Clinical trial NCT03442985
Conditions: Exostoses, Multiple Hereditary
Keywords: Multiple osteochondromas Osteochondroma Palovarotene Hereditary multiple exostoses HME MO Retinoic acid receptor gamma agonist Retinoic acid receptor agonist
Sponsor: Clementia Pharmaceuticals Inc.
Start date: 2018-03-22; Completion date: 2020-10-30
Enrollment: 193 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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).

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.

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Palovarotene 2.5 mg intervention 2: Palovarotene 5.0 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Subjects received a weight-adjusted dose equivalent of 2.5 mg palovarotene, once daily, for up to 24 months. intervention 2: Subjects received a weight-adjusted dose equivalent of 5.0 mg palovarotene, once daily, for up to 24 months. intervention 3: Subjects received placebo, once daily, for up to 24 months.

Protocol documents:
Prot_000.pdf: 



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PROTOCOL PVO-2A-201, AMENDMENT 2 
 
PAGE 3 OF 114 
CLEMENTIA PHARMACEUTICALS INC. 
 
23 APRIL 2019 
PROPRIETARY AND CONFIDENTIAL 
Protocol Amendment Summary 
This second amendment to the protocol for Study PVO-2A-201 was finalized on 23 April 2019.  
The following table summarizes major and minor changes. 
Section 
Change 
Rationale 
Major changes that affect the clinical conduct of the study: 
 
Synopsis (Table 1) 
Section 5.4 
Section 8.4.6 
 
Stipulated that only clinically significant 
abnormal clinical laboratory results at the 
EOT, which includes hematology 
parameters, will require retesting at the 
safety follow-up visit, rather than all 
abnormal clinical laboratory findings. 
To limit unnecessary procedures to only 
those that are clinically significant, 
thereby decreasing subject burden. 
Section 5.1  
Section 6.4 
Changed the definition of FOCBP from 
Tanner 2+ to age >13 years or 
post-menarchal, whichever is earlier. 
To align with published guidelines on 
pregnancy testing of adolescents 
participating in clinical research. 
Synopsis (Table 1) 
Section 8.4.6 (Table 7) 
Added 25-hydroxyl vitamin D assessments 
at the discretion of the Investigator to 
evaluate changes in BMD. 
To provide additional relevant laboratory 
measures for changes in bone density. 
Section 8.5.3 
Amended the requirement for a 
confirmatory DXA scan to only those that 
would result in a dose modification (ie, 
>5% loss in spine aBMD and -1 change 
from baseline in height-adjusted z-score in 
lumbar spine BMD). 
The emerging BMD data showed 
significant variability and multiple false 
positives due to technical issues related to 
DXA assessments in children. Limiting 
confirmatory scans to those that may 
result in a dose modification decreases 
subject burden and radiation exposure 
without affecting subject safety. 
Other changes that affect the clinical conduct of the study: 
 
Synopsis 
Section 4.1 
Removed some of the age restrictions on 
subject enrollment for sites in the EU. 
To indicate that enrollment is now open to 
subjects from 2 to <7 years of age at all 
clinical sites.  The change was made 
following the favorable DMC assessment 
of the 6-month bone safety data from at 
least 20 skeletally immature subjects in 
the FOP program.  This update, which is 
applicable to EU sites only, was 
implemented in accordance with 
previously established and approved 
plans. 
Section 6.4 
Defined effective and highly effective 
forms of birth control. 
To align with the CTFG guidance for 
effective contraception.  Note that this 
change has been in effect since 13 
September 2018 per an addendum to the 
protocol and will now be formally 
incorporated into the protocol. 
Section 8.4.6 
Added that the Investigator should review 
the subject’s condition to determine 
whether a missed clinical laboratory test or 
non-evaluable test should be repeated for 
that time point. 
To provide guidance to the Investigator 
regarding missed clinical laboratory tests 
or non-evaluable laboratory tests. 
3


PROTOCOL PVO-2A-201, AMENDMENT 2 
 
PAGE 4 OF 114 
CLEMENTIA PHARMACEUTICALS INC. 
 
23 APRIL 2019 
PROPRIETARY AND CONFIDENTIAL 
Section 
Change 
Rationale 
Synopsis and Table 1 
Section 4.1 Overview of 
Study Design 
Section 8.1 Overview of 
Study Procedures 
Stipulated that subjects enrolled in Japan 
will have on-site clinic visits every 3 
months. 
Requested by the Japanese regulatory 
authority. 
Minor changes that do not affect the clinical conduct of the study:  
General 
 
Corrected minor errors, clarifications, and 
formatting inconsistencies; updated 
persons responsible for study conduct. 
To provide a current and clear 
presentation. 
Title page 
Groups Responsible for the 
Conduct of the Study 
Changed to sponsor address. 
The sponsor’s headquarters relocated sine 
the last protocol amendment 
Groups Responsible for the 
Conduct of the Study 
Revised the vendor contract information. 
To ensure that contact information is 
up-to-date. 
Section 1.3.3 
Provided the FOP clinical study numbers 
and updated safety data from these studies. 
To present the most recent safety data 
from the FOP program. 
Section 4.3.3.4 (Table 5) 
Updated observed palovarotene 
pharmacokinetic values in the pediatric 
population. 
To present the most recent 
pharmacokinetic data from the FOP 
program. 
CTFG, Clinical Trial Facilitation Group; DMC, Data Monitoring Committee; DXA, dual x-ray absorptiometry; EOT, end of 
treatment; EU, European Union; FOCBP, females of childbearing potential; FOP, fibrodysplasia ossificans progressiva. 
 
4


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PROTOCOL PVO-2A-201, AMENDMENT 2 
 
PAGE 7 OF 114 
CLEMENTIA PHARMACEUTICALS INC. 
 
23 APRIL 2019 
PROPRIETARY AND CONFIDENTIAL 
Protocol Synopsis 
Title 
MO-Ped Trial: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Efficacy 
and Safety Study of Palovarotene in Subjects with Multiple Osteochondromas. 
Sponsor 
Clementia Pharmaceuticals Inc. 
Objectives 
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 less than 15 years of age were to be 
enrolled first.  Younger subjects (2 to <7 years of age) were to be enrolled after the 6-
month bone safety data from at least 20 skeletally immature subjects in the palovarotene 
fibrodysplasia ossificans progressiva (FOP) program were deemed favorable by the 
independent Data Monitoring Committee (DMC).   On 28 January 2019, a favorable 
decision by the DMC permitted enrollment of subjects from 2 to 14 years of age in the 
European Union. 
7


PROTOCOL PVO-2A-201, AMENDMENT 2 
 
PAGE 8 OF 114 
CLEMENTIA PHARMACEUTICALS INC. 
 
23 APRIL 2019 
PROPRIETARY AND CONFIDENTIAL 
Protocol Synopsis 
Study Design (cont.) 
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 or the 
subject is in enrolled in Japan.  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). 
Number of Subjects 
Approximately 240 subjects will be enrolled; 80 per treatment group. 
Number of Sites 
Approximately 30 investigational sites. 
Study Population 
 
Inclusion Criteria 
Subjects must meet all the following criteria to be eligible for enrollment: 
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 mutation 
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 
assessed 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-evidence 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. 
8


PROTOCOL PVO-2A-201, AMENDMENT 2 
 
PAGE 9 OF 114 
CLEMENTIA PHARMACEUTICALS INC. 
 
23 APRIL 2019 
PROPRIETARY AND CONFIDENTIAL 
Protocol Synopsis 
Study Population  
(cont.) 
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 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 years of age or is post-menarchal, whichever is 
earlier. 
11. Subjects must be accessible for treatment with study drug and follow-up. 
 
Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for enrollment: 
1. A weight <10 kg. 
2. Other known syndromic conditions such as Langer-Giedion or Potocki-Shaffer 
syndromes. 
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. 
9


PROTOCOL PVO-2A-201, AMENDMENT 2 
 
PAGE 10 OF 114 
CLEMENTIA PHARMACEUTICALS INC. 
 
23 APRIL 2019 
PROPRIETARY AND CONFIDENTIAL 
Protocol Synopsis 
Investigational Product 
Dose/Route/Regimen 
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. 
Palovarotene 2.5 mg (adjusted for weight as shown in the table) / taken orally with food / 
at approximately the same time once daily, preferably immediately following the first 
meal of the day, for 24 months. 
Palovarotene 5.0 mg (adjusted for weight as shown in the table) / taken orally with food / 
at approximately the same time once daily, preferably immediately following the first 
meal of the day, for 24 months. 
Weight range  
category 
5.0-mg  
Equivalent 
2.5-mg  
Equivalent 
10 to <20 kg 
2.5 mg 
1.0 mg 
20 to <40 kg 
3.0 mg 
1.5 mg 
40 to <60 kg 
4.0 mg 
2.0 mg 
≥60 kg 
5.0 mg 
2.5 mg 
 
 
 
 
Comparator Product 
Dose/Route/Regimen 
Placebo is supplied as powder-filled hard gelatin capsules / taken orally with food /  
at approximately the same time once daily, preferably immediately following the first 
meal of the day, for 24 months. 
Efficacy Endpoints 
Primary Efficacy Endpoint 
The primary efficacy endpoint will compare palovarotene with placebo on the 
annualized rate of new OCs as assessed by whole body MRI. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints will compare palovarotene with placebo on the following: 
• 
The change from baseline in the total volume of OCs as assessed by whole 
body MRI at Months 12 and 24. 
• 
The proportion of subjects with no new OCs as assessed by whole body MRI at 
Months 12 and 24. 
• 
The annualized rate of new or worsening deformities as assessed by 
radiographic imaging of both upper and lower limbs. 
• 
The annualized rate of MO-related surgeries. Surgeries include any procedure 
indicated for the treatment of MO, such as an excision of a symptomatic OC or 
correction of a limb deformity. 
10


PROTOCOL PVO-2A-201, AMENDMENT 2 
 
PAGE 11 OF 114 
CLEMENTIA PHARMACEUTICALS INC. 
 
23 APRIL 2019 
PROPRIETARY AND CONFIDENTIAL 
Protocol Synopsis 
Efficacy Endpoints 
(cont.) 
Exploratory Efficacy Endpoints  
Exploratory endpoints will compare palovarotene with placebo on the following: 
• 
The change from baseline in the total volume of cartilage caps of OCs as 
assessed by whole body MRI at Months 12 and 24. 
• 
The annualized rate of new or worsening functional limitations.  Functional 
limitations are defined as restrictions in joint range of motion. 
• 
The effect of pain on daily activities, as assessed with the Patient Reported 
Outcomes Measurement Information System (PROMIS) pain interference 
pediatric item bank at Months 6, 12, 18, and 24. 
• 
Pain intensity, as assessed with the Faces Pain Scale – Revised (FPS-R) at 
Months 6, 12, 18, and 24. 
• 
Quality of life, as assessed with the Pediatric Quality of Life Inventory 
(PedsQL, version 4.0) at Months 6, 12, 18, and 24. 
Other Endpoints 
Pharmacokinetic Endpoint 
• 
To evaluate the pharmacokinetics of palovarotene at steady-state. 
Palatability Endpoint 
• 
To evaluate the palatability of drug product versus placebo when sprinkled onto 
specific foods following the first dose and at Month 1. 
Safety Assessments 
• 
Adverse events and serious adverse events: adverse event severity will be 
assessed and reported according to criteria defined in the protocol (mild, 
moderate, severe). 
• 
Adverse events known to be associated with retinoids (eg, mucocutaneous 
events) will be further graded according to the Common Terminology Criteria 
for Adverse Events (CTCAE), Version 4.03. 
• 
Electrocardiograms, vital signs (temperature, respiratory rate, blood pressure, 
and heart rate), physical examination, body weight and height, and laboratory 
parameters (hematology, biochemistry, and urinalysis). 
• 
Pregnancy tests (blood or urine) performed each month for female subjects of 
childbearing potential. 
• 
Growth will be assessed by 
o 
Measures of linear height (by stadiometer) and bilateral knee height 
(by knee caliper) in triplicate every 6 months.   
o 
Growth plate assessment by radiographs of the knee and hand/wrist 
every 6 months. 
o 
Bilateral bone (ulna, radius, tibia, fibula, and femur) lengths by 
radiograph every 12 months.  
• 
Bone mineral density at the lumbar spine, hip, and mid-third radius will be 
assessed with DXA every 6 months. 
• 
Presence of potential osteonecrosis of the hip, shoulders, and knees assessed by 
MRI every 12 months. 
• 
Sexual development: Tanner staging will be performed at baseline and every 
12 months.  
• 
Columbia-Suicide Severity Rating Scale (C-SSRS): subjects 8 years of age and 
older will be assessed for suicidal ideation and behavior every 3 months using 
the age appropriate form of the C-SSRS. 
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PROTOCOL PVO-2A-201, AMENDMENT 2 
 
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PROPRIETARY AND CONFIDENTIAL 
Protocol Synopsis 
Genotyping 
Central laboratory genotyping will confirm the presence of a disease-causing Ext1 or 
Ext2 mutation prior to randomization.  Any subject found not to have a relevant 
mutation will not be randomized. 
Monitoring 
A Data Monitoring Committee (DMC) will oversee the safety of subjects during the 
study.  The DMC can recommend changes to the conduct of the study or temporarily 
stop the study at any time for significant safety concerns.  The DMC Charter includes 
safety stopping and dose modification rules.  One interim efficacy analysis is planned 
when subjects complete 12 months of treatment (see Statistical Analysis).  Based on the 
interim results, the DMC may recommend stopping the study early for efficacy or 
futility, or moving subjects from one palovarotene treatment group to the other. 
Statistical Analysis 
The primary efficacy endpoint is the annualized rate of new OCs as assessed by whole 
body MRI.  The primary efficacy analysis comparing the rate of OCs between 
palovarotene-treated subjects and placebo-treated subjects will be conducted using a 
negative binomial regression model.  Covariates in the model will include treatment 
group indicators, baseline age, sex, and Ext1/2 mutation status.  An offset variable equal 
to the log of the number of years of follow-up will also be included. 
The estimated rate ratio comparing the rate of OCs between palovarotene-treated 
subjects and placebo-treated subjects and the associated Wald statistics will be used for 
hypothesis testing.  The primary efficacy hypothesis testing will compare 5.0-mg 
palovarotene with placebo and 2.5-mg palovarotene with placebo; the multiple 
comparisons will be accounted for with a Bonferroni adjustment.  There will be one 
interim efficacy analysis (planned for when all subjects complete 1 year of treatment) 
and a final analysis.  The O’Brien-Fleming alpha-spending function will be used to 
specify the alpha-level threshold for determining treatment effect significance at the 
interim and final analyses.  Assuming 50% statistical information at the interim analysis, 
the one-sided p-value significance threshold used in the interim analysis comparing the 
5.0-mg palovarotene and placebo groups and the 2.5-mg palovarotene and placebo 
groups is 0.0007.  Likewise, the one-sided p-value significance threshold in the final 
analysis will be 0.0122.  Study success is defined as having one or both palovarotene 
groups demonstrate a statistically significant treatment effect. 
The sample size was determined via simulation using information from an MO patient 
registry.  Assuming 80 subjects will be randomized to each treatment group, and a 50% 
palovarotene treatment effect in one treatment group and no effect in the other, the 
probability of declaring study success at the interim analysis is 0.34, whereas the overall 
probability of study success is 0.87.  If there is a 50% palovarotene treatment effect for 
both dosage regimens, the probability of declaring study success at the interim analysis 
is 0.49 and the overall probability of study success is 0.95. 
 
 
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Table 1.   
Schedule of Assessments 
 
Screening 
Baseline1/  
Treatment 
Treatment 
End of 
Treatment 
Safety  
Follow-up3 
 
-35 Days 
Study 
Day 1 
Month 1  
±7 Days 
Months 3, 9, 
15, 21 
±7 Days2 
Months 6, 18 
±7 Days 
Month 12 
±7 Days 
Month 24 
±7 Days 
4 Weeks 
After EOT 
6 Months 
After EOT 
Assessment/Procedure 
Site 
Site 
Remote4  
Remote4 
Site 
Site 
Site 
 Remote3,4 
Site 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
Assessment of inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
MRI sedation screening5 
X 
 
 
 
 
 
 
 
 
Knee and hand/wrist radiograph for 
assessment of growth plate6 
X 
 
 
 
X 
X 
X 
 
X 
Genotyping7 
X 
 
 
 
 
 
 
 
 
Linear growth assessment (via stadiometry) 
and bilateral knee height (via caliper)8 
 
X 
 
 
X 
X 
X 
 
X 
Medical history 
X9 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
X 
X 
X 
 
X 
Hearing and visual acuity tests10 
 
X 
 
 
 
X 
X 
 
 
Tanner staging11 
 
X 
 
 
 
X 
X 
 
 
Columbia-Suicide Severity Rating Scale12 
X 
 
 
X 
X 
X 
X 
 
 
PedsQL, PROMIS, FPS-R13 
 
X 
 
 
X 
X 
X 
 
 
Joint range of motion14 
 
X 
 
 
X 
X 
X 
 
 
Body weight 
X 
X 
 
X 
X 
X 
X 
 
 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
X 
X 
 
 
 
X 
X 
 
 
Hematology 
X 
X 
 
X15 
X 
X 
X 
X3 
X3 
Biochemistry (includes lipids) 
X 
X 
 
X15 
X 
X 
X 
X3 
X3 
Parathyroid hormone16  
 
X 
 
X16 
 
 
Pharmacokinetics17 
 
 
X 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
X15 
X 
X 
X 
X3 
X3 
Blood pregnancy test18 
X 
 
 
X 
X 
X 
X 
 
 
Urine pregnancy test19 
 
X 
Every month except at visits where blood samples are obtained20 
X 
X 
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PROPRIETARY AND CONFIDENTIAL 
 
Table 1.   
Schedule of Assessments 
 
Screening 
Baseline1/  
Treatment 
Treatment 
End of 
Treatment 
Safety  
Follow-up3 
 
-35 Days 
Study 
Day 1 
Month 1  
±7 Days 
Months 3, 9, 
15, 21 
±7 Days2 
Months 6, 18 
±7 Days 
Month 12 
±7 Days 
Month 24 
±7 Days 
4 Weeks 
After EOT 
6 Months 
After EOT 
Assessment/Procedure 
Site 
Site 
Remote4  
Remote4 
Site 
Site 
Site 
 Remote3,4 
Site 
Whole body MRI10 
 
X 
 
 
 
X 
X 
 
 
Radiographs of upper/lower limbs  
(weight bearing)10 
 
X 
 
 
 
X 
X 
 
 
DXA10 
 
X 
 
 
X 
X 
X 
 
X 
Randomization via IWRS 
 
X 
 
 
 
 
 
 
 
Study drug dispensing21 
 
X 
 
 
X 
X 
 
 
 
Study drug accounting 
 
 
 
 
X 
X 
X 
 
 
Study drug treatment22 
 
Study drug treatment (QD) 
 
 
Palatability of sprinkled drug product23 
 
X 
X 
 
 
 
 
 
 
Prior/concomitant medications 
At every subject contact 
Inquiry of MO-related surgeries 
At every subject contact 
Adverse events 
At every subject contact 
1 
Baseline procedures are to be performed prior to any study drug administration. 
2 
Visit times should follow the original scheduled visit whenever possible. 
3 
Two safety follow-up visits are required for subjects who do not participate in the open-label extension study.  Only clinically significant abnormal safety laboratory 
result(s) observed at the end-of-treatment visit are to be repeated at the safety follow-up visit.  If the safety laboratory results are normal or if abnormalities are not clinically 
significant at the 4-week safety follow-up visit, they do not need to be repeated at the 6-month safety follow-up visit.  The 4-week safety follow-up visit will be performed 
remotely at the subject’s home by qualified study personnel, or at a local medical facility, unless the Investigator deems that a clinic visit is necessary. 
4 
Remote visits will take place at Months 1, 3, 9, 15, 21, and 4 weeks after EOT.  If deemed necessary by the Investigator or the subject is enrolled in Japan, remote visits will 
be substituted with site visits. In months where there is no scheduled clinic visit, remote visits for urine pregnancy testing will be performed at the subject’s home by 
qualified study personnel, or at a local medical facility, unless the Investigator deems that a clinical visit is necessary. 
 
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5        Any subject deemed by the Investigator to require procedural sedation will be assessed by a pediatric sedation team to determine the subject’s tolerance for MRI and the 
level of sedation required for completion of the MRI procedures.  Screening will be performed by a pediatric sedation team based on (but not limited to) age, gender, the 
ASA-PS class, and comorbidities. 
6 
Hand/wrist and knee radiographs will be obtained at screening and every 6 months.  Whenever possible, the left hand and left knee should be used.  However, if a surgical 
procedure has been performed in the past year then the other limb should be used.  The same hand/wrist and knee should be used in the subsequent assessments.  The 
screening hand and knee radiographs will be used to determine bone age at screening and serve as baseline for safety assessments.  Once a subject has achieved 100% 
skeletal maturity (ie, complete fusion of growth plates) as determined by the knee and hand/wrist radiographs, further radiographs will not be necessary.  If 100% skeletal 
maturity is not achieved at both anatomical regions, then only the region that is still maturing needs to be monitored. 
7       Genotyping will be conducted on each subject, regardless of whether prior genotyping was performed. 
8       Measurements of linear growth (via stadiometer) and bilateral knee height (via caliper) will be performed in triplicate.  If a subject does not exhibit any growth from the 
preceding 6-month height measure, the subject will have his/her height reassessed after 3 months at the site to confirm growth retardation. 
9  
Medical history at screening will include prior MO-related surgeries and all history related and not related to MO. 
10  
Assessments/procedures may be performed within a ±4-week visit window. 
11 
Tanner staging will continue on an annual basis until Tanner Stage V is reached. 
12 
C-SSRS for subjects 8 years of age and older.  The screening C-SSRS will be used as baseline. 
13 
For the PedsQL, the teen report form will be used for ages 13-18; the child report form for ages 8-12; the parent report form for young children ages 5-7 and the parent 
report for toddlers ages 2-4; the PROMIS assessment will use the pain interference pediatric short form for subjects ages 8-14 years and parent proxy short form for ages 
2-7 years; the FPS-R is appropriate for the assessment of pain intensity for subjects from ≥4 years of age. 
14 
Range of motion will be measured using a goniometer by a treatment-blinded, trained assessor.  
15  
Hematology, biochemistry, and urinalysis at Months 15 and 21 are waived if no clinically significant laboratory abnormalities are observed during the first 12 months of 
study treatment. 
16 
Parathyroid hormone levels will be obtained at baseline and assessed with 25-hydroxy vitamin D, as-needed by the Investigator, for evaluation of changes in BMD. 
17 
Pharmacokinetic sampling should be performed at Month 1.  A qualified site personnel may obtain pharmacokinetic samples during a remote visit.  Samples will be 
obtained pre-dose, and at 3, 6, 10, and 24 hours post-dose.  If samples cannot be obtained at Month 1, then one additional attempt will be made at a subsequent visit. 
18 
In FOCBP, serum pregnancy tests will be performed at visits where blood sampling was obtained. 
19 
On Study Day 1, a urine pregnancy test will be performed instead of a serum pregnancy test to confirm eligibility for FOCBP.  Urine pregnancy tests will be performed at 
the EOT safety follow-up visits for FOCBP. 
20  
Remote visits for urine pregnancy testing will be conducted in FOCBP only.  Urine pregnancy tests will not be performed at visits where blood samples are obtained 
(except for Study Day 1; see Note 15).  Urine pregnancy remote visits will occur on Months 2, 4, 5, 7, 8, 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, and Months 15 and 21 if no 
blood samples were obtained. 
21  
Study drug may be dispensed at 3-month intervals if necessary. 
22 
Palovarotene or placebo will be administered as 2.5- or 5.0-mg weight-adjusted equivalent doses as in Table 6.  
23  
Palatability will we assessed with a 5-point hedonic face scale in subjects ≥4 years of age who sprinkle the drug product or placebo onto a spoonful of specific foods. 
ASA-PS, American Society of Anesthesiologists – Physical Status; BMC, bone mineral content; BMD, bone mineral density; C-SSRS, Columbia–Suicide Severity Rating Scale; 
DXA, dual x-ray absorptiometry; EOT, end of treatment; FOCBP, females of child-bearing potential; FPS-R; Faces Pain Scale – Revised; IWRS, Interactive Web Response 
System; MRI, magnetic resonance imaging; OLE, open-label extension; PedsQL, Pediatric Quality of Life Inventory; PROMIS, Patient-Reported Outcomes Measurement 
Information System; QD, once daily. 
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PROPRIETARY AND CONFIDENTIAL 
 
