A Phase 3, Efficacy and Safety Study of Oral Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva (FOP)
Phase: PHASE3
Conditions: Fibrodysplasia Ossificans Progressiva
Sponsor: Clementia Pharmaceuticals Inc.

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PAGE 2 OF 151 
 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
Protocol Signature Page 
 
A Phase 3, Efficacy and Safety Study of Oral Palovarotene for the Treatment of 
Fibrodysplasia Ossificans Progressiva (FOP) 
 
Protocol Number: PVO-1A-301 
 
Signature of Approval for Protocol PVO-1A-301  
(Amendment 5: 30 October 2020) 
 
 
CLEMENTIA PHARMACEUTICALS INC. 
, MD 
 
NAME: 
 
 
 
 
 
SIGNATURE: 
 
DATE:  
 
 
 
 
 
 
 
 
 
PI
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PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 3 OF 151 
 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
Protocol Amendment 5 Summary of Changes 
This fifth amendment to the protocol for Study PVO-1A-301 was finalized on 30 October 2020. 

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PAGE 4 OF 151 
 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
Location/Section Number 
Change 
Rationale 
Major changes that affected the clinical conduct of the study: 
Protocol Synopsis 
Table 1, Table 3 
Section 1.1.3.2.2 
Palovarotene Phase 2 
Interventional Studies 
Section 2.4 Secondary 
Objectives for Part C 
Section 3.1 Overview of 
Study Design 
Section 3.2 Study Rationale 
Section 5.3 Subject 
Withdrawal or Early 
Termination from Study 
Section 7.1 Screening, 
Recruitment, and Informed 
Consent 
Section 7.2.2 Physical 
Examination 
Section 7.2.3 Body Weight 
and Linear Growth 
Section 7.2.4 Vital Signs 
7.2.8 Adverse Events 
Section 7.2.9 Concomitant 
Medications 
Section 7.3.2 Knee and 
Hand-wrist Radiographs 
Section 7.3.5 Serum Lipids 
Section 7.3.6 Liver Enzymes 
Section 7.3.7 
Lipase/Amylase 
Section 7.3.8 Central 
Nervous System 
through 7.3.9 Hearing and 
Visual Disturbances 
Section 7.4.1 Low-dose 
Whole Body Computed 
Tomography 
Section 7.8 Temporary 
Measure (Procedures Related 
to COVID-19 Pandemic) 
Section 8.5.3 Safety  
Section 9.1.10 Follow-up of 
Adverse Events and Serious 
Adverse Events 
 
Part C was added for skeletally immature 
subjects who stopped taking study 
medication for any reason before 
completion of Part A/B.  Part C includes 
yearly visits for up to a 2-year follow-up 
period following last dose. No dosing will 
occur during Part C.  
Assessments obtained in Part C include 
yearly linear height, knee height, weight, 
physical exam, vital signs, radiographic 
assessments of the knee and hand-wrist, 
low-dose WBCT imaging excluding head, 
adverse events, and concomitant 
medications. 
Participation in Part C will continue only as 
long as subjects remain skeletally immature. 
The up to 2-year period for Part C would 
begin the last day the subject stopped 
receiving study drug in Part A/B.  However, 
the maximum participation in the trial will 
not be extended beyond 48 months for Parts 
A, B, and C in total.  
 
Secondary objective added for Part C to 
monitor off treatment longer-term safety in 
skeletally immature subjects off treatment.  
Safety will be summarized for Part C.  
To implement safety measures 
based on DMC recommendations 
given the serious identified risk of 
premature physeal closure. Part C 
is being implemented to ensure that 
assessments of safety are offered 
for up to 2 years to subjects who 
were skeletally immature at the 
time they stopped taking study 
medication for any reason before 
completion of Part A/B. A 2 year 
follow up is an adequate timeframe 
to assess growth and physeal 
changes off palovarotene treatment.  
 

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PAGE 5 OF 151 
 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
Location/Section Number 
Change 
Rationale 
Synopsis 
Section 3.1 Overview of the 
Study Design 
Section 3.2 Study Rationale 
Section 5.1 Study Population 
 
 
 
 
 
 
 
 
 
 
As of 04Dec2019 all subjects < 14 years of 
age were required to interrupt study drug 
due to a partial clinical hold placed on the 
palovarotene clinical development program 
by the US FDA. Treatment will 
subsequently not be restarted in children 
<14 years of age.  
As a consequence of the FDA 
partial clinical hold subjects 
remained off treatment for a 
prolonged period of time.  As such 
a significant gap in dosing occurred 
which would render any further 
data to inform additional 
benefit/risk uninterpretable in this 
patient population. Part C was 
added to ensure continued 
collection of safety data off 
treatment for these subjects and 
any subjects who stopped treatment 
for any other reason.  
Section 7.3.3 Bone Safety 
Management Plan 
Section 7.4.1 Low-dose, 
Whole Body Computed 
Tomography 
Added assessments for spinal health carried 
out on low dose WBCT scans collected in 
the study.  
Emerging data from PVO-2A-201 
trial in the multiple 
osteochondroma indication has 
suggested a potential effect of PVO 
on bone mineral accrual. As such 
assessments were added to further 
characterize this risk in FOP 
subjects. 
Section 3.1 Overview of 
Study Design 
Section 7.1 Screening, 
Recruitment, and Informed 
Consent 
Section 7.8 Temporary 
Measures (Procedures 
Related to COVID) 
Integrated protocol amendment 4 addendum 
previously created to describe temporary 
measures applied during the COVID 
pandemic. Additional update to these 
temporary measures to clarify that 
radiographic assessments are required for 
subjects (who were skeletally immature at 
their last assessment) as part of the minimal 
safety procedures prior to re-initiation of 
palovarotene.   
To integrate protocol amendment 4 
addendum. To assess skeletal 
maturity in subjects ≥14 years re-
initiating treatment in order to 
ensure appropriate safety follow up 
as well as determine if weight-
based dosing is required. 
Other changes that did not affect the clinical conduct of the study: 
Section 7.2.8 Adverse Events 
Section 9.1.10 Follow up of 
Adverse Events and Serious 
Adverse Events 
Collection of SAE reports, including deaths, 
will continue until 30 days past end of 
study. 
 
Clarification of end date of 
collection of SAE (including) death 
reports. 
Table 1 
Corrected table 1 header. 
Integration of administrative 
change from protocol amendment 4 
addendum. 
Groups responsible for study 
conduct 
Revised the vendor contact information. 
To ensure that contact information 
is up-to-date. 

PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 6 OF 151 
 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
Location/Section Number 
Change 
Rationale 
Section 7.3.5 Lipid Profile 
Section 7.3.6 Liver Enzymes 
Section 7.3.7 
Lipase/Amylase 
Added to text that assessments during flare-
up-based treatment in Parts A/B (complete 
lipid, liver enzyme, and lipase/amylase 
profiles) will be performed as part of the 
biochemistry testing at Flare-up Cycle 
Safety Day 1 and then every 12 weeks 
thereafter until treatment of the last flare-up 
or traumatic event within a Flare-up Cycle 
is completed. 
To align text with Table 2 
General 
Corrected minor errors and formatting 
irregularities. Added clarifications.  
Renumbered tables as required. 
To provide a consistent 
presentation. 
 

PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 7 OF 151 
 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
Groups Responsible for Study Contact 
Task 
Vendor or Responsible Group 
Trial Oversight and Management 
Medical Writing 
Clementia Pharmaceuticals Inc. 
1000, de la Gauchetière, suite 1200 
Montreal, Quebec, Canada H3B 4W5 
 
Tel: 1.514.940.3600 
Fax: 1.888.966.0135 
Data Management 
 
Pharmaceutical Product Development Inc. (PPD) 
PPD Data Management Lead 
Email: 
 
PPD 
3900 Paramount Parkway 
Morrisville, NC 27560 
Tel: 
 
 
 
PPD Study Manager 
Email: 
 
PPD 
 
 
Tel: 
 
Electronic Data Capture System 
 
Medidata Project Manager 
Email: 
 
Medidata 
 
 
Tel: 
 
Clinical Monitoring 
 
PPD Clinical Team Manager (Global) 
Email: 
 
PPD 
. 
 Greece 
Tel: 
 
Cell: 
 
Medical Monitoring 
 
PPD 
 
PPD 
 
 
24-Hour Safety Hotline: 1.800.201.8725 
Safety Fax: 1.888.488.9697 
Safety Email: wilsafety@ppd.com 
ePIP.ppd.com 
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CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
Task 
Vendor or Responsible Group 
Central Laboratory 
PPD Project Manager 
Email: 
PPD Laboratories 
, 
Tel: 
Central Electrocardiogram Laboratory 
BioTelemetry Project Manager 
Email: 
BioTelemetry Research 
Tel: 
Clinical Trial Material Logistics 
Marken Project Manager 
Email:
Marken 
Tel: 
Cell: 
Imaging Core Laboratory 
PAREXEL Project Manager 
Email: 
PAREXEL International 
 USA, 
Tel: 
Statistical Analysis Support 
Cytel 
, Biostatistics, 
Email: 
Cytel Inc. 
Tel: 
Bioanalytical Laboratory 
 BS 
Q2 Solutions Project Manager 
Email: 
Q2 Solutions 
Tel: 
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PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 9 OF 151 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
Task 
Vendor or Responsible Group 
Genetics Laboratory 
Genetic Diagnostic Laboratory, Laboratory Manager 
University of Pennsylvania 
Tel: 
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PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 10 OF 151 
 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
Protocol Synopsis 
Title 
MOVE Trial: A Phase 3, Efficacy and Safety Study of Oral Palovarotene for the 
Treatment of Fibrodysplasia Ossificans Progressiva (FOP) 
Sponsor 
Clementia Pharmaceuticals Inc. 
Objectives 
Primary Objectives  
• 
To evaluate the efficacy of palovarotene in decreasing heterotopic 
ossification (HO) in adult and pediatric subjects with FOP as assessed by 
low-dose, whole body computed tomography (WBCT), excluding head, as 
compared to untreated subjects from Clementia’s FOP natural history study 
over 24 months. 
• 
To evaluate the safety of palovarotene in adult and pediatric subjects with 
FOP. 
Secondary Objectives  
• 
To evaluate the effect of palovarotene on flare-up rate and proportion of 
subjects reporting at least one flare-up. 
• 
To evaluate the effect of palovarotene on range of motion (ROM) as 
assessed by the Cumulative Analogue Joint Involvement Scale for FOP 
(CAJIS). 
• 
To evaluate the effect of palovarotene on physical function using 
age-appropriate forms of the FOP-Physical Function Questionnaire 
(FOP-PFQ). 
• 
To evaluate the effect of palovarotene on physical and mental health using 
age-appropriate forms of the Patient Reported Outcomes Measurement 
Information System (PROMIS) Global Health Scale. 
• 
To evaluate the pharmacokinetics of palovarotene. 
Secondary Objective (Part B) 
• 
To continue to provide palovarotene to adult and pediatric subjects with 
FOP and to monitor longer-term safety. 
Secondary Objective (Part C) 
• 
To implement safety measures based on DMC recommendations in order 
to ensure that assessments of safety continue for up to 2 years post last 
dose of study treatment for skeletally immature subjects.    
 
