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An Efficacy and Safety Study of Palovarotene for the Treatment of MO (MO-Ped)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03442985
Recruitment Status : Terminated (Trial was terminated early to analyze the accumulated data and evaluate the efficacy, safety and future of palovarotene in MO.)
First Posted : February 22, 2018
Results First Posted : August 1, 2022
Last Update Posted : August 1, 2022
Sponsor:
Information provided by (Responsible Party):
Ipsen ( Clementia Pharmaceuticals Inc. )

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).

Condition or disease Intervention/treatment Phase
Exostoses, Multiple Hereditary Drug: Palovarotene 2.5 mg Drug: Palovarotene 5.0 mg Other: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 193 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Multicenter, randomized, double-blind, placebo-controlled
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Palovarotene in Subjects With Multiple Osteochondromas
Actual Study Start Date : March 22, 2018
Actual Primary Completion Date : March 24, 2020
Actual Study Completion Date : October 30, 2020


Arm Intervention/treatment
Experimental: Palovarotene 2.5 mg daily regimen Drug: Palovarotene 2.5 mg
Subjects received a weight-adjusted dose equivalent of 2.5 mg palovarotene, once daily, for up to 24 months.

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

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




Primary Outcome Measures :
  1. Annualized Rate of New Osteochondromas (OCs) [ Time Frame: Month 12 ]
    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).


Secondary Outcome Measures :
  1. Mean Change From Baseline in the Total Volume of New OCs at Month 12 [ Time Frame: Baseline (Day 1) and 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.

  2. Percentage of Participants With No New OCs [ Time Frame: Month 12 ]
    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.

  3. Annualized Rate of New or Worsening Deformities [ Time Frame: Month 12 ]
    The annualized rate of new or worsening deformities as assessed by radiographic imaging of both upper and lower limbs.

  4. Annualized Rate of MO-Related Surgeries [ Time Frame: Month 12 ]
    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.

  5. Maximum Observed Plasma Drug Concentrations at Steady State (Cmax,ss) of Palovarotene [ Time Frame: Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose ]
    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.

  6. Minimum Observed Plasma Drug Concentrations at Steady State (Cmin,ss) of Palovarotene [ Time Frame: Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose ]
    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.

  7. Time to Maximum Observed Drug Concentration at Steady State (Tmax,ss) of Palovarotene [ Time Frame: Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose ]
    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.

  8. Area Under the Plasma Concentration-Time Curve at Steady State From Time 0 to 24 Hours After Dosing (AUC0-24,ss) of Palovarotene [ Time Frame: Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose ]
    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.

  9. Number of Participants With Palatability of Sprinkled Palovarotene and Placebo [ Time Frame: Day 1 and Month 1 ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 14 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03442985


Locations
Show Show 31 study locations
Sponsors and Collaborators
Clementia Pharmaceuticals Inc.
Investigators
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Study Director: Ipsen Medical Director Ipsen
  Study Documents (Full-Text)

Documents provided by Ipsen ( Clementia Pharmaceuticals Inc. ):
Study Protocol  [PDF] April 23, 2019
Statistical Analysis Plan  [PDF] May 14, 2020

Additional Information:
Publications:
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Responsible Party: Clementia Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT03442985    
Other Study ID Numbers: PVO-2A-201
2017-002751-28 ( EudraCT Number )
First Posted: February 22, 2018    Key Record Dates
Results First Posted: August 1, 2022
Last Update Posted: August 1, 2022
Last Verified: July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ipsen ( Clementia Pharmaceuticals Inc. ):
Multiple osteochondromas
Osteochondroma
Palovarotene
Hereditary multiple exostoses
HME
MO
Retinoic acid receptor gamma agonist
Retinoic acid receptor agonist
Additional relevant MeSH terms:
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Osteochondroma
Exostoses, Multiple Hereditary
Osteochondromatosis
Exostoses
Osteophyte
Hyperostosis
Bone Diseases
Musculoskeletal Diseases
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Osteochondrodysplasias
Bone Diseases, Developmental
Neoplastic Syndromes, Hereditary
Genetic Diseases, Inborn