Table of Contents 
Protocol Synopsis ...........................................................................................................................................7 
Table of Contents .........................................................................................................................................16 
1 
Introduction ........................................................................................................................................23 
1.1 
Multiple Osteochondromas ......................................................................................................23 
1.2 
The Exostosin Gene Mutation ..................................................................................................24 
1.3 
Overview of Palovarotene ........................................................................................................24 
1.3.1 
Nonclinical Data ......................................................................................................24 
1.3.2 
Primary Pharmacology .............................................................................................25 
1.3.3 
Palovarotene Safety .................................................................................................26 
1.4 
Evaluation of Study Benefits and Risks ...................................................................................28 
1.4.1 
Risk/Benefit Justification for Age Range ................................................................28 
1.4.2 
Potential to Ameliorate the Condition Under Investigation ....................................28 
1.4.3 
Potential Risks Associated With Palovarotene ........................................................28 
1.4.4 
Potential Risks Associated With Study Procedures .................................................29 
2 
Study Objectives ................................................................................................................................32 
2.1 
Primary Objective .....................................................................................................................32 
2.2 
Secondary Objectives ...............................................................................................................32 
2.3 
Exploratory Objectives .............................................................................................................32 
3 
Study Endpoints .................................................................................................................................32 
3.1 
Primary Efficacy Endpoint .......................................................................................................32 
3.2 
Secondary Efficacy Endpoints .................................................................................................32 
3.3 
Pharmacokinetic Endpoint ........................................................................................................33 
3.4 
Palatability Endpoint ................................................................................................................33 
3.5 
Exploratory Efficacy Endpoints ...............................................................................................33 
3.6 
Safety Endpoints .......................................................................................................................33 
4 
Study Design ......................................................................................................................................34 
4.1 
Overview of Study Design .......................................................................................................34 
4.2 
Study Rationale ........................................................................................................................35 
4.3 
Dosage Rationale ......................................................................................................................35 
4.3.1 
Nonclinical Efficacy Data ........................................................................................36 
4.3.2 
Nonclinical Safety Data ...........................................................................................36 
4.3.2.1 
The Fsp1-Ext1CKO Mouse Model of Multiple Osteochondromas (Non-GLP 
Study) .......................................................................................................................36 
4.3.2.2 
Nonclinical Juvenile Toxicity Study ........................................................................37 
4.3.3 
Clinical Data ............................................................................................................37 
4.3.3.1 
Clinical Safety Data in COPD .................................................................................37 
4.3.3.2 
Clinical Safety Data in FOP .....................................................................................37 
4.3.3.3 
Predicted Exposure to Palovarotene ........................................................................37 
4.3.3.4 
Observed Exposure for Weight-Based Dosing of Palovarotene ..............................38 
4.3.4 
Summary and Conclusions ......................................................................................39 
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4.4 
Justification for Placebo Control ..............................................................................................39 
4.5 
Clinical Meaningfulness of the Efficacy Endpoints .................................................................40 
4.6 
End of Study Definition ...........................................................................................................41 
4.7 
Study Termination ....................................................................................................................41 
5 
Selection of the Study Population ......................................................................................................41 
5.1 
Inclusion Criteria ......................................................................................................................41 
5.2 
Exclusion Criteria .....................................................................................................................42 
5.3 
Subject Withdrawal or Early Termination from Study ............................................................43 
5.4 
Safety Follow-up ......................................................................................................................44 
6 
Study Treatments ...............................................................................................................................44 
6.1 
Identity of Study Drug ..............................................................................................................44 
6.2 
Placebo .....................................................................................................................................44 
6.3 
Concomitant Medications .........................................................................................................44 
6.3.1 
Pain Medications ......................................................................................................44 
6.3.2 
Restrictions on Prior and Concomitant Medications ...............................................45 
6.4 
Other Restrictions .....................................................................................................................45 
7 
Study Drug Administration and Management ...................................................................................47 
7.1 
Packaging, Labeling, and Storage ............................................................................................47 
7.2 
Randomization and Blinding ....................................................................................................47 
7.3 
Administration ..........................................................................................................................48 
7.4 
Dose Modification ....................................................................................................................48 
7.5 
Study Drug Accountability .......................................................................................................49 
7.6 
Assessment of Subject Compliance .........................................................................................49 
8 
Study Procedures and Assessments ...................................................................................................49 
8.1 
Overview of Study Procedures .................................................................................................49 
8.2 
MRI Sedation Screening ..........................................................................................................50 
8.3 
Efficacy Assessments ...............................................................................................................50 
8.3.1 
Assessment of Osteochondroma Number and Volume by Whole Body MRI ........50 
8.3.2 
Assessment of Joint Deformity by Radiograph .......................................................51 
8.3.3 
Surgeries Related to Multiple Osteochondromas ....................................................51 
8.3.4 
Functional Limitations .............................................................................................52 
8.3.5 
The Pediatric Quality of Life Inventory ...................................................................52 
8.3.6 
Pain Interference ......................................................................................................52 
8.3.7 
Pain Intensity ...........................................................................................................53 
8.4 
Safety Assessments ..................................................................................................................53 
8.4.1 
Medical History .......................................................................................................53 
8.4.2 
Physical Examination ...............................................................................................53 
8.4.3 
Body Weight ............................................................................................................53 
8.4.4 
Vital Signs ................................................................................................................53 
8.4.5 
Electrocardiograms ..................................................................................................53 
8.4.6 
Clinical Laboratory Tests .........................................................................................54 
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8.4.7 
Pregnancy Testing ....................................................................................................55 
8.4.8 
Adverse Events ........................................................................................................56 
8.5 
Special Safety Assessments ......................................................................................................56 
8.5.1 
Bone Safety Management Plan ................................................................................56 
8.5.2 
Knee and Hand/Wrist Radiographs for Bone Age ...................................................56 
8.5.3 
Bone Densitometry ..................................................................................................57 
8.5.4 
Growth Assessment .................................................................................................57 
8.5.5 
Bone Lengths ...........................................................................................................58 
8.5.6 
Osteonecrosis ...........................................................................................................58 
8.5.7 
Tanner Staging .........................................................................................................58 
8.5.8 
Mucocutaneous Effects ............................................................................................58 
8.5.9 
Columbia-Suicide Severity Rating Scale .................................................................59 
8.5.10 
Serum Lipids ............................................................................................................59 
8.5.11 
Liver Enzymes .........................................................................................................59 
8.5.12 
Lipase/Amylase ........................................................................................................60 
8.5.13 
Central Nervous System ..........................................................................................60 
8.5.14 
Hearing and Visual Disturbances .............................................................................60 
8.5.15 
Teratogenicity ..........................................................................................................61 
8.6 
Pharmacokinetics ......................................................................................................................61 
8.7 
Palatability of Sprinkled Drug Product ....................................................................................62 
9 
Data Collection, Management, and Quality Assurance .....................................................................62 
9.1 
Data Capture and Management ................................................................................................62 
9.2 
Data Quality Assurance ............................................................................................................62 
10 
Statistical Considerations ...................................................................................................................63 
10.1 Sample Size Determination ......................................................................................................63 
10.2 Disposition of Subjects .............................................................................................................63 
10.3 Analysis Populations ................................................................................................................63 
10.4 Statistical Methods ...................................................................................................................64 
10.4.1 
Extent of Exposure ...................................................................................................64 
10.4.2 
Analyses of Efficacy Endpoints ...............................................................................64 
10.4.2.1 Primary Efficacy Analysis .......................................................................................64 
10.4.2.2 Secondary Efficacy Analyses ..................................................................................65 
10.4.3 
Analyses of Safety Data ...........................................................................................65 
10.4.3.1 Adverse Events ........................................................................................................65 
10.4.3.2 Special Safety Assessments .....................................................................................66 
10.4.3.3 Clinical Laboratory and Other Safety Findings .......................................................66 
10.4.4 
Pharmacokinetics Analysis ......................................................................................66 
10.5 Interim Analysis .......................................................................................................................66 
11 
Monitoring and Reporting ..................................................................................................................67 
11.1 Good Clinical Practice Monitoring ..........................................................................................67 
11.2 Safety Monitoring and Reporting .............................................................................................67 
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11.2.1 
Adverse Event Definition ........................................................................................67 
11.2.2 
Serious Adverse Event or Adverse Drug Reaction Definition ................................68 
11.2.3 
Severity of Adverse Events ......................................................................................68 
11.2.4 
Causality Assessment ...............................................................................................68 
11.2.5 
Action Taken with Study Drug ................................................................................69 
11.2.6 
Outcome of Adverse Event ......................................................................................69 
11.2.7 
Adverse Event Documentation ................................................................................69 
11.2.8 
Reporting of Serious Adverse Events ......................................................................70 
11.2.9 
Reporting of Pregnancy ...........................................................................................70 
11.2.10 
Follow-up of Adverse Events and Serious Adverse Events ....................................70 
11.2.11 
Reporting Concomitant Medications .......................................................................71 
11.3 Data Monitoring Committee ....................................................................................................71 
12 
Ethical, Regulatory, and Administrative Requirements .....................................................................71 
12.1 Ethical Conduct of the Study ....................................................................................................71 
12.2 Ethics Board Approval .............................................................................................................71 
12.3 Informed Consent Procedures ..................................................................................................72 
12.4 Subject Confidentiality .............................................................................................................73 
12.5 Publications and Clinical Data Reporting ................................................................................73 
12.6 Administrative Requirements ...................................................................................................74 
12.6.1 
Amendments to the Protocol ....................................................................................74 
12.6.2 
Protocol Deviations ..................................................................................................74 
12.6.3 
Retention of Subject Records and Study Files .........................................................74 
12.7 Liability and Insurance .............................................................................................................74 
13 
Investigator Agreement ......................................................................................................................75 
14 
References ..........................................................................................................................................76 
15 
Appendices .........................................................................................................................................81 
Appendix 1 
CYP450-3A4 Inducers or Inhibitors: Exclusionary Medications ..........................81 
Appendix 2 
Pediatric Quality of Life Inventory ........................................................................82 
Appendix 3 
PROMIS Pain Interference Scales ..........................................................................90 
Appendix 4 
The Faces Pain Scale – Revised .............................................................................92 
Appendix 5 
Retinoid-Specific Adverse Events Assessed by CTCAE Severity Criteria ...........93 
Appendix 6 
Columbia-Suicide Severity Rating Scale ...............................................................94 
Appendix 7 
Five-point Hedonic Face Scale .............................................................................106 
Appendix 8 
Declaration of Helsinki .........................................................................................107 
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PROPRIETARY AND CONFIDENTIAL 
 
List of Tables 
Table 1.   
Schedule of Assessments ...................................................................................................13 
Table 2.  
American Society of Anesthesiologists Physical Status Classification .............................30 
Table 3.  
Estimated Yearly Radiation Exposure ...............................................................................31 
Table 4.  
Predicted Pharmacokinetic Parameters in the Pediatric Population Using a Weight-
Based Dosage Regimen .....................................................................................................38 
Table 5.  
Observed Pharmacokinetic Parameters in the Pediatric Population With a 
Weight-based Dosing Regimen .........................................................................................38 
Table 6.  
Weight-Adjusted Palovarotene Doses for Skeletally Immature Subjects ..........................48 
Table 7. 
Clinical Laboratory Parameters .........................................................................................55 
List of Figures 
Figure 1.  
Study Design Schematic Highlighting Key Milestones .....................................................34 
Figure 2.   
Dose Response of Palovarotene to Inhibit OC Formation in Fsp1-Ext1CKO Mice ............36 
Figure 3. 
Chemical Structure of Palovarotene ..................................................................................44 
 
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PROPRIETARY AND CONFIDENTIAL 
 
List of Abbreviations 
Abbreviation 
Expanded Form 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ASA-PS 
American Society of Anesthesiologists Physical Status 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-24h 
area under the plasma concentration-time curve over 24 hours 
BEIR 
biologic effects of ionizing radiation 
BMD 
bone mineral density 
BMP 
bone morphogenetic protein 
CFR 
Code of Federal Regulations 
Cmax 
maximum or peak measured plasma concentration 
COPD 
chronic obstructive pulmonary disease 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
CYP450 isoform 
DMC 
Data Monitoring Committee 
DXA 
dual x-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ED50 
dose at half-maximum response 
EOT 
end-of-treatment 
EU 
European Union 
Ext 
exostosin gene 
FAS 
Full Analysis Set 
FDA 
United Sates Food and Drug Administration 
FGF 
fibroblast growth factor 
FOCBP 
female of child-bearing potential 
FOP 
fibrodysplasia ossificans progressiva 
FPS-R 
Faces Pain Scale – Revised 
Fsp1-Ext1CKO 
fibroblast-specific protein 1 conditional Ext1 knockout 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
HDL 
high-density lipoprotein 
HO 
heterotopic ossification 
HS 
heparan sulphate 
HNSTD 
highest non-severely toxic dose 
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List of Abbreviations 
Abbreviation 
Expanded Form 
HSPG 
heparan sulphate proteoglycans 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IOR 
Instituto Orthopedico Rizzoli 
IRB 
Institutional Review Board 
LDL 
low-density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MO 
multiple osteochondromas 
MRI 
magnetic resonance imaging 
OC 
osteochondroma 
OMIM 
Online Mendelian Inheritance in Man 
PCS 
potentially clinically significant 
PedsQL 
Pediatric Quality of Life Inventory 
PG 
proteoglycans 
PP 
Per Protocol Set 
PS 
Pharmacokinetic Set 
PROMIS 
Patient Reported Outcomes Measurement Information System 
QD 
once daily 
RAR 
retinoic acid receptor 
RARγ 
retinoic acid receptor gamma 
REM 
Registry for Multiple Exostoses 
ROM 
range of motion 
SS 
Safety Set 
SD 
standard deviation 
SOP 
standard operating procedure 
ULN 
upper limit of normal 
US 
United States 
VLDL 
very low-density lipoprotein 
 
 
 
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1 
Introduction 
1.1 
Multiple Osteochondromas 
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, with almost complete penetrance (>95%).  About 10% of 
individuals with MO have de novo mutations.  Although rare, with prevalence estimated at 1 per 
50,000 population in the United States (US) and Europe, MO is among the most common 
inherited skeletal disorders.1–3 
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).3–5  
Osteochondromas are caused by dysplasia in the periphery of the growth plate due to a 
disruption in chondrocyte maturation and perichondral bone formation.6  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.4  Thus, MO is a disease that 
manifests exclusively in children, with a mean age at diagnosis/onset of about 4 years.1,7 
Patients with MO have considerable variability in the number of anatomical sites with OCs.  An 
analyses of registry data from 529 European-based pediatric and adult patients with MO showed 
62% had from 5-20 OCs and 19% had more than 20 OCs.8  In most patients, OCs involve the 
hands, proximal humerus, distal radius and ulna, distal femur, and the proximal and distal tibia 
and fibula.  Less common sites include the proximal femur the vertebrae, talus, clavicle, 
navicular bone, proximal radius, and pubis.1,9  The development and growth of OCs often result 
in a broad range of skeletal sequelae.  About two-thirds of patients with MO experience 
orthopedic complications such as limb-length discrepancies, restricted range of motion, varus 
and valgus deformities, short stature, spinal stenosis, and scoliosis.4,5,9  The severity of the 
sequelae varies considerably, from patients with few OCs experiencing minimal restrictions in 
joint range of motion, minimal deformities, and no pain; to those with severe physical disabilities 
and pain.1,2,8   
With the high incidence of OCs near joints, impaired articular function is a common reason for 
restricted movement and physical dysfunction affecting patients’ quality of life and social well-
being.  Positive correlations are observed between the number of OCs, disease severity, and 
number of surgeries, with the latter negatively correlated with quality of life.8,10  Yet excisions 
are common—a US-based analysis of medical records reported 66% of patients with MO having 
at least one operation to remove OCs.9  
Pain is another prominent clinical feature of MO that has a pervasive effect on quality of life.  In 
a national cohort study of 283 patients with MO in the Netherlands (including 99 children with a 
mean age of 9 years), pain was present in 76% of cases.2  In children, pain affected sleep, and 
was exacerbated by walking, cycling, sports, playing, and lifting objects.  Additionally, MO 
resulted in functional limitations in school, such as difficulty with (or withdrawal from) sports, 
and problems with writing and the use of computers.  Difficulties associated with MO persisted 
into adulthood and continued after the growth of OCs had ceased.  Adults reported cessation of 
sporting activities, and some either needed to change their occupation or were medically unfit to 
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work.  A similar study of Italian subjects found that 46% of adults and 27% of children were 
unable to participate in sports activity due to MO.10 
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.4,11  Thus, there is a significant unmet medical need 
for a medicinal therapy to prevent the formation and growth of OCs. 
1.2 
The Exostosin Gene Mutation 
Exostosin 1 and 2 genes encode for glycosyltransferases that catalyze the biosynthesis of linear 
heparan sulphate (HS) chains on specific proteoglycans (PGs).  Both Ext1 and Ext2 genes are 
needed for HS synthesis, as the proteins form multimeric complexes in the Golgi.  
Loss-of-function mutations in either Ext1 (on chromosome 8q23-24) or Ext2 (on chromosome 
11p11-p12) cause premature termination of Ext proteins, which leads to disrupted interactions 
and lower enzymatic activity resulting in the production of short HS chains and reduced 
production of HSPGs.6,12   
The HS chains of HSPGs affect several signaling proteins critical to skeletal development, such 
as Indian Hedgehog, fibroblast growth factor (FGF), Wnt, and bone morphogenetic protein 
(BMP).  The HSPGs function as co-receptors for some of these proteins, but can also influence 
their distribution, stability, and action on target cells.13  The pathogenesis of MO is thought to 
result from a deficiency of HS and HSPG production resulting from Ext mutations, causing 
dysregulation of factors such as Indian Hedgehog and FGF, and increased BMP bioactivity with 
increased pSmad1/5/8 signaling.  Increased local BMP expression leads to the differentiation of 
perichondrial chondrocytes to hypertrophic chondrocytes, which ultimately results in the growth 
of OCs oriented 90 degrees from the growth plate.6,11 
1.3 
 