Study Design 
A Phase 3, multicenter, open-label study in adult and pediatric subjects with FOP 
will be conducted in three parts: Part A, the main part of the study; Part B, the 24- 
month extension; and Part C, the up-to-2-year post last dose of study treatment 
follow-up for skeletally immature subjects.  Sources of subjects eligible for 
enrollment in Part A of the MOVE Trial will include: (1) subjects from Study 
PVO-1A-001 (the natural history study [NHS]);  (2) additional subjects clinically 
diagnosed with FOP with the R206H ACVR1 mutation or other FOP variants 
reported to be associated with progressive HO (who have not previously 
participated in any Clementia-sponsored study); and (3) Phase 2 Study PVO-1A-
202 or Study PVO-1A-204 subjects who cannot receive the chronic/flare-up 
regimen due to country of residence or those traveling long distances to participate 
in the Phase 2 trial.  Up to a maximum of 110 subjects will be enrolled into the 
MOVE Trial (up to 99 with the R206H mutation and no previous exposure to 
palovarotene, and up to 11 with other mutations or previous participation in the 
Phase 2 trials), and receive chronic dosing for up to 24 months and undergo flare-
up-based treatment should they experience an eligible flare-up or traumatic event 
as confirmed by the Investigator.   

PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 11 OF 151 
 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
Protocol Synopsis 
As of 04Dec2019 all subjects < 14 years of age were required to interrupt study 
drug due to a partial clinical hold placed on the palovarotene clinical development 
program by the US FDA. Treatment will subsequently not be restarted in children 
<14 years of age.  
The efficacy of palovarotene treatment in the MOVE Trial Part A, as measured by 
the change in new HO volume, will be compared to that observed in untreated 
subjects who participated in the NHS. 
Study Design (cont.) 
 
In Part B, the study will be extended for an additional 24 months in order to 
provide the chronic/flare-up palovarotene dosing regimen to all subjects until 
commercial availability and to obtain longer-term safety data.  No new subjects 
will be enrolled into Part B.  
Chronic Treatment: Part A 
Subjects will receive orally administered 5 mg palovarotene once daily 
(weight-adjusted for skeletally immature subjects [ie, subjects under the age of 
18 years with less than 90% skeletal maturity on hand-wrist radiography at 
Screening]) as chronic dosing for up to 48 months.  Note: all weight-based dosing, 
both chronic and flare-up, will cease when subjects achieve ≥90% skeletal 
maturity based on hand-wrist radiography, but radiographic assessment of the 
growth plate (performed at Study Months 6, 12, 18, and 24) will continue until 
these subjects achieve 100% closure of the growth plate at both locations.  
Additional radiographic assessments will be performed at Study Months 3, 9, 15, 
or 21 in those subjects who (1) received the flare-up dosing regimen in the period 
of time since their last radiographic assessment; and (2) had not achieved 100% 
skeletally maturity on their last radiographic assessment.  All subjects will 
undergo the procedures and assessments specified in the Schedule of Assessments 
in Table 1, including low-dose, WBCT (excluding head) at Screening and at site 
visits at Months 6, 12, 18, and 24.   
 
In order to ensure consistent interpretation of the acquired images, a central 
imaging laboratory will perform blinded reads of all images obtained in this study 
as well as those obtained from the natural history study (control group) using 
standardized procedures as documented in the Image Acquisition Guidelines and 
Independent Review Charter.  Remote visits (eg, at home, at a local medical 
facility, or via video-conference or telephone contact from clinical site personnel) 
will occur at Week 6 and at Study Months 3, 9, 15, and 21 unless the Investigator 
deems that a site visit is necessary; urine pregnancy tests will be performed each 
month for females of childbearing potential (FOCBP).  
Chronic Treatment: Part B 
The assessments conducted in Part A will continue into Part B except that WBCT 
imaging will be performed annually thereafter at Months 36 and 48. 
Flare-up-Based Treatment: Parts A and B 
Subjects will report potential flare-up symptoms to site personnel; such symptoms 
include, but are not limited to pain, swelling, redness, decreased range of motion, 
stiffness, and warmth.  Only one symptom is required to define a flare-up.  If these 
symptoms are consistent with previous flare-ups, include a subject-reported onset 
date, and are confirmed by the Investigator as associated with a flare-up, subjects 
will immediately begin flare-up-based treatment.  Flare-up-based dosing should 
also be initiated if the Investigator confirms the presence of a substantial high-risk 
traumatic event likely to lead to a flare-up. 

PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 12 OF 151 
 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
Protocol Synopsis 
 
• 
Palovarotene 20 mg for 4 weeks (28 days) once daily.  The first dose will be 
taken upon flare-up or traumatic event confirmation by the Investigator 
(Flare-up Day 1).   
To be followed by: 
• 
Palovarotene 10 mg for 8 weeks (56 days) once daily.  For a total flare-up 
treatment duration of 12 weeks (84 days). 
Study Design (cont.) 
If the Investigator deems it necessary, the subject can be evaluated at the clinical 
site to confirm the presence of a flare-up.  Based on clinical signs and symptoms 
as determined by the Investigator, treatment may be extended in 4-week intervals 
while on-treatment with 10 mg palovarotene, and continue until the flare-up 
resolves and the 4-week extension treatment has been completed. 
Subjects will be provided with the appropriate dose of study drug to be used to 
initiate treatment with palovarotene when a flare-up or traumatic event is 
confirmed by the Investigator. 
 
Flare-up dosing will be weight-adjusted in subjects under the age of 18 years with 
less than 90% skeletal maturity on hand-wrist radiography at Screening. 
Should a subject experience an intercurrent flare-up (defined as a new flare-up 
location or marked worsening of original flare-up), or substantial traumatic event 
likely to lead to a flare-up, at any time during flare-up-based treatment, the 
12-week dosing regimen will restart upon new intercurrent flare-up or traumatic 
event confirmation by the Investigator (ie, 4 weeks of 20 mg palovarotene 
followed by 8 weeks of 10 mg palovarotene [or weight-based equivalents]).  A 
Flare-up Cycle will include the first flare-up or traumatic event and any 
subsequent intercurrent flare-ups or traumatic events during the same dosing 
period.  Flare-Up Cycle Safety Day 1 is defined as the first day that study drug is 
administered for the first flare-up or traumatic event during that cycle.  Safety 
assessments will be performed at Flare-up Cycle Safety Day 1 and then every 12 
weeks thereafter until treatment of the last flare-up or traumatic event in the cycle 
is completed.  If any flare-up in a cycle has not resolved after 12 weeks, treatment 
and safety assessments will be extended, and 10 mg palovarotene (or the 
weight-based equivalent) will be administered in 4-week intervals until all 
flare-ups resolve and flare-up-based treatment has been completed.  It is possible 
that subjects may experience more than one Flare-up Cycle during the study. 
 
Subjects receiving flare-up-based treatment will undergo the procedures and 
assessments specified in the Schedule of Assessments in Table 2.  All assessments 
will occur remotely, unless the Investigator deems it necessary to evaluate subjects 
at the clinical site. 
Once all flare-ups in a cycle have resolved and flare-up-based treatment has been 
completed, subjects will resume chronic treatment with 5 mg palovarotene once 
daily (weight-adjusted doses for skeletally immature subjects). 
Subjects currently receiving flare-up-based treatment in Study PVO-1A-202 or 
Study PVO-1A-204 will not enroll into Study PVO-1A-301 until flare-up 
treatment is complete and at least 4 weeks have elapsed since the last flare-up 
symptom. 
Off-treatment Part C: No study drug will be administered in Part C.  For 
skeletally immature subjects in Part C, added Year 1 (Y1) and Year 2 (Y2) post 
last dose of study treatment assessments that include linear height, knee height, 
weight, physical exam, vital signs, radiographic assessments of the knee and hand-
wrist, low-dose WBCT imaging, adverse events, and concomitant medications. 
Once subjects reach skeletal maturity their participation in Part C will end. The 

PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 13 OF 151 
 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
Protocol Synopsis 
total duration of participation, on and off treatment, is a maximum of 4 years (±1 
month). 
 
Number of Subjects 
Up to a maximum of 110 subjects will be enrolled; up to 99 of the enrolled 
subjects will have the R206H mutation and will not have been previously treated 
with palovarotene. 
Total Number of Sites 
Approximately 20 international investigational sites. 
Study Population 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for enrollment: 
1. Written, signed, and dated informed subject/parent consent; and for subjects 
who are minors, age-appropriate assent (performed according to local 
regulations). 
2. Male or female at least 4 years of age. 
 
3. Previous participation in the NHS; or clinically diagnosed with FOP, with 
the R206H ACVR1 mutation or other FOP variants reported to be 
associated with progressive HO (who have not previously participated in 
any Clementia-sponsored study); or participants in Study PVO-1A-202 or 
Study PVO-1A-204 who cannot currently receive the chronic/flare-up 
regimen due to country of residence or those traveling long distances to 
participate in the Phase 2 trial. 
4. No flare-up symptoms within the past 4 weeks, including at the time of 
enrollment. 
 
5. Females of child-bearing potential must have a negative blood or urine 
pregnancy test (with sensitivity of at least 50 mIU/mL) prior to 
administration of palovarotene.  Male and FOCBP subjects must agree to 
remain abstinent from heterosexual sex during treatment and for 1 month 
after treatment or, if sexually active, to use two effective methods of birth 
control during and for 1 month after treatment.  Additionally, sexually 
active FOCBP subjects must already be using two effective methods of birth 
control 1 month before treatment is to start.  Specific risk of the use of 
retinoids during pregnancy, and the agreement to remain abstinent or use 
two effective methods of birth control will be clearly defined in the 
informed consent and the subject or legally authorized representatives (eg, 
parents, caregivers, or legal guardians) must specifically sign this section. 
 
6. Must be accessible for treatment and follow-up, and be able to undergo all 
study procedures.  Subjects living at distant locations from the 
investigational site must be able and willing to travel to a site for the initial 
and all on-site follow-up visits.  Subjects must be able to undergo low-dose, 
WBCT (excluding head) without sedation. 
 
Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for enrollment: 
1. Weight <10 kg. 
2. If 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. 

PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 14 OF 151 
 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
Protocol Synopsis 
3. Exposure to synthetic oral retinoids other than palovarotene within 4 weeks 
prior to screening. 
4. Concurrent treatment with tetracycline or any tetracycline derivatives due to 
the potential increased risk of pseudotumor cerebri. 
5. History of allergy or hypersensitivity to retinoids, gelatin, or lactose (note 
that lactose intolerance is not exclusionary). 
Study Population (cont.) 
6. Concomitant medications that are strong inhibitors or inducers of 
cytochrome P450 (CYP450) 3A4 activity; or kinase inhibitors such as 
imatinib (see Section 5.2.1). 
7. Amylase or lipase >2x above the upper limit of normal (ULN) or with a 
history of chronic pancreatitis. 
8. Elevated aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) >2.5x ULN. 
9. Fasting triglycerides >400 mg/dL with or without therapy. 
10. Female subjects who are breastfeeding. 
 
11. Subjects with uncontrolled cardiovascular, hepatic, pulmonary, 
gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, 
psychiatric, or other significant disease. 
12. Subjects experiencing suicidal ideation (type 4 or 5) or any suicidal 
behavior within the past month as defined by the Columbia-Suicide Severity 
Rating Scale (C-SSRS). 
 
