Primary Objective• To evaluate the efficacy of two dosage regimens of palovarotene compared with placebo in preventing new osteochondromas (OCs) in subjects with multiple osteochondromas (MO) due to exostosin 1 (Ext1) or exostosin 2 (Ext2) mutations…
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Source
Brief title
Condition
- Musculoskeletal and connective tissue disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Preventing new osteochondromas (OCs) in subjects with multiple osteochondromas
(MO) due to exostosin 1 (Ext1) or exostosin 2 (Ext2) mutations when comparing
palovarotene with placebo.
Secondary outcome
Secondary objectives will be to compare the following effects of palovarotene
with placebo:
• The volume of OCs as assessed by magnetic resonance imaging (MRI).
• The proportion of subjects with no new OCs.
• The rate of new or worsening skeletal deformities.
• The rate of MO-related surgeries.
Additional secondary objectives:
• Overall palovarotene safety.
• The pharmacokinetics of palovarotene at steady state.
• The palatability of drug product when sprinkled onto specific foods.
Exploratory Objectives
Exploratory objectives will be to compare the following effects of palovarotene
with placebo:
• The changes in volume of OC cartilage caps as assessed by MRI.
• The rate of new or worsening functional limitations.
• Pain and pain interference due to OCs.
• Quality of life.
Background summary
Multiple osteochondromas (MO), or multiple hereditary exostoses (MHE), is an
autosomal-dominant skeletal disorder primarily caused by loss-of-function
mutations in exostosin 1 (Ext1) or exostosin 2 (Ext2) genes. Although rare,
with prevalence estimates in the United States (US) and Europe at 1 per 50,000
population, MO is among the most common inherited skeletal disorders.
The key clinical features of MO are benign cartilage-capped bone tumors
emerging from the growth plates of long bones, ribs, vertebrae, and pelvis,
known as osteochondromas (OCs).
Osteochondromas begin to develop and continue to grow during the first and
second decades of life, and cease development and growth when growth plates
close at puberty. Thus, MO is a disease that manifests exclusively in
children, with a mean diagnosis/onset of about 4 years of age.
Currently there is no medicinal treatment to prevent the development of OCs and
the clinical sequelae of skeletal deformities, functional limitations, and
pain. Surgical excisions are performed when OCs cause pain, restrict function,
or lead to cosmetic complaints, but carry a risk of irreversible damage to
growth plates. Thus, there is a significant unmet medical need for a medicinal
therapy to prevent the formation and growth of OCs.
It is hypothesized that palovarotene compared to placebo will prevent the
formation of new OCs in subjects with MO.
The primary objective of Study PVO-2A-201 is to compare the efficacy of two
dosage regimens of palovarotene with placebo in preventing the formation of new
OCs in subjects with MO due to Ext1 or Ext2 mutations.
Secondary study objectives are to compare the effect palovarotene treatment
with placebo on the volume of OCs and on the proportion of subjects with no new
OCs as assessed by whole body MRI; and on the annualized rates of new or
worsening skeletal deformities and MO-related surgeries. The overall safety of
palovarotene and treatment effects on linear growth and the growth plate will
also be evaluated. The pharmacokinetics of palovarotene at steady-state will
also be evaluated as a secondary objective.
Study objective
Primary Objective
• To evaluate the efficacy of two dosage regimens of palovarotene compared with
placebo in preventing new osteochondromas (OCs) in subjects with multiple
osteochondromas (MO) due to exostosin 1 (Ext1) or exostosin 2 (Ext2) mutations.
Secondary Objectives
Secondary objectives will be to compare the following effects of palovarotene
with placebo:
• The volume of OCs as assessed by magnetic resonance imaging (MRI).
• The proportion of subjects with no new OCs.
• The rate of new or worsening skeletal deformities.
• The rate of MO-related surgeries.
Additional secondary objectives:
• Overall palovarotene safety.
• The pharmacokinetics of palovarotene at steady state.
• The palatability of drug product when sprinkled onto specific foods.
Exploratory Objectives
Exploratory objectives will be to compare the following effects of palovarotene
with placebo:
• The changes in volume of OC cartilage caps as assessed by MRI.
• The rate of new or worsening functional limitations.