Overview of Palovarotene 
Palovarotene is 4-[(E)-2-(5,5,8,8-tetramethyl-3-pyrazol-1-ylmethyl-5,6,7,8-tetrahydro-
naphthalen-2-yl)-vinyl]-benzoic acid, an orally bioavailable retinoic acid receptor gamma 
(RARγ) selective agonist.  Palovarotene was in-licensed from Roche Pharmaceuticals (Roche) 
following the completion of Phase 2 studies in subjects with chronic obstructive pulmonary 
disease (COPD); this program was discontinued due to lack of efficacy and is being developed 
by Clementia Pharmaceuticals Inc. for the treatment of fibrodysplasia ossificans progressiva 
(FOP) and MO.  In a MO mouse model, palovarotene potently inhibits OC formation by 
decreasing BMP signaling through the overall reduction in the abundance of phosphorylated 
Smads (pSmad1/5/8) (data on file).  
1.3.1 
Nonclinical Data 
The toxicology of palovarotene was extensively characterized in rodent and non-rodent studies, 
including single-dose, repeat-dose (sub-chronic and chronic), reproductive toxicity, genotoxicity, 
and phototoxicity studies in support of clinical studies in humans.  Toxicity studies of four 
metabolites of palovarotene were also performed.  A juvenile toxicology program included a 
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3-week dose range-finding study and a 6-week Good Laboratory Practice (GLP) toxicology 
study in juvenile rats.  
The GLP juvenile rat toxicology results mirror the toxicity profile of palovarotene observed in 
older rats, where effects occur primarily in the skeleton and skin.  The skeletal effects of 
palovarotene in 3-week postpartum juvenile rats (corresponding to a human age of >2 years) 
included decreased bone growth with effects on bone size, shape, and density; and on growth in 
general, with some evidence of reversibility at 0.5 mg/kg/day.  Changes in bone mass and 
geometry were considered related to the effect on skeletal growth and development and not 
directly related to an effect on bone tissue mineral density, as only bone mineral density (BMD) 
evaluated by dual x-ray absorptiometry (DXA) was affected, not BMD evaluated by peripheral 
quantitative computed tomography.  As an areal BMD assessment, BMD per DXA was 
influenced by the size of the bone.   
The effects observed in the high-dose group (1.2 mg/kg/day) were more severe and more 
widespread, including growth plate abnormalities, small bone size and abnormal shape, and 
avascular necrosis (AVN) of the hip.  Notably, there were no clinical observations observed in 
this dose group except that the animals were small for their age.  Skeletal effects were limited in 
that they were mild and showed evidence of reversibility when dosing was stopped.  The 
predicted exposures of the highest weight-based equivalent daily doses of 5.0 mg to be used in 
Study PVO-2A-201 are expected to be below the systemic exposure in juvenile rats at 0.5 
mg/kg/day (AUC0-24h, 855 h•ng/mL after first dose, 365 h•ng/mL after last dose). 
A detailed summary of these studies and the observed effects is provided in the Investigator’s 
Brochure. 
1.3.2 
Primary Pharmacology 
A study using a fibroblast-specific protein 1 (Fsp1) conditional Ext1 knockout (Fsp1-Ext1CKO) 
mouse model of MO evaluated the efficacy of orally administered palovarotene for preventing 
OCs.14  This novel model, based on Ext1 ablation targeted to the perichondrium, develops bony 
protrusions by 4 weeks of age in bones of the limbs, ribs, and vertebrae consistent with the 
histological features of OCs in humans, and displays rib cage deformity and swelling of the 
chondro-osseous junction consistent with the clinical features of MO. 
Fsp1-Ext1CKO mice received three doses of palovarotene (low dose, 0.269 mg/kg; mid dose, 
0.882 mg/kg; high dose, 1.764 mg/kg) for 28 consecutive days starting at Day 14 postpartum 
(P14 cohort), or for 21 consecutive days starting at Day 21 postpartum (P21 cohort).  At the end 
of treatment (Day 42 postpartum), whole-mount skeletal preparations were prepared from each 
animal, in which OCs were identified and counted on the ribs and long bones under a dissection 
microscope.  The data demonstrated that palovarotene treatment had a statistically significant 
(p<0.0001) effect on the inhibition of OC formation in a dose dependent manner compared with 
vehicle controls at all doses and at all starting ages.  Greater efficacy was observed with earlier 
and longer dosing in the P14 cohort compared with the P21 cohort (see Section 4.3.2.1).  
Examination of the whole-mount skeletal preparations also revealed that swelling of the 
chondro-osseous junction at the rib bones and the deformity of the rib cage were considerably 
reduced with palovarotene daily treatment. 
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1.3.3 
Palovarotene Safety  
The initial human experience with palovarotene was based on ten completed clinical 
pharmacology studies in healthy subjects, three multiple dose-ranging studies in subjects with 
COPD/emphysema, and two Phase 2 studies in subjects with COPD.  Across these studies, over 
800 subjects received at least one dose of palovarotene, with 91 healthy volunteers receiving one 
or two doses between 0.02 and 50 mg; 124 healthy volunteers receiving multiple doses between 
0.02 and 10 mg for up to 4 weeks; and 611 subjects with COPD receiving multiple doses 
between 0.2 and 5 mg daily for up to 24 months.  Additional human experience is from the 
clinical development program in FOP, including one pharmacokinetic (ethnobridging) study in 
Japanese and non-Asian healthy volunteers and two Phase 2 studies that evaluated four 
palovarotene dosage regimens: 
• Episodic flare-up based treatment 
o 5 mg once daily for 14 days followed by 2.5 mg once daily for 28 days 
(5/2.5-mg regimen in Study PVO-1A-201) 
o 10 mg once daily for 14 days followed by 5 mg once daily for 28 days 
(10/5-mg regimen in Studies PVO-1A-201 and PVO-1A-202/Part A) 
o 20 mg once daily for 28 days followed by 10 mg once daily for 56 days 
(20/10-mg regimen in Study PVO-1A-202/Part B)  
• Chronic/flare-up based treatment with 5 mg daily doses and the 20/10-mg regimen at the 
time of a flare-up (chronic/episodic 20/10-mg regimen in Study PVO-1A-202/Parts B 
and C).   
Note that Study PVO-1A-202 includes data from Study PVO-1A-204 in France. 
The adverse effects of systemic retinoids are well described in the literature.15  The most 
common are mucocutaneous toxicities (cheilitis, dry skin, pruritus, and conjunctivitis), 
ophthalmologic effects (dry eyes and blepharoconjunctivitis), myalgias and arthralgias, 
neurologic effects (headache, fatigue, and lethargy), elevated triglycerides, and abnormal liver 
function tests and amylase levels.  Palovarotene is a gamma receptor selective agonist, 
contrasting with other non-selective retinoids such as all-trans retinoic acid and isotretinoin that 
target equally the alpha, beta, and gamma retinoid receptors. 
In subjects with COPD receiving 5-mg palovarotene daily for up to 24 months, the most 
frequently reported adverse events were associated with subjects’ underlying disease: COPD, 
bronchitis, upper and lower respiratory tract infection, dyspnea, cough, influenza, pneumonia, 
and infective exacerbations of COPD.  The incidence of these events was similar in the placebo 
and palovarotene groups.  
Consistent with other retinoids, palovarotene-treated subjects with COPD had a higher incidence 
of mucocutaneous and dermatologic adverse events than placebo-treated subjects.  The most 
frequently reported mucocutaneous and dermatologic events included dry skin, dry lips, pruritus, 
rash, erythema, and cheilitis.  In general, the incidence, total number, intensity, and duration of 
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mucocutaneous and dermatologic events increased with increasing palovarotene dose.  Most of 
these events were mild or moderate in severity and generally resolved without sequelae after 
completion of palovarotene treatment.  These events were primarily treated with symptomatic 
therapy including analgesics, emollients, lip moisturizers, artificial tears, and topical steroids. 
Laboratory abnormalities occurring in subjects treated with palovarotene included elevations of 
serum amylase, lipase, triglycerides, and liver enzymes.  These laboratory abnormalities were 
transient and not accompanied by clinical symptoms, except for the one healthy volunteer in the 
palovarotene/ketoconazole drug-drug interaction study who had acute pancreatitis. 
The most commonly reported adverse events across all palovarotene dosage regimens in the FOP 
interventional studies were mucocutaneous and dermatologic events such as dry skin and lips, 
erythema, and pruritus.  In general, the incidence and intensity of mucocutaneous and 
dermatologic events increased with increasing palovarotene dose.  Most of these events were 
mild or moderate in severity; the most severe were serious adverse events (SAEs).  
Musculoskeletal events such as arthralgia, pain in extremity, and condition aggravated were also 
commonly reported.  Condition aggravated is the Medical Dictionary for Regulatory Activities 
(MedDRA) preferred term used to capture reports of FOP flare-ups that are unique to the FOP 
population. 
No subjects discontinued treatment or required a dose reduction during episodic flare-up 
treatment with the 10/5-mg regimen in Studies PVO-1A-201 and PVO-1A-202/Part A.  Four 
subjects discontinued from Study PVO-1A-202/Parts B and C and two subjects discontinued 
from Study PVO-1A-301 due to adverse events. 
No emerging safety signal has been identified for clinical safety laboratory assessments or 
electrocardiograms (ECGs) in the FOP or MO studies. 
The potential effects of retinoids on bone and long bone growth are most relevant to children.  
Premature epiphyseal closure has been reported in three children receiving high-dose isotretinoin 
(between 0.5 and 3.5 mg/kg/day) long term (>4.5 years) for severe dermatologic conditions.16  
Irreversible changes have not been observed in other conditions.  For example, in a key study of 
the use of isotretinoin in children with FOP,17 patients with a median age of 14 years (range, 3 to 
21 years) received isotretinoin daily (median dose of 1.7 mg/kg; range, 0.5 to 8 mg/kg) for a 
median treatment duration of 3 years (range, 4 months to 10 years).  Seven of the patients (33%) 
developed dense metaphyseal bands (growth arrest lines) after 1 year of therapy; all bands 
disappeared after a dose reduction to 2 mg/kg/day.18 
Subjects with open epiphyses enrolled in Study PVO-2A-201 and in the Phase 2 and 3 studies 
in FOP undergo knee and hand/wrist radiographs (anterior/posterior view) for assessment of 
epiphyseal growth plate; and linear and knee height measurements for assessment of growth.  
Overall, at baseline across the FOP studies, the most common epiphyseal growth plate 
abnormality were growth recovery lines (dense metaphysical lines) and sclerosis of adjacent 
growing bone.  Subjects rarely had new or worsening post-baseline growth recovery lines and 
new sclerosis on follow-up radiographs.  Potential premature partial closure of the epiphysis is 
closely monitored, and data are reviewed quarterly by an independent Data Monitoring 
Committee (DMC). 
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There were no apparent delays in linear height or knee height. 
Further information on palovarotene is available in the Investigator’s Brochure.  
1.4 
Evaluation of Study Benefits and Risks 
1.4.1 
Risk/Benefit Justification for Age Range 
Nonclinical data from the MO mouse model (Section 1.3.2) and preliminary clinical data in FOP 
provide evidence supporting the potential therapeutic benefit of palovarotene for treating MO.  
The risks of palovarotene in pediatric subjects with MO are based on the safety profile derived 
from juvenile rat toxicology and clinical studies (Section 1.3.3).  Based on the sponsor’s 
comprehensive benefit/risk evaluation from these data, subjects to be enrolled in PVO-2A-201 
will include those from the ages of 2 to 14 years, with a genetic diagnosis of MO and evidence of 
disease progression. 
1.4.2 
Potential to Ameliorate the Condition Under Investigation 
Synthesizing the following nonclinical data in MO and nonclinical and clinical data from a 
related condition (FOP) supports the potential for palovarotene to inhibit OC growth and 
development:   
• Retinoid signaling is a strong inhibitor of chondrogenesis.19 
• Unliganded RAR transcriptional repressor activity is needed for chondrogenic 
differentiation.20,21  RARγ agonists exert their action on bone formation by suppressing 
the downstream effectors of BMP signaling, namely the phosphorylated Smads through 
the ubiquitin-proteosomal degradation pathway. 
• In vivo animal pharmacology consistently demonstrated the ability of palovarotene to 
reduce OC numbers in a dose dependent manner.  These results suggest that 
weight-adjusted daily doses equivalents to 2.5 and 5.0 mg should be effective with 
minimal skeletal adverse effects. 
• The clinical efficacy data in the FOP clinical program support the hypothesis that 
palovarotene has a beneficial effect of reducing chondrogenesis and subsequent 
endochondral ossification in FOP.  
Therefore, the benefits of palovarotene to subjects will be the potential inhibition of OC growth 
and the ensuing reduction of clinical sequelae of pain, limb deformities, and functional 
limitations.  Moreover, if palovarotene is effective in diminishing the development and growth of 
OCs, the need for surgical excision should be reduced. 
1.4.3 
Potential Risks Associated With Palovarotene 
Potential risks of palovarotene in subjects with MO were compiled from four sources: literature 
on the treatment of children with systemic nonspecific retinoids, the palovarotene juvenile 
toxicology program, palovarotene clinical safety data from over 800 adult subjects including 
200 healthy volunteers and 611 subjects with COPD, and the preliminary safety data from the 
Phase 2 studies in subjects with FOP (PVO-1A-201 and PVO-1A-202). 
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The palovarotene dosage regimen of 2.5 or 5.0 mg once daily (weight adjusted) for 24 months is 
based on animal pharmacology and nonclinical and clinical safety data.  These doses were 
chosen to evaluate palovarotene’s potential for inhibiting OC growth while minimizing risk 
(described further in Section 4.3).  Weight-based dosing will further minimize the risk of 
palovarotene by minimizing the excursions above the anticipated Cmax and AUC values in 
subjects with a lower weight.  These dosages have been well tolerated in previous and ongoing 
clinical trials in adults and children, with mucocutaneous adverse events that are manageable. 
These events were primarily treated with symptomatic therapy including analgesics, emollients, 
lip moisturizers, artificial tears, and topical steroids or, if necessary, dose de-escalation or 
discontinuation.  Current clinical safety data in pediatric subjects with FOP receiving episodic 
treatment with palovarotene, up to weight-adjusted daily dosages of 20 mg for 4 weeks and 
10 mg for 8 weeks, revealed no treatment-related effects on growth plate or linear height.   
Study PVO-2A-201 will include safety monitoring for any potential skeletal effects associated 
with growth plates, linear growth, bone mineral density (BMD), and osteonecrosis.  Monitoring 
for potential growth plate and linear growth abnormalities will be performed with hand/wrist and 
knee plain radiographs and linear and knee height measurements every 6 months; and with 
bilateral radiographic evaluations of long bone lengths (ulna, radius, tibia, fibula, and femur) 
every 12 months.  To monitor for potential effects of palovarotene on bone mineral deposition 
and BMD, DXA of the lumbar spine, hip (one side), and mid-third radius (one side) will occur 
every 6 months.  Based on skeletal abnormalities in juvenile rats, including avascular necrosis of 
the femoral head, MRI scans obtained every 12 months for the assessments of OCs will also be 
evaluated for potential osteonecrosis of the hip, shoulders, and knees. 
Based on these safety measures, the risks of palovarotene represent minor increases over 
minimal risks, can be monitored in the clinic, and are manageable.  In addition, the potential for 
a direct benefit associated with palovarotene as described is sufficient to support the inclusion of 
pediatric subjects into the clinical program despite the potential risks.   
1.4.4 
Potential Risks Associated With Study Procedures 
Risks associated with procedures in Study PVO-2A-201 include blood draws, sedation for 
magnetic resonance imaging (MRI), and radiation exposure from radiographs and DXA. 
The per-protocol clinical laboratory assessments obtained from blood sampling and blood 
pressure measurements are necessary for the safety monitoring of palovarotene.  Risks are being 
minimized by employing experienced personnel to minimize the loss of blood volume. 
Study PVO-2A-201 includes procedures such as whole body MRI and yearly radiographs to 
obtain a standardized assessment of the MO disease state.  These imaging procedures exceed the 
standard of care, which focuses only on the anatomical regions with OC symptoms.  Magnetic 
resonance imaging is the best imaging modality to evaluate the morphology and size of OCs and 
to visualize the effect of OCs on surrounding anatomical structures.22  Also, MRI can better 
image and accurately evaluate the OC cartilage cap compared with imaging with radiographs or 
computerized tomography.  This is particularly relevant to young children in whom cartilage 
comprises a greater proportion of the OC relative to the osseous component.  The use of whole 
body MRI also permits the assessment of disease processes across all anatomical regions in one 
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session without exposing pediatric subjects to radiation.22,23   Limiting radiation exposure in 
pediatric subjects is of particular importance given that the potential risk for cancer induction in 
this population is about 10 times higher than in adults.24  Consequently, MRI will be the primary 
imaging modality to assess the number and size of OCs.   
While the risks associated with MRI are minimal, obtaining evaluable images requires that 
subjects remain motionless for approximately 1 to 2 hours depending on the MRI facility.  This 
procedural risk was evaluated and mitigated in accordance with recommendations by the 
Pediatric Ethics Subcommittee on sedation for non-therapeutic procedures.25  The MRI 
acquisition parameters in Study PVO-2A-201 were developed in consultation with pediatric MRI 
radiologists with expertise in MO and have been previously tested in children.  Clinical sites 
have well-established pediatric medical facilities with a dedicated pediatric MRI imaging service 
and procedural sedation teams.   
The ability of young children under 7 years of age to undergo non-sedated MRI is highly 
variable.  To determine the depth of sedation necessary for MRI acquisition and the ability of 
these subjects to undergo sedation, a pediatric sedation team will perform screening based on, 
but not limited to, age, gender, the American Society of Anesthesiologists (ASA) Physical Status 
(PS) class (Table 2), and comorbidities.  
Table 2.  
American Society of Anesthesiologists Physical Status Classification 
Class I 
A normally healthy patient 
Class II 
A patient with mild systemic disease (eg, controlled reactive airway disease) 
Class III 
A patient with severe systemic disease (eg, a child who is actively wheezing) 
Class IV 
A patient with severe systemic disease that is a constant threat to life  
(eg, a child with status asthmaticus) 
Class V 
A moribund patient who is not expected to survive without the operation  
(eg, a patient with severe cardiomyopathy requiring heart transplantation) 
Table from reference.26 
When procedural sedation is required, sedation should not exceed the level that is absolutely 
required to successfully perform the MRI acquisition.  Procedural sedation for MRI will adhere 
to the standard practice of the clinical site, which may include general anesthesia as this provides 
a well-controlled environment for successful image acquisition and subject safety.27  During 
MRI acquisition, the pediatric sedation team must have close monitoring and rescue equipment 
in place to respond to any complication.  Subjects and their parents will be appraised of the 
benefits and risks of sedation for MRI as part of informed consent and child assent.  Under these 
circumstances and risk mitigation, the procedural sedation for MRI can be considered a minor 
increase over a minimal risk per criteria described by the Pediatrics Ethics Subcommittee of the 
FDA Pediatric Advisory Committee.28,29  
To ensure consistent assessment of joint deformities, radiographs of both forearms and lower 
extremities will be obtained at baseline and every 12 months.  Because joint deformities are 
common clinical sequelae of OCs, yearly radiographic assessment of deformed/affected limbs 
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are considered standard of care, and necessary for evaluation and treatment decisions.  The 
evaluation of a wide range of MO-related deformities, from potentially unaffected joints to major 
deformities, is necessary to standardized assessments across the broad spectrum of deformities 
that occur with MO.   
The radiation exposure in Study PVO-2A-201 is dependent on age-related radiosensitivity.  
Considering the scaling factors for the relative sensitivity,30 the estimated yearly total exposures 
for subjects are as in Table 3. 
Table 3.  
Estimated Yearly Radiation Exposure 
Age Range 
(Years) 
Cumulative for 
Study (mSv) 
Annual Exposure 
(mSv) 
2-7 
3.78 
1.89 
8-12 
3.30 
1.65 
13-17 
2.65 
1.33 
One additional set of DXA and growth plate assessments will be performed in 
subjects who do not participate in the open-label extension study. These 
assessments will be performed 6 months after the end-of-treatment and will 
increase the cumulative radiation exposure slightly from 0.04 to 0.07 mSv, 
depending on the age of the subject. 
These exposures are below the annual background radiation of 3 mSv and below the 5-mSv per 
year value recommended by the US Food and Drug Administration (FDA) (dated 02 February 
2015), based on US 21 CFR 361.1.31  The sponsor recognizes that subjects will undergo several 
radiographic examinations throughout their lifetime and have elevated cumulative radiation 
exposure compared with unaffected children.  However, should palovarotene be effective the risk 
of deformities would be reduced, and consequently the need for future radiographs. 
Exposure above the average annual background radiation levels of 3 mSv has the potential to 
increase the risk of malignancy in later life.  The Biologic Effects of Ionizing Radiation (BEIR) 
VII report defines low doses of radiation ranging from 0 to 100 mSv;32 and that a linear, 
no-threshold, dose-response relationship between exposure and subsequent cancer represents the 
best model to estimate risk.  On average, assuming a sex and age distribution similar to that of 
the entire US population, the BEIR VII lifetime risk model predicts that approximately one in 
100 individuals would develop cancer (solid cancer or leukemia) from a dose of 100 mSv, while 
approximately 42 of 100 individuals would develop solid cancer or leukemia from other causes.  
Lower radiation doses would produce proportionally lower risks.  For example, it is predicted 
that approximately one in 1000 individuals would develop cancer from exposure to 10 mSv, 
although statistical limitations make it difficult to evaluate cancer risk in humans at doses less 
than 100 mSv. 
Study PVO-2A-201 is designed to minimize radiation exposure in subjects, while maintaining 
the ability to assess palovarotene’s potential treatment benefit (preventing OC growth and 
subsequent deformities) and its potential adverse effects on growth plates.  By incorporating 
MRI and limiting radiographs for deformity assessments to 12-month intervals, it is proposed 
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that the potential radiation exposure resulting from participation in this study is acceptable and 
represents a minimal risk. 
2 
Study Objectives 
2.1 
Primary Objective 
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. 
2.2 
Secondary Objectives 
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. 
2.3 
Exploratory Objectives 
The effect of palovarotene versus placebo on the change in volume of OC cartilage caps as 
assessed by MRI, the annualized rates of new functional limitations, pain due to OCs, pain 
interference on daily activities, and quality of life are exploratory objectives.   
3 
Study Endpoints 
3.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint will compare palovarotene with placebo on the annualized rate of 
new OCs as assessed by whole body MRI. 
3.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints will compare palovarotene with placebo on the following: 
• The change from baseline in the total volume of OCs as assessed by whole body MRI at 
Months 12 and 24. 
• The proportion of subjects with no new OCs as assessed by whole body MRI at Months 
12 and 24. 
• The annualized rate of new or worsening deformities as assessed by radiographic imaging 
of both upper and lower limbs. 
• The annualized rate of MO-related surgeries.  Surgeries include any procedure indicated 
for the treatment of MO, such as an excision of a symptomatic OC or correction of a limb 
deformity. 
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PROPRIETARY AND CONFIDENTIAL 
 
3.3 
Pharmacokinetic Endpoint 
This study will evaluate the pharmacokinetics of palovarotene at steady-state.  
3.4 
Palatability Endpoint 
This study will evaluate the palatability of drug product versus placebo when sprinkled onto 
specific foods following the administration of the first dose (Day 1) and at Month 1 (to coincide 
with pharmacokinetic assessments). 
3.5 
Exploratory Efficacy Endpoints 
Exploratory endpoints will compare measures of joint function, pain, and quality of life across 
palovarotene and placebo treatment groups as follows: 
• The change from baseline in the total volume of cartilage cap of OCs as assessed by 
whole body MRI at Months 12 and 24. 
• The annualized rate of new or worsening functional limitations.  Functional limitations 
are defined as restrictions in joint range of motion. 
• The effect of pain on daily activities, as assessed with the Patient-Reported Outcomes 
Measurement Information System (PROMIS) pain interference pediatric item bank at 
Months 6, 12, 18, and 24. 
• Pain intensity, as assessed with the Faces Pain Scale – Revised (FPS-R) at Months 6, 12, 
18, and 24. 
• Quality of life, as assessed with the Pediatric Quality of Life Inventory (PedsQL, 
version 4.0) at Months 6, 12, 18, and 24. 
Further details on secondary and exploratory endpoints are provided in Section 8.3. 
3.6 
Safety Endpoints 
The following safety endpoints will be evaluated over 24 months of treatment: 
• The incidence and severity of adverse events at all time points. 
• The incidence and severity of adverse events known to be associated with retinoids 
(eg, mucocutaneous events) at all time points. 
• Electrocardiograms, vital sign measurements (temperature, respiratory rate, blood 
pressure, and heart rate), physical examination, body weight, and laboratory parameters 
(hematology, biochemistry, and urinalysis). 
• Growth will be assessed by 
o Height and knee height measures. 
o Growth plate assessments. 
• Ulnar, radial, tibial, fibular, and femoral lengths by radiograph. 
• Bone mineral density at lumbar spine, hip, and mid radius as assessed by DXA.  
33


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4.1
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34


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CLEMENTIA PHARMACEUTICALS INC. 
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PROPRIETARY AND CONFIDENTIAL 
 
program were deemed favorable by the independent DMC.  On 28 January 2019, a favorable 
decision by the DMC permitted enrollment of subjects from 2 to 14 years of age in the EU. 
Subjects will follow all procedures and undergo all assessments as specified in the Schedule of 
Assessments in Table 1.  Details on the primary and secondary assessments of efficacy and the 
assessment of safety are provided in Section 8.  At the end of the study, subjects may be eligible 
for participation in an open-label extension study (PVO-2A-202).  
4.2 
Study Rationale 
In MO, the ability of palovarotene to prevent OC formation is supported by a novel 
Fsp1-Ext1CKO mouse model of MO (Section 1.3.2), which demonstrated a dose-dependent 
inhibition of OC development.  If results in Fsp1-Ext1CKO mice translate to humans, it is 
reasonable to expect that palovarotene will provide a significant therapeutic benefit in pediatric 
patients by preventing OCs and their debilitating sequelae.  Based on the dose-exposure 
response, daily doses of 2.5 and 5.0 mg are anticipated to provide maximal efficacy with a safe 
and tolerable profile. 
In addition to MO, Clementia is developing palovarotene for the proposed indication of the 
treatment of FOP.  Fibrodysplasia ossificans progressiva (OMIM #135100) is an ultra-rare and 
serious life-threatening disease characterized by painful, recurrent episodes of soft tissue 
swelling (flare-ups) and extraskeletal bone formation, known as heterotopic ossification (HO), in 
muscles, tendons, and ligaments.  Multiple osteochondromas and FOP share the pathogenic 
process of excess BMP signaling resulting in chondrogenesis and ensuing endochondral 
ossification.  Thus, the efficacy of palovarotene in treating FOP provides further insight as to the 
clinical utility of palovarotene in inhibiting OC formation in subjects with MO. 
Preliminary data from the Phase 2 FOP program from 103 prospectively assessed flare-ups 
demonstrate that palovarotene prevents HO formation.  Compared with placebo/untreated flare-
ups, the palovarotene 10/5-mg episodic regimen (described in Section 1.3.3) reduced the 
proportion of flare-ups with new HO by 45%; and decreased the volume of new HO at the flare-
up location by 75%.  There was a 65% reduction in the proportion of flare-ups with new HO and 
a 98% reduction in new HO volume in flare-ups treated with the palovarotene chronic/flare-up 
20/10-mg regimen compared with placebo/untreated flare-ups.  Additional details of efficacy in 
the FOP program are provided in the Investigator’s Brochure. 
Study PVO-2A-201 is intended to support the indication of palovarotene for the treatment of 
MO. 
4.3 
Dosage Rationale 
The dosage rationale for Study PVO-2A-201 is based on a synthesis of nonclinical efficacy and 
safety data, predicted exposure from weight-adjusted doses of palovarotene, preliminary 
pharmacokinetic data from subjects with FOP, and clinical safety data from subjects with COPD 
and FOP.  The following sections summarize the relevance of each component underlying the 
rationale for using weight-adjusted doses of 2.5 or 5.0 mg palovarotene once daily during the 
24-month treatment period. 
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4.3.1 
Nonclinical Efficacy Data 
Efficacious exposures of palovarotene for the treatment of MO are based on data from 
Fsp1-Ext1CKO mice, in which a P14 cohort received 4 weeks of dosing starting at 14 days 
postpartum and a P21 cohort received 3 weeks of dosing starting at 21 days postpartum (see 
Section 1.3.2).   
As no pharmacokinetic data were available from Fsp1-Ext1CKO mice, drug exposure (area under 
the concentration-time curve from 0 to 24 hours, AUC0-24h) was extrapolated from 
pharmacokinetic data in adult wild-type mice, with the assumption that the pharmacokinetics of 
palovarotene in these mice were similar to juvenile Fsp1-Ext1CKO mice.   
A single palovarotene dose at 1 mg/kg in adult mice resulted in an average AUC0-24h of 
292 ng•h/mL.  The extrapolated AUC0-24h for the palovarotene doses were 79 ng•h/mL for the 
low dose, 258 ng•h/mL for the mid dose, and 515 ng•h/mL for the high dose.  The percentage 
decrease in total OC numbers at rib and limb bones are presented as a function of the 
extrapolated exposure in Figure 2; the AUC0-24h at the dose at half-maximum response (ED50) is 
57-60 ng•h/mL for the P14 cohort and 125-173 ng•h/mL for the P21 cohort. 
Figure 2.   Dose Response of Palovarotene to Inhibit OC Formation in Fsp1-Ext1CKO Mice 
 
Cohort 
ED50 
(ng•h/mL) 
 
Cohort 
ED50 
(ng•h/mL) 
4w P14 
60 
 
4w P14 
57 
3w P21 
173 
 
3w P21 
125 
4w P14, 4 weeks of dosing starting at 14 days postpartum; 3w P21, 3 weeks of 
dosing starting at 21 days postpartum; ED50, dose at half-maximum response; OCs, 
osteochondromas. 
4.3.2 
Nonclinical Safety Data 
4.3.2.1 The Fsp1-Ext1CKO Mouse Model of Multiple Osteochondromas (Non-GLP Study) 
In the previously described Fsp1-Ext1CKO mouse model of MO (Sections 1.3.2 and 4.3.1) bone 
lengths were assessed at the end of treatment to determine the effect of palovarotene on bone 
growth.  In the P14 cohort, limb lengths were reduced at mid and high doses of palovarotene 
from 3% to 22%, with most reductions from 12% to 18%.  No reductions were observed with the 
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palovarotene low-dose group.  Moreover, no reduction was noted at any dose in the P21 cohort, 
suggesting that potential skeletal effects are dose and age dependent. 
4.3.2.2 Nonclinical Juvenile Toxicity Study 
In juvenile rats, the threshold for dose-limiting skeletal toxicity increased with age, and the 
skeletal effects of palovarotene showed evidence of reversing after dosing was stopped at 
0.5 mg/kg/day, which was designated as the highest non-severely toxic dose (HNSTD).  The 
systemic exposure (ie, AUC0-24h) in juvenile rats at 0.5 mg/kg/day was 855 ng•h/mL after the 
first dose and 365 ng•h/mL after the last dose. 
4.3.3 
Clinical Data 
4.3.3.1 Clinical Safety Data in COPD 
Palovarotene has been administered to over 800 adult subjects, including over 200 healthy 
volunteers and 611 subjects with COPD, with 450 subjects with COPD receiving daily dosing of 
5.0 mg palovarotene for up to 24 months.  Adverse events associated with the use of 
palovarotene were dose-related, similar to those reported for other retinoids, and primarily 
related to mucocutaneous events (eg, rash, dry skin, cheilitis).  At daily dosing of 5.0 mg, 16.8% 
of palovarotene recipients discontinued due to adverse events versus 9.5% of placebo recipients.  
4.3.3.2 Clinical Safety Data in FOP 
Per safety data available at the time of study design, most adverse events in subjects with FOP 
treated with palovarotene were associated with systemic retinoids, were mild or moderate in 
severity, and similar to adverse events observed in subjects with COPD.  Updated safety data 
from FOP studies are provided in Investigator’s Brochure (Section 6.4.2). 
4.3.3.3 Predicted Exposure to Palovarotene 
A pharmacokinetic analysis was performed to determine the appropriate weight-adjusted doses 
for pediatric subjects to provide similar exposure as adults (ie, ≥60 to 80 kg) receiving either 
2.5 or 5.0 mg palovarotene daily.  The analysis was based on the pharmacokinetic data from two 
single-dose studies and five multiple-dose studies, which collectively included 137 healthy 
volunteers who received at least one dose of palovarotene.  The AUC and maximum plasma 
concentration (Cmax) predictions for body weight are summarized in Table 4.  Weight-based 
regimens provided exposures across the different weight categories ranging from 85 to 
147 ng•h/mL for the 2.5-mg equivalent doses and 211 to 294 ng•h/mL for the 5.0-mg equivalent 
doses. 
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Table 4.  
Predicted Pharmacokinetic Parameters in the Pediatric Population Using 
a Weight-Based Dosage Regimen 
 
 
2.5-mg Equivalent 
 
5.0-mg Equivalent 
Weight Category  
10 to  
<20 kg 
>20 to  
40 kg 
>40 to  
60 kg 
≥60 to  
80 kg 
 
10 to  
<20 kg 
>20 to  
40 kg 
>40 to 
 60 kg 
≥60 to  
80 kg 
Actual dose, mg 
 
1.0 
1.5 
2.0 
2.5 
 
2.5 
3.0 
4.0 
5.0 
AUC0-24h, h•ng/mL 
 
85-91 
107-126 118-143 115-147  211-227 214-252 235-285 231-294 
Cmax, ng/mL 
 
14-15 
18-21 
20-24 
20-25 
 
34-37 
36-41 
40-48 
40-50 
AUC0-24h, area under the plasma concentration-time curve from 0 to 24 hours; Cmax, maximum plasma 
concentration. 
4.3.3.4 Observed Exposure for Weight-Based Dosing of Palovarotene 
Table 5 summarizes the mean and median AUC0-24h values for skeletally immature subjects with 
FOP receiving 2.5- and 5.0-mg equivalent daily doses of palovarotene compared with fixed 
doses in adults.  Skeletally mature subjects received fixed-dose regimens, while the skeletally 
immature subjects <18 years of age received weight-adjusted equivalent doses.  The observed 
exposures using weight-based dosing tended to be lower than fixed dosing but should be 
interpreted with caution as the number of subjects providing samples in the 2.5-mg group is low.  
These results will be updated as data become available. 
Table 5.  
Observed Pharmacokinetic Values in the Pediatric Population With a 
Weight-based Dosing Regimen 
 
Palovarotene 2.5 mg QD 
Palovarotene 5.0 mg QD 
 
Fixed Dose 
Weight-Adjusted 
Equivalent 
Fixed Dose 
Weight-Adjusted 
Equivalent 
 
(N=4) 
(N=3) 
(N=27) 
(N=141,2) 
AUC0-24h, ng•h/mL 
 
 
 
 
Mean (SD) 
177 (86) 
98 (73) 
 305 (131) 
249 (105) 
Median  
149 
78 
296 
207 
Min, max 
107, 302 
37, 179 
92, 667 
134, 448 
AUC Ratio (A/P) 
 
 
 
