registry aims to collect demographic, clinical, functional and radiographic information from patients with HME in order to establish phenotypic predictors of severity of the disease and potential association with genotypic patterns

Height, Ulnar Length and Forearm Function in Multiple Hereditary Exostoses

Analysis of the Relationship Among Height, Ulnar Length and Forearm Function in Patients With Multiple Hereditary Exostoses and Association With the Genotypic Pattern

proportional ulnar length (PUL) is the ratio between ulnar lenght and the height of the patient

identify potential association among the genotypic pattern (EXT1 or EXT2) and phenotypic presentation

elbow, forearm and wrist range of motion (ROM) measured by a goneometer

EQ-5D is a standardised measure of health-related quality of life developed by the EuroQol Group

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Establishing the Genetic Profile of Multiple Hereditary Exostoses (HME) in Families of BC	NCT00473850	Exostoses, Mult...		-	University of British Columbia
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
Gene Mutations and Orthopaedic Symptoms Correlation of Multiple Hereditary Exostoses: Multicentre Project	NCT00474331	Exostoses, Mult...		-	University of British Columbia
Establishing the Genetic Profile of Multiple Hereditary Exostoses (HME) in Families of BC	NCT00473850	Exostoses, Mult...		-	University of British Columbia
The Health-Related Quality of Life in Patients With Hereditary Multiple Exostoses	NCT00474448	Exostoses, Mult...		-	University of British Columbia
Height, Ulnar Length and Forearm Function in Multiple Hereditary Exostoses	NCT05914298	Exostoses, Mult...	blood and bucca... PUL Range of motion	-	Istituto Ortopedico Rizzoli

Spots Global Cancer Trial Database for exostoses, multiple hereditary