• Pain and pain interference due to OCs.
• Quality of life.
Study design
Study PVO-2A-201 will be a multicenter, randomized, double-blind, placebo
controlled study assessing various aspects of disease progression in pediatric
subjects with MO. The primary efficacy analysis will compare the effect of two
palovarotene dosage regimens with placebo on the rate of new OCs over 2 years.
The study will also compare the changes from baseline in the total volume of
OCs as assessed by MRI, the rate of new or worsening skeletal deformities, the
rate of new or worsening functional limitations, the rate of MO-related
surgeries, pain due to OCs, and quality of life. To ensure consistency in
assessments of OCs and deformities, imaging by whole body MRI and radiographs
of the upper and lower extremities will be interpreted by a treatment-blinded
central imaging laboratory using standardized procedures.
For sites in the European Union, subjects from 7 to 15 years of age may be
enrolled first. Younger subjects (2 to <7 years of age) will be enrolled after
the 6-month bone safety data from at least 20 skeletally immature subjects in
the palovarotene fibrodysplasia ossificans progressiva (FOP) program are deemed
favorable by the independent Data Monitoring Committee (DMC).
Prior to enrollment, tolerance for the MRI procedure will be assessed in
subjects <=7 years of age and in subjects who are deemed by the Investigator to
require procedural sedation. A pediatric sedation team will perform
assessments of the level of procedural sedation the subject may require to
complete an MRI session.
At baseline, eligible subjects will be examined with whole body MRI and
radiographs of the upper and lower limbs to determine the number, size, and
location of OCs, joint deformities, and other skeletal abnormalities.
On Study Day 1, eligible subjects will be randomized 1:1:1 to one of two active
treatments (weight-adjusted daily dose equivalent to 2.5- or 5.0-mg
palovarotene, administered orally) or placebo, stratifying by age, sex, and
Ext1/2 mutation. Alternating on-site and remote visits (eg, at home or at a
local medical facility) will occur every 3 months unless the Investigator deems
that a site visit is necessary. Urine pregnancy tests will be performed each
month for females of childbearing potential. At the site visits every 6
months, most procedures performed at baseline (including knee and hand/wrist
radiographs for the assessment of growth plates and dual x-ray absorptiometry
[DXA]) will be repeated. Whole body MRIs and upper/lower limb radiographs will
be performed every 12 months. Subjects will undergo all assessments and
procedures specified in the Schedule of Assessments provided in Table 1.
At the end of the study, subjects will have the option of participating in an
open-label extension study (PVO-2A-202).
Intervention
Palovarotene is supplied as powder-filled hard gelatin capsules. The capsules
may be swallowed whole or opened and the contents added onto specific foods as
specified in the dosing instructions.
Study burden and risks
The study medicine may cause side effects and discomforts.
The most frequent side effects associated with palovarotene, including those
reported so far in studies evaluating palovarotene include effects on skin and
mucous membranes (e.g. the inside of your nose and mouth), including: dry skin,
dry lips, itching, rash, redness of the skin, flaking, peeling or scratching of
skin, inflammation of the lips, dry mouth, dry eyes, hair loss,
Additional side effects include muscle aches, nausea, headaches feeling
irritable, anxious and tired, and dizziness.
During the study the following procedures will be done:
Knee and hand/wrist radiograph for assessment of growth plate at screening and
at 4 visits, ECG at screenng and at 3 visits, MRI at 3 visits, Radiographs of
upper/lower limbs (weight bearing) at 3 visits and DEXA at 5 visits.
Furthermore, subjects will be asked to complete questionnaires. Questions will
be raised about how subject is feeling and other medicines taking.
Blood samples, including PK samples will be taken. This may require an
overnight stay at a hotel close to the hospital. If applicable pregnancy tests
will be performed.
De La Gauchetiere West, Suite 1200 1000
Montreal, Quebec H3B 4W5
CA
De La Gauchetiere West, Suite 1200 1000
Montreal, Quebec H3B 4W5
CA
Listed location countries
Age
Inclusion criteria
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.
Exclusion criteria
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-002751-28-NL |
| ClinicalTrials.gov | NCT03173560 |
| CCMO | NL67312.028.18 |