 
Mean (SD) 
1.2 (0.7) 
0.8 (0.6) 
 1.3 (1.1) 
1.1 (0.4) 
Median 
0.9 
0.6 
1.0 
0.9 
Min, max 
0.6, 2.2 
0.3, 1.4 
0.3, 5.8 
0.5, 1.9 
1 One 18-year-old subject (54.4 kg) was dosed using weight-based equivalent for 5 and 10 mg.  
2 One 13-year-old subject (27.9 kg) was dosed using weight-based equivalent for 5 mg.  
AUC0-24h, area under the plasma concentration-time curve from 0 to 24 hours; A/P, actual versus predicted; 
QD, once daily. 
One other parameter that is known to impact systemic exposure of palovarotene is food.  For the 
FOP clinical studies, all subjects are instructed to administer study medication at approximately 
the same time each day and following a full meal. 
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4.3.4 
Summary and Conclusions 
The dosage selection for Study PVO-2A-201 was based on the efficacy and safety data from 
Fsp1-Ext1CKO mice and juvenile toxicity.  While high-dose palovarotene resulted in a greater 
reduction of OCs in Fsp1-Ext1CKO mice, the extrapolated exposure exceeds the HNSTD 
identified in juvenile toxicology studies.  Based on the adverse skeletal effects observed in 
nonclinical models, chronic dosing targeting systemic exposures at or below 365 ng•h/mL are 
planned to minimize potential skeletal toxicity.  This exposure would provide near maximal 
effects on OC development (Figure 2; based on the flat part of the dose-response curve in the 
MO mouse model) and corresponds to a 5.0-mg dose in humans (Table 4; ≥60 to 80 kg).  The 
minimum exposure to achieve 50% efficacy based on the P21 cohort is 125-173 ng•h/mL  
(Figure 2), which corresponds approximately to the 2.5-mg dose in humans. 
Accordingly, the weight-adjusted palovarotene doses of 2.5 and 5.0 mg once daily were chosen 
to evaluate palovarotene’s potential for inhibiting OC growth while minimizing risk.  These 
doses have been well tolerated in previous and ongoing clinical studies in adults and children, 
with mucocutaneous adverse events that are manageable.  Study PVO-2A-201 will include safety 
monitoring to identify any potential skeletal effects associated with the growth plates, bone 
mineral density, and linear growth.  Modalities will include hand/wrist and knee plain 
radiographs; DXA of the lumbar spine, hip, and mid-third radius; linear and knee height 
measurements (Section 8.5); and treatment-emergent adverse event monitoring (Section 11.2). 
4.4 
Justification for Placebo Control 
The design of Study PVO-2A-201 incorporates a placebo control to provide rigorous hypothesis 
testing and unequivocal scientific data to evaluate the efficacy and safety profile of palovarotene 
in the MO patient population.  The use of placebo will, by necessity, expose some subjects to a 
treatment with no potential for direct benefit.  There is currently no biomarker or efficacy 
endpoint that is sensitive to changes in MO severity or progression over a reasonably brief 
period.  Because the development and growth of OCs are slow, concurrent with the growth of the 
subject, treatment durations from 1 to 2 years may be required to discern effects of active 
treatment on changes in the number and volume of OCs. 
To assess safety and efficacy and to potentially stop the study based on pre-specified rules, an 
interim analysis is planned when all subjects complete 12 months of treatment.  If the study was 
stopped early for success, subjects may be offered enrollment into an open-label extension study.  
The use of placebo over the 2-year treatment duration is ethically justified in this study for the 
following reasons:  
• As there is no current medical therapy for the inhibition of OC growth, subjects 
randomized to placebo are not being denied alternative or effective treatment. 
• The risk of placebo treatment is minimal.  The risk of not receiving a potential effective 
treatment is that the subject may develop pain, a joint deformity, or a functional 
limitation as part of the natural progression of MO.  As Study PVO-2A-201 is the first 
clinical study in subjects with MO, there are no clinical data demonstrating that 
palovarotene can reduce OC development and growth.  Therefore, at present, there is a 
clinical equipoise between palovarotene and placebo. 
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• All subjects will benefit from the knowledge gained about their health status through 
study assessments and frequent physician evaluation of their disease.  There may be 
greater opportunity for intervention if medically indicated. 
• The randomization ratio of 1:1:1 to 2.5- or 5.0-mg palovarotene or placebo gives subjects 
a 67% probability of being assigned active treatment. 
• All subjects who enroll in the study will remain on their current concomitant pain 
medications.  Subjects may increase pain medication if symptoms increase during the 
study or undergo surgical excision for progressive pain, a deformity, or a functional 
limitation as per the standard of care.  If subjects experience increased or persistent 
clinical disease progression, they have the option to withdraw from the study at any time.  
• Subjects participating in this study may be eligible to participate in the proposed 
open-label extension study (PVO-2A-202) in which all subjects will receive 
palovarotene. 
4.5 
Clinical Meaningfulness of the Efficacy Endpoints 
The multiplicity of symptoms associated with MO is reflected in the diversity of clinical 
measures used to determine disease severity and/or progression.  Clinical features of MO such as 
deformity, presence of dislocations, functional limitations, the number and/or location of OCs, 
the age of MO onset, reduced stature, and number of surgical procedures have been used to 
define disease severity and progression.7,12,33,34  Moreover, as no medical treatment currently 
exists for MO, there are no registrational endpoints defined for MO clinical studies.   
To derive clinically meaningful efficacy endpoints to support the marketing authorization of 
palovarotene, data from the Instituto Orthopedico Rizzoli (IOR) Registry for Multiple Exostoses 
(REM) were analyzed.  The REM is a standardized registry that includes patients from two 
different European MO referral centers coordinated by the Medical Genetics and Rare 
Orthopaedic Diseases Department and Clinical Bioinformatics Laboratory of the IOR in 
Bologna, Italy.  The rates of new OCs, functional limitations, deformities, and surgical 
procedures over time were assessed in 190 pediatric patients included in the REM.  The results 
provided guidance for the design of Study PVO-2A-201 with respect to subject eligibility, 
endpoint selection, sample size estimation, and study duration. 
Complementing the REM analysis, a review of published literature provided support for the 
clinical meaningfulness of the chosen efficacy endpoints.  The primary efficacy endpoint will 
assess the efficacy of palovarotene in terms of inhibition of new OC growth, analogous to the 
efficacy demonstrated in Fsp1-Ext1CKO mice (Section 1.3.2).  Osteochondromas are a 
pathognomonic feature of MO associated with disease severity.  A greater OC burden is 
associated with more skeletal deformities and functional limitations, and associated with 
increased pain.8,35   The secondary endpoint assessing the annual change from baseline in total 
OC volume by whole body MRI will also assess the efficacy of palovarotene in terms of 
reducing OC burden.  Additional secondary endpoints will assess the efficacy of palovarotene in 
terms of rates of new or worsening skeletal deformities and MO-related surgeries, whereas 
exploratory endpoints will assess the rate of new or worsening functional limitations and patient 
reported outcomes on pain and quality of life.  By inhibiting the development and growth of 
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PROPRIETARY AND CONFIDENTIAL 
 
OCs, it is anticipated that there will be a reduction in limb deformities, functional limitations, 
and pain, reducing the need for MO-related surgeries.  Reducing the number of surgeries is itself 
clinically meaningful; a retrospective review of medical records indicated that more surgeries 
reduce quality of life in patients with MO.10  So by reducing OC burden, reducing skeletal 
sequelae, and the need for MO-related surgeries, an improved quality of life is also anticipated 
with palovarotene treatment.  Together, the efficacy endpoints provide a comprehensive and 
clinically meaningful assessment of MO that is suitable for the age range of subjects that will be 
enrolled in the study. 
4.6 
End of Study Definition 
A subject is at the end of the study if he or she has completed all phases of the study, including 
the safety follow-up visit 6 months after the end of treatment at Month 24 (for subjects who 
terminate early or those who elect not to participate in the open-label extension study), or the last 
scheduled follow-up procedure as in the Schedule of Assessments (Table 1). 
4.7 
Study Termination 
This study may be prematurely terminated if, in the opinion of the Investigator or the sponsor, 
there is reasonable cause.  Written notification documenting the reason for study termination will 
be provided to the Investigator or the sponsor by the terminating party.  Circumstances that may 
warrant termination include, but are not limited to the following: 
• Determination of unexpected, significant, or unacceptable risk to subjects. 
• Failure to enroll subjects at an acceptable rate. 
• Insufficient adherence to protocol requirements. 
• Insufficient complete and/or evaluable data. 
• Plans to modify, suspend, or discontinue the development of palovarotene. 
Study termination may also occur under the auspices of a DMC.  Based on the interim analysis, 
the DMC may recommend stopping the study early for efficacy or futility.  Additional details are 
provided in Section 11.3. 
5 
Selection of the Study Population 
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into consideration 
when deciding whether this protocol is suitable for a subject.  Subjects may be rescreened once 
for disqualifying laboratory abnormalities.  
5.1 
Inclusion Criteria 
Subjects must meet all the following criteria to be eligible for enrollment: 
1. Written, signed, and dated informed subject/parent consent and age-appropriate assent 
(performed according to local regulations). 
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2. A clinical diagnosis of MO with a disease-causing Ext1 or Ext2 mutation confirmed by a 
central laboratory. 
3. A chronological age from 2 to 14 years (inclusive) for male and female subjects. 
4. Female subjects must be premenarchal at screening. 
5. A bone age at screening of ≤14 years, 0 months per the Greulich-Pyle method, as 
ascertained 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 an MO-related complication. 
7. If a subject had a prior surgery for MO, the subject should not be screened until 8 weeks 
post-surgery to allow for 12 weeks of stabilization of symptoms prior to first dose.  
Surgical orthopedic implants are allowed if they were in situ ≥12 weeks prior to the 
baseline MRI. 
8. If a subject is currently receiving pain medications, they may participate in the study 
provided that the dose is 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 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 years of age or is post-
menarchal, whichever is earlier. 
11. Subjects must be accessible for treatment with study drug and follow-up. 
5.2 
Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for enrollment: 
1. A weight under 10 kg. 
2. Other syndromic conditions such as Langer-Giedion or Potocki-Shaffer syndromes. 
3. Any subject with neurologic signs suggestive of spinal cord impingement.   
4. 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.  No washout is required prior to the first 
dose of study drug. 
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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) above 
2.5×ULN. 
11. Fasting triglycerides above 400 mg/dL with or without therapy. 
12. Uncontrolled cardiovascular, renal, hepatic, pulmonary, gastrointestinal, endocrine, 
metabolic, ophthalmologic, immunologic, psychiatric, or other significant disease 
including diseases requiring glucocorticoid treatment with ≥0.2 mg/kg or up to 10 mg 
prednisone or prednisone equivalent per day. 
13. Subjects experiencing suicidal ideation (type 4 or 5) in the past month or any suicidal 
behavior within the past year as defined by the C-SSRS. 
14. Unable or unwilling to complete the study or all study-related procedures, including 
imaging. 
15. Any surgical implant that is contraindicated for MRI. 
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. 
5.3 
Subject Withdrawal or Early Termination from Study 
Subjects can voluntarily withdraw from the study at any time for any reason.  The study 
personnel should make all reasonable efforts to determine the reason for withdrawal.  Subjects 
will be considered lost to follow-up if no response is received despite repeated attempts to 
contact them. 
Study drug administration for individual subjects can be discontinued by the Investigator if 
he/she believes the subjects’ safety is at risk.  Additional details regarding study drug dose 
modification are provided in Section 7.4. 
In the event of an early discontinuation of the study drug, subjects should be encouraged to 
complete all study assessments and continue in the study until the end of study.  In the event of 
an early termination from the study, the study personnel should make all reasonable efforts to 
have the subject complete all study assessments for Month 24 per the Schedule of Assessments 
(Table 1). 
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5.4 
Safety Follow-up 
Subjects who do not continue to the open-label extension study or who end treatment early will 
require two safety follow-up visits: 4 weeks and 6 months after the last dose at the 
end-of-treatment visit.  The end-of-treatment visit will document adverse events related to skin 
and bone parameters.  The safety follow-up  will include clinical laboratory assessments of 
ongoing clinically significant abnormal findings to determine whether any are resolved or 
stabilized; the pregnancy status for a female of childbearing potential (FOCBP) will also be 
determined.  Additional safety follow-up may be required past the 6-month follow-up to ensure 
that ongoing adverse events have resolved or stabilized. 
6 
Study Treatments 
6.1 
Identity of Study Drug 
Palovarotene is a white to off-white crystalline powder with the chemical name 4-[(E)-2-
(5,5,8,8-tetramethyl-3-pyrazol-1-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-benzoic 
acid, an orally bioavailable RARγ selective agonist.  The structure of palovarotene is shown in 
Figure 3. 
Figure 3. 
Chemical Structure of Palovarotene 
 
6.2 
Placebo 
Placebo will be supplied as powder filled hard gelatin capsules that are indistinguishable from 
palovarotene capsules and contain the same ingredients except for palovarotene.  The capsules 
may be swallowed whole or opened and the contents added onto specific foods. 
6.3 
Concomitant Medications 
It is important to be aware of and document all concomitant medications including prescription, 
non-prescription, and herbal medications.   
Medications that are taken in the screening period will be documented as prior medications.  
Medications taken after the first dose of study drug has been administered will be documented as 
concomitant medications.  All concomitant medications taken during the study must be recorded 
in the CRF with indication (as appropriate), daily dose and start and stop dates of administration.  
Subjects will be queried about concomitant medication at each study visit. 
6.3.1 
Pain Medications 
Pain medications, including but not limited to acetaminophen, nonsteroidal anti-inflammatory 
drugs, or opioids taken to treat pain associated with OCs will be documented in the electronic 
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case report form (eCRF).  Adjustments in pain medications should be undertaken after evaluation 
of the subject’s pain symptoms; the increase in pain should be captured as an adverse event.  
Changes in dosing or pain medication must be documented in the eCRF with indications for use. 
6.3.2 
Restrictions on Prior and Concomitant Medications 
Several human CYP450 (CYP) isoforms (3A4, 2C8, and 2Cl9) oxidize palovarotene to its 
metabolites.  However, CYP3A4 is the major isoform responsible for the in vitro transformation.  
In healthy humans, palovarotene exposure at steady-state increased approximately three-fold 
with ketoconazole (a strong CYP3A4 inhibitor), decreased approximately 10-fold with 
rifampicin (a strong CYP3A4 inducer), and did not change consistently with midazolam (a 
CYP3A4 substrate).  Palovarotene did not impact the pharmacokinetics of midazolam, a standard 
CYP3A4 substrate, or the pharmacokinetics of prednisone.  Based on this information, 
concomitant medication guidelines during study treatment (ie, from the time of signature of the 
Informed Consent Form [ICF] to the end of study) are as follows: 
• Strong CYP3A4 inhibitors should not be taken concomitantly with palovarotene 
(Appendix 1).  If the subject requires such a medication, then contact the medical 
monitor. 
• Strong CYP3A4 inducers should not be taken concomitantly with palovarotene 
(Appendix 1).  If the subject requires such a medication, then contact the medical 
monitor. 
• It is acceptable to use CYP3A4 substrate drugs (those metabolized by CYP3A4) 
concomitantly with palovarotene. 
The following medications are also not allowed during the study: 
• Vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, herbal 
preparations, or fish oil.  No washout is required prior to starting study drug. 
• Synthetic oral retinoids are not permitted 4 weeks prior to enrollment or during the study. 
• Concomitant use of tetracyclines and retinoids has been associated with benign 
intracranial hypertension.  Therefore, use of tetracycline, or tetracycline derivatives, is 
prohibited during the study.  Should the subject experience a medical condition that 
requires treatment with tetracycline and/or doxycycline, study drug should be 
discontinued for the duration of tetracycline treatment and the medical monitor should be 
notified.  Prior to restarting treatment with palovarotene an appropriate wash-out period 
of 3 days must be considered.  If the duration of study drug interruption in context of 
treatment with tetracyclines exceeds 7 days, the subject should be withdrawn from the 
study. 
6.4 
Other Restrictions 
Males of reproductive potential and females of childbearing potential that have reached puberty 
must agree to undergo physician-approved reproductive education.  The Investigator must 
discuss the adverse effects of the study therapy on reproduction with these subjects and their 
caregiver(s).  In alignment with the guidance on pregnancy testing of adolescents participating in 
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research,36 an FOCBP is defined as a female subject who is ≥13 years of age or is post-
menarchal, whichever is earlier.  
Medically supervised serum pregnancy tests with a sensitivity of at least 50 mIU/mL must be 
conducted in FOCBP, including those who commit to abstinence.  Both male subjects of 
reproductive potential and FOCBP subjects must, as appropriate to age and at the discretion of 
the Investigator, either commit to true abstinence from heterosexual contact or agree to use two 
effective methods of birth control during and for 1 month after treatment.  Abstinence is only 
acceptable as “true abstinence.”  True abstinence occurs when it is in line with the preferred and 
usual lifestyle of the subject. 
Additionally, heterosexually active FOCBP subjects must already be using two effective 
methods of contraception 1 month before treatment begins.  Two effective forms of birth control 
consist of the concurrent use of AT LEAST one highly effective method of birth control 
comprising the following: 
•  Established use of oral, transdermal, or intravaginal combined (estrogen and 
progesterone containing) hormonal method of contraception. 
•  Established use of oral (excluding mini-progesterone-only pill), injectable, or 
implantable progesterone-only hormonal contraception. 
•  Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
•  Male sterilization (with the appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate). For female subjects on the study, the vasectomized male partner 
should be the sole partner for that subject. 
• Bilateral tubal occlusion.  
Note that two hormonal forms cannot be used together.  
Other effective methods of birth control include the following: 
• Barrier forms (always used with spermicide) – diaphragm, cervical cap 
• Barrier forms (used with or without spermicide) – male latex condom 
• Others – vaginal sponge (contains spermicide) 
The following are unacceptable forms of birth control: 
• Progestin only “mini-pill” 
• Female condom 
• Natural family planning (periodic abstinence such as calendar, ovulation, symptothermal, 
post-ovulation methods, rhythm method, or breastfeeding) or withdrawal. 
It is well recognized that retinoids are teratogens associated with a high risk for fetal 
abnormalities in women who become pregnant during treatment with such agents.  The 
agreement to remain abstinent from heterosexual sex or to use two effective methods of birth 
control will be clearly defined in the ICF.  Subjects or legally authorized representatives (eg, 
parents, caregivers, or legal guardians) must sign this specific section per institutional practice.  
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In addition, pregnancy testing (via blood or urine) will be performed before and during study 
drug administration and at the end of treatment. 
In the event of a pregnancy, a female subject must be instructed to stop taking the study drug and 
immediately inform the Investigator.  Pregnancies occurring up to 30 days after the completion 
of the study drug must also be reported to the Investigator.  The Investigator should report all 
pregnancies and the pregnancies of female partners of male subjects within 24 hours of notice to 
the sponsor.  The Investigator should counsel the subject and discuss the risks of continuing with 
the pregnancy, and the possible effects on the fetus.  Monitoring of the subject should continue 
until conclusion of the pregnancy; the health status of the baby will be verified. 
7 
Study Drug Administration and Management 
7.1 
Packaging, Labeling, and Storage 
Study drug supplies provided for this study will be manufactured under Good Manufacturing 
Practices and will be suitable for human use.  Palovarotene will be provided in powder-filled 
opaque 0EL oblong hard gelatin capsules using standard USP/EP/JP grade excipients in the 
following dosage strengths: 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, and 5.0 mg.   
Placebo will be supplied as powder-filled hard gelatin capsules indistinguishable from 
palovarotene capsules containing the same ingredients except for palovarotene.  
Study drug will be stored in a secured area at the study site with limited access.  All study drug is 
to be stored at room temperature (not above 30°C/86°F) and protected from light and humidity. 
7.2 
Randomization and Blinding 
Treatment will be assigned through randomization performed using a centralized Interactive 
Web Response System (IWRS).  Approximately 240 subjects will be randomized to one of three 
treatment groups (2.5-mg palovarotene, 5.0-mg palovarotene, placebo) with a 1:1:1 ratio.  
Randomization will be stratified by age (≤7 years, >7 years), sex, and gene mutation (Ext1/Ext2).  
Blocks of fixed size will be used within each of the eight strata determined by the unique 
combinations of the stratification variables. 
The Investigators, site staff, sponsor, subjects, contract research organization (CRO), and central 
imaging laboratory will remain blinded to treatment.  The Investigator may unblind a subject’s 
treatment only in an emergency for which it is medically imperative that the identity of the 
treatment administered be revealed.  To unblind the subject’s treatment, the Investigator will 
follow the study’s unblinding procedure.  Whenever possible, the Investigator should contact the 
medical monitor or designee prior to unblinding. 
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7.3 
Administration 
Subjects will receive orally administered palovarotene 2.5 or 5.0 mg (weight-adjusted as in  
Table 6) or placebo once daily for up to 24 months. 
Table 6.  
Weight-Adjusted Palovarotene Doses for Skeletally 
Immature Subjects 
Weight Range Category 
5.0-mg Equivalent 
2.5-mg Equivalent 
10 to <20 kg 
2.5 mg 
1.0 mg 
20 to <40 kg 
3.0 mg 
1.5 mg 
40 to <60 kg 
4.0 mg 
2.0 mg 
≥60 kg 
5.0 mg 
2.5 mg 
 