13. Simultaneous participation in another interventional clinical research study 
(other than palovarotene studies) within 4 weeks prior to Screening; or 
within five half-lives of the investigational agent, whichever is longer. 
14. 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. 
Investigational Product 
Palovarotene 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. 
Dose/Route/Regimen for 
Chronic Dosing 
Palovarotene: 5 mg daily or weight-based equivalents for those subjects who are 
skeletally immature (<90%) at entry into the study / taken orally with food / at 
approximately the same time each day.  For 5 mg palovarotene, weight equivalent 
doses for <20 kg, 20 to <40 kg, 40 to <60 kg, and ≥60 kg will be 2.5 mg, 3 mg, 
4 mg, and 5 mg, respectively. 
Dose/Route/Regimen for 
Flare-Up Dosing 
Palovarotene initiated at the start of an eligible flare-up: 20 mg for 4 weeks 
(28 days), 10 mg for 8 weeks (56 days) for a total of 12 weeks (84 days) (may be 
extended in 4-week intervals if flare-up is ongoing and continue until flare-up 
resolves) / weight-adjusted for skeletally immature subjects (<90%) / taken orally 
with food / at approximately the same time each day. 
The weight-adjusted palovarotene doses for skeletally immature subjects and dose 
de-escalation for flare-up and chronic dosing are: 
 
Weight range 
category 
20-mg 
Equivalent 
15-mg 
Equivalent* 
10-mg 
Equivalent 
7.5-mg 
Equivalent* 
5-mg 
Equivalent 
2.5-mg 
Equivalent* 
<20 kg 
10 mg 
7.5 mg 
5 mg 
3 mg 
2.5 mg 
1 mg 
20 to <40 kg 
12.5 mg 
10 mg 
6 mg 
4 mg 
3 mg 
1.5 mg 
40 to <60 kg 
15 mg 
12.5 mg 
7.5 mg 
5 mg 
4 mg 
2 mg 
≥60 kg 
20 mg 
15 mg 
10 mg 
7.5 mg 
5 mg 
2.5 mg 
* In the event of dose de-escalation from 20-mg, 10-mg, or 5-mg equivalents, respectively.   

PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 15 OF 151 
 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
Protocol Synopsis 
Comparator 
In this single-arm treatment study, the control reference group will be the 
untreated subjects who participated in the NHS. 
Assessments of Efficacy 
Primary Endpoint: 
The annualized change in new HO volume as assessed by low-dose, WBCT 
(excluding head) compared to untreated subjects from the NHS over 24 months. 
Secondary Endpoints assessed in Parts A and B: 
1. The proportion of subjects (key secondary endpoint) with any new HO. 
2. The change from baseline in the number of body regions with new HO. 
3. The proportion of subjects reporting flare-ups. 
4. The flare-up rate per subject-month exposure. 
Assessments of Efficacy 
(cont.) 
Exploratory Endpoints assessed in Parts A and B: 
1. Change from baseline in ROM assessed by CAJIS. 
2. Change from baseline in physical function using age appropriate forms of 
the FOP-PFQ. 
3. Change from baseline in physical and mental function for subjects 
≥15 years old and mental function for subjects <15 years old using age 
appropriate forms of the PROMIS Global Health Scale. 
Assessments of Safety 
Safety evaluations will include adverse event (AE) and serious AE (SAE) 
reporting, electrocardiograms, vital signs (temperature, respiratory rate, blood 
pressure, and heart rate), physical examination, body weight and height, laboratory 
parameters (hematology, biochemistry, and urinalysis), urine pregnancy tests for 
FOCBP, and concomitant medication reporting.  Concomitant medications will 
include treatment per standard of care, which may or may not include 
corticosteroids (eg, prednisone at 2 mg/kg PO to a maximum dose of 100 mg 
daily) for 4 days. 
 
Evaluation of subjects under the age of 18 enrolled with open epiphyses will 
include knee (anterior/posterior [AP] view) and hand-wrist radiographs 
(posterior/anterior [PA] view) for assessment of epiphyseal growth plate and distal 
femoral angle; tibial and femoral long bone lengths; and standardized stadiometry 
and knee height for assessments of linear growth (in triplicate).  If there is 
evidence of partial or complete premature growth plate closure (with or without 
growth deceleration) study drug may be continued, interrupted, de-escalated, or 
discontinued.  Dose modification decisions will be made by the Investigator upon 
review of the subject’s clinical and radiographic information, and following 
discussion of the risk/benefit with the subject/parent.  The Investigator may 
consult with the sponsor and the DMC. 
In addition, bilateral hand-wrist and knee growth plate morphology will be 
assessed by WBCT scan safety read (performed every 6 months up to Month 24 in 
Part A, and annually thereafter in Parts B and C).  Bilateral hip growth plate 
morphology will also be assessed for avascular necrosis in all subjects.  Limb/joint 
AEs in these subjects will be evaluated by clinical and radiographic assessments 
as deemed appropriate by the Investigator.   
 
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, 14 June 2010. 

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PAGE 16 OF 151 
 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
Protocol Synopsis 
 
Subjects 8 years of age and older will be assessed for suicidal ideation and 
behavior every 3 months using the age-appropriate C-SSRS and at all visits during 
a Flare-up Cycle. 
The Data Monitoring Committee (DMC) will assess the safety of the subjects 
during the course of the study.  The DMC can recommend temporary or 
permanent stopping of the study at any time if there are significant safety 
concerns.  The DMC can also make recommendations for potential dose 
modifications for individual subjects in the event of treatment-related adverse 
bone effects.  The DMC Charter includes recommended safety stopping rules (see 
Section 7.7). 
Clinical Genotyping 
On Screening/Study Day 1, a blood sample will be collected and the ACVR1 
gene-coding region will be sequenced to assess for the presence of an 
FOP-associated mutation of the ACVR1 gene for new subjects or for subjects who 
have not undergone previous genotyping as part of Study PVO-1A-001.  Subjects 
enrolling from Study PVO-1A-202 or Study PVO-1A-204 do not need to undergo 
repeat genotyping.  Any subject enrolled who does not have an ACVR1 mutation 
known to be associated with FOP will be discontinued.  If the Investigator has any 
reason to believe a subject does not possess an FOP mutation, enrollment may be 
delayed until the genotype is confirmed. 
Pharmacokinetics 
Pharmacokinetics of palovarotene will be assessed at the first 3-month safety 
assessments during chronic-based treatment; if samples cannot be obtained during 
the first 3-month safety assessment, then they can be obtained during any 
subsequent 3-month safety visit in Part A (ie, up to Month 24).  Pharmacokinetics 
will also be assessed twice during flare-up-based treatment: once during the 20-
mg regimen at any time between Study Days 4 to 28, and once during the 10-mg 
regimen at any time between Study Days 32 to 84, for the first treated flare-up 
only.  If this is not possible for the first treated flare-up, pharmacokinetic blood 
samples can be obtained during any subsequent flare-up dosing cycle.  
Pharmacokinetic blood samples will be collected at predose and 3, 6, 10, and 
24 hours post-dose for the three time points listed above. 
The following palovarotene pharmacokinetic parameters will be determined where 
possible by model independent analysis using WinNonlin™: Cmax,ss, Cmin,ss, Tmax,ss, 
AUC0-24ss, λz, t½z, and CL/F. 
Statistical Analysis 
Analysis Populations 
The Principal Enrolled Population (Principal EP) includes all subjects with the 
R206H ACVR1 mutation who have not previously been treated with palovarotene 
and who sign the informed consent form and meet all eligibility criteria of the 
MOVE Trial. 
The Principal Full Analysis Set (Principal FAS) includes all enrolled subjects in 
the Principal EP who have a baseline HO volume measurement and at least one 
post-baseline HO volume measurement in the MOVE Trial.  For efficacy 
comparisons to the NHS, the Principal FAS will also include subjects enrolled in 
the NHS with available baseline and at least one post-baseline HO volume 
measurements. 
 
The Principal Per-Protocol Set (Principal PPS) is a subset of the Principal FAS 
including subjects with no major protocol deviations that are expected to interfere 
with assessments of the primary endpoint, and with at least 80% compliance to the 
study drug regimen, assessed over the first 24 months of participation in Part A.  
For efficacy comparisons to the NHS, the Principal PPS will also include subjects 
in the NHS with available baseline and at least one post-baseline HO volume 

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PAGE 17 OF 151 
 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
Protocol Synopsis 
measurement and with no major protocol deviations over 24 months that are 
expected to interfere with assessments of the primary endpoint. 
The Principal Safety Set (Principal SS) includes all enrolled subjects receiving 
at least one dose of palovarotene in the MOVE Trial.  For safety comparisons to 
the NHS, the Principal SS will also include subjects enrolled in the NHS with 
available post-baseline follow-up.  
The Principal Pharmacokinetic Set (Principal PS) includes all enrolled subjects 
receiving at least one dose of palovarotene and providing evaluable 
pharmacokinetics data in the MOVE Trial. 
Statistical Analysis (cont.) 
Subjects who do not have the R206H ACVR1 mutation or who have received 
previous treatment with palovarotene in PVO-1A-202 or PVO-1A-204 will 
comprise the Supplementary EP, the Supplementary FAS, the Supplementary 
PPS, the Supplementary SS, and the Supplementary PS, with these populations 
defined analogously as above for the subjects with the R206H ACVR1 mutation. 
 
Primary Efficacy Analysis 
The primary efficacy endpoint is the annualized change in new HO volume (as 
assessed by low-dose WBCT, excluding head) over 24 months in Part A.  The 
primary efficacy analysis comparing the annualized change in new HO volume 
between subjects treated with palovarotene and untreated subjects will be 
conducted using a Bayesian compound Poisson distribution in the Principal FAS.  
The Principal FAS is used to match the NHS population which was restricted to 
subjects with the R206H mutation and no previous palovarotene exposure.  
Hypothesis testing will be performed using random samples generated via Gibbs 
sampling from the posterior distribution of the treatment effect variables.  The 
primary efficacy endpoint will be summarized for the Supplementary FAS. 
 
There will be three early interim efficacy analyses and one final analysis.  The 
first interim analysis will occur when 35 subjects complete 1-year of follow-up; 
the second and third interim analyses will occur when all subjects enrolled in the 
Principal EP have completed (ie, have WBCT data) 12 months and then 18 
months of follow-up, respectively.  The interim analyses will include the Month 6 
WBCT results when that is the only observation available from a subject in the 
current study.   
 
An O’Brien-Fleming alpha spending function will be used to specify the alpha 
level threshold for determination of treatment effect significance at each interim 
analysis and the final analysis.  Using the percentage of patient years of follow-up 
as an approximation to the statistical information available at each analysis and 
assuming a one-sided, overall type I error rate of 2.5%, the one-sided significance 
thresholds are 0.0058, 0.0103, 0.0156, and 0.0190 for the first, second and third 
interim analyses, and the final analysis, respectively.  Study success will be 
declared if the posterior probability that palovarotene reduces the annualized 
change in new HO volume is greater than 1 minus the one-sided significance 
threshold.  For example, the posterior probability that palovarotene reduces the 
annualized change in new HO volume must be greater than 0.9810 to declare 
study success at the final analysis.  A futility analysis was conducted for the 
second interim analysis based on the pre-specified criteria using square-root 
transformation and on additional analyses without the square-root transformation.  
Based on feedback received by the DMC following the second interim analysis, 
the futility analysis conducted at the third analyses will use the predefined model 
with and without square-root transformation to assess whether the study shows 
insufficient evidence of efficacy.  If the efficacy criteria have not been met by the 
final analysis of Part A the study may be terminated.   

PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 18 OF 151 
 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
Protocol Synopsis 
 
Efficacy will be described for Parts A and B together. 
 
Sample Size Determination 
The sample size was determined via simulation based on the available WBCT HO 
volumes from the NHS, and the observed efficacy of palovarotene treatment in the 
Phase 2 studies.  With the NHS contributing untreated follow-up information on 
approximately 90 subjects, and 80 subjects originally planned for enrollment into 
the current study in the Principal FAS population (including approximately 45 
from the NHS), the probability of declaring statistical significance is 0.51, 0.79, 
0.89 at the first, second, and third interim analyses, respectively, if palovarotene 
treatment reduces the mean number of body regions with new HO in 1 year by 
30%, and reduces the new HO volume conditional on new HO in a body region by 
50% compared to the NHS control group.  The overall power of the study is 0.92. 
The increase in the number of enrolled subjects will not substantially change the 
power of the trial or have a significant impact on the primary or secondary 
statistical analyses. 
 

PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 19 OF 151 
 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
 
Table 1. 
Schedule of Assessments for Chronic Treatment 
 
Part A 
(Main Study) 
Part B 
(Extension) 
Parts A & B 
Assessment/Procedure 
Screening/ 
Study Day 11 
Site Visit 
(-1 month) 
Every  
Month 
Remote Visit2 
(±1 week) 
Week 6 
Telephone 
Contact 
(±1 week) 
Months 3, 9,  
15, 21   
Remote Visit2 
(±2 weeks) 
Months 6,  
12, 18, 24 
Site Visit3 
(±1 month) 
Every  
Month 
Remote Visit2 
(±1 week) 
Months 27, 33, 
39, 45   
Remote Visit2 
(±2 weeks) 
Months 30, 36,  
42, 48 
Site Visit3 
(±1 month) 
EOT/EOS 
Site Visit3 
(±1 month) 
Informed consent/assent4,5 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
Knee and hand-wrist radiographs6 
X 
 
 
X7 
X 
 
X7 
X 
X 
Linear and knee height growth assessments 
(<18 years)6 
X 
 
 
 
X 
 
 
X 
X 
Medical history (including FOP history) 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
X 
 
 
X 
X 
Hearing test 
X8 
 
 
 
Months 12, 24 
only 
 
 
Months 36, 48  
only 
X 
Linear height (subjects ≥18 years) 
X 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
X 
 
X 
X 
X 
Electrocardiogram 
X 
 
 
 
X 
 
 
X 
X 
Dispense study drug9 
X 
 
As needed from Study Day 1 through Month 48 
Study drug treatment 
 
Continuous from Study Day 1 through Month 48 
Dispense/review subject diary 
 
Dispense diary as needed and review at every subject contact10 
Subject diary assessment for onset of flare-up 
symptoms 
 
From Study Day 1 through Month 48 
Vital signs 
X 
X 
X 
 
X 
X 
X 
C-SSRS (age-appropriate)11 
X 
 
 
X 
X 
 
X 
X 
X 
Assess for child-bearing status (females only) 
and pregnancy prevention measures (females 
and males) 
X 
 
 
X 
X 
 
X 
X 
X 
Hematology 
X4 
X 
 
 
X 
X 
Biochemistry (includes lipids, serum 
pregnancy test) 
X4 
X 
 
 
X 
X 
Urinalysis12 
X4 
 
X 
 
 
X 
X 
Pregnancy test13 
 
X 
 
 
 
X 
 
 
X 
FOP-PFQ (age-appropriate) 
X 
 
 
 
X 
 
 
X 
X 
PROMIS Global Health Scale 
X 
 
 
 
X 
 
 
X 
X 

PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 20 OF 151 
 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
 
Table 1. 
Schedule of Assessments for Chronic Treatment 
 
Part A 
(Main Study) 
Part B 
(Extension) 
Parts A & B 
Assessment/Procedure 
Screening/ 
Study Day 11 
Site Visit 
(-1 month) 
Every  
Month 
Remote Visit2 
(±1 week) 
Week 6 
Telephone 
Contact 
(±1 week) 
Months 3, 9,  
15, 21   
Remote Visit2 
(±2 weeks) 
Months 6,  
12, 18, 24 
Site Visit3 
(±1 month) 
Every  
Month 
Remote Visit2 
(±1 week) 
Months 27, 33, 
39, 45   
Remote Visit2 
(±2 weeks) 
Months 30, 36,  
42, 48 
Site Visit3 
(±1 month) 
EOT/EOS 
Site Visit3 
(±1 month) 
CAJIS 
X 
 
 
 
X 
 
 
X 
X 
Low-dose, WBCT scan (excluding head)14 
X 
X 
 
 
Months 36, 48  
only 
X 
Prior/concomitant medications 
 
At every subject contact10 
Adverse events15 
 
At every subject contact10 
Pharmacokinetic blood sample16 
 
 
 
Month 3 only 
 
 
 
 
 
Genotyping17 
X 
 
 
 
 
 
 
 
 
1 
The first day that study drug is administered will be defined as Study Day 1. 
2 
Assessments other than knee and hand-wrist radiographs will be performed remotely (eg, at the subject’s home by qualified study personnel, at a local medical facility, or via 
video-conference or telephone contact from clinical site personnel) unless the Investigator deems that a site visit is necessary.  Monthly remote visits will only be conducted for FOCBP 
subjects. 
3 
Subjects who decide to stop treatment more than 1 month after an annual visit but who remain in the study will undergo all assessments included in an annual visit as part of their EOT 
assessments.  If the next annual visit is in less than 6 months, the EOT will serve as their EOS assessments and will conclude their participation in the study if subjects decide not to 
participate in Part C.  If the next annual visit is in more than 6 months, these subjects will be assessed again at the next annual visit and undergo all assessments included in an annual visit.  
This will serve as their EOS assessment and will conclude their participation in the study if subjects decide not to participate in Part C. 
4 
May be obtained remotely.  
5 
Subjects currently receiving flare-up-based treatment in Study PVO-1A-202 or Study PVO-1A-204 will not enroll into Study PVO-1A-301 until flare-up treatment is complete and at least 4 
weeks have elapsed since the last flare-up symptom.   
6 
At Screening, subjects under the age of 18 years will undergo knee (AP view) and hand-wrist radiographs (PA view, preferable on the left side) to determine whether they have open 
epiphyseal growth plates and to assess the distal femoral angle; they will also undergo standardized measurements of linear and knee height.  (Subjects enrolling from the NHS or the Phase 
2 studies that underwent knee and hand-wrist radiographs within 1 month of Screening will not need to have radiographs repeated at Screening.)  Those subjects found to be skeletally 
immature will continue knee and hand-wrist radiographs, and linear and knee height measurements (all in triplicate) at Months 6, 12, 18, 24, 30, 36, 42, and 48.  Limb/joint AEs in these 
subjects will be evaluated by any clinical and radiographic assessments deemed appropriate by the Investigator.  Once a subject has achieved 100% skeletal maturity (confirmed by 
radiography and defined by growth plate closures), knee and hand-wrist radiographs will no longer be required.  In addition, once a subject is 18 years old, linear and knee height growth 
assessments will no longer be required.  If 100% skeletal maturity is not achieved at both locations, then only the location that is still maturing would need to be monitored. 
7 
Knee and hand-wrist radiograph assessments will be performed at Months 3, 9, 15, 21, 27, 33, 39, or 45 (±2 weeks) in those subjects who (1) received flare-up dosing in the period of time 
since their last assessment; and (2) had not achieved 100% skeletally maturity on their last assessment. These radiographic assessments will be conducted at the clinical site unless the 
Investigator determines they can be performed at a local medical facility.  All assessments will be performed at the clinical site if the radiographs cannot be performed locally. 

PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 21 OF 151 
 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
 
Table 1. 
Schedule of Assessments for Chronic Treatment 
 
Part A 
(Main Study) 
Part B 
(Extension) 
Parts A & B 
Assessment/Procedure 
Screening/ 
Study Day 11 
Site Visit 
(-1 month) 
Every  
Month 
Remote Visit2 
(±1 week) 
Week 6 
Telephone 
Contact 
(±1 week) 
Months 3, 9,  
15, 21   
Remote Visit2 
(±2 weeks) 
Months 6,  
12, 18, 24 
Site Visit3 
(±1 month) 
Every  
Month 
Remote Visit2 
(±1 week) 
Months 27, 33, 
39, 45   
Remote Visit2 
(±2 weeks) 
Months 30, 36,  
42, 48 
Site Visit3 
(±1 month) 
EOT/EOS 
Site Visit3 
(±1 month) 
8 
The initial hearing test may be obtained at Month 6 (or at the next possible visit) if it was not performed at Screening. 
9 
Except at EOT/EOS/Month 48. 
10 
Includes telephone contact by clinical site personnel at Week 6. 
11 
C-SSRS will be used for subjects 8 years of age and older.  The adult form will be used for subjects 12 years and older; the pediatric form will be used for subjects 8 to 11 years old. 
12 
If urinalysis results are abnormal, then a microscopic evaluation should be completed. 
13 
Pregnancy testing will be performed monthly for females of child-bearing potential.  A urine pregnancy test will be performed only when a serum pregnancy test is not obtained. 
14 
The last low-dose, WBCT scan (excluding head) from the NHS will be used as the baseline assessment for those subjects enrolling from the NHS as long as the scans were performed within 
1 month of Screening/Study Day 1.  The last low-dose, WBCT scan (excluding head) from Study PVO-1A-202 or Study PVO-1A-204 will be used as the baseline assessment for those 
subjects on chronic treatment enrolling from the Phase 2 study, as long as the scans were performed within 6 months of Study Day 1.  All other subjects (ie, subjects who will start chronic 
treatment during Study PVO-1A-301) will undergo a low-dose, WBCT scan (excluding head) at Screening/Study Day 1. 
15  
At each AE assessment, the Investigator must ask the subject about any joint-related complaints. 
16 
Blood samples for pharmacokinetic assessment will be collected during the first 3-month safety assessment at predose and 3, 6, 10, and 24 hours post-dose; if samples cannot be obtained 
during the first 3-month safety assessment, then they can be obtained during any subsequent 3-month safety visit up to Month 24. 
17 
Blood samples may be obtained remotely for new subjects or for subjects who have not undergone previous genotyping as part of Study PVO-1A-001.  Subjects enrolling from Study PVO-
1A-202 or Study PVO-1A-204 do not need to undergo repeat genotyping. 
CAJIS = Cumulative Analogue Joint Involvement Scale for FOP, C-SSRS = Columbia-Suicide Severity Rating Scale, EOS = end of study, EOT = end of treatment, FOP = Fibrodysplasia 
Ossificans Progressiva, PFQ = physical function questionnaire; PROMIS = Patient Reported Outcomes Measurement Information System, WBCT = whole body computed tomography. 
 
