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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Exostoses, Multiple Hereditary

Intervention / Treatment
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* Drug: Palovarotene 2.5 mg
* Drug: Palovarotene 5.0 mg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicenter, randomized, double-blind, placebo-controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Palovarotene 2.5 mg daily regimen<br> | Drug: Palovarotene 2.5 mg<br>* Subjects received a weight-adjusted dose equivalent of 2.5 mg palovarotene, once daily, for up to 24 months.<br>|
| Experimental: Palovarotene 5.0 mg daily regimen<br> | Drug: Palovarotene 5.0 mg<br>* Subjects received a weight-adjusted dose equivalent of 5.0 mg palovarotene, once daily, for up to 24 months.<br>|
| Placebo Comparator: Placebo regimen<br> | Other: Placebo<br>* Subjects received placebo, once daily, for up to 24 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple osteochondromas, Osteochondroma, Palovarotene, Hereditary multiple exostoses, HME, MO, Retinoic acid receptor gamma agonist, Retinoic acid receptor agonist