The first day that study drug is administered for treatment will be defined as Study Day 1.  
Details for handling, preparing, storing, and discarding study drug will be provided to subjects 
and caregivers.  Medications will be taken with food, at approximately the same time once daily, 
preferably immediately following the first meal of the day.  The initial amount of study drug 
provided will be sufficient for once daily dosing for 3 or 6 months. 
Because younger pediatric subjects may have difficulty swallowing intact capsules, subjects or 
caregivers may sprinkle the contents of the capsule onto a spoonful of specific foods (as 
specified in the dosing instructions) to facilitate study drug administration. The study drug 
should be ingested immediately following the first meal of the day.  The capsule should be 
swallowed whole, or if sprinkled onto a spoonful of food, the entire serving must be eaten.  
Subjects should be told to avoid foods that are known to induce or inhibit the activity of the 
CYP3A4 enzyme (eg, grapefruit, pomelo, or juices containing these fruits).  Due to the potential 
for dermal absorption of palovarotene, subjects and caregivers will be instructed to wear 
protective gloves when handling study drug capsules.  Pregnant persons should not handle study 
drug capsules. 
7.4 
Dose Modification 
Skin and mucous membrane reactions are the most common adverse effects associated with 
treatment with retinoids.  Therefore, to mitigate possible adherence issues due to expected 
adverse events, a guidance describing recommended treatment for the most common 
mucocutaneous adverse events will be distributed to each subject at the initiation of study 
treatment. 
Should a subject experience an adverse event that is not tolerated, but would not require 
immediate discontinuation of study drug (eg, skin rash), the subject will be instructed to contact 
the study site immediately.  The Investigator will assess the adverse event and determine an 
appropriate treatment or mitigation strategy.  The Investigator will assess the adverse event and 
if appropriate, will instruct the subject to decrease the frequency of study drug dosing to every 
other day for 1 month or until the adverse event is resolved, whichever is longer.  The subject 
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will be followed until resolution or improvement of the adverse event.  Once the adverse event 
has resolved or sufficiently improved, the subject should resume once daily dosing.  If the 
adverse event recurs and is again intolerable upon resuming once daily dosing, the subject should 
return to every other day dosing for the remainder of the study.  Should the adverse event remain 
intolerable after the dose modification to every other day dosing then the study drug will be 
discontinued, and the subject will continue to be followed with all study procedures performed 
per protocol.  Should a subject experience an adverse event that requires immediate 
discontinuation of the study drug (eg, acute pancreatitis) then the study drug will be 
discontinued, and the subject will be followed until resolution or stabilization.  Details on 
adverse event reporting are provided in Section 11.2. 
Dose modification may also be required due to potential bone safety findings as described in the 
Bone Safety Management Plan (see Section 8.5.1).  To address potential adverse effects of the 
study drug on bone density and growth, the study treatment may be modified or discontinued 
should subjects fulfill the criteria described in Section 8.5.3 for changes in BMD and 
Section 8.5.4 for changes in linear growth.  
7.5 
Study Drug Accountability 
The Investigator has the ultimate responsibility for study drug accountability at the study site.  
The Investigator or a designated individual (eg, pharmacist or other appropriate personnel) will 
maintain records of the study drug’s delivery to the study site, inventory at the site (used and 
unused product containers), use by each subject, and return of unused medication to the sponsor 
or alternative disposition. 
The study drug must be kept in a locked area that is monitored for temperature at least once per 
day.  Access to study drug will be restricted to authorized study personnel and used only in 
accordance with the approved protocol.  At the end of the study, any remaining study drug 
supplies will be returned to the sponsor or its designee.  The sponsor or its designee will ensure 
that a final report of study drug accountability is prepared and maintained by the Investigator.  
The Investigator agrees not to supply or administer study drug to any person except subjects in 
this study. 
7.6 
Assessment of Subject Compliance 
Adherence to study drug intervention will be based on the amount of study drug dispensed to the 
subject and returned to the site. 
Any issues related to adherence will be discussed with the subjects and their caregivers.  Subjects 
and/or caregivers should be encouraged to call the site between visits should any issues related to 
the study drug or adherence arise. 
8 
Study Procedures and Assessments 
8.1 
Overview of Study Procedures 
Study procedures are summarized in the Schedule of Assessments (Table 1).  The anticipated 
length of study participation in Study PVO-2A-201 is 26 months, which may be extended if 
additional safety follow-up is needed.  At the end of the study, subjects will have the option to 
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participate in an open-label extension study.  Details of the extension study will be provided in a 
separate study protocol. 
Site visits will occur at screening, baseline, and at Months 6, 12, 18, and 24.  Remote visits will 
occur at subjects’ homes or at local medical facilities between site visits at Months 1, 3, 9, 15, 
and 21.  Remote visits will be switched to site visits if preferred by the subject and site 
personnel, or the subject is enrolled in Japan.  
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside the control of the Investigator, that may make it unfeasible to perform the 
test.  In these cases, the Investigator will take all steps necessary to ensure the safety and 
well-being of the subject.  When a protocol-required test cannot be performed, the Investigator 
and/or delegate will document the reason and any applicable corrective and preventive actions in 
the source document.  
8.2 
MRI Sedation Screening 
At the screening visit, tolerance for the MRI procedure will be assessed in all 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 procedural tolerance and include the level of 
sedation a subject will require to complete the MRI scanning session.  The assessment will be 
based on, but not limited to, age, gender, ASA-PS class (Table 2), and comorbidities.  The 
screening will determine a priori the appropriate depth of sedation required to perform whole 
body MRI and the ability of subjects to tolerate MRI with the selected sedative. 
8.3 
Efficacy Assessments 
8.3.1 
Assessment of Osteochondroma Number and Volume by Whole Body MRI 
Whole body MRI will be performed at baseline and at Months 12 and 24, and at early 
termination for subjects who terminate participation prior to study completion.  The MRI may be 
performed within ±4 weeks of a study visit to allow flexibility of scheduling.  Full details of MRI 
procedures will be provided in a separate imaging acquisition guideline document. 
To obtain evaluable images, the subject must be still for 1 to 2 hours.  Distraction may be 
employed to allow MRI without sedation.  When procedural sedation is required, the depth of 
sedation should not exceed the level that is absolutely required to successfully perform the MRI 
acquisition.  The choice of sedative agent and method will be based on the subject status and 
clinical experience of the pediatric sedation team.  Procedural sedation for whole body MRI will 
adhere to the standard practice of the clinical site, which may include general anesthesia as this 
provides a well-controlled environment allowing for airway management to ensure subject 
safety.27  During the sedated MRI acquisition, the pediatric sedation team must have close 
monitoring and rescue equipment in place to respond to any complication.  Imaging acquisition 
will be terminated if a complication of sedation arises. 
Interpretation of the MRIs will document the number and anatomic distribution of OCs, the 
volume of total body OCs, and the volume of the total cartilage cap at baseline and at Months 12 
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and 24.  All images will be interpreted by a treatment-blinded, central imaging laboratory using 
standardized procedures detailed in an imaging read charter. 
8.3.2 
Assessment of Joint Deformity by Radiograph 
Radiographs to assess limb deformity will be performed at baseline and at Months 12 and 24.  
Radiographs may be performed within ±4 weeks of a study visit to allow flexibility of 
scheduling.  Assessments will comprise weight-balanced, full-length anterior/posterior 
radiographs of the lower extremities and lateral and anterior/posterior radiographs in supination 
and pronation of the forearms.  Full details for radiographic procedures will be provided to the 
site for consistency of image acquisition.  A central imaging laboratory with trained readers who 
are blinded to treatment will read radiographs to ensure consistent assessments. 
MO-related deformities will not be recorded as adverse events.  Major MO-related deformities 
will include, but may not be limited to the following measurements: 
Upper Extremities 
• Ulnar length and ulnar length/linear height ratio 
• Radial articular angle 
• Status of radiocapitellar articulation (normal, displaced, subluxation, dislocated) 
Lower Extremities 
• Lateral distal tibial angle to assess ankle valgus or varus deformity  
• Medial proximal tibial angle to assess knee valgus or varus deformity 
• Femoral neck shaft angle 
• Lateral distal femoral angle 
• Leg length discrepancy  
Lengths of paired bones (radius, ulna, tibia, and fibula) will also be assessed. 
Descriptions of these and other additional measurements to assess MO-related deformities and 
criteria for a new or worsening deformity will be defined in the imaging read charter provided to 
the central image reader. 
8.3.3 
Surgeries Related to Multiple Osteochondromas 
MO-related surgeries performed after subject enrollment will be documented in the eCRF.  The 
documentation will include the indications for each procedure.  Planned or unplanned 
MO-related surgery will not be recorded as adverse events unless it results in complications, 
prolongation of hospitalization, or meets any other criteria for a serious adverse event. 
An MO-related surgery is a secondary efficacy endpoint, which may include excisions to remove 
symptomatic OCs (pain, neurovascular, or tendon impingement) or procedures to correct 
deformities and/or functional limitations.  However, surgical practices for the correction of 
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deformities differ across study sites and geographic regions.  To provide standards for assessing 
these surgical events for efficacy endpoints, corrections for deformities of a ≥10° angle 
deviation, 2.5-cm leg length discrepancy, or restricted joint movement will be counted as an 
endpoint event.  Planned surgeries within 6 months of enrollment to remove symptomatic OCs 
present at baseline, or to correct deformities present at baseline, will be recorded but not 
contribute to the endpoint.  Similarly, surgical procedures that are a continuation of a previous 
procedure, such as removal of a surgical plate for guided growth, will not be counted as a 
separate MO-related surgery endpoint event. 
8.3.4 
Functional Limitations 
A functional limitation will be defined as a restriction in joint range of motion.  Range of motion 
will be assessed using a goniometer, by a treatment-blinded, trained assessor at baseline and at 
Months 6, 12, 18, and 24.  Whenever possible, the same assessor should be used to standardize 
the performance of procedures and to minimize variability.  The following joint ranges of motion 
will be assessed: 
• Hip extension/flexion 
• Knee flexion and extension 
• Shoulder flexion 
• Elbow flexion, extension, supination, and pronation 
• Ankle dorsiflexion and plantarflexion 
Details on how to perform measures for joint range of motion will be provided in a manual.  A 
functional limitation is defined as a deviation >2 standard deviations from the mean range of 
motion per age category and gender versus normal individuals.  Normative values are from the 
normal ranges of motion in individuals from 2 to 19 years of age as published in the Normal 
Joint Range of Motion Study conducted by the Center of Disease Control and Prevention 
(CDC).37  A worsening restriction is defined as a further decrease of >5º or >20% of the CDC 
age category-by-gender mean range of motion, whichever is greater. 
8.3.5 
The Pediatric Quality of Life Inventory 
The Pediatric Quality of Life Inventory (PedsQL) version 4.0 is a reliable and validated pediatric 
quality-of-life survey for children from the ages of 2 to 18 years, designed to measure core health 
dimensions outlined by the World Health Organization.  It comprises 23 items, with eight items 
assessing physical health and 15 items assessing psychosocial health.38   The Parent Proxy 
Report form for toddlers will be used for subjects 2 to 4 years of age, the Parent Proxy Report 
will be used for subjects 5 to 7 years of age, the Child Self Report will be used for subjects from 
8 to 12 years of age, and the Teen Self Report will be used for subjects 13 years of age and older 
(Appendix 2). 
8.3.6 
Pain Interference 
To assess the effect of pain on subject well-being, this study will use the Patient-Reported 
Outcomes Measurement Information System (PROMIS) pain interference pediatric item bank 
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(Appendix 3).  The PROMIS pain interference items assesses the extent to which pain hinders 
social, psychological, physical, recreational activities and sleep over the preceding 7 days.39   
The pain interference short forms are universal rather than disease-specific.  For this study, 
self-report forms will be used for subjects 8 to 17 years of age and parent proxy forms will be 
used for subjects from 2 to 7 years of age. 
8.3.7 
Pain Intensity 
Pain will be further evaluated using the six-face Faces Pain Scale – Revised (FPS-R), which is a 
pediatric subject self-report measure of acute pain intensity (Appendix 4).  The FPS-R was 
adapted from the original FPS to make it possible to score pain on a numeric rating scale from 
0 (no pain) to 10 (very much pain).  The validity of the FPS-R is supported by strong correlations 
with visual analogue scales in pediatric patients from 4 to 12 years of age.40,41  The FPS-R is 
appropriate for the assessment of pain intensity for pediatric subjects ≥4 years of age. 
8.4 
Safety Assessments 
8.4.1 
Medical History 
A complete medical history is to be documented at screening.  All MO-related surgeries 
performed prior to enrollment should be documented in the MO specific history eCRF. 
8.4.2 
Physical Examination 
A comprehensive physical examination will be performed by a physician at screening, baseline, 
every 6-months (Months 6, 12, 18, and 24), and at the 6-month safety follow-up and will monitor 
whether objective changes occur.  Any post-baseline abnormal findings assessed as clinically 
significant will be recorded as an adverse event. 
8.4.3 
Body Weight 
Body weight will be recorded at screening, baseline, and every 3 months. 
8.4.4 
Vital Signs 
Vital signs (temperature, respiratory rate, blood pressure, and heart rate) will be assessed at 
screening, baseline, every 3 months during site and remote visits during treatment and safety 
follow-up, if appropriate.  Blood pressure and heart rate will be obtained following a resting 
period of at least 5 minutes.  Blood pressure should be measured on the same arm and in the 
same position unless physical changes such as onset of deformities preclude repeat measures on 
the original arm.  The instruments (the one at the site and the one for the remote visit) should 
also remaining consistent at each visit. 
8.4.5 
Electrocardiograms 
A 12-lead electrocardiogram (ECG) will be performed at screening, baseline, and at Months 12 
and 24.  Measures should be obtained with subjects in the supine position following a resting 
period of 5 minutes.  Any post-baseline abnormal ECG assessed as clinically significant will be 
recorded as an adverse event. 
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8.4.6 
Clinical Laboratory Tests 
Blood and urine samples for each subject will be collected for hematology, biochemistry 
(includes lipids and serum pregnancy test, when applicable), and urinalysis assessments at 
screening, baseline, and every 3 months. Parathyroid hormone is obtained at baseline.  Samples 
may be collected at other times if medically necessary.  If no clinically significant abnormalities 
in hematology, biochemistry, or urinalysis are observed after 12 months of dosing, the frequency 
of clinical laboratory testing may be decreased to every 6 months to decrease subject burden. 
Blood/urine pregnancy testing is discussed in Section 8.4.7.  The blood volume drawn at each 
visit will be approximately 6 mL, representing less than 2.5% of total blood volume.  An extra 
3 mL will be collected at screening for the genotyping sample and 10 mL will be required at 
Month 1 for pharmacokinetic samples (Section 8.6).  Thus, the total blood volume drawn from a 
subject over the course of the entire study (screening to 24 months, totaling 11 visits) will be 
approximately 75 mL.  Should a subject have clinically significant abnormal laboratory results at 
the end-of-treatment visit and not participate in the open-label extension study, an additional 2 to 
12 mL may be collected at the safety follow-up visits, and 4 weeks and 6 months after the end-of 
treatment.  If the safety laboratory results are normal or if abnormalities are not clinically 
significant at the 4-week safety follow-up visit, they do not need to be repeated at the 6-month 
safety follow-up visit.  When multiple blood samplings are performed at one visit, as with 
pharmacokinetic blood samples, an intravenous blood drawing catheter may be used to minimize 
needle punctures.  If the total drawn blood volume exceeds the limits established by the clinical 
site for pediatric subjects, then priority will be given to the key safety laboratory tests.  This will 
ensure that the total blood volume drawn is within the established limits. 
Sample collection and preparation will be performed by qualified and trained study personnel at 
the study site and/or the subject’s home per protocol, according to the clinical laboratory manual 
and applicable regulations.  To ensure consistent generation and interpretation of results, a 
central testing laboratory will perform analyses of clinical laboratory samples.  Samples will be 
packaged and shipped to the designated laboratory for testing. 
The Investigator will be copied on all laboratory reports and will review and assess the clinical 
significance of all results that are outside of normal limits.  Any post-baseline abnormal 
laboratory value assessed as clinically significant will be recorded as an adverse event. 
The Investigator will be notified of any protocol-specified laboratory test that could not be 
obtained.  The Investigator will assess whether test attempts should be repeated for the current 
time point or whether to reassess the subject at the next scheduled visit according to the subject’s 
current clinical status (eg, adverse events, vital signs) and previous laboratory results. 
Table 7 presents the clinical laboratory parameters that will be assessed in this study. 
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Table 7. 
Clinical Laboratory Parameters 
Biochemistry 
Sodium 
Globulin 
Potassium 
Alkaline phosphatase (ALP) 
Chloride 
Aspartate transaminase (AST) 
Bicarbonate 
Alanine transaminase (ALT) 
Blood urea nitrogen 
Gamma glutamyl transferase (GGT) 
Creatinine 
Uric acid 
Calcium 
Total thyroxine (T4) 
Inorganic phosphorous 
Free T4 
Glucose  
Thyroid-stimulating hormone 
Total bilirubin 
Amylase 
Total proteins 
Lipase 
Albumin 
Parathyroid hormone (at baseline)3 
Lipid Profile1 
Triglycerides 
High-density lipoprotein (HDL) 
Total cholesterol 
Low-density lipoprotein (LDL) 
 