 
 

PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 22 OF 151 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 20200 
PROPRIETARY AND CONFIDENTIAL 
Table 2. 
Schedule of Assessments for Flare-up-based Treatment (Subjects with a 
Flare-Up in Parts A and B) 
 
FLARE-UP CYCLE SAFETY ASSESSMENTS 
Remote Visits1,2 (±4 days) 
Assessment/Procedure 
Flare-up Cycle  
Safety Day 13 
Every 12 Weeks3 
Vital signs and body weight 
X 
X 
Hematology4 
X 
X 
Biochemistry (includes lipids)4 
X 
X 
Urinalysis4,5 
X 
X 
Columbia-Suicide Severity Rating Scale 
X 
X 
Pregnancy testing6  
X 
Every 4 weeks 
Study drug dispensing 
As needed from Cycle Day 1 to end of treatment of last flare-up in a cycle7 
Study drug treatment 
Continuous from Cycle Day 1 to end of treatment of last flare-up in a cycle3,8,9 
Dispense/review subject diary 
Dispense diary as needed and review at every subject contact 
Prior/concomitant medications 
At every subject contact 
Adverse events 
At every subject contact 
 
 
 
FLARE-UP TREATMENT AND PHARMACOKINETICS8 
Treatment/Assessment/Procedure 
Flare-up Day 14,11,12 
High Dose 
Treatment 
Low Dose Treatment 
Flare-up treatment (first flare-up or 
restart for intercurrent flare-up)10,11 
X 
Week 1 to 4 
(4 weeks) 
Weeks 4 to 12 
(8 weeks) 
4-Week Extension 
(if applicable) 
Flare-up(s) status/end date 
confirmation10 
X 
 
End of Week 12 
End of Each 4-Week 
Extension 
Pharmacokinetic blood sample13 
 
X 
X 
1 
All visit windows are ±4 days. 
2 
Remote visits will be performed at the subject’s home by qualified study personnel or at a local medical facility, unless the 
Investigator deems that a site visit is necessary.  Remote visits during treatment extension, if applicable, will occur every 12 
weeks until all flare-ups within a cycle have resolved and treatment has been completed. 
3 
A Flare-up Cycle will include the first flare-up and any subsequent intercurrent flare-ups or traumatic events during the 
same dosing period.  Flare-Up Cycle Safety Day 1 is defined as the first day that study drug is administered for the first 
flare-up or traumatic event upon confirmation by the Investigator.  Flare-up cycle safety assessments will be performed on 
Flare-up Cycle Safety Day 1 and then every 12 weeks thereafter until treatment of the last flare-up or traumatic event 
within a Flare-up Cycle is completed.  If treatment of the last flare-up or traumatic event in a cycle resolves within 4 weeks 
of the last flare-up cycle safety assessment, then another flare-up cycle safety visit does not need to be performed.  Once all 
flare-ups in a cycle have resolved and flare-up-based treatment has been completed, subjects will resume chronic treatment 
with 5 mg palovarotene once daily (weight-adjusted doses for skeletally immature subjects).  It is possible that subjects 
may experience more than one Flare-up Cycle during the study.  Note that the Flare-up Cycle Safety assessments will also 
be applicable to any treated high-risk traumatic event likely to lead to a flare-up.  
4 
Subjects with normal or non-clinically significant abnormal laboratory results observed within 1 month of starting flare-up-
based treatment will not need to have Flare-up Cycle Safety Day 1 laboratory tests repeated.  The Investigator will 
determine whether subjects with clinically significant abnormal laboratory results in the most recent assessment will need 
to be re-assessed prior to beginning flare-up-based treatment.  The only exception is for pregnancy testing, which must be 
performed at the start of each Flare-up Cycle and every 4 weeks thereafter until treatment of the last flare-up or traumatic 
event is completed.  However, if a pregnancy test was performed within 4 weeks prior to the start of treatment for a flare-up 
or traumatic event, treatment will not be delayed pending repeat pregnancy testing. 
5 
If urinalysis results are abnormal, then a microscopic evaluation should be completed.   
6 
Pregnancy testing will be performed for females of child-bearing potential.  A urine pregnancy test will be performed only 
when a serum pregnancy test is not obtained.  

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PROPRIETARY AND CONFIDENTIAL 
7 
Subjects will be provided with the appropriate dose of study drug to be used to initiate treatment when a flare-up or 
traumatic event is confirmed by the Investigator.  Flare-up-based treatment can begin immediately after the Investigator 
confirms the presence of an eligible flare-up or traumatic and prior to availability of safety laboratory results, unless the 
Investigator determines that the results are required prior to treatment initiation (eg, clinically significant abnormal 
laboratory test results requiring follow-up). 
8 
A flare-up, or substantial high-risk traumatic event likely to lead to a flare-up, will be treated with a minimum of 4 weeks 
(28 days) of 20 mg palovarotene, followed by 8 weeks (56 days) of 10 mg palovarotene (or weight-based equivalent) for a 
total of 12 weeks (84 days).  If the flare-up has not resolved after 12 weeks, treatment will be extended in 4-week intervals 
until the flare-up resolves.  
9 
Should a subject experience an intercurrent flare-up, or substantial high-risk traumatic event likely to lead to a flare-up, at 
any time during flare-up-based treatment, the 12-week (84 day) dosing regimen will restart upon confirmation by the 
Investigator (ie, 4 weeks of 20 mg palovarotene followed by 8 weeks of 10 mg palovarotene [or weight-based equivalents]). 
This may occur more than once during a Flare-up Cycle. 
10 
Flare-up status will be assessed at Flare-up Day 1 for every flare-up and flare-up end date will be recorded when a flare-up 
resolves.  Flare-up status will also be assessed at Week 12 of the initial flare-up (if only one flare-up) or the last ongoing 
intercurrent flare-up (if more than one flare-up); if any flare-up is still ongoing, the on-going flare-up(s) will be assessed 
every 4 weeks until the last flare-up has resolved. 
11 
Flare-up Day 1 is the first day of treatment for a flare-up/substantial high-risk traumatic event (after confirmation by the 
Investigator). 
12 
Flare-ups will be evaluated remotely, or by telephone or video-conferencing, unless the Investigator deems that a site visit 
is necessary.  This will include subject-reported current flare-up location, symptoms, and probable causes. 
13 
Pharmacokinetics of palovarotene dosing will be assessed twice: once during the 20-mg regimen at any time between Study 
Days 4 and 28 and once during the 10-mg regimen at any time between Study Days 32 and 84, for the first treated flare-up 
only.  If not possible for the first treated flare-up, pharmacokinetic blood samples can be obtained during any subsequent 
flare-up dosing up to Month 24.  Blood samples will be collected at predose and 3, 6, 10, and 24 hours post-dose. 
 
Note: study procedures that require sedation will not be performed. 
 
 
 
 

PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 24 OF 151 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
Table 3. 
Schedule of Assessments for Part C 
 
Y1 and Y2/SC Post Treatment 
Site Visit1 
Assessment/Procedure 
Informed consent2, 3 
X 
Knee and hand-wrist radiographs4, 5 
X 
Linear and knee height growth assessments (<18 years) 
X 
Physical examination 
X 
Body weight2 
X 
Vital signs2 
X 
Low-dose, WBCT scan (excluding head) 
X 
Prior/concomitant medications2 
At every subject contact 
Adverse events6 
At every subject contact 
1 
Year 1 (Y1), Year 2 (Y2 visits following the last dose of study medication will be done within the 4-year total study duration 
from enrolment in Part A. 
Y1 to be completed in the window of ≥6 - <18 months post last dose of study medication.  If Part A or B EOS date is within the 
Y1 window then the EOS will serve as the Y1 visit.  If Part A or B EOS date is prior to Y1 window then Y1 should be scheduled 
≥ 6 months from Part A or B EOS date but still within the Y1 window.  If Y1 is completed within 6 months of when  Month 48 
(Part B) is to occur, then Y1 will serve as the Part C study completion (SC) visit. 
Y2 to be completed ≥18 – 24 months post last dose of study medication and will serve as the Part C study completion (SC) visit.  
If Part A or B EOS date is within the Y2 window then the EOS will serve as the Y2 visit (Y2 not required) as well as the Part C 
study completion (SC) visit.  If Part A or B EOS date or Y1 date (if applicable) is prior to Y2 window then Y2 should be 
scheduled ≥ 6 months from the Part A or B EOS date or the Y1 date, whichever is later, but still within the Y2 window. 
If subjects had their last dose of study medication and completed Part A or B EOS more than 2 years prior to their consent for 
Part C, then these subjects will complete Y2 following their consent for Part C and no later than 48 months (+1 month) from 
Study Day 1 (first day that study drug is administered).  This will serve as their Part C study completion (SC) visit and will 
conclude their participation in the study. 
2 
Assessments may be performed remotely (eg, at the subject’s home by qualified study personnel, at a local medical facility, or 
via videoconference or telephone contact from clinical site personnel) unless the Investigator deems that a site visit is necessary.   
3 
Part C informed consent is required prior to conducting Part C assessments/procedures. 
4 
Subjects found to be skeletally immature will continue knee and hand-wrist radiographs, and linear and knee height 
measurements (all in triplicate) at Year 1 (Y1) and Year 2 (Y2).  Limb/joint AEs in these subjects will be evaluated by any 
clinical and radiographic assessments deemed appropriate by the Investigator.  Once a subject has achieved 100% skeletal 
maturity (confirmed by radiography and defined by growth plate closures), knee and hand-wrist radiographs will no longer be 
required and this will serve as their Part C study completion.  In addition, once a subject is 18 years old, linear and knee height 
growth assessments will no longer be required.  If 100% skeletal maturity is not achieved at both locations, then only the location 
that is still maturing would need to be monitored. 
5 
Knee and hand-wrist radiograph assessments will be conducted at the clinical site unless the Investigator determines they can be 
performed at a local medical facility.  All assessments will be performed at the clinical site if the radiographs cannot be 
performed locally. 
6 
At each AE assessment, the Investigator must ask the subject about any joint-related complaints. 
EOS = end of study, SC = study completion 
 

