A Phase 2, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Palovarotene in Subjects with Multiple Osteochondromas
- Conditions
- Multiple Osteochondromas or Multiple Hereditary Exostoses10028396
- Registration Number
- NL-OMON48469
- Lead Sponsor
- Clementia Pharmaceuticals Inc
- Brief Summary
Trial ended prematurely
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 10
1. Written, signed, and dated informed subject/parent consent and age
appropriate assent (performed according to local regulations)., 2. A clinical
diagnosis of MO with a disease-causing Ext1 or Ext2 mutations confirmed by a
central laboratory., 3. Male and female subjects with a chronological age of
2-14 years, inclusive., 4. Female subjects must be premenarchal at screening.,
5. Bone age at screening of <=14 years, 0 months per the Greulich-Pyle method as
assesed by a central reader., 6. Symptomatic MO, defined as the occurrence of
any one of the following at screening:, • Five or more clinically-evident OCs
and the presence of a new or enlarging OC in the preceding 12 months.
• Five or more clinically-evident OCs and the presence of a painful OC.
• A skeletal deformity.
• A joint limitation.
• Prior surgery for a MO-related complication., 7. If a subject had a prior
surgery for MO, the subject should not be screened until at least 8 weeks
post-surgery to allow for at least 12 weeks of stabilization of symptoms prior
to first dose. Surgical orthopedic implants are allowed if they were in situ
for >=12 weeks prior to the baseline MRI., 8. If a subject is currently
receiving pain medications, the dose must be stable (ie, <20% variance) for 2
weeks prior to screening., 9. The ability to undergo whole body MRI with or
without sedation/general anesthesia., 10. Male and female subjects of child
bearing potential who are heterosexually active must agree to use two highly
effective methods of birth control, one of which must be highly effective
during treatment, and for 1 month after treatment discontinuation, unless they
commit to true abstinence from heterosexual sex. Heterosexually active females
of child bearing potential (FOCBP) must also agree to start effective methods
of birth control at screening. An FOCBP is defined as a female who is 13 or
older of age or is post-menarchal, whichever is earlier, 11. Subjects must be
accessible for treatment with study drug and follow-up.
1. A weight <10 kg., 2. Other known syndromic conditions such as Langer-Giedion
or Potocki Shaffer., 3. Any subject with neurologic signs suggestive of spinal
cord impingement., 4. If subject is currently using vitamin A or beta carotene,
multivitamins containing vitamin A or beta carotene, or herbal preparations,
fish oil, and unable or unwilling to discontinue use of these products during
palovarotene treatment. For eligibility, no washout is required prior to the
first dose of study drug., 5. Exposure to synthetic oral retinoids within 4
weeks prior to enrollment., 6. Concurrent treatment with tetracycline or any
tetracycline derivatives, due to the potential increased risk of pseudotumor
cerebri., 7. History of allergy or hypersensitivity to retinoids, gelatin or
lactose (other than lactose intolerance)., 8. Concomitant medications that are
strong inhibitors or inducers of cytochrome P450 (CYP450) 3A4 activity., 9.
Amylase or lipase >2 times the above the upper limit of normal (>2×ULN) or with
a history of chronic pancreatitis., 10. Elevated aspartate aminotransferase
(AST) or alanine aminotransferase (ALT) >;2.5x ULN., 11. Fasting triglycerides
>400 mg/dL with or without therapy., 12. Subjects with uncontrolled
cardiovascular, renal, hepatic, pulmonary, gastrointestinal, endocrine,
metabolic, ophthalmologic, immunologic, psychiatric, or other significant
disease. These include subjects requiring glucocorticoid at doses >0.2mg/kg or
up to 10 mg prednisone equivalent daily. , 13. Subjects experiencing suicidal
ideation (type 4 or 5) or any suicidal behavior within the past month or any
suicidal behavior within the past year as defined by the Columbia-Suicide
Severity Rating Scale (C SSRS)., 14. Subjects unable or unwilling to complete
the study or all study-related procedures, including imaging., 15. Any surgical
implant that is contraindicated for MRI. Dental braces are permitted., 16.
Participation in any clinical research study within 4 weeks prior to enrollment
or simultaneous participation in any clinical research study., 17. Any reason
that, in the opinion of the Investigator, would lead to the inability of the
subject and/or family to comply with the protocol.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Preventing new osteochondromas (OCs) in subjects with multiple osteochondromas<br /><br>(MO) due to exostosin 1 (Ext1) or exostosin 2 (Ext2) mutations when comparing<br /><br>palovarotene with placebo.</p><br>
- Secondary Outcome Measures
Name Time Method <p>Secondary objectives will be to compare the following effects of palovarotene<br /><br>with placebo:<br /><br>• The volume of OCs as assessed by magnetic resonance imaging (MRI).<br /><br>• The proportion of subjects with no new OCs.<br /><br>• The rate of new or worsening skeletal deformities.<br /><br>• The rate of MO-related surgeries.<br /><br><br /><br>Additional secondary objectives:<br /><br>• Overall palovarotene safety.<br /><br>• The pharmacokinetics of palovarotene at steady state.<br /><br>• The palatability of drug product when sprinkled onto specific foods.<br /><br>Exploratory Objectives<br /><br>Exploratory objectives will be to compare the following effects of palovarotene<br /><br>with placebo:<br /><br>• The changes in volume of OC cartilage caps as assessed by MRI.<br /><br>• The rate of new or worsening functional limitations.<br /><br>• Pain and pain interference due to OCs.<br /><br>• Quality of life.</p><br>