Very low-density lipoprotein (VLDL) 
Hematology 
Hemoglobin 
Platelets 
Hematocrit 
White blood cell count (including differentials) 
Red blood cell count 
Neutrophils 
Packed cell volume 
Lymphocytes 
Mean corpuscular volume 
Monocytes 
Mean corpuscular hemoglobin 
Eosinophils 
Mean corpuscular hemoglobin concentration Basophils 
Urinalysis2 
pH 
Blood (free hemoglobin) 
Protein 
Nitrite 
Glucose 
Urobilinogen 
Ketones 
Specific gravity  
Bilirubin 
Color and appearance 
1 
Non-fasting lipid profile will be obtained.  If the triglyceride is abnormal, a fasting triglyceride should 
be repeated. 
2 
If results are abnormal, then a microscopic evaluation should be completed. 
3  
Tests for parathyroid hormone and 25-hydroxy vitamin D may be performed as-needed to evaluate 
clinically significant changes in bone mineral density. 
8.4.7 
Pregnancy Testing 
Pregnancy testing will be conducted on subjects of child-bearing potential at screening, baseline, 
and every month thereafter until completion of the 4-week safety follow-up (if applicable).  If the 
screening sample is positive, the subject will not be enrolled.  Urine pregnancy testing will be 
performed on the months that do not coincide with site or remote visits that have blood sampling.  
For site and remote visits requiring blood sampling for safety (ie, every 3 months), a serum 
pregnancy test will be performed (with sensitivity of at least 50 mIU/mL).  Any positive 
pregnancy test during study participation will result in immediate discontinuation of the study 
drug. 
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8.4.8 
Adverse Events 
Adverse event monitoring will be conducted throughout the study.  The adverse event and 
serious adverse event reporting period begins at the time of informed consent and continues 
through study completion.  The Investigator will follow-up on all adverse events to the end of the 
reporting period or until the symptoms stabilize and follow-up is no longer necessary. 
Definitions, documentation, and reporting of adverse events are described in Section 11.2.  
Serious adverse events must be reported within 24 hours of awareness as described in 
Section 11.2.8.  If a subject or female partner of a male subject becomes pregnant during the 
study, they will be followed throughout their pregnancy and the health status of the baby will be 
verified (Section 11.2.9). 
Attention should be paid to mucocutaneous effects, serum lipids, liver enzymes, and other 
potential retinoid side effects (see details listed in Section 8.5).  In addition, limb/joint adverse 
events in subjects with open epiphyses will be evaluated by clinical or radiographic assessments 
deemed appropriate by the Investigator. 
8.5 
Special Safety Assessments 
Considering the established safety profile of the currently marketed oral systemic retinoids and 
hypothesized potential concerns, clinical and laboratory monitoring of select adverse events and 
laboratory abnormalities in subjects in this study is indicated.  Specific safety concerns that will 
be monitored in the study are described in the subsections that follow.  
8.5.1 
Bone Safety Management Plan 
To enhance subject safety monitoring, a Bone Safety Management Plan has been developed to 
supplement per-protocol safety monitoring.  The plan provides further details for monitoring of 
growth plates (Section 8.5.2), bone density (Section 8.5.3), growth (Sections 8.5.4 and 8.5.5), 
and osteonecrosis (Section 8.5.6).  The Bone Safety Management Plan will be provided to each 
clinical site, must be signed by the clinical site Investigator, and will be appended to the Data 
Monitoring Committee Charter.  
8.5.2 
Knee and Hand/Wrist Radiographs for Bone Age 
All subjects will undergo left hand/wrist and left knee radiographs at screening unless surgery 
was performed on that limb within the preceding 12 months.  If such surgery did occur, the 
contralateral limb should be imaged.  Subsequent radiographs should be performed on the same 
limbs imaged at screening.  The screening hand and knee radiographs will be used to determine 
bone age and serve as baseline for safety assessments.  To be eligible for the study, the screening 
bone age must be ≤14 years, 0 months as assessed by a central reader using the Greulich-Pyle 
method. 
Due to the theoretical potential for palovarotene to cause adverse effects on long bone growth, all 
subjects will undergo knee and hand/wrist radiographs (anterior/posterior view) at screening and 
every 6 months (Months 6, 12, 18, and 24), and at the 6-month safety follow-up visit, if 
appropriate.   
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Once a subject has achieved 100% skeletal maturity (ie, complete fusion of growth plates) as 
determined by the knee and hand/wrist radiographs, further radiographs will no longer be 
necessary.  If 100% skeletal maturity is not achieved at both anatomical locations, then only the 
location that is still maturing needs to be monitored. 
A central imaging laboratory will read all radiographs to ensure consistent assessment of the 
radiographs for growth plates abnormalities.  The Investigator will be provided with all results 
and will review and assess abnormal results for clinical significance.  Any post-baseline 
abnormal results assessed as clinically significant will be recorded as an adverse event. 
8.5.3 
Bone Densitometry 
Due to the potential effects of palovarotene on bone mineral deposition, bone mineral content 
(BMC), areal bone mineral density (aBMD), and bone area at the lumbar spine, hip, and the 
mid-third radius will be assessed with DXA at baseline, every 6 months (Months 6, 12, 18, and 
24), and at the 6-month safety follow-up, if appropriate.  Scans may be performed within 
±4 weeks of a study visit to allow flexibility of scheduling.  To optimize subject positioning for 
DXA, the unaffected or the least affected hip or radius should be scanned, with subsequent scans 
performed on the same region.  Analyses will be conducted to evaluate BMC, aBMD, and bone 
area (percentage changes from baseline) in the lumbar spine, hip, and mid-third radius.  Spine 
BMC and aBMD z-scores (changes from baseline) will be calculated (per availability of 
reference data) and adjusted for height. 
The following summarizes the stepwise process for evaluating decreases in aBMD and 
aBMD-loss-triggered stopping criteria: 
1. An aBMD loss of 5% in the lumbar spine, hip, and/or the one-third radius from baseline 
will be set as an alert threshold for further evaluation. 
2. An aBMD decrease of 5% or more from baseline in the spine and a change from baseline 
in the height-adjusted spine aBMD z-score of ≤-1 will require a repeat DXA scan to 
confirm that differences are not artefactual (eg, due to subject positioning).  Relevant 
laboratory assessments, such as those for parathyroid hormone and 25-hydroxy vitamin 
D, may be obtained as needed to determine the underlying causes of bone mass loss.  If 
aBMD loss in the spine (aBMD loss ≥5% and height-adjusted spine aBMD z-score of 
≤-1) is confirmed, and no other factors account for the changes (eg, due to prolonged 
immobility), the subject should discontinue the study drug. 
3. Any aBMD loss in a subject found in other anatomical regions meeting the 5% alert 
threshold will be provided to the Investigator.  These subjects will continue the study and 
be re-evaluated at the next regularly scheduled 6-month assessment.  Equivocal cases will 
be discussed with the medical monitor. 
8.5.4 
Growth Assessment 
Growth will be assessed in all subjects by a stadiometer for linear growth and by measuring the 
knee-height in both knees at baseline, every 6 months (Months 6, 12, 18, and 24), and at the 6-
month safety follow-up visit, if appropriate.  Measurements will be performed in triplicate at the 
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study site by trained and qualified study personnel.  The stadiometric measurement instructions 
will include practices that reduce measurement error including calibration of equipment, proper 
subject positioning, and measurement capture.  To standardize the performance of procedures 
and minimize measurement variability, the same examiner should be used whenever possible. 
If a subject does not exhibit any linear growth (measured by stadiometer) from the preceding 6-
month height measure, the subject will visit the site to have his/her linear height reassessed after 
3 months to confirm growth retardation.  Negative height gains will not be acted on until 
confirmation, as this most likely represents measurement error.  Questionable observations will 
be discussed with the medical monitor and may warrant an additional 3-month evaluation period 
prior to dose modification.  If a lack of linear growth is confirmed, and no other reason for a 
normally expected lack of growth is evident (such as achievement of post-pubertal growth), the 
study drug regimen will be modified to every other day dosing.  As the potential effects of 
retinoids on long bone development is dose dependent, this dosage modification is expected to 
ameliorate retinoid-associated growth retardation.  If growth arrest continues despite dosage 
modification, the study drug will be permanently discontinued.  If the growth improves, subjects 
will continue with the modified regimen. 
8.5.5 
Bone Lengths 
Linear lengths of the ulna, radius, tibia, fibula, and femur will be assessed with bilateral upper 
and lower extremity anterior/posterior radiographs at baseline and at Months 12 and 24.  
8.5.6 
Osteonecrosis 
Due to the presence of AVN of the femoral head in wild-type rats receiving high-dose 
palovarotene (Section 1.3.1), whole body MRI scans obtained for the primary efficacy analysis 
will undergo safety reads by two blinded independent radiologists for signs of osteonecrosis at 
the hips, shoulders, and knees.  If the assessment indicates possible or probable osteonecrosis, 
then palovarotene will be discontinued while further assessment is performed to determine 
whether osteonecrosis is definite.  If osteonecrosis is definite, then palovarotene will be 
permanently discontinued. In the event of an early discontinuation of the study drug, subjects 
should be encouraged to complete all study assessments and continue in the study until the end 
of study. 
8.5.7 
Tanner Staging 
To assess growth and development, Tanner staging will be performed at baseline and at 
Months 12 and 24.  Tanner staging will no longer be necessary once Stage V is reached. 
8.5.8 
Mucocutaneous Effects  
At every visit during the treatment period, subjects will be monitored for adverse events, which 
includes mucocutaneous events (eg, dry skin, itching, redness, rash, flaking and peeling of the 
skin, dry lips, chapped lips, cheilitis, dry eyes, and conjunctivitis).  In addition to the severity 
assessments of mild, moderate, and severe (Section 11.2.3), all mucocutaneous adverse events 
will be rated according to the most recent version of the Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.03, 14 June 2010 (Appendix 5). 
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To minimize the occurrence of mucocutaneous effects, preventive therapy (skin emollients, lip 
moisturizers, artificial tears, or other helpful treatments) should be used.  Additional 
symptomatic therapy may be given if deemed necessary by the Investigator. 
Although palovarotene has not been proven to be phototoxic, precautionary measures for 
phototoxicity are recommended.  Excessive exposure to sun should be avoided and protection 
from sunlight when it cannot be avoided (use of sunscreens, protective clothing, and use of 
sunglasses). 
Dose modification is recommended for intolerable mucocutaneous effects that would otherwise 
result in discontinuation from the study.  Dose modification procedures are described in 
Section 7.4. 
8.5.9 
Columbia-Suicide Severity Rating Scale 
In accordance with the Guidance for Industry Suicidal Ideation and Behavior – Prospective 
Assessment of Occurrence in Clinical Trials (2012),42 all subjects 8 years of age and older will 
be assessed for suicidal ideation and behavior using the C-SSRS (Appendix 6).  The pediatric 
form will be used for subjects 8 to 11 years of age and the adult form will be used for subjects 
12 years of age and older.  Study personnel administering the questionnaire will receive formal 
training to ensure accuracy and consistency in application of the instrument. 
Subjects will be assessed at screening, baseline, and every 3 months during each site and remote 
visit during the treatment period.  Study personnel administering the questionnaire will receive 
formal training to ensure accuracy and consistency in application of the instrument.   
Any subject experiencing suicidal ideation (type 4 or 5) in the past month or any suicidal 
behavior within the past year as defined by the C-SSRS will not be eligible to receive study drug.  
Any subject experiencing type 4 or type 5 suicidal ideation or any suicidal behavior during 
treatment will have the study drug immediately withheld.  The Investigator will refer all such 
subjects to a mental health professional for evaluation and counseling as appropriate. 
8.5.10 
Serum Lipids 
With oral retinoid therapy, elevations in triglycerides may occur after 2 to 4 weeks of treatment. 
To minimize discomfort of pediatric subjects, a complete non-fasting lipid profile will be 
obtained from all subjects as part of the biochemistry testing at screening and every 3 months.  If 
no abnormalities are observed after 12 months of dosing, serum lipid monitoring may be 
decreased to every 6 months.  
If a non-fasting serum triglyceride test result is abnormal, a fasting lipid panel should be 
repeated.  If fasting serum triglyceride levels are ≥800 mg/dL, the study drug should be 
immediately discontinued, with follow-up assessments performed per protocol. 
8.5.11 
Liver Enzymes 
Monitoring liver enzymes is required to establish the clinical safety profile of palovarotene.  
Alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), 
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total bilirubin, and gamma glutamyl transferase (GGT) determinations will be made per the 
Schedule of Assessments (Table 1).   
Treatment should be discontinued if any of the following occur: 
• AST or ALT≥5 × ULN 
• Jaundice is observed 
• ALT>3 × ULN if accompanied with any bilirubin increase, abdominal pain, malaise, 
nausea, and /or vomiting 
Liver toxicity evaluation will follow the FDA Guidance for Industry Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation (July 2009).43  If no abnormalities are observed after 
12 months of dosing, liver enzyme monitoring may be decreased to every 6 months.  
8.5.12 
Lipase/Amylase 
Amylase and lipase will be monitored in all subjects as part of the biochemistry testing at 
screening and every 3 months.  If no abnormalities are observed after 12 months of dosing, 
amylase and lipase monitoring may be decreased to every 6 months. 
Lipase and/or amylase increases during the study should be further evaluated to exclude the 
occurrence of pancreatitis.  With symptoms of pancreatitis or with persistent elevations that 
cannot be explained, the study drug should be discontinued per the Investigator’s judgment, 
with follow-up assessments performed per protocol. 
8.5.13 
Central Nervous System 
Retinoid use has been associated with several cases of benign intracranial hypertension (also 
known as pseudotumor cerebri), with some involving concomitant use of tetracyclines. 
The cases of benign intracranial hypertension had symptoms and signs of severe headache, 
nausea and vomiting, and visual disturbances, and may have been associated with papilledema.  
Headache generally occurs within 3 to 4 hours of starting therapy and remits spontaneously. 
However, subjects with a headache of unusual characteristics (eg, severity, location, pattern) 
should have contact with the Investigator.  In case of such a headache, it is at the Investigator’s 
discretion whether to refer subjects for neurological and/or ophthalmological examination to rule 
out benign intracranial hypertension. 
8.5.14 
Hearing and Visual Disturbances 
Hearing and visual acuity testing will occur at baseline and at Months 12 and 24 with a visit 
window of ±4 weeks to allow for flexibility in scheduling.  Hearing will be assessed with 
age-appropriate audiometry testing (play behavior or conventional).  The assessments will 
determine auditory thresholds in response to frequency-specific stimuli (ie, pure tone).  Speech 
threshold audiometry may be performed for subjects unable to undergo pure tone audiometry.  
Subjects with a hearing impairment at baseline or an impairment identified during testing should 
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receive an appropriate hearing evaluation to determine the severity and type (conductive, 
sensorineural, or mixed) of hearing impairment.  
Impaired hearing has been reported in subjects taking retinoids.  Subjects who experience 
tinnitus or hearing impairment during the study should be referred to specialized care on an 
ad hoc basis for further evaluation.  The subject with a confirmed diagnosis of clinically 
significant hearing impairment (assessed as related to the study drug by the Investigator) will be 
discontinued from treatment. 
Corneal opacities have occurred in subjects receiving retinoids and were reversible upon drug 
discontinuation.  Subjects with unexplained visual impairment and corneal opacity should be 
referred for further ophthalmologic evaluation. 
Decreased night vision has been reported during retinoid therapy.  Because the onset in some 
subjects can be sudden, subjects should be informed and warned to be cautious when driving or 
operating vehicles at night. 
8.5.15 
Teratogenicity 
Palovarotene must not be used by female subjects who are or become pregnant.  There is an 
extremely high risk that severe birth defects will result if pregnancy occurs while taking 
palovarotene in any amount, even for brief periods.  Potentially, any fetus exposed during 
pregnancy can be affected.  There are no accurate means of determining whether an exposed 
fetus has been affected. 
Birth defects that have been documented following exposure to retinoids include abnormalities 
of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and 
parathyroid glands.  Cases of IQ scores less than 85 with or without other abnormalities have 
been reported.  There is an increased risk of spontaneous abortion; premature births are also 
reported. 
Documented external abnormalities with other retinoids include skull abnormality, ear 
abnormalities (including anotia, micropinna, small or absent external auditory canals), eye 
abnormalities (including microphthalmia), facial dysmorphia, and cleft palates.  Documented 
internal abnormalities with other retinoids include central nervous system abnormalities (such as 
cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve 
deficit), cardiovascular and thymus gland abnormalities, and parathyroid hormone deficiency.  In 
some cases, certain abnormalities previously noted with other retinoids resulted in death. 
8.6 
Pharmacokinetics 
The steady-state pharmacokinetics of palovarotene will be assessed at Month 1.  
Pharmacokinetic samples may be obtained at the site or obtained by a visiting nurse during the 
remote visit at the discretion of the subject and investigator.  Sparse pharmacokinetic blood 
sampling will be collected before dosing and at 3, 6, 10, and 24 hours post-dose.  
Pharmacokinetic sampling may be repeated at a subsequent visit if the first attempt was 
unsuccessful. 
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Palovarotene plasma concentrations will be determined using a validated liquid 
chromatography-mass spectrometry method.  Exploration of any relationships with palovarotene 
exposure will be performed.   
The time of sample collection relative to the time of dosing on the sparse sampling days will be 
recorded.  Detailed instructions for the collection, storage, labeling, and shipment of all samples 
will be provided in the clinical laboratory manual.  
8.7 
Palatability of Sprinkled Drug Product 
The palatability of drug product versus placebo sprinkled onto a spoonful of specific foods will 
be assessed following administration of the first dose (Day 1) and at Month 1 (concurrent with 
PK assessment).  Only subjects ≥4 years of age will be assessed.  The subject will be asked to 
mark how much he/she liked the capsule contents on a 5-point hedonic face scale 
(Appendix 7).44  As the concentration of palovarotene within the capsules is low, the 
predominant taste is that of the inactive component lactose, which is slightly sweet (ie, nearly 
tasteless). 
9 
Data Collection, Management, and Quality Assurance 
9.1 
Data Capture and Management 
The sponsor will provide the clinic sites with an electronic case report system. 
Electronic CRFs will be completed for each subject.  It is the Investigator’s responsibility to 
ensure the accuracy, completeness, and timeliness of data entered in each subject’s eCRF.  
Source documentation supporting eCRF data should indicate subjects’ participation in the study 
and document the dates and details of study procedures, adverse events, and subject status. 
The Investigator or designated representative should complete the eCRF according to the 
completion guidelines. 
9.2 
Data Quality Assurance 
As per Good Clinical Practice (GCP) guidelines, the sponsor or designee will be responsible for 
implementing and maintaining quality assurance and quality control systems for this study. 
Participating sites, the study database, and study documentation, including subject medical 
records, may be subject to a quality assurance audit during the study.  In addition, inspections 
may be conducted by regulatory authorities at their discretion. 
If sites receive a request for an inspection, or written or oral inquiries from a regulatory authority 
regarding any aspect of the institution’s or investigator’s activities related to this study, the 
Investigator must immediately notify the sponsor of the request.  Following the inspection and/or 
audit, the Investigator must notify the sponsor of any violation or deficiency noted by the 
regulatory authority. 
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10 Statistical Considerations 
10.1 
Sample Size Determination 
The sample size required for this Phase 2 study was determined by simulation.  The annualized 
rate of new OCs is assumed to be 1.15 based on analyses of the IOR REM (Section 4.5).   
Osteochondroma counts are assumed to follow a negative binomial distribution parameterized 
with a variance inflation factor of 2.0. 
Multiple comparisons between the 5.0-mg palovarotene and placebo groups and the 2.5-mg 
palovarotene and placebo groups will be adjusted using the Bonferroni method.  Therefore, the 
sample size simulations were conducted with a one-sided, overall type I error rate of 1.25% for 
each active treatment group comparison with placebo.   
There will be one interim analysis (when all subjects complete 12 months of treatment) and a 
final analysis.  At the interim and final analyses, the O’Brien-Fleming alpha-spending function 
will be used to specify the alpha level threshold for determination of treatment effect 
significance.  Assuming 50% statistical information at the interim analysis, the one-sided p-value 
significance threshold used in the interim analysis comparing the 5.0-mg palovarotene and 
placebo groups and the 2.5-mg palovarotene and placebo groups is0.0007.  Likewise, the 
one-sided p-value significance threshold in the final analysis will be 0.0122.   Study success is 
defined as having one or both palovarotene treatment arms demonstrate a statistically significant 
treatment effect. 
Assuming 80 subjects will be randomized to each treatment group and a 50% palovarotene 
treatment effect in one treatment arm and no effect in the other, the probability of declaring study 
success at the interim analysis is 0.34, whereas the overall probability of study success is 0.87.  If 
there is a 50% palovarotene treatment effect for both dosages, the probability of declaring study 
success at the interim analysis is 0.49 and the overall probability of study success is 0.95.  
The number of subjects per group accounts for 15% who may discontinue the study.  Success at 
each analysis is achieved if one or both of the palovarotene treatment groups is significantly 
superior versus placebo. 
10.2 
Disposition of Subjects 
Screened subjects will be defined as any patient who has signed the informed consent form. 
10.3 
Analysis Populations 
The Randomized Set will include any subject allocated to a randomized treatment group, 
regardless of whether or not the study drug was administered.  
The Full Analysis Set (FAS) will include randomized subjects who receive at least one dose of 
study drug.  Analyses using the FAS will be according to the treatment group allocated by 
randomization and not the actual treatment received. 
The Per-Protocol Set (PP) will be a subset of the FAS and include subjects with no major 
protocol deviations that will interfere with the assessment of the primary efficacy endpoint and 
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subjects with at least 80% compliance to the dosage regimen.  This subset will be described 
further in the Statistical Analysis Plan (SAP). 
The Safety Set (SS) will be a subset of the Randomized Set and include randomized subjects 
who receive at least one dose of study drug.  The SS will be analyzed according to the 
randomized treatment received, unless otherwise specified. 
The Pharmacokinetic Set (PS) will be a subset of the SS and include subjects with evaluable 
pharmacokinetics data. 
10.4 
Statistical Methods 
10.4.1 
Extent of Exposure 
The extent of study treatment exposure and compliance will be summarized for the SS.  The 
duration of study drug exposure is defined as [last dose date – first dose date + 1 day] regardless 
of unplanned intermittent discontinuations. 
Treatment compliance, the number of dose interruptions, and the percentage of subjects with 
compliance <80% will be summarized.  
10.4.2 
Analyses of Efficacy Endpoints 
10.4.2.1 Primary Efficacy Analysis 
The primary efficacy endpoint is the annualized rate of new OCs as assessed by whole body 
MRI.  The primary efficacy analysis comparing the rate of OCs between palovarotene-treated 
subjects and placebo-treated subjects will be conducted using a negative binomial regression 
model using the FAS.  Covariates in the model will include treatment group indicators, baseline 
age, sex, and Ext1/2 mutation status.  Robust variance estimation will be used and an offset 
variable equal to the log of the number of years of follow-up will be included. 
The estimated rate ratio comparing the rate of OCs between palovarotene-treated subjects and 
placebo-treated subjects and the associated Wald statistics will be used for hypothesis testing.  
The primary efficacy hypothesis testing will compare the 5.0-mg palovarotene and placebo 
groups and the 2.5-mg palovarotene and placebo groups; the multiple comparisons will be 
accounted for with a Bonferroni adjustment.  There will be one interim efficacy analysis 
(planned for when all subjects complete 12 months of treatment) and a final analysis.  The 
O’Brien-Fleming alpha-spending function will be used to specify the alpha level threshold for 
treatment effect significance at the interim and final analyses.  Assuming 50% statistical 
information at the interim analysis, the one-sided p-value significance threshold used in the 
interim analysis in the 5.0-mg palovarotene versus placebo groups comparison and the 2.5-mg 
palovarotene versus placebo groups comparison is 0.007.  Likewise, the one-sided p-value 
significance threshold in the final analysis will be 0.0122.   Study success is defined as having 
one or both palovarotene treatment groups demonstrate a statistically significant treatment effect. 
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10.4.2.2 Secondary Efficacy Analyses 
The change from baseline in the total volume of OCs as assessed by whole body MRI at 
Month 24 will be analyzed using a mixed model for repeated measures, with baseline total 
volume of OCs, baseline age, sex, and Ext1/2 mutation status as covariates and treatment group, 
visit, and treatment group by visit interaction as factor variables. 
The proportion of subjects with no new OCs as assessed by whole body MRI will be analyzed 
with logistic regression using the same covariates included in the primary analysis described in 
Section 10.4.2.1. 
The annualized rate of new and worsening deformities and MO-related surgeries will be 
analyzed as described from the primary endpoint analysis. 
10.4.3 
Analyses of Safety Data 
All safety analyses will be performed on the SS.  For the safety analyses, the baseline value is 
defined generally as the last available value before randomization.  Safety analyses and the 
summary of results will be according to treatment group. 
10.4.3.1 Adverse Events 
Adverse event observation periods are as follows: 
• Pre-treatment adverse events are adverse events that developed or worsened following 
informed consent but prior to the first dose of study drug. 
• On-treatment adverse events are adverse events that developed or worsened from the first 
administration date of the study drug to the last administration date of the study drug. 
The on-study period will include pre-treatment and on-treatment observation periods.  
Summaries of treatment-emergent adverse events will include all on-treatment adverse events. 
All adverse events will be MedDRA coded.  Mucocutaneous adverse events will be further 
graded according to CTCAE, Version 4.03, 14 June 2010 (Appendix 5). 
Tables of the incidence of adverse event will be presented by system organ class and preferred 
term.  Multiple occurrences of the same event in the same subject will be counted only once in 
the tables. 
The incidence of treatment-emergent adverse events and adverse events associated with retinoids 
will be tabulated by severity (Section 11.2.3), and by relationship to treatment.  In tabulating the 
severity of adverse events, the highest severity will be assigned to a subject with more than one 
occurrence of the same adverse event.  Relationships of the adverse events to treatment will be 
categorized as not related, possibly related, probably related, or definitely related (defined in 
Section 11.2.4).  The highest level of association will be reported in subjects with differing 
relationships for the same adverse event.  Retinoid-associated adverse events will be tabulated by 
CTCAE grade. 
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Listings of adverse events and serious adverse events for all subjects will be provided.  The 
listings will include the severity of the event, its relationship to treatment, the actions taken 
regarding treatment, and the outcome of the event. 
The incidence of adverse events leading to study drug interruption and study drug 
discontinuations will also be summarized by treatment group, with details provided in the 
listings.   
10.4.3.2 Special Safety Assessments 
Linear growth as assessed by linear height, knee heights, and bone lengths of the tibia, femur, 
tibia, ulna, and radius will be summarized by time.  In addition, z-scores of linear heights will be 
summarized by time. 
Abnormalities in the hand/wrist and knee growth plates and changes from baseline will be 
summarized by time. Details of subjects with growth plate abnormalities will be provided in a 
listing.  
The BMD and the percentage change from baseline of BMD at the lumbar spine, hip, and mid 
radius; and the height-adjusted z-score of areal BMD at the lumbar spine and hip will be 
summarized by time.  Details of subjects developing osteonecrosis during the study will be 
provided in a listing. 
Details of subjects with any type 4 or 5 suicide ideations in the C-SSRS or any suicide behavior 
during the study will be provided in a listing. 
10.4.3.3 Clinical Laboratory and Other Safety Findings 
Changes in ECGs, vital signs (temperature, respiratory rate, blood pressure, and heart rate), body 
weight, laboratory parameters (hematology, biochemistry, and urinalysis) will be assessed 
descriptively, with pre-treatment, on-treatment, and change from pre-treatment values calculated. 
Any post-baseline findings assessed as clinically significant will be recorded as adverse events.  
The number and percentage of subjects with new potentially clinically significant (PCS) values 
will be summarized.  Subjects with pre-existing PCS values at pre-treatment will not be 
considered to have new onset values on-treatment. 
10.4.4 
Pharmacokinetics Analysis 
Serum concentrations of palovarotene will be summarized by visit using arithmetic and 
geometric means, standard deviations, standard errors of the means, coefficients of variation, 
minimums, medians, and maximums. 
10.5 
Interim Analysis 
An interim efficacy and safety analysis will occur when all subjects have completed the 
12 months of treatment.  The analysis will be conducted by a treatment-blinded, external vendor 
under the auspices of a DMC (see Section 11.3) to assess whether efficacy is sufficiently 
demonstrated prior to study completion.  The DMC may recommend stopping the study early for 
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efficacy based on the available interim efficacy and safety data.  If the study is stopped early for 
efficacy, all subjects will be offered enrollment in the open-label extension study.  The Month 24 
primary efficacy analysis and the pre-specified significance thresholds are described in Section 
10.4.2.1. 
A futility analysis will be conducted concurrently with the interim efficacy analysis.  Based on 
the results of this analysis, the DMC may recommend stopping the study early due to insufficient 
efficacy.  The DMC may also recommend moving subjects from one palovarotene treatment 
group to another based on the futility analysis results and available safety data. 
11 Monitoring and Reporting 
11.1 
Good Clinical Practice Monitoring 
The sponsor or their representative will monitor the study for compliance with GCP.  The 
monitors will verify that the rights and well-being of subjects are respected, that the reported 
study data are accurate, complete, and verifiable from source documents, and finally that the 
conduct of the study is in accordance with the current approved protocol/amendments, GCP, and 
regulatory requirements. 
Original subject records must be made available for reviews conducted by the sponsor or their 
representative. 
11.2 
Safety Monitoring and Reporting 
11.2.1 
Adverse Event Definition 
An adverse event is any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product during a study and that does not necessarily have 
a causal relationship to treatment.  Therefore, an adverse event can be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of the study drug, regardless of its assessment of relatedness. 
Disease, signs, symptoms, and/or laboratory abnormalities already existing prior to informed 
consent are not considered adverse events unless they reoccur after the subject has recovered 
from the pre-existing condition or they represent an exacerbation in intensity or frequency. 
Only a clinically-significant laboratory test abnormality, ECG, physical examination finding, or 
other objective finding should be reported as an adverse event, whether it represents an 
exacerbation or a new abnormality. 
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11.2.2 
Serious Adverse Event or Adverse Drug Reaction Definition 
A serious adverse event, experience, or reaction is an untoward medical occurrence at any dose 
that results in any of the following outcomes:  
• Death. 
• Life threatening situation (the subject was at risk of death at the time of the event), which 
does not refer to the hypothetical risk of death if the adverse event was more severe or 
was to progress. 
• Inpatient hospitalization or prolongation of existing hospitalization. 
• Persistent or significant disability/incapacity. 
• Congenital anomaly/birth defect (any structural abnormality in subject offspring that 
occurs after intrauterine exposure to treatment). 
• Other medically important event (important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered a serious adverse event 
when, based upon medical judgment, they may jeopardize the subject or may require 
intervention to prevent one of the outcomes listed above.  Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in subject 
hospitalization or the development of drug dependency or drug abuse). 
11.2.3 
Severity of Adverse Events 
The term “severity” is used to describe the intensity of a specific adverse event.  The severity of 
adverse events will be categorized as follows: 
• Mild: adverse events that are easily tolerated with no disruption of normal daily activity. 
• Moderate: adverse events that cause sufficient discomfort to interfere with daily activity 
and/or require simple therapeutic treatments. 
• Severe: adverse events that incapacitate and prevent usual activity or require systemic 
drug therapy or other treatment. 
Adverse events known to be associated with retinoids (eg, mucocutaneous) will be further graded 
according to CTCAE, Version 4.03 (Appendix 5).  Sites will be provided with specific criteria 
for the coding of adverse events. 
11.2.4 
Causality Assessment 
For purposes of reporting adverse events, the assessment of causality will require that 
Investigators assess the relationship of any adverse event to the study drug.  To promote 
consistency across assessments, investigators should take the following definitions into 
consideration, along with good clinical and scientific judgment when determining the 
relationship of the study drug to an adverse event: 
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• Definitely related: A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to the study drug administration, and which cannot be 
explained by concurrent disease or other drugs or chemicals.  The response to withdrawal 
of the study drug (dechallenge) should be clinically plausible. 
• Probable: A clinical event, including laboratory test abnormality, occurring in a plausible 
time relationship to the study drug administration, and which is unlikely to be explained 
by concurrent disease or other drugs or chemicals.  The response to withdrawal of the 
study drug (dechallenge) should be clinically plausible. 
• Possible: A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the study drug, but which could also be explained by 
concurrent disease or other drugs or chemicals.  Information on the study drug 
withdrawal (dechallenge) may be lacking or unclear. 
• Not related: A clinical event that has no temporal relationship to the study drug or has a 
much more likely alternative etiology. 
11.2.5 
Action Taken with Study Drug 
The action taken to remedy reported/observed adverse events will be defined as follows: 
1. None 
2. Study drug dosage modified 
3. Study drug dosage interrupted 
4. Study drug permanently discontinued 
11.2.6 
Outcome of Adverse Event 
The outcome of adverse events will be recorded as follows: 
1. Event resolved with no sequelae 
2. Event resolved with sequelae 
3. Event ongoing 
4. Death 
11.2.7 
Adverse Event Documentation 
An Adverse Event Report or Serious Adverse Event Report will be completed for all adverse 
events.  Signs and symptoms of each adverse event should be described in detail: nature, date of 
onset, end date, duration, severity, relationship to study drug, action taken, and outcome. 
69


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extension, two follow-up safety visits 4 weeks and 6 months after completion of study drug 
treatment (the end-of-treatment visit) will be performed.  Adverse events will be assessed at 
every site and remote visit.  The Investigator will follow-up on all adverse events up to the end 
of the reporting period or until the symptoms stabilize and follow-up is no longer necessary. 
11.2.11 Reporting Concomitant Medications 
All concomitant medication taken by the subject during the study and the reason for use of the 
medication must be recorded in the source document.  See Section 6.3 for restrictions on 
concomitant medications. 
11.3 
Data Monitoring Committee 
A DMC will be established to review safety data periodically and on an ad hoc basis as outlined 
in the DMC Charter.  The DMC Charter will be maintained separately from the study protocol.  
The DMC can recommend a temporary or permanent stop of the study at any time if there are 
significant safety concerns.  The DMC Charter includes recommended safety stopping rules.  
The DMC will also review the results of pre-planned interim analysis (see Section 10.5).  
Safety information from both MO and FOP DMC safety reviews will be shared across the 
clinical programs.  The FOP DMC will review the 6-month bone safety data from at least 20 
skeletally immature FOP subjects.  Assuming that the safety profile is deemed favorable by the 
FOP DMC, the MO DMC will be notified of the initiation of enrollment of 2- to <7-year-old 
subjects in the EU. 
The DMC will include members with relevant clinical expertise.  The methodology and the 
operating procedures for the safety reviews will be developed by DMC members in collaboration 
with the sponsor and will be documented in the DMC Charter.  
12 Ethical, Regulatory, and Administrative Requirements 
12.1 
Ethical Conduct of the Study 
This clinical study will be conducted in accordance with the protocol and with the ethical 
principles in the Declaration of Helsinki (Appendix 8), inclusive of any subsequent 
amendment(s); and principles consistent with the International Council for Harmonisation Good 
Clinical Practice (ICH GCP),45 European Union Directive 2001/20/EC,46 United States Food and 
Drug Administration (FDA) Code of Federal Regulations, and other applicable local regulatory 
requirements, whichever affords the greater subject protection. 
12.2 
Ethics Board Approval  
The IRB/IEC will comply with ICH GCP and local regulatory requirements.  The IRB/IEC will 
consist of at least five qualified and experienced members with varying backgrounds, including 
at least one member whose primary interest is in a non-scientific area and one member who is 
independent from the study site.  The committee will review the science, medical aspects, and 
ethics of the clinical study. 
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The following documents will be submitted to the IRB/IEC for review: 
• The final study protocol and amendment(s). 
• The Investigator’s Brochure. 
• Written ICF and consent/assent form updates. 
• Written information to be provided to subjects/caregivers. 
• Subject recruitment procedures. 
• Information about payments and compensation available to subjects and caregivers. 
• Investigators’ curriculum vitae and/or other documentation evidencing qualifications. 
Any other documents that the IRB/IEC may need to fulfill its responsibilities will be provided to 
the committee. 
The study protocol and informed consent documents to be used in Study PVO-2A-201 must be 
approved by the IRB/IEC prior to study initiation.  The IRB/IEC will notify the Investigator 
and/or the sponsor in writing, clearly identifying the study, the documents reviewed, and the date 
of approval.  The committee will also provide a list of members, their qualifications, and their 
affiliations.  The IRB/IEC will conduct a continuing review of the ongoing study at appropriate 
intervals. 
The Investigator will be responsible for ensuring the initial approval of the study protocol, 
written ICF, consent form updates, subject recruitment materials, and other documents.  The 
Investigator and/or the sponsor is also responsible to promptly report to the IRB/IEC all changes 
in the research activities and all serious adverse events likely to affect the subject safety or the 
conduct of the study.  The Investigator will not make any changes in the research without 
approval from the sponsor and without submitting for review and approval by the IRB/IEC, 
except where necessary to eliminate apparent immediate hazards to subjects. 
12.3 
Informed Consent Procedures 
Of note, the word “caregiver(s)” is used throughout this protocol to denote legally authorized 
representatives of subjects who are under the age of majority according to local regulations. 
Prior to a subject’s enrollment, the Investigator and/or delegate must fully explain to the subjects 
and/or caregivers all aspects of the study that are relevant to the decision of participation in the 
study.  The subject’s and/or caregiver’s informed consent is documented by means of a written, 
signed, and dated ICF (and age-appropriate assent form if the subject is a minor) per local 
requirements, prior to the start of the study.  The ICF will be written in a language and in a 
manner understandable to the subjects/caregivers.  The Investigator and/or delegate will also sign 
the ICF.  Any modifications to the ICF required by the Investigator prior to submission to the 
IRB/IEC or requested by the IRB/IEC must be submitted to the sponsor or designee for approval 
prior to the implementation of the ICF. 
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One signed and dated copy of the ICF will be given to the subject/caregiver and one signed and 
dated original copy will be maintained by the Investigator in the study file until the end of the 
study. 
The Investigator should clearly indicate the subject’s participation in a clinical study in his/her 
medical chart. 
Institutions, investigators, CROs, and other persons/organizations under this protocol shall abide 
by all requirements applicable to the use and disclosure of subjects' protected health information 
(such as the requirements provided for under the Health Insurance Portability and Accountability 
Act in the United States, the Personal Information and Electronics Document Act in Canada, the 
European Union Directive on Data Protection, and any other similar regulations or legislation). 
Additional considerations concerning informed consent of subjects is discussed in the overall 
evaluation of risks and benefits of this study in Section 1.4. 
12.4 
Subject Confidentiality 
Any research information obtained about the subject in this study will be kept confidential.  A 
subject will not be identified by name, only by subject number.  The subject’s name or any 
identifying information will not appear in any published reports related to this study. 
Information obtained from a subject’s participation in this study may be disclosed with his/her 
consent to healthcare providers for obtaining appropriate medical care.  The subject’s medical 
records/charts and tests that include his/her name may be made available to the appropriate CRO, 
the sponsor and its potential partners, and any regulatory authority.  This is for verifying 
information obtained for this study.  Confidentiality will be maintained throughout the study 
within limits of the law. 
A subject’s name will not be given to anyone except the researchers conducting the study, who 
have pledged an oath of confidentiality.  All identifying information will be kept in a secure area 
under the supervision of the study investigator and will not be transferred outside of the study 
site. 
A subject may take away his/her permission to collect, use, and share information about him/her 
at any time.  If this situation occurs, the subject will not remain in the study.  No additional 
information that identifies the subject will be gathered after that date.  However, the information 
about the subject that has already been gathered and transferred may still be used and given to 
others, as described above, to preserve the scientific integrity and quality of the study. 
12.5 
Publications and Clinical Data Reporting 
All information regarding palovarotene supplied by the sponsor to the Investigator is privileged 
and confidential information.  The Investigator agrees to use this information to accomplish the 
study and will not use it for other purposes without written consent from the sponsor.  It is 
understood that there is an obligation to provide the sponsor with complete data obtained during 
the study.  The information obtained from the clinical study will be used for the development of 
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palovarotene and may be disclosed to the regulatory authority(ies), other investigators, corporate 
partners, or consultants as required. 
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer reviewed scientific or medical journals.  A publications committee 
comprising investigators from the study and representatives from the sponsor, as appropriate, 
will be formed to oversee the publication of the study results, and will reflect the experience of 
all participating study sites.  Subsequently, individual investigators may publish results from the 
study in compliance with their agreement with the sponsor. 
12.6 
Administrative Requirements 
12.6.1 
Amendments to the Protocol 
Modifications to the protocol are only possible through approved protocol amendments 
authorized by the study sponsor.  All protocol amendments will be approved by the appropriate 
regulatory authorities as well as each IRB/IEC prior to implementation.  The Investigator must 
not implement any deviations from or changes to the protocol, except where it is necessary to 
eliminate an immediate hazard to the subject. 
12.6.2 
Protocol Deviations 
The protocol must be read thoroughly, and the instructions followed exactly.  A major deviation 
from the protocol must be reported as soon as possible to the sponsor.  The governing reporting 
guidelines for protocol deviations must be adhered to by the Investigator. 
12.6.3 
Retention of Subject Records and Study Files 
To enable evaluations and/or audits from the regulatory authorities, the appropriate CRO, or the 
sponsor, the Investigator agrees to keep records, including the identity of all subjects (sufficient 
information to link records, eCRFs, and hospital records), all original signed ICFs, copies of all 
eCRFs, source documents, and detailed records of treatment disposition.  The Investigator should 
retain these records according to federal and local regulations or as specified in the Clinical Trial 
Agreement, whichever is longer. 
If the Investigator relocates, retires, or for any reason withdraws from the study, then the sponsor 
should be prospectively notified.  The study records must be transferred to an acceptable 
designee, such as another investigator, another institution, or to the sponsor.  The Investigator 
must obtain written permission from the sponsor before disposing of any records. 
12.7 
Liability and Insurance 
The sponsor has subscribed to an insurance policy covering, in its terms and conditions, its legal 
liability for certain injuries to participating persons arising out of this research performed strictly 
in accordance with the scientific protocol as well as with applicable law and professional 
standards. 
 