P R  O T O C O L P V O- 1 A -3 0 1, A M E N D M E N T 5
P A G E 2 5 O F 1 5 1
C L E M E N TI A P H AR  M A C E U TI C A L S IN C .
3 0 O C T O B ER
2 0 2 0
P R  O PR I E T AR Y  A N D C O N FI D E N TI A L
T a ble of C o nte nts
Pr ot oc ol S y n o psis........................................................................................................................................ 1 0
Ta ble of C o nte nts ........................................................................................................................................ 2 5
List of A b bre viati o ns .................................................................................................................................. 2 9
I ntr o d ucti o n .......................................................................................................................................... 3 1
1. 1 
Bac k gr o u n d ................................................................................................................................ 3 1
1. 1. 1 
Fi br o d ys plasia Ossifica ns Pr o gressi va ....................................................................... 3 1
1. 1. 2 
C urre nt T hera pe utic O pti o ns f or Fi br o d ys plasia Ossifica ns Pr o gressi va................... 3 2
1. 1. 3  
O ver vie w of Pal o var ote ne .......................................................................................... 3 2
1. 1. 3. 1  
N o ncli nical Data......................................................................................................... 3 3
1. 1. 3. 2
Cli nical Data ............................................................................................................... 3 4
1. 1. 3. 2. 1 
Pal o var ote ne P har mac o ki netics ............................................................................... 3 4
1. 1. 3. 2. 2 
Pal o var ote ne P hase 2 I nter ve nti o nal St u dies ........................................................... 36
1. 1. 3. 2. 3 
Pal o var ote ne Safet y ................................................................................................. 37
St u d y O bjecti ves ................................................................................................................................... 37
2. 1 
Pri mar y O bjecti ves..................................................................................................................... 37
2. 2 
Sec o n dar y O bjecti ves................................................................................................................. 37
2. 3 
Sec o n dar y O bjecti ve ( Part B) .................................................................................................... 3 8
2. 4 
Sec o n dar y O bjecti ve ( Part C) .................................................................................................... 3 8
St u d y Desi g n ........................................................................................................................................ 3 8
3. 1  
O ver vie w of t he St u d y Desi g n ................................................................................................... 3 8
3. 2 
St u d y R ati o nale.......................................................................................................................... 4 2
3. 3  
D ose J ustificati o n....................................................................................................................... 4 4
3. 4  
A p pr o priate ness of Meas ures..................................................................................................... 4 5
3. 4. 1 
I ma gi n g....................................................................................................................... 4 5
3. 4. 2  
Meas ures of F u ncti o nal Disa bilit y a n d Ge neral Healt h ............................................. 46
St u d y E n d p oi nts ................................................................................................................................... 47
4. 1 
Pri mar y E n d p oi nt ....................................................................................................................... 47
4. 2 
Sec o n dar y E n d p oi nts ................................................................................................................. 47
4. 3 
E x pl orat or y E n d p oi nts ............................................................................................................... 47
Selecti o n of St u d y P o p ulati o n .............................................................................................................. 47
5. 1 
St u d y P o p ulati o n........................................................................................................................ 47
5. 1. 1 
I ncl usi o n Criteria........................................................................................................ 47
5. 1. 2 
E xcl usi o n Criteria....................................................................................................... 4 8
5. 2 
Pri or a n d C o nc o mita nt Me dicati o ns a n d Ot her St u d y R estricti o ns ........................................... 4 9
5. 2. 1 
Pri or a n d C o nc o mita nt Me dicati o ns f or S u bjects R ecei vi n g Pal o var ote ne................ 4 9
5. 2. 2  
Ot her R estricti o ns....................................................................................................... 5 0
5. 3
S u bject Wit h dra wal or Earl y Ter mi nati o n fr o m St u d y .............................................................. 5 1
5. 4 
R e place me nt of S u bjects............................................................................................................ 5 1
St u d y Dr u g A d mi nistrati o n .................................................................................................................. 5 2

P R  O T O C O L P V O- 1 A -3 0 1, A M E N D M E N T 5
P A G E 26
O F 1 5 1
C L E M E N TI A P H AR  M A C E U TI C A L S IN C .
3 0 O C T O B ER
2 0 2 0
P R  O PR I E T AR Y  A N D C O N FI D E N TI A L
6 . 1 
I de ntit y of St u d y Dr u g ............................................................................................................... 5 2
6 . 2 
Pac ka gi n g, La beli n g, a n d St ora ge.............................................................................................. 5 2
6 . 3 
R a n d o mizati o n a n d Bli n di n g ..................................................................................................... 5 2
6 . 4
A d mi nistrati o n ........................................................................................................................... 5 2
6 . 5  
D ose M o dificati o n ..................................................................................................................... 5 3
6 .6 
St u d y Dr u g Acc o u nta bilit y ........................................................................................................ 5 4
6 .7  
Assess me nt of S u bject C o m plia nce ........................................................................................... 5 4
St u d y Pr oce d ures a n d Assess me nts...................................................................................................... 5 4
7 . 1 
Scree ni n g, R ecr uit me nt, a n d I nf or me d C o nse nt ........................................................................ 5 4
7 . 2 
Safet y Assess me nts.................................................................................................................... 5 5
7 . 2. 1  
Me dical Hist or y.......................................................................................................... 5 5
7 . 2. 2 
P h ysical E xa mi nati o n ................................................................................................. 5 5
7 . 2. 3 
B o d y Wei g ht a n d Li near Gr o wt h Assess me nts.......................................................... 5 5
7 . 2. 4  
Vital Si g ns .................................................................................................................. 56
7 . 2. 5 
Electr ocar di o gra m ...................................................................................................... 56
7 . 2.6 
Cli nical La b orat or y Tests ........................................................................................... 57
7 . 2.7 
Pre g na nc y Testi n g ...................................................................................................... 5 8
7 . 2. 8  
A d verse E ve nts........................................................................................................... 5 9
7 . 2. 9
C o nc o mita nt Me dicati o ns ........................................................................................... 5 9
7 . 3 
S pecial Safet y Assess me nts ....................................................................................................... 5 9
7 . 3. 1 
C ol u m bia- S uici de Se verit y R ati n g Scale ................................................................... 5 9
7 . 3. 2 
K nee a n d Ha n d- Wrist R a di o gra p hs............................................................................ 6 0
7 . 3. 3
B o ne Safet y Ma na ge me nt Pla n .................................................................................. 6 0
7 . 3. 4
M uc oc uta ne o us Effects ( S ki n a n d M uc o us Me m bra ne T o xicit y Pr ofile) .................. 6 1
7 . 3. 5 
Ser u m Li pi ds .............................................................................................................. 6 1
7 . 3.6 
Li ver E nz y mes............................................................................................................ 6 1
7 . 3.7 
Li pase/ A m ylase.......................................................................................................... 6 2
7 . 3. 8 
Ce ntral Ner v o us S yste m............................................................................................. 6 2
7 . 3. 9  
Heari n g a n d Vis ual Dist ur ba nces ............................................................................... 6 2
7 . 3. 1 0 
Terat o ge nicit y............................................................................................................. 6 3
7 . 4 
Efficac y Assess me nts................................................................................................................. 6 4
7 . 4. 1 
L o w- D ose, W h ole B o d y C o m p ute d T o m o gra p h y...................................................... 6 4
7 . 4. 2
F O P - P h ysical F u ncti o n Q uesti o n naire ....................................................................... 6 4
7 . 4. 3 
PR  O MI S Gl o bal Healt h Scale.................................................................................... 6 4
7 . 4. 4 
C u m ulati ve A nal o g ue J oi nt I n v ol ve me nt Scale ......................................................... 6 5
7 . 5 
P har mac o ki netics ....................................................................................................................... 6 5
7 .6  
Ge n ot y pi n g................................................................................................................................. 6 5
7 .7
Data M o nit ori n g C o m mittee ...................................................................................................... 6 6
7 . 8 
Te m p orar y Meas ures ( Pr oce d ures R elate d t o C O VI D - 1 9 Pa n de mic) ....................................... 6 6
Statistical C o nsi derati o ns ..................................................................................................................... 6 9
8. 1  
Ge neral C o nsi d erati o ns .............................................................................................................. 6 9

P R  O T O C O L P V O- 1 A -3 0 1, A M E N D M E N T 5
P A G E 27
O F 1 5 1
C L E M E N TI A P H AR  M A C E U TI C A L S IN C .
3 0 O C T O B ER
2 0 2 0
P R  O PR I E T AR Y  A N D C O N FI D E N TI A L
8. 2 
Sa m ple Size Deter mi nati o n........................................................................................................ 6 9
8. 3  
Dis p ositi o n of S u bjects .............................................................................................................. 7 0
8. 4  
A nal ysis P o p ulati o ns.................................................................................................................. 7 0
8. 5 
Statistical Met h o ds..................................................................................................................... 7 1
8. 5. 1 
E xte nt of E x p os ure ..................................................................................................... 7 1
8. 5. 2  
A nal yses of Efficac y E n d p oi nts ................................................................................. 7 1
8. 5. 2. 1 
Pri mar y Efficac y A nal ysis.......................................................................................... 7 1
8. 5. 2. 2 
Sec o n dar y Efficac y A nal ysis...................................................................................... 7 3
8. 5. 3 
Safet y.......................................................................................................................... 7 3
8. 5. 3. 1  
A d verse E ve nts........................................................................................................... 7 4
8. 5. 4 
S uici de I deati o n.......................................................................................................... 7 4
8. 5. 5 
Cli nical La b orat or y Fi n di n gs...................................................................................... 7 4
8.6 
P har mac o d y na mics .................................................................................................................... 7 4
8.7 
I nteri m A nal yses ........................................................................................................................ 7 5
Pr oce d ural, Et hical, R e g ulat or y, a n d A d mi nistrati ve C o nsi derati o ns .................................................. 7 5
9. 1  
A d verse E ve nt a n d Seri o us A d verse E ve nt D oc u me ntati o n, Se verit y Gra di n g, a n d 
R e p orti n g.................................................................................................................................... 7 5
9. 1. 1  
A d verse E ve nt ............................................................................................................ 7 5
9. 1. 2 
Seri o us A d verse E ve nt or A d verse Dr u g R eacti o n .................................................... 7 6
9. 1. 3  
A d verse E ve nt D oc u me ntati o n................................................................................... 7 6
9. 1. 4 
Se verit y of A d verse E ve nts ........................................................................................ 7 6
9. 1. 5 
Ca usalit y Assess me nt ................................................................................................. 7 7
9. 1.6  
Acti o n Ta ke n Wit h St u d y Dr u g.................................................................................. 7 7
9. 1.7  
O utc o me of A d verse E ve nt ........................................................................................ 7 7
9. 1. 8 
R e p orti n g of Seri o us A d verse E ve nt .......................................................................... 7 8
9. 1. 9 
Pre g na nc y ................................................................................................................... 7 8
9. 1. 1 0 
F oll o w- U p of A d verse E ve nts a n d Seri o us A d verse E ve nts ...................................... 7 9
9. 2  
A d mi nistrati ve R e q uire me nts .................................................................................................... 7 9
9. 2. 1 
I nf or me d C o nse nt F or m ............................................................................................. 7 9
9. 2. 2 
Et hical C o n d uct of t he St u d y...................................................................................... 7 9
9. 2. 3 
Et hics B oar d A p pr o val ............................................................................................... 8 0
9. 2. 4 
S u bject C o nfi de ntialit y............................................................................................... 8 1
9. 2. 5
A me n d me nts t o t he Pr ot oc ol ...................................................................................... 8 1
9. 2.6 
Pr ot oc ol De viati o ns .................................................................................................... 8 1
9. 2.7 
St u d y Ter mi nati o n...................................................................................................... 8 1
9. 2. 8 
R ete nti o n of S u bject R ec or ds a n d St u d y Files ........................................................... 8 2
9. 3  
Data Q ualit y Ass ura nce ............................................................................................................. 8 2
9. 4  
M o nit ori n g ................................................................................................................................. 8 2
9. 5  
Data Ca pt ure a n d Ma na ge me nt.................................................................................................. 8 3
9.6
Lia bilit y a n d I ns ura nce ............................................................................................................... 8 3
9.7 
P u blicati o n a n d Cli nical Data R e p orti n g ................................................................................... 8 3