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13 Investigator Agreement 
I have read Protocol PVO-2A-201, Amendment 2, dated 23 April 2019: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of 
Palovarotene in Subjects with Multiple Osteochondromas. 
I agree to conduct the study as detailed herein and in compliance with ICH Guidelines for Good 
Clinical Practice and applicable regulatory requirements and to inform all who assist me in the 
conduct of this study of their responsibilities and obligations. 
 
 
_____________________________________________________________________________ 
Investigator (printed name) 
 
 
___________________________________________  
_____________________________ 
Investigator signature  
 
 
 
 
 
Date 
 
 
_____________________________________________________ 
_____________________________________________________ 
_____________________________________________________ 
Study site or name of institution and location (printed) 
 
75


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76


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CLEMENTIA PHARMACEUTICALS INC. 
23 APRIL 2019 
PROPRIETARY AND CONFIDENTIAL 
 
13.  Jones KB, Pacifici M, Hilton MJ. Multiple hereditary exostoses (MHE): elucidating the 
pathogenesis of a rare skeletal disorder through interdisciplinary research. Connect Tissue 
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14.  Inubushi T, Lemire I, Irie F, Yamaguchi Y. Palovarotene inhibits osteochondroma 
formation in a mouse model of multiple hereditary exostoses. J Bone Miner Res. 
2018;33(4):658-666. doi:10.1002/jbmr.3341 
15.  Mills CM, Marks R. Adverse reactions to oral retinoids. An update. Drug Saf. 
1993;9(4):280-290. 
16.  DiGiovanna JJ. Isotretinoin effects on bone. J Am Acad Dermatol. 2001;45(5):S176-182. 
doi:10.1067/mjd.2001.113721 
17.  Glaser DL, Economides AN, Wang L, et al. In vivo somatic cell gene transfer of an 
engineered Noggin mutein prevents BMP4-induced heterotopic ossification. J Bone Joint 
Surg Am. 2003;85-A(12):2332-2342. 
18.  Zasloff MA, Rocke DM, Crofford LJ, Hahn GV, Kaplan FS. Treatment of patients who 
have fibrodysplasia ossificans progressiva with isotretinoin. Clin Orthop. 1998;(346):121-
129. 
19.  Pacifici M, Cossu G, Molinaro M, Tato F. Vitamin A inhibits chondrogenesis but not 
myogenesis. Exp Cell Res. 1980;129(2):469-474. 
20.  Weston AD, Chandraratna RAS, Torchia J, Underhill TM. Requirement for RAR-mediated 
gene repression in skeletal progenitor differentiation. J Cell Biol. 2002;158(1):39-51. 
doi:10.1083/jcb.200112029 
21.  Weston AD, Blumberg B, Underhill TM. Active repression by unliganded retinoid 
receptors in development: less is sometimes more. J Cell Biol. 2003;161(2):223-228. 
doi:10.1083/jcb.200211117 
22.  Duque Orozco MDP, Abousamra O, Rogers KJ, Thacker MM. Magnetic Resonance 
Imaging in Symptomatic Children With Hereditary Multiple Exostoses of the Hip. J 
Pediatr Orthop. April 2016. doi:10.1097/BPO.0000000000000772 
23.  Chavhan GB, Babyn PS. Whole-body MR imaging in children: principles, technique, 
current applications, and future directions. Radiogr Rev Publ Radiol Soc N Am Inc. 
2011;31(6):1757-1772. doi:10.1148/rg.316115523 
24.  Thukral BB. Problems and preferences in pediatric imaging. Indian J Radiol Imaging. 
2015;25(4):359-364. doi:10.4103/0971-3026.169466 
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25.  US Food and Drug Administration. Background Document: Meeting of the Pediatric Ethics 
Subcommittee of the Pediatric Advisory Committee. Silver Spring, MD: US Food and Drug 
Administration; 2015. 
https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisory
Committee/ucm433451.htm. Accessed August 26, 2017. 
26.  American Academy of Pediatrics, American Academy of Pediatric Dentistry, Cote CJ, 
Wilson S, the Work Group on Sedation. Guidelines for Monitoring and Management of 
Pediatric Patients During and After Sedation for Diagnostic and Therapeutic Procedures: 
An Update. Pediatrics. 2006;118(6):2587-2602. doi:10.1542/peds.2006-2780 
27.  Arlachov Y, Ganatra RH. Sedation/anaesthesia in paediatric radiology. Br J Radiol. 
2012;85(1019):e1018-e1031. doi:10.1259/bjr/28871143 
28.  Pediatric Ethics Subcommittee. Background Document. Meeting of the Pediatric Ethics 
Subcommittee of the Pediatric Advisory Committee. FDA Pediatric Advisory Committee; 
2015. 
https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisory
Committee/ucm416405.htm. Accessed May 18, 2018. 
29.  Pediatric Ethics Subcommittee. Minutes of the Pediatric Ethics Subcommittee of the 
Pediatric Advisory Committee. FDA Pediatric Advisory Committee; 2015. 
https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisory
Committee/ucm416405.htm. Accessed May 18, 2018. 
30.  Alessio AM, Kinahan PE, Manchanda V, Ghioni V, Aldape L, Parisi MT. Weight-based, 
low-dose pediatric whole-body PET/CT protocols. J Nucl Med Off Publ Soc Nucl Med. 
2009;50(10):1570-1577. doi:10.2967/jnumed.109.065912 
31.  US Federal Government. Code of Federal Regulations Title 21.  Section 361.1: Radioactive 
drugs for certain research uses. Electronic Code of Federal Regulations. 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=361. 
Accessed November 21, 2017. 
32.  National Research Council (U.S.), ed. Health Risks from Exposure to Low Levels of 
Ionizing Radiation: BEIR VII Phase 2. Washington, D.C: National Academies Press; 2006. 
33.  Porter DE, Lonie L, Fraser M, et al. Severity of disease and risk of malignant change in 
hereditary multiple exostoses. A genotype-phenotype study. J Bone Joint Surg Br. 
2004;86(7):1041-1046. 
34.  Jo AR, Jung ST, Kim MS, Oh CS, Min BJ. An Evaluation of Forearm Deformities in 
Hereditary Multiple Exostoses: Factors Associated With Radial Head Dislocation and 
Comprehensive Classification. J Hand Surg. 2017;42(4):292.e1-292.e8. 
doi:10.1016/j.jhsa.2017.01.010 
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35.  Mordenti M, Ferrari E, Pedrini E, et al. Validation of a new multiple osteochondromas 
classification through Switching Neural Networks. Am J Med Genet A. 2013;161A(3):556-
560. doi:10.1002/ajmg.a.35819 
36.  Larcher V, Brierley J. Developing guidance for pregnancy testing of adolescents 
participating in research: ethical, legal and practical considerations. Arch Dis Child. 
2016;101(10):980-983. doi:10.1136/archdischild-2016-310725 
37.  Centers for Disease Control and Prevention. Normal Joint Range of Motion Study. Centers 
for Disease Control and Prevention. https://www.cdc.gov/ncbddd/jointrom/index.html. 
Published November 29, 2010. Accessed August 26, 2017. 
38.  Hullmann SE, Ryan JL, Ramsey RR, Chaney JM, Mullins LL. Measures of general 
pediatric quality of life: Child Health Questionnaire (CHQ), DISABKIDS Chronic Generic 
Measure (DCGM), KINDL-R, Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic 
Core Scales, and Quality of My Life Questionnaire (QoML). Arthritis Care Res. 
2011;63(S11):S420-S430. doi:10.1002/acr.20637 
39.  Jacobson CJ, Kashikar-Zuck S, Farrell J, et al. Qualitative Evaluation of Pediatric Pain 
Behavior, Quality, and Intensity Item Candidates and the PROMIS Pain Domain 
Framework in Children With Chronic Pain. J Pain Off J Am Pain Soc. 2015;16(12):1243-
1255. doi:10.1016/j.jpain.2015.08.007 
40.  Hicks CL, von Baeyer CL, Spafford PA, van Korlaar I, Goodenough B. The Faces Pain 
Scale-Revised: toward a common metric in pediatric pain measurement. Pain. 
2001;93(2):173-183. 
41.  International Association for the Study of Pain. Faces Pain Scale - Revised Home. 
https://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1519. Published 2017. 
Accessed June 12, 2017. 
42.  US Food and Drug Administration. Guidance for Industry: Suicidal Ideation and Behavior: 
Prospective Assessment of Occurrence in Clinical Trials. 
https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm31515
6.htm. Accessed June 7, 2017. 
43.  US Food and Drug Administration. Guidance for Industry. Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation. Silver Spring, MD: US Food and Drug Administration; 
2009. 
https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm07227
8.htm. 
44.  Cheung LC, Nguyen M, Tang E, et al. Taste evaluation of a novel midazolam tablet for 
pediatric patients: In vitro drug dissolution, in vivo animal taste aversion and clinical taste 
perception profiles. Int J Pharm. 2018;535(1-2):194-200. 
doi:10.1016/j.ijpharm.2017.10.060 
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45.  International Conference on Harmonisation. Efficacy Guidelines : ICH Topic E6 - Good 
Clinical Practice (GCP) Guideline. 
http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html. Accessed 
August 28, 2017. 
46.  European Commission. Directive 2001/20/EC - Public Health - European Commission. 
Public Health. /health/human-use/clinical-trials/directive_en. Accessed August 28, 2017. 
 
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PROPRIETARY AND CONFIDENTIAL 
 
15 Appendices 
Appendix 1 
CYP450-3A4 Inducers or Inhibitors: Exclusionary Medications 
Strong Inducers 
Half-life (h) 
 
Strong Inhibitors 
Half-life (h) 
Carbamazepinea 
18-55, 12-17 
 
Boceprevir 
3.4 
Phenobarbital 
53-140 
 
Clarithromycin 
5-7 
Phenytoin 
24 
 
Conivaptan 
5-8 
Rifabutin 
16-69 
 
Delavirdine 
6 
Rifampin 
3-4 
 
Fluvoxamine 
8-28 
St John’s Wortb 
43.1 
 
Grapefruit juice 
Not available 
Troglitazone 
16-34 
 
Imatinib 
18-20 
Avasimibe 
20 
 
Indinavir 
1.4-2.2 
 
 
 
Itraconazolec 
15-27, 64 
 
 
 
Ketoconazole 
8 
 
 
 
Lopinavir/ritonavir 
5-6 
 
 
 
Mibefradil 
17-25 
 
 
 
Nefazodone 
2-4 
 
 
 
Nelfinavir 
3.5-5 
 
 
 
Posaconazole 
20-66 
 
 
 
Ritonavir 
3-5 
 
 
 
Saquinavir 
7-12 
 
 
 
Telaprevir 
9-11 (at steady state) 
 
 
 
Telithromycin 
10 
 
 
 
Troleandomycin  
1.1 
 
 
 
Voriconazole 
6-9 (dose-dependent) 
 
 
 
Suboxone 
24-42 
a  Half-life 18-55 hours after a single dose and 12-17 hours after multiple doses. 
b Major ingredient hyperium’s half-life. 
c Half-life 15-27 hours after a single dose and 64 hours at steady-state. 
 
81


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PROPRIETARY AND CONFIDENTIAL 
 
Appendix 3 
PROMIS Pain Interference Scales 
Pediatric Self-Report Form (For Subjects Aged 8 to 17 Years) 
 
 
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Parent Proxy Form (Subjects Aged 2 to 7 Years) 
 
 
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PROPRIETARY AND CONFIDENTIAL 
 
Appendix 4 
The Faces Pain Scale – Revised 
Scale for Subjects Aged ≥4 Years 
 
 
 
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PROPRIETARY AND CONFIDENTIAL 
 
Appendix 5 
Retinoid-Specific Adverse Events Assessed by CTCAE Severity Criteria 
Adverse Event 
CTCAE Page Number 
(Version 4.03, 14 June 2010) 
Corneal ulcer 
22 
Conjunctivitis 
22 
Dry eye 
23 
Keratitis 
24 
Night blindness 
24 
Cheilitis 
30 
Dry mouth 
33 
Mucositis oral 
45 
Pancreatitis 
48 
Pharyngitis 
81 
Alanine aminotransferase increased 
107 
Aspartate aminotransferase increased 
107 
Blood bilirubin increased 
107 
Lipase increased 
111 
Serum amylase increased 
112 
Hypertriglyceridemia 
116 
Alopecia 
179 
Dry skin 
179 
Erythroderma 
180 
Photosensitivity 
183 
Pruritus 
184 
Rash maculo-papular 
185 
Skin and subcutaneous tissue disorders – other, specify 
187 
 
 
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PROPRIETARY AND CONFIDENTIAL 
 
Appendix 6 
Columbia-Suicide Severity Rating Scale 
Pediatric C-SSRS for Screening (Subjects Aged 8 to 11 Years) 
 
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SUICIDAL IDEATION 
Ask questions 1 and 2. if both are negative, proceed to "Suicidal Behavior" section. if the answer to question 2 is 'yes", ask 
Past 1 
questions 3, 4 and 5. if the answer to question 1 and/or 2 is "yes", complete "intensity of Ideation " section below. 
~fonth 
1. Wish to be Dead 
Subje-ct endorses thoughts about a wish to be dead or not alive anymore, or wish to fall as!eep and not wake up. 
Ye.-s 
~o 
Hc1'e )'OJI tlumglu abom being 'had o,. wltar;, would be like to b.- di'ad? 
0 
0 
Hc1'e sou ,,·islud ycm wen• dead or wislred yoiA co1Jld go to slup and 11e1·n · wake up? 
Do you e.•n · "·ish )'OJI were11 't alfre anymore? 
If yes, describe: 
2. Non-S~ifk Actiw Sukiclal Thoughts 
Yes 
~o 
Ge.nel'al, non-specific thoughts of wanting to end one's life/commit suicide (e.g., 'T vtil thought abou1 killing nt.J'S6lf') without thoughts o f ways to kill 
oneself/associated methods, intent, or plan during the assessment period. 
0 
0 
Hc1•e sou tlumglu abom doing somerlti11g 10 make yo1Jndf 1101 cfi.w cuymore? 
Hc1•e sou Juul any tlro,,glus abom J..·illing younelf? 
If yes, describe: 
3. Actiw Suicidal Ideation "ith Any l\lethocls (Not Plan) nithout Intent to Act 
Yes 
~o 
Subje-ct endorses thoughts of suicide and has thought o f at feast one method during the assessment period. This is different than a specific plan with time, place 
or method details wo1led out (e.g., thought of method to kill self but not a specific plan). Includes person who wou!d say, "I thought about taking an 0'\'61dost!l 
0 
0 
but] ,Je\'6T mad6 a sp6cific plan as to wh6n, ,~·ht!lr6 or how I would actual/JI do it ... and] ,~·<mid llttVt'lr go through with it. .. 
Hr.1'e )'Oil tl1ougl11 abo111 }iqw1 you ,roll id do tlrat or lro,,• you irould make sounelf trot ali1•e atr.rmo,.e (kill )'Otll'selj)? U11at did sou tltillk r.bom? 
If yes, describe: 
4. Actiw Suicidal Ideation "ith Some Intent to Act, mthout Specific Plan 
Yes 
~o 
Active suicidal thoughts o f killing oneself and subject reports having some intent to act on su ch thou ghts, as opposed to "J }10\'6 th6 thoughts but I definitci.ly 
will not do 01t)'tM,1g about tht!lm. 
0 
0 
U7reu J'Oll t11ougl11 abo111 mr.kiug younelf trot aHiv a tr.rm ore (or killing .rounelf), tfitf sou tltitrk tlrat tit is "·cs somnl1ing .roll miglit a<mr.1/y tfo? 
n1;s is dijf,rem ffom (as opposed to) Jtr.i•i11g tire t/tougJits bm kuo,ri,,g YOll ll'Oltfdu 't do Cllj't/ti11g about fr. 
If yes, describe: 
5. Actiw Suicidal Ideation "ith Spec.ific. Plan and Intent 
Yes 
~o 
Thoughts of killing oneself with details of plan fully or partially wo1led out and subject has some intent to cany it out. 
Hr.1'e )'Oil e1'er tfu·itfnf /tow or w/u,, you "·ollltf make )'Ollrself 11ot aliv' ansmorelkill younelf? Hr.1'e sou e1'e1· plr.mu d 0111 (wor·kc·d 0111 tire details of) lum1 
0 
0 
J'Oll iroultf do it? 
U1rat "·as J'OllT plan? 
U7reu )'Oil made 1/iis plr.u (or· workc·d 0111 tlreu derails), was a,,y pen of.rou tliink;ug abo111 aa1.1al/y doing it? 
If yes, describe: 
INTENSITY OF IDEATION 
The follo...,;ngfeature should be rated witll respect to tlte most severe f)pe ofideafion (i.e., 1-5 from above, with 1 being the least severe and 
5 being the most severe). 
Most 
Most Sel'l?re It/ea/ion: 
Severe 
Type# (l-5) 
Description of It/ea/ion 
f requency 
How man.r limes ltal'l?you ltad tltese tltougltts? 
Write response 
--
(1) Only one time (2) A few times 
(3) A lot 
(4) All the time (0) Don't know/Not applicable 
© 2008 Research Foundation for Mental Hygiene, Inc. 
C-SSR.S-Children's Baseline!Screening (Vernon 6/23/10) 
Page 1 of 2 
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SUICIDAL BEHAVIOR 
fCheck all that awlv, so lonJ! as tllese are separate events; must ask about all fl,ves) 
Past 1 Year 
Actual Attempt: 
Yes 
No 
A potentially self· injurious act committed with at feast some v..iish to die, as a rcult of ac:r. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%. If there is 011,)' intent/desire to die associated with the act, then it can be considered an actual :;uicide attempt. Tit ere does 1101 
hm·e to be OllJ' injury OT han11, just the potential for injury or h:um. If per:son pulls trigger while gun is in mouth btrt gun is broken so no injury results, 
D 
D 
this is considered an attempt. 
Inferring Intent: Even if an individual denies intentfwish to die, it may be infen-ed clinically &-om the behavior or circtullS'tlnces. For e:umple, a highly lethal 
act that is d early not an accident so no other intent but suicide can be infen-ed (e.g., gunshot to head, jumping from window of a high floor/stoty). Also, if 
someone denies intent to die, but they thought that what they did cou!d be lethal. intent may be infen-ed. 
Ditl you el'<'r do a11rtlti11g to try· to kill yourself or wake yourself not alfre anymore? 11'7taf ditl you tlo? 
Ditlyou el'<'r /111rtyourselfo11purpose?11'1(1' tlid.ro11 do fltaf? 
Dill yon ___ as a way to e/ll/ your life? 
Total # of 
Ditlyo11 wa11f to die (el'<'/I a little) wlte11 you __ ? 
Atmnpts 
Were you try,.i11g to make yourself not alfre anymore wlteu you __ ? 
Or tlid you think if was possible yon could haw diet/ from __ ? 
---
Or did.ro11 do it pure(rfor other reasons, not at all to e/ll/your life or kill.ro11n elf (like to make yourself/eel better, or get 
s·o111etl1i11g else to happen)? (Self-Injurious Beha\.ior without suicidal intent) 
If yes, describe: 
Yes No 
Has subject engaged in l'ion-Suiddal Self-Injmious Beha,ior? 
D 
D 
Yes No 
Has subject engaged in Self-Injmious Beha,ior, ilntent unknomi? 
D 
D 
Inte1111pted Attempt: 
\Vb.en the person is intenupted (by an outside circumstance) from starting the potentially self-injurious act (if 11otfor that, actual attempt would hav6 
Yes 
No 
oc.~urrcid). 
D 
D 
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt rather than an intenupted attempt. 
Sh:ooting: Person has gun pointed towards~ 
gun is taken a\\ray by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
ev~ 
if the gun faih to fire, it i.s an attempt. Jumping: Person i:s poised to jump, is grabbed and taken down from ledge.. H~~g: Person has noose around 
necl; but has not yet started to hang · is stopped from doing so-. 
Total # of 
Has flt ere been a fime wlte11 you sfarletl fo do something lo make yourself not alive anymore (e/ll/ your life or kill.roun e/f) b11t 
inteniipted 
someone or someflti11g stoppetlyou before you acf11al(v dill 01(1'f/ti11g? W1tal dillyo11 tlo? 
If yes, describe: 
---
Aborted Attempt: 
\Vb.en person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Yes 
No 
Examples are similar to interrupted attempts, except that the individual stops himfherself, instead of being stopped by something else.. 
D 
D 
Has flt ere been a fime wlte11 you sfarletl fo do something lo make yourself not alive anymore (e/ll/ your life or kill.roun e/f) b11t 
l'Ofl d1011getlyour mbu/ (stoppetlyourse/f) before you act11al(v dill a11.rtlii11g? JV/tat didyo11 do? 
Total # of 
If yes, describe: 
aborted 
---
P.-eparatot1' Acts or Beha,ior: 
Yes 
No 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thc0ught, such as assembling a specific 
method (e.g., buying pills, purchasing a gun) or preparing for one's death by suicide (e.g.~ giving things away, \\Tiring a suicide note). 
D 
D 
Ha1·e you t/011e a11yt/d11g to gel ready to make yourself not alfre anymore (to eud.ro11r life or kill yourself)-like gfri11g flti11gs 
aH~a:v, writing a goodbye note, getting tltiugs yo1111eed to kill yourself? 
If yes, describe: 
Suicidal Beha,ior: 
Yes 
No 
Swicidal behavior was present during the assessment period? 
D 
D 
Answer/or A ctual A ttempts On~\' 
i).1ost Recent 
Most Lethal 
InitiaJJFirst 
A.ttempt 
Attempt 
Attempt 
Vate: 
Date: 
Date: 
Actual Lethality/Meclical Damage: 
£,ue.r Codci 
Emer Code 
£,ue.r Cod6 
0. No physical clama.ge or very minor physical clauu.ge {e.g., :;uiiace scratch.es). 
I. Minor physical damage (e.g., lethargic speech; first-dep:ee· bw:ns; mild bleeding; sprains). 
2. Mode.rate physical dauu.ge; medical attention needed (e.g. ~ conscious but sleepy, somewhat responsive; second-dep'ee 
bums; bleeding of major vessel). 
3. Moderately severe physical damage; medical hospitalization and likely intensive ca.re t'equired (e.g., comatose with 
---
---
---
t'efl.exes intact; third-degree bums less than 20% of body-; extensive blood loss but can recover; major fractw'es). 
4. Severe physical damage; medfral hospitalization with intensive care required (e.g., comatose without t'eflexes; third-
degree butns over 2~/o of body; extensive blood loss with unstable vital signs; maj or damage to a vital area). 
5. Death 
Potential Lethality: Only Answer if Actual Lethality=O 
£,ue.r Codci 
Emer Code 
£,ue.r Cod6 
illety lethality of actual attempt if no medical damage (the following examples, wbi!e having no actual medical damage, had 
potential for Vet)' serious lethality: put gun in mouth and pull~d the bigger but gun faih to fu'e so no medical damage; laying 
on. tl'ain tracks with oncoming train but pulled away befot'e run over). 
0 = Behavior not likely to t'esult in injury 
---
---
---
1 = Behavior l.ikely to result in injwy but not likely to cause death 
2 = Behavior l.ikely to result in death despite available medical care 
e 2008 Research Foundation for ~1ental Hygi.ene, Inc. 
C-SSRS-Children s Baselme/Scr'fflllllg (Vem on 6123/ 10) 
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S UICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to "Suicidal Behavior" section. If the answer to question 2 is 'yes", 
Sint'e La:t 
ask questions 3, 4 and 5. If the answer to question 1 and/or 2 is 'yes", complete "Intensity of Ideation" section below. 
Yhit 
1. Wish to be Dead 
Subject endorses though.ts about a wish to be dead or not alive an)m ore, or wish to fall asleep and not wake up. 
Y e'> 
No 
Hew you tl1011gl11 abom b<'ina dc'ad or wltar it would b<' lik<' 10 be duul? 
D 
0 
Hew ycm ,,.;s/r.·dyou irere duul orwisludyou "'"'Id go 10 sl<'<'P a,,d 1ui•e1· .. rah• up? 
Do you wislr you wnw1 '1aliwcnymor~? 
If yes, de<:.cribe: 
2. Non-Spec.ific. Actiw Suicidal Thoughts 
Yes 
No 
Ge.nen l, non-specific thoughts of wanting to end one's tife/conuni.t suicide (e.g., "J\'ta thought about killing nt.J•sslf') without thoughts of ways to kill 
oneself/associated method~ intent, or plan during the assessment period. 
D 
0 
Hew ycm tlumg/11 abom doing somnlti,,g to mck<' yo1Jndf 1101 clh•e anymore! 
Hew you Juul any thoughts abom J..·i/Hug yo11nelf? 
If yes, de<:.cribe: 
3. Ac.tiw Suicidal Ideation "ith Any Methods (Not Plan) nithout Intent to Act 
Y•s 
No 
Subject endorses though.ts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan). Includes person who would say, "I thought about taking an 
D 
0 
O\'erdo.st!l but I r16'l'Q'11ladt!l a .specific plan a.s to whsn. whsr6 or how ] would act!Sal(ydo it ... mid ] would r1e1wr go through with it. .. 
Hew )'Oil tl1011gl11 abom lum1 .ro11 "·011id '10 tlrar or· how )'Oil i1·0111" make .ro11nelf uor ali1•e a".rmor·t' (k;t/ .ro111·st>lf)? U7rar did .rou rliink abom? 
If yes, de<:.c1ibe: 
4. Ac.tiw Suicidal Ideation "ith Some Intent to Act, nithout Specific Plan 
Yes 
No 
Active suicidal thoughts of killing oneself and subject reports having some inted to act on such thoughts, as opposed to "I hO\'t!l th6 thoughts but I 
diifiriitely w;// not do anything about them. 
D 
0 
U7re11 )'Oil rlroug/11 abollt mckiug .ro11nelf uor ali1•e a".rmore (or· killing .ro111·s1lf), '1i'1 .rou tl1iuk tlrar 1J1is was somnlii11g )'Oil might ca1lal~1
1 '10? 
I ii is is diff~1't'mfrom (as oppost>d ro) lia1•i,,g tire 1l101lglus bm kuowi,,g yoll ,rcll1"u 't '10 a11y1hi11g cbom it. 
If yes, de<:.c1ibe: 
5. Ac.tiw Suicidal Ideation "ith Specific Plan and Intent 
Yes 
No 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to cany it out. 
Haw )'Oil duidt>d Ito,,• 01· wlieu )'Oil "'·0111" make .ro111·ulf uo1 alit•e a"J'lrlOUA'ill yollnt'lf? Ha11e you pie mud Ollf (ll·orkt>d Ollt tlu dnails of) Ito,,• .fOll 
D 
0 
wo1tl'1 do it? 
U7rat ,res J'Ollr·pla,,? 
U7re11 )'Oil mcde this plr.11 (01· wo1·k.·d 0111 tlreu '1nails), "'·as a,,.rpon of you tl1iukiua abollt cauall.r doing it? 
If yes, de<:.c1ibe: 
INTENSITY OF IDEATION 
The followi11gfeaturr: should be rated with respect to tlte most severe f)pe of ideation (i.e., 1-5 Ji-om above, ,.;tit 1 bei11g the least severe 
a11d 5 being Ille most severe). 
Most 
Most Sewre ltleatiou: 
Severe 
Tt•ve # f1-5) 
Descrivtiou of ltleatiou 
f requency 
How mau.r times haw .rou had these thoughts? 
w;;re re.spouse 
--
(1) Only one time (2) A ftw times (3) A lot 
(4) AU the rime 
(0) Don't know/Not applicable 
© 2008 Research Fo undation for Mental Hygiene, Inc. 
C-SSRS- Children's Since last Visit {Version 6/23/ 10) 
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SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to "Suicidal Behavior" section. If the answer to question 2 is "yes", 
Past 
ask questions 3, 4 and 5. If the answer to question 1 and/or 2 is "yes", complete "Intensity of Ideation" section below. 
I Month 
1. Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Yes 
No 
Have you wished you were dead or wished you could go to sleep and not wake up? 
D 
D 
If yes. describe: 
2. Non-Specific Active Suicidal Thoughts 
General. non-specific thoughts of wanting to end one's life/commit suicide (e.g., "I've thought ahout killing myself') without thoughts of ways to kill 
Yes 
No 
oneself/associated methods, intent, or plan. 
D 
D 
Have you actually had a11y thoughts of killing yourself? 
If yes. describe: 
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
Yes 
No 
place or method details worked out (e.g., thought of method to kill self but not a "l'ecific plan). Includes person who would say, "/thought about taking an 
D 
D 
overdose but I never made a specific plan as to when, where or how I would actually do it ..... and I would never go through with it. " 
Have you been thinking about how you might do this? 
If yes, describe: 
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts as opposed to "I have the thoughts but I 
Yes 
No 
definitely will not do anything about them. " 
D 
D 
Have you had these thoughts and had some intention of acting on them? 
If yes, describe: 
5, Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Yes 
No 
Have you started to work out or worked out the details of how to kill yourself? Do you illlendto carry out this pllUI? 
D 
D 
If yes. describe: 
INTENSITY OF IDEATION 
The followingfeatures should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe 
and 5 being the most severe}. Ask about time he/she was feeling the most suicidal. 
Most 
Most Severe Ideation: 
Severe 
---
~-----------------------~ 
Type# (1-5) 
Description of Ideation 
Frequency 
How lllllllY times have you had these thoughts? 
--
(1) Less than once a week (2) Once a week (3) 2-5 times in week (4) Daily or almost daily 
(5) Many times each day 
Duration 
When you have the thoughts, how 1011g do they last? 
(1) Fleeting -few seconds or minutes 
(4) 4-8 hours/most of day 
--
(2) Less than 1 hour/some of the time 
(5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts 
(4) Can control thoughts with a lot of difficulty 
--
(2) Can control thoughts with little difficulty 
(5) Unable to control thoughts 
(3) Can control thoughts with some difficulty 
(0) Does not attempt to control thoughts 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting 011 
thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide 
(4) Deterrents most likely did not stop you 
--
(2) Deterrents probably stopped you 
(5) Deterrents definitely did not stop you 
(3) Uncertain that deterrents stopped you 
(O) Does not apply 
Reasons for Ideation 
What sort of reasons did you have/or thinking about wanting to die or killing yourself? Was it to end the pain or stop the way 
you were feeling (in other words you could11 't go on living with this pai11 or how you werefeeli11g) or was it to get atte11tion, 
revenge or a readion from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others 
(4) Mostly to end or stop the pain (you couldn'tgo on 
--
(2) Mostly to get attention, revenge or a reaction from others 
living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others 
(5) Completely to end or stop the pain (you couldn"t go on 
and to end/stop the pain 
living with the pain or how you were feeling) 
(O) Does not applv 
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Adult C-SSRS After Screening (Subjects Aged ≥12 Years)
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SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to "Suicidal Behavior" section. If the answer to question 2 is "yes", 
Since Last 
ask questions 3, 4 and 5. If the answer to question 1 and/or 2 is "yes", complete "Intensity of Ideation" section below. 
Visit 
1. Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Yes 
No 
Have you wished you were dead or wished you could go to sleep and not wake up? 
D 
D 
If yes, describe: 
2. Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one's life/commit suicide (e.g., "I've thought about killing myself') without thoughts of ways to kill 
Yes 
No 
oneself/associated methods, intent, or plan during the assessment period. 
D 
D 
Have you actually had IUIY thoughts of killing yourself? 
If yes. describe: 
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Yes 
No 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan). Includes person who would say, "I thought ahout taking an 
D 
D 
overdose but I never made a specific plan as to when, where or how I would actually do it ... and I would never go through with it. " 
Have you been thinking about how you might do tltis? 
If yes, describe: 
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to "I have the thoughts but I 
Yes 
No 
definitely will not do anything about them. " 
D 
D 
Have you had these thoughts and had some intention of acting on them? 
If yes, describe: 
5. Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to cany it out. 
Yes 
No 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
D 
D 
If yes. describe: 
INTENSITY OF IDEATION 
Thefollowingfeatures should be rated with respect to the most severe type of ideation (i.e., 1-5from above, with I being the least severe 
and 5 being the most severe). 
Most 
Most Severe Ideation: 
Severe 
--
Type# (1-5) 
Description of Ideation 
Frequency 
How many times have you had these thoughts? 
--
(I) Less than once a week (2) Once a week (3) 2-5 times in week 
(4) Daily or almost daily (5) Many times each day 
Duration 
Whe11 you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes 
(4) 4·8 hours/most of day 
--
(2)Lessthan I hour/some of the time 
(5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(!)Easily able to control thoughts 
(4) Can control thoughts with a lot of difficulty 
--
(2) Can control thoughts with little difficulty 
(5) Unable to control thoughts 
(3) Can control thoughts with some difficulty 
(O) Does not attempt to control thoughts 
Deterrents 
Are there things - anyone or anything (eg.,family, religion, pain of death) - that stoppedyo11fro111 wanting to die or acting on 
thoughts of committing suicide? 
(I) Deterrents definitely stopped you from attempting suicide 
(4) Deterrents most likely did not stop you 
--
(2) Deterrents probably stopped you 
(5) Deterrents definitely did not stop you 
(3) Uncertain that deterrents stopped you 
(O) Does not apply 
Reasons for Ideation 
What sort of reasons did you have/or thinking abo11t wanting to die or killing yourself? Was it to end the pain or stop the way 
you were feeling (in other words you couldn't go on living with this pain or how you were fee/i11g) or was it to get attention, 
revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others 
(4) Mostly to end or stop the pain (you couldn't go on 
--
(2) Mostly to get attention, revenge or a reaction from others 
living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others 
(5) Completely to end or stop the pain (you couldn't go on 
and to end/stop the pain 
living with the pain or how you were feeling) 
(O) Does not apply 
Version 1/14/09 
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Appendix 7 
Five-point Hedonic Face Scale 
Hedonic Face Scale for Palatability of Sprinkled Drug Product (Subjects Aged ≥4 Years) 
 