P R  O T O C O L P V O- 1 A -3 0 1, A M E N D M E N T 5
P A G E 2 8 O F 1 5 1
C L E M E N TI A P H AR  M A C E U TI C A L S IN C .
3 0 O C T O B ER
2 0 2 0
P R  O PR I E T AR Y  A N D C O N FI D E N TI A L
9. 8 
C o or di nati n g I n vesti gat or .......................................................................................................... 8 3
I n vesti gat or A gree me nt ........................................................................................................................ 8 4
R efere nces ............................................................................................................................................ 8 5
A p pe n dices.................................................................................................................................................. 8 8
A p pe n di x 1.  C u m ulati ve A nal o g ue J oi nt I n v ol ve me nt Scale f or F O P ...................................................... 8 8
A p pe n di x 2 A.  A d ult F O P- P h ysical F u ncti o n Q uesti o n naire ( Self- C o m plete d f or S u bjects A ge 
1 5 Y ears a n d Ol der).................................................................................................................... 8 9
A p pe n di x 2 B.  Pe diatric F O P- P h ysical F u ncti o n Q uesti o n naire ( Self- C o m plete d f or S u bjects A ges 8 
t o 1 4 Y ears)................................................................................................................................ 9 1
A p pe n di x 2 C.  Pe diatric F O P- P h ysical F u ncti o n Q uesti o n naire ( Pr o x y- C o m plete d f or S u bjects A ges 
5 t o 1 4 Y ears) ............................................................................................................................. 9 3
A p pe n di x 2 D.  Pe diatric F O P- P h ysical F u ncti o n Q uesti o n naire ( Pr o x y- C o m plete d f or S u bjects A ges 
2 t o 4 Y ears)............................................................................................................................... 9 5
A p pe n di x 3.  CY P 4 5 0 3 A 4 I n d ucers or I n hi bit ors: E xcl usi o nar y Me dicati o ns.......................................... 97
A p pe n di x 4.  Met h o ds of Birt h C o ntr ol ...................................................................................................... 9 8
A p pe n di x 5 A.  A d ult C ol u m bia- S uici de Se verit y R ati n g Scale ( S u bjects A ges 1 2 Y ears a n d Ol der)....... 9 9
A p pe n di x 5 B.  Pe diatric C ol u m bia- S uici de Se verit y R ati n g Scale ( S u bjects A ges 8 t o 1 1 Y ears).......... 1 0 5
A p pe n di x 6 .  R eti n oi d- S pecific A d verse E ve nts t o be Assesse d f or Se verit y b y C T C A E Criteria 
( Versi o n 4. 0 3, 1 4 J u ne 2 0 1 0).................................................................................................... 1 1 1
A p pe n di x 7 .  G ui da nce f or I n d ustr y Dr u g-I n d uce d Li ver I nj ur y: Pre mar keti n g Cli nical E val uati o n ...... 1 1 2
A p pe n di x 8 A.  PR  O MI S Gl o bal Healt h Scale ( Self- C o m plete d f or S u bjects A ge 1 5 Y ears a n d Ol der) . 1 4 0
A p pe n di x 8 B.  PR  O MI S Pe diatric Gl o bal Healt h Scale ( Self- C o m plete d f or S u bjects A ges 8 t o 
1 4 Y ears)................................................................................................................................... 1 4 2
A p pe n di x 8 C.  PR  O MI S Pe diatric Gl o bal Healt h Scale ( Pr o x y- C o m plete d f or S u bjects A ges Less 
T ha n 1 5 Y ears)......................................................................................................................... 1 4 3
A p pe n di x 9.  Declarati o n of Helsi n ki ....................................................................................................... 1 4 4
List of T a bles
Ta ble 1.
Sc he d ule of Assess me nts f or C hr o nic Treat me nt ....................................................................... 1 9
Ta ble 2.
Sc he d ule of Assess me nts f or Flare- U p Base d Treat me nt ( S u bjects wit h a Flare- U p i n Parts 
A a n d B)...................................................................................................................................... 2 2
Ta ble 3.
Sc he d ule of Assess me nts f or Part C ........................................................................................... 2 4
Ta ble 4.
Wei g ht- A dj uste d Pal o var ote ne D oses f or S keletall y I m mat ure (< 9 0 %) S u bjects a n d D ose 
De -escalati o n D osi n g f or All S u bjects ....................................................................................... 4 1
Ta ble 5.
Cli nical La b orat or y Para meters .................................................................................................. 5 8
Ta ble 6 .
P o wer of M O V E St u d y Pri mar y Efficac y A nal ysis Ass u mi n g 8 0 S u bjects E nr olle d wit h t he 
R 2 06  H M utati o n a n d N o Pre vi o us Pal o var ote ne E x p os ure........................................................ 7 0
List of Fi g ures
Fi g ure 1. C he mical Str uct ure of Pal o var ote ne ........................................................................................... 5 2

PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 29 OF 151 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
List of Abbreviations 
Abbreviation 
Definition 
ACVR1/ALK2 
activin receptor type IA/activin-like kinase 2 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AP 
anterior/posterior view 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMP 
bone morphogenetic protein 
CAJIS 
Cumulative Analogue Joint Involvement Scale for FOP 
CI 
confidence interval 
CL/F 
apparent total clearance after oral administration 
Cmax 
maximum or peak measured plasma concentration 
COPD 
chronic obstructive pulmonary disease 
COVID 
Corona virus disease 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end-of-study 
EOT 
end-of-treatment 
EP 
Enrolled Population 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FOCBP 
female of child-bearing potential (who is a pre-menopausal female 
[≥12 years old or at onset of menses, whichever is earlier]) capable 
of becoming pregnant 
FOP 
Fibrodysplasia Ossificans Progressiva 
FOP-PFQ 
FOP-Physical Function Questionnaire 
GCP 
Good Clinical Practices 
GGT 
gamma glutamyl transferase 
HDL 
high-density lipoprotein 
HED 
human equivalent dose 
HO 
heterotopic ossification 
IC50 
concentration of drug producing 50% inhibition 
ICF 
informed consent form 

PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 30 OF 151 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
Abbreviation 
Definition 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LDL 
low-density lipoprotein 
LOQ 
limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MSC 
mesenchymal stem cell 
NHS 
Natural History Study 
OMIM 
Online Mendelian Inheritance in Man 
PA 
posterior/anterior view 
PCS 
potentially clinically significant 
PO 
per os 
PPS 
Per Protocol Set 
PROMIS 
Patient Reported Outcomes Measurement Information System 
PS 
Pharmacokinetic Set 
RAR 
retinoic acid receptor 
RARγ 
retinoic acid receptor gamma 
ROM 
range of motion 
SAE 
serious adverse event 
SAP 
statistical analysis plan  
SD 
standard deviation 
SS 
Safety Set 
t½ 
apparent terminal elimination half-life 
Tmax 
time of maximum or peak measured plasma concentration at steady-state 
ULN 
upper limit of normal 
US 
United States 
VLDL 
very low-density lipoprotein 
WBCT 
whole body computed tomography 
wLME 
weighted linear mixed effects 
 
 
 

P R  O T O C O L P V O- 1 A -3 0 1, A M E N D M E N T 5
P A G E 3 1 O F 1 5 1
C L E M E N TI A P H AR  M A C E U TI C A L S IN C .
3 0 O C T O B ER
2 0 2 0
P R  O PR I E T AR Y  A N D C O N FI D E N TI A L
I ntr o d ucti o n
1. 1 
B ac k gr o u n d
1. 1. 1
Fi br o d ys pl asi a Ossific a ns Pr o gressi v a
Fi br o d ys plasia Ossifica ns Pr o gressi va ( F O P) ( O MI M # 1 3 5 1 0 0) is a rare, se verel y disa bli n g 
disease c h aracteriz e d b y heter ot o pic ossificati o n ( H O) i n m uscles, te n d o ns, a n d li ga me nts ofte n 
ass ociate d wit h pai nf ul, r ec urre nt e pis o des of s oft tiss ue s welli n g (flare- u ps).  Lesi o ns be gi n i n 
earl y c hil d h o o d a n d le a d t o pr o gressi ve a n k yl oses of maj or j oi nts wit h res ulta nt l oss of 
m o ve me nt.  Pr o g n osis is p o or a n d life e x p ecta nc y is re d uce d.  F O P is ca use d b y a n acti vati n g 
m utati o n i n t he b o ne m or p h o ge n etic pr otei n ( B M P) t y pe I rece pt or, or acti vi n rece pt or t y pe I A 
( A C VR 1), als o k n o w n as acti vi n-li ke- ki nase 2 ( A LK 2) t y pe I rece pt or.  M ost patie nts  wit h F O P
(a p pr o xi matel y 97 % ) ha v e t he sa me p oi nt m utati o n, R 2 06 H . T he I nter n ati o nal F O P Ass ociati o n, 
a U S- base d p atie nt gr o u p or ga nizati o n, re p orts a p pr o xi matel y 8 0 0 c o nfir me d cases of F O P 
gl o ball y .1 T he pre vale nce is esti mate d at a p pr o xi matel y 1. 36
per milli o n i n di vi d uals, wit h n o 
ge o gra p hic, e t h nic, racial, or ge n der prefere n ce.2 F O P is mis dia g n ose d a p pr o xi matel y 8 0 % of 
t he ti me res ulti n g i n great har m t o patie nts.3 T he pre osse o us flare- u ps t hat c haracteri ze t he 
disease ha v e bee n misi nter pret e d as l y m p he de ma, s oft tiss ue sarc o ma, or j u ve nile fi br o mat osis, 
ofte n res ulti n g i n har mf ul di a g n ostic bi o psies t hat e xacer bate t h e pr o gressi o n of t he disease, 
a n d/ or u n necessar y c he m ot hera pe utic i nter ve nti o ns.  I n di vi d uals wit h F O P a p pear n or mal at birt h 
e xce pt f or t he pat h o g n o m o nic malf or mati o n of t he great t oes, w hic h are t y picall y s h ort (lac k a
p hala n ge) a n d de viate d i n hall u x val g us .4
Heter ot o pic ossificati o n is e pis o dic a n d c u m ulati v e t hr o u g h o ut life, res ulti n g i n se g me nts, s heets, 
a n d ri b b o ns of e xtr a b o ne de vel o pi n g t hr o u g h o ut t he b o d y a n d acr oss j oi nts, pr o gressi vel y 
restricti n g m o ve me nt.  R a pi dl y gr o wi n g b o n y s p urs ha ve bee n k n o w n t o pr otr u de t hr o u g h t he 
s ki n ca usi n g pai n a n d a ris k of i nfecti o ns.5 O nl y t he t o n g ue, heart, a n d dia p hra g m m uscle are 
s pare d f or reas o ns t hat ha ve yet t o be el uci d ate d.  As y m metric H O i n t he ri b ca ge a n d s u bse q ue nt 
c o ntralateral gr o wt h c a n lea d t o a ra pi d pr o gressi o n i n s pi nal def or mit y a n d ca use res pirat or y
i ns ufficie nc y.  A n k yl oses of t he te m p or o ma n di b ul ar j oi nts res ults i n se vere t o ot h deca y a n d 
mal n utriti o n.  Peri o ds of flare- u p acti vit y are i nters perse d wit h vari a ble-le n gt h i nter vals of 
a p pare ntl y q uies ce nt disease i n t he a bse n ce of o b vi o us cli nical s y m pt o ms.  I n s o me s u bj ects, t he 
prese nce of s u bsta ntial s oft tiss ue e de ma a n d m us cle necr osis o bser ve d i n i ma gi n g perf or me d 
wit hi n 7 d a ys of flare- u p s y m pt o m - o nset s ug gests t hat t he pr ocess t hat ulti matel y lea ds t o ne w 
H O f or mati o n starts bef ore cli nical s y m pt o ms are re p orte d.  F O P mi g ht be si milar t o ot her 
c hr o nic diseas es t hat are c haracteri ze d b y ac ute e x acer bati o ns/rela pses, f oll o we d b y 
varia ble-l e n gt h peri o ds of a p pare nt disease q ui esce nce (e g, rela psi n g/re mitti n g m ulti ple 
scler osis) wit h o ut cli nical s y m pt o ms.
T he maj orit y of patie nts wit h F O P are c o nfi ne d t o a w heel c hair b y t he t hir d deca d e of life, a n d 
re q uire care gi ver assista nce t o perf or m dail y li vi n g acti vities. R es pirat or y i ns ufficie nc y lea ds t o a 
mar ke dl y s h orte ne d s ur vi val (K a pla n- Meier s ur vi val = 56 years) wit h car di ores pirat or y fail ure 
a n d p ne u m o nia t he m ost c o m m o n ca uses of deat h .6 ,7