 
 
From Cheung et al (2012).44 
 
 
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Appendix 8 
Declaration of Helsinki 
 
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"The heath of my patient wl be my first consideration, n and the Internat ional Code of 
Medical Et hics declares that, "A physician shal act in t he patient's best interest when 
provi::ling medical care .. • 
4. 
It is the duty of t he physician to promote .and saf eguard the health, well-being 
and rights of pat ients, incllding those who are involved in medical research. The 
physician's knowledge .and conscience are dedicated to the fulfiknent of this duty. 
5. 
Medical progress is based on research t hat ultimately must inck.lde studies 
involving human subjects. 
6. 
The pri'nary purpose of medical research ilvolving human subjects is to 
understand t he causes. development and effects of diseases and improve preventive. 
diagnostic and therapeutic ilterventDns (methods, procedures and treatments). Even 
the best proven interventions must be evaluat ed continually through research for thei' 
safety, effect iveness. effic:iency. accessibity and qualty. 
7. 
Medical research is subject to ethical standards that promote and ensure 
respect for an human subjects and protect their health and rights. 
8. 
Whie the primary purpose of medical research is to generat e new knowledge. 
this goal can never take precedence over the rights and interests of individual 
research subjects. 
9. 
It is the duty of physicians who are involved in medical research to protect the 
IWe. health, dignity, i'ltegrity, right to seW-determi'lation, privacy, and confidentially of 
personal ilformation of research subjects. The responsibity for the protection of 
research subjects must always rest with the physician or other heath care 
professionals and never wlh the research subjects, even though they have given 
consent. 
10. 
Physicians must consiler the ethical legal and regulatory norms and 
standards for researctn involving human subjects in their own countries as wel as 
applicab~ internatDnal norms and standards. No national or international ethical. legal 
or regulatory requi'ement shouk:i reduce or eirnirnat e any of the protectDns for 
research subjects set forth i1 this Declaration. 
11. 
Medical research shouk:i be conducted in a manner that minimises possible 
harm to the envi"onment. 
12. 
Medical research involving human subjects must be conducted onty' by 
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individuals with the appropriate ethics and scientlic education. training and 
qualifications. Research on patients or healthy volunteers requires the supervision of a 
competent and approp riately quaftied physician or other heath care professional 
13. 
Groups that are underrepresented in medical research shoukj be provided 
appropriate access to participatDn in research. 
14. 
Physicians who combine medical research with medical care shoukj involve 
their patients i'l research onty to the extent that this is j.Jstified by its potent ial 
preventive. diagnostic or therapeutic: value and if the physician has good reason to 
believe that parti:ipatio n i1 the research study wl not adverset,i affect the health of 
the patients who serve as research subjects. 
15. 
Appropriate compensatDn and treatment for subjects who are harmed as a 
result of participating i'l research must be ensured. 
Risks. Burdens and Benefits 
16. 
In medical practice and i'l medical research, most i'lt erventions i'lvotve risks 
and burdens. 
Medical research involving human subjects. may onty' be conducted if the 
importance of the objective outweighs the risks and burdens to the research subjects. 
17. 
AD medical research involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to ttie i'ldividuals and groups involved in 
the research ii comparison wlh foreseeable benefits to them and to other indivDuals 
or groups affected by the condti:>n under investigation. 
Measures to minimise the risks must be implemented. The risks must be 
cont inuousty' monlored, assessed and documented by t he researcher. 
18. 
Physicians may not be involved in a research study involving human subjects 
unless they are confident that the risks have been adequately assessed and can be 
satisfactorily managed. 
When the risks are found to outweigh t he potential benefits or when there 6 
conclusive proof of defiintive outcomes. physiciarns must assess whether to continue. 
modify or immediately stop the study. 
Vulnerable Grouo.s and lndlvlduals 
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19. 
Some groups and ildividuats are particularly vulnerable and may hav.e an 
ilcreased Hkeihood of bei"lg wronged or of i'lcurrilg additional harm. 
Al wtierable groups and i'ldM::luals should receNe specifically consi::tered 
protectDn. 
20. 
Medical research wlh a wtierable group is onty' justified if the research is 
responsive to the health needs or priorities of this group and the research c.annot be 
carried out i'l a non~vu Iner able group. In addl:Dn, this group shoukj stand to benefit 
from the knowledge, practices or ilterventions that result from the research. 
Scientific Requirements and Research> Protocols 
21. 
Medical research ilvolving human subjects must conform to genera~ 
accepted scientlic principles, be based on a thorough knowledge of the scientlic 
literature, other relevant sources of i'lformatDn, and adequate laboratory arnd, as 
appropriate, aninal experi'nentation. The wefare c f animals used for research must 
be respect ed. 
22. 
The design and performance of each research study i'lvolving human subjects 
must be cearty descrbed and j.Jstified in a research protocol. 
The protocol sh.-0uld contail a statement o·f the ethical considerations. ilvolved 
and should indicate how the principles in this DeclaratDn have been addressied. The 
protocol should ilcllde information regardilg funding, sponsors. ilstl:utional 
affliations. pot ential conflicts of interest, ilcentives for subjects and ilformatDn 
regarding provisions for treating and/or compens.ati'lg subjects who are harmed as a 
consequence of participatDn in the research study. 
In clnical trials, the protocol must atso descrbe appropriate arrangements for 
post-trial prov!;ions. 
Research Ethics Committees 
23. 
The research protocol must be submitted for consDeratDn, comment, 
guidance and approval to the concerned research ethics committee before the study 
begils. This commttee must be transparent in its functioni'lg, must be ildependent of 
the researcher, the sponsor and any other undue influence and must be duty qualied. 
It must take ilto consi:leratDn the laws and regulations of the country or countries i'l 
which the research is tio be performed as well as applicable i'lternatDnal norms and 
4/8 
110


PROTOCOL PVO-2A-201, AMENDMENT 2 
 
PAGE 111 OF 114 
CLEMENTIA PHARMACEUTICALS INC. 
23 APRIL 2019 
PROPRIETARY AND CONFIDENTIAL 
 
 
standards but these must not be allowed to reduce or eliminate any of the protections 
for research subjects set forth in this DeclaratDn. 
The commttee must have the right to monlor ongoi'lg studies. The researcher 
must provi::le monloring information to the conmittee, especially information about 
any serious adverse events. No amendment to the protocol may be made w·ithout 
consideration and approval by the committee. After the end of the study, the 
researchers must subml a final report to the committee containilg a summ.ary of the 
study's findilgs and conclusDns. 
Privacy and Conflilent!allty 
24. 
Every precaution must be taken to protect the privacy of research subjects 
and the confidentialty of their personal informaOOn. 
Informed Consent 
25. 
Partic~atDn by individuats capable of givi'lg informed consent as subjects i'l 
medical research must be voluntary. Although it may be appropriate to cons1ult: family 
members or communty leaders, no ildividual capable of givi'lg informed consent may 
be enroled in a research study unless he or she freet,i agrees. 
26. 
In medical research involving human subjects capable of giving informed 
consent, each potentia I subject must be adequately informed of the aims, methods, 
sources of funding, any possible conflicts of ilterest, institutDnal affiliations of the 
researcher. the anticipated benefits and potential risks of the study and the 
discomfort I may ental. post~study provisDns and any other relevant aspects of the 
study. The potential subject must be informed of the right to refuse to participate in 
the study or to withdraw consent to participate at any time without reprisal Special 
attention shoukj be giv.en to the specific information needs of indivi::lual potential 
subje<:ts as wen as to tile methods used to dei-letr the information. 
After ensuring that the potential subject has understood the informatDn, the 
physician or another appropriately qualified individual must then seek the potential 
subject's freety.given i'lformed consent, preferably in wrling. If the consent cannot be 
expressed in wrli'lg, the non-written consent must be formally documented and 
wlnessed. 
Al medical research subjects shouk:i be given the option of bei'lg informed 
about the general outc10me and resuts of the study. 
5/8 
111


PROTOCOL PVO-2A-201, AMENDMENT 2 
 
PAGE 112 OF 114 
CLEMENTIA PHARMACEUTICALS INC. 
23 APRIL 2019 
PROPRIETARY AND CONFIDENTIAL 
 
 
27. 
When seeking informed consent for participation in a research study the 
physician must be particularly cautious if the potential subject is in a dependent 
relationship wlh the ptnysician or may consent under duress. In such situations the 
ilformed consent must be sought by an appropriatety' qualified ildividual who is 
completely independent of this relatDnship. 
28. 
For a potential research subject who is incapab~ of giving ilformed consent, 
the physician must seek i'lformed consent from the legaty' authorised representatt.te. 
These individuals must not be included in a research study that has no likeih ood of 
benefit for them unless it is intended to promote the heath of the group rep resented 
by the potential subject, the research cannot inst ead be performed with persons 
capable of providing informed consent. and t he research entails only milinal risk and 
mi'limal burden. 
29. 
When a potential research subject who is deemed incapable of gM'lg informed 
consent is able to gN'e assent to dec:isions about p artic:ipatDn il research. ttne 
physician must seek that assent in addl:Dn to the consent of the legaty' auttnorised 
representative. The potential subject's dissent shoukj be respected. 
30. 
Research invotvilg subjects who are phys icalty or mentally incapable of giving 
consent. for examp~. unconscious pat~nts. may be done only W the physical or 
mental condl:ion that p revents gM'lg ilformed consent is a necessary charact eristic 
of the research group. In such ci"cumstances the physician must seek informed 
consent from the legalty authorised representathle. If no such representative is 
avalable and if the research cannot be delayed. t he study may proceed without 
i'lformed consent provi::led that the specific reasons for involving subjects with a 
condl:Dn that renders them unab~ to give informed consent have been stated in the 
research protocol and the study has been approved by a research ethics commttee. 
Consent to remain in the research must be obtairned as soon as possible from the 
subject or a legaty' authorised representative. 
31. 
The physician must fully inform the patient which aspects of their care are 
related to the research. The refusal of a patient to participate in a study or the 
patient's decision to withdraw from the study mu:st never adversely affect ttne patient· 
physician relationship. 
32. 
For medical research usi'lg ijentifiable human material or data, such as 
research on material or data contained in biobanlcs or sinlar repositories. physicians 
must seek ilformed consent for its collect ion. storage and/or reuse. There may be 
exceptional stuations where consent woukj be irnpossi:>le or impracticab~ to obtail 
6/8 
112


PROTOCOL PVO-2A-201, AMENDMENT 2 
 
PAGE 113 OF 114 
CLEMENTIA PHARMACEUTICALS INC. 
23 APRIL 2019 
PROPRIETARY AND CONFIDENTIAL 
 
 
for such research. In such situatDns the research may be done onty' after 
consideration and approval of a research ethics commttee. 
Use of Placebo 
33. 
The benefits, risks, burdens and effectiveness of a new intervention must be 
tested against those of the best proven interventiln(s), except in the followi'lg 
circumstances: 
Where no proven intervention exists, the use of placebo. or no intervention, is 
acceptable; or 
Where for compe.,g and scientifically sou nd methodobgical reasons the use 
of any i'ltervention less effective than the best proven one. the use of placebo. or no 
interventDn is nec:essa ry to determine the efficacy or safety of an i'ltervention 
and the patients who receive any interventDn less effective than the best 
proven one, placebo. or no intervenOOn will not be subject to additional risks of serious 
or irreversible harm as a result of not receivi'lg the best proven i'l terven tion ~ 
Extreme care must be taken to avoD abuse of this option. 
Post-Trlal Provisions 
34. 
In advance of a clnical trial sponsors, researchers and host country 
governments shouk:i make provisions for post~tria l access for an partic~ants who stHI 
need an intervention i:ientlied as beneficial in the trial This information must also be 
disclosed to participants during the informed consent process. 
Research Registration and Publlcatlon and Dissemination of 
Results 
35. 
Every research study i'lvotving human subjects must be registered in a publicly 
accessi:>le database before recruitment of the first subject. 
36. 
Researchers, authors, sponsors, editors and publishers all have ethical 
obligatDns with regard to the publication and dissemination of the resuts of research. 
Researchers have a duty to make publicly avalable the resuts of their research on 
human subjects and are accountable for the completeness and accuracy of their 
reports. All parties sho·uk:i adhere to accepted guidelines for ethical reporti'lg. Negative 
and inconclusive as well as posl:ive results must be published or otherwise made 
7/8 
113


PROTOCOL PVO-2A-201, AMENDMENT 2 
 
PAGE 114 OF 114 
CLEMENTIA PHARMACEUTICALS INC. 
23 APRIL 2019 
PROPRIETARY AND CONFIDENTIAL 
 
 
pubicty' available. Sources of funding, instlut:Dnal affiliations and conflicts of interest 
must be declared in the publication. Reports of research not in accordance wlh the 
principles of this DeclaraOOn should not be accepted for publication. 
Unproyen Interventions In Cllnlcal Practice 
37. 
In t he treatmernt of an ildividual patient , where proven interventions do not 
exist or other known irnterventions have been ilefifec:t ive, the physician. after seeking 
expert advice, wlh informed consent from t he patient or a legaty' authorised 
representative, may us.e an unproven interventDn if in the physician's judgement it 
offers hope of saving lfe, re-establishilg health orr alleviating suffering. This 
ilterventDn should subsequent ly be made the object of research, designed to 
evallate ls safety and effi:acy. In all cases. new information must be recorded and, 
where appropriate, made publicly availab~. 
C W>rtd Medlca.I Association, Inc. • All Rlghts reserved. 
C Asoclaci6n m edica m undlal - lbdos los derechos reservados .• 
C L'Assodatlon Medicate Mondlate - b us drolts reserves. 
8/8 
114

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Efficacy and 
Safety Study of Palovarotene in Subjects with Multiple Osteochondromas
Study PVO-2A-201 (MO-Ped Trial)
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled Efficacy and 
Safety Study of Palovarotene in Subjects with Multiple Osteochondromas
Study PVO-2A-201 (MO-Ped Trial)
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OVERVIEW AND INVESTIGATIONAL PLAN
1.1
Study design
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1.2
Objectives 
1.2.1
Primary Objective
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1.2.2
Secondary Objectives
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1.2.3
Exploratory Objectives
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1.3
Determination of sample size
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1.4
Study plan
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1.5
Modifications to the statistical section of the protocol
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1.6
Statistical modifications from Protocol 
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2
STATISTICAL AND ANALYTICAL PROCEDURES
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2.1
Analysis endpoints
2.1.1
Demographic and baseline characteristics
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2.1.2
Prior or concomitant medications
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2.1.3
Efficacy endpoints
2.1.3.1.
Primary efficacy endpoint
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2.1.3.2.
Secondary efficacy endpoints
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2.1.3.3.
Exploratory efficacy endpoints
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2.1.4
Safety endpoints
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2.1.4.1.
Adverse event variables
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Table 1. Retinoid-associated adverse events by CTCAE severity criteria
Adverse Event
CTCAE 
Page 
Number
(Version 4.03, 14 June 2010)
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2.1.4.2.
Deaths
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2.1.4.3.
Laboratory safety variables
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Table . Clinical laboratory parameters
Biochemistry:
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Lipid Profile1:
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2.1.4.4.
Electrocardiogram variables
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2.1.4.5.
Vital Signs 
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2.1.4.6.
Physical Exams
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2.1.4.7.
Columbia-Suicide Severity Rating Scale
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2.1.4.8.
Knee and hand/wrist radiographs for assessment of epiphyseal growth plate
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2.1.4.9.
Bone Densitometry
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2.1.4.10.
Linear Growth Assessment
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2.1.4.11.
Osteonecrosis
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2.1.4.12.
Long bone Length
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Tanner Staging
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2.1.5
Palatability of sprinkled drug product
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Disposition of subjects
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2.3
Analysis populations
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Statistical methods
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Prior or concomitant medication
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Analyses of efficacy endpoints
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Analyses of primary efficacy endpoint
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Analyses of secondary efficacy endpoints
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2.4.5.2.
Deaths
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Analyses of laboratory variables
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2.4.5.4.
Analyses of ECG variables
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2.4.5.5.
Analyses of vital sign variables
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Analyses of Columbia-Suicide Severity Rating Scale variables
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Analyses of knee and hand/wrist radiographs for growth plate assessment 
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2.4.5.8.
Analyses of bone densitometry
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Analyses of pharmacokinetic endpoints
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3
INTERIM ANALYSIS
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5
REFERENCES
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6
APPENDICES
6.1
PROMIS T-Score Conversions
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6.2
Potentially Clinically Significant Abnormalities criteria
PCS criteria for laboratory parameters
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6.3
Reference Values for Normal Joint Range of Motion
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