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1.1.2 Current Therapeutic Options for Fibrodysplasia Ossificans Progressiva 
Currently there are no effective medical treatment options to prevent the formation of heterotopic 
bone in FOP, nor have there been well-controlled trials of other therapeutics in this disease.  
Treatments are aimed at the symptomatic management of the disease.  Removal of heterotopic 
bone and other trauma are avoided. Surgical trauma to tissues is likely to induce additional bone 
formation;3,8 and intramuscular immunizations; blocks for dental work; muscle fatigue; blunt 
muscle trauma from bumps, bruises, or falls; or influenza-like viral illnesses can trigger flare-ups 
leading to HO formation.9  Falls are a severe form of trauma; in one survey of FOP patients, 
flare-ups were induced in two-thirds of falls and resulted in permanent loss of movement in 93% 
of patients.Error! Reference source not found.  Glucocorticoids are used to manage symptoms of flare-ups 
affecting major joints of the appendicular skeleton and jaw, especially when used immediately 
after the onset of a flare-up.  Non-steroidal anti-inflammatory agents, cyclooxygenase-2 
inhibitors, mast cell stabilizers, and leukotriene inhibitors are reported by patients to manage 
chronic pain and ongoing disease progression. 
The identification of the recurrent point mutation that causes FOP in all classically affected 
individuals provides a specific target for drug development.Error! Reference source not found.  An 
innovative therapeutic approach that can be evaluated in FOP includes diverting the responding 
mesenchymal stromal cells to a soft tissue fate.12,13,14  This pathway is the mechanism by which 
palovarotene is believed to prevent HO in animal models of FOP. 
1.1.3 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.  Palovarotene is an orally bioavailable retinoic acid 
receptor gamma (RARγ) selective agonist in-licensed from Roche following the completion of 
Phase 2 studies in COPD patients (program discontinued due to lack of efficacy), and is being 
developed by Clementia Pharmaceuticals Inc. as a re-purposed drug for the treatment of FOP. 
RARγ agonists potently impair heterotopic endochondral ossification by redirecting 
prechondrogenic mesenchymal stem cells (MSCs) to a nonosseous soft tissue fate.  The rationale 
for testing retinoids as inhibitors of HO was based on the observation that retinoid signaling is a 
strong inhibitor of chondrogenesisError! Reference source not found. and that unliganded RAR 
transcriptional repressor activity is needed for chondrogenic differentiation.14,15  Inhibition of HO 
with non-selective retinoids or RARα receptor agonists has also been achieved but to a lesser 
degree.Error! Reference source not found. 
RARγ is expressed in chondrogenic cells and chondrocytesError! Reference source not found. where it 
also operates as an unliganded transcriptional repressor.Error! Reference source not found.  Hence, an 
RARγ agonist-based anti-HO therapy could be very effective because it would target both 
chondrogenic cells and chondrocytes.  It has been shown that RARγ agonists exert their action 
on bone formation through post-translational regulation of BMP signaling by inhibiting Smad 
phosphorylation and promoting proteasome-regulated degradation of Smads specific to the BMP 
signaling pathway.  Thus, RARγ agonists could directly prevent the activating mutation in the 
BMP type I receptor of FOP patients.  Inhibition of both prechondrogenic and chondrogenic cells 
is also thought to occur through possible stimulation of Wnt-β-catenin signaling.18,19  

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The process of HO consists of two major phases: a catabolic phase of inflammation and tissue 
destruction followed by an anabolic phase of tissue neogenesis involving the formation of a 
transient cartilaginous scaffold and its replacement with mature heterotopic bone.  A key feature 
of all HO is the formation of a bridging cartilaginous scaffold that is under control of the BMP 
and possibly the Wnt-β-catenin signaling pathways.  RARγ agonists affect both BMP and 
Wnt-β-catenin signaling and interfere with the building of the cartilaginous scaffold, thereby 
disrupting the bridge and derailing HO.Error! Reference source not found. 
Palovarotene has been evaluated in various animal models of HO including a BMP-implant 
model, a constitutively-active receptor model (Q207D), and a highly physiological human 
mutation knock-in model (R206H).  Following injury, the results consistently demonstrate 
dose-dependent reductions in HO with palovarotene across the models, and significant reduction 
in spontaneous (non-injury) HO with chronic treatment.  The data from the injury-based Q207D 
mouse model of FOP demonstrated that a human equivalent dose (HED) of 20 mg palovarotene 
may be required for the greatest inhibition of HO across all injury conditions. 
In addition to the injury-based model, palovarotene has also been effective in preventing HO 
formation in a spontaneous HO model (Prrx1-R206H model) that recapitulates many of the 
phenotypic features of FOP seen in patients including malformed great toes.  An average HED of 
approximately 5 mg palovarotene administered daily by oral gavage to young Prrx1-R206H mice 
markedly reduced the formation of spontaneous HO, suggesting that daily dosing with 
palovarotene may be an important component of the treatment regimen in humans. 
1.1.3.1 Nonclinical Data 
The toxicology of palovarotene has been 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 detailed summary of these studies 
and the observed effects is provided in the Investigator’s Brochure. 
The toxicology profile of palovarotene in animals is similar to that which is expected for a 
retinoid based on the extensive data available for compounds in this class of agents.Error! Reference 
source not found.  The toxic potential of this molecule was evaluated in rats dosed daily for up to 6 
months and in dogs dosed daily for up to 9 months.  Initial chronic toxicity studies at dose levels 
up to 0.15 mg/kg/day in rats (6-month study) and 0.006 mg/kg/day in dogs (9-month study) did 
not induce any observed palovarotene-related changes.  These studies identified these top doses 
as the no-observed-effect-level for chronic exposure.  Further studies at higher dose levels 
characterized the toxic potential of this molecule after similar chronic administration periods in 
these two species.  The maximum tolerated dose following chronic exposure was 0.6 mg/kg/day 
in rats and 0.04 mg/kg/day in dogs.  Moreover, in order to evaluate the toxicity profile of 
metabolites at high exposure levels, 6-month studies were conducted in rats and 9-month studies 
were conducted in dogs with a mixture of metabolites M2, M3, M4a, and M4b given orally.  The 
toxicity profile of these metabolites was similar to that of parent drug in rats and dogs. 
The dose limiting toxicities in adult animals were primarily mucocutaneous effects, with 
mild/moderate and reversible chondrodystrophy observed at the clinically relevant dose of 

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1 mg/kg/day in 7 to 8-week old rats.  The toxicity of palovarotene has also been evaluated in a 
6-week repeat-dose oral toxicity study in juvenile rats (3 weeks old at the start of dosing).  These 
results did not reveal any toxicities not observed in older animals, with the primary toxicologic 
effects related to bone.  At a dose level that produced systemic exposures similar to those 
predicted in patients, skeletal effects were relatively limited and mild and showed evidence of 
reversing when dosing stopped, even though juvenile rats were exposed to palovarotene over a 
period of skeletal development that would be similar to chronic daily dosing from age 2 to 
12 years in humans. 
In rat and dog mass balance studies, recovery of the administered [14C]-palovarotene dose was 
complete within 7 days, and elimination of the dose, which was mostly complete within the first 
24 hours after dosing, was exclusively biliary/fecal.  At least 68% and 50% of the administered 
dose was absorbed in rats and dogs, respectively.  After the once-daily [14C]-palovarotene oral 
dose administration for 5 days in rats, radioactivity was slowly, but extensively distributed into 
tissues, with the highest exposures seen in the adrenal cortex, adrenal medulla, liver, and the 
walls of the small intestine and caecum.  Radioactivity in all tissues decreased 8 hours after the 
last dose, except for the radioactivity in the adrenal cortex. 
Inhibition of the six human CYP450 isoforms by palovarotene was moderate, suggesting a low 
probability that palovarotene would inhibit the clearance of concomitantly administered drugs.  
The IC50 values for all metabolites against human CYP450 3A4 were very high (>100 µM).  The 
oxidative metabolism of the parent drug was primarily by CYP450 3A4. 
1.1.3.2 Clinical Data 
1.1.3.2.1 Palovarotene Pharmacokinetics 
The data describing the clinical pharmacokinetics (PK) of palovarotene are based on 
12 completed Phase 1 clinical pharmacology studies in healthy subjects, including a single 
ascending dose study; a multiple ascending dose study; five drug-drug interaction (DDI) studies 
with ketoconazole (a strong cytochrome P450 [CYP] 3A4 inhibitor), rifampicin (a strong 
CYP3A4 inducer), inhibition and induction potential with midazolam (a CYP3A4 substrate), and 
prednisone (a weak CYP3A4 inhibitor); a bioequivalence study; a [14C]-radiolabeled single-dose 
mass balance study; a single-dose age and sex study; a single-dose bridging study in Japanese 
and non-Asian subjects; a definitive food-effect/mode of administration study (as part of the 
midazolam induction potential study mentioned above); a thorough QT study and a study 
evaluating the concentration of palovarotene in seminal fluid.  Pharmacokinetic data were also 
collected in two multiple-dose studies in subjects with COPD, and three multiple-dose studies in 
subjects with FOP (one completed Phase 2 study, one ongoing Phase 2 study, and one ongoing 
Phase 3 study).  A population PK model was developed for palovarotene using data obtained 
after single- and multiple-dose oral administration to healthy volunteers and subjects with COPD 
and FOP. 
To date, over 1200 subjects have received at least one dose of palovarotene across the following 
indications:  

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• 309 healthy volunteers received single or multiple doses between 0.02 and 50 mg for up 
to 4 weeks 
• 611 subjects with COPD received multiple doses between 0.2 and 5 mg daily for up to 24 
months  
• 164 subjects with FOP received multiple doses between 2.5 and 20 mg once daily for up 
to 4 years, and  
• approximately 129 subjects with MO received multiple doses of 2.5 or 5.0 mg once daily 
for up to 18 months.  In addition, seven FOP subjects received palovarotene in an early 
access program (EAP)  
In healthy subjects, the palovarotene pharmacokinetics were linear and dose-proportional up to a 
single dose of 50 mg or a multiple dose of 10 mg under a fed condition.  The plasma 
palovarotene Tmax was approximately 4 hours and its T½ was approximately 8 hours.  The 
calculated effective half-life was between 5 to 10 hours.  With repeated administration, 
steady-state palovarotene plasma concentrations were attained by day 3. 
In a study of Japanese versus non-Asian healthy volunteers, mean plasma concentrations after 5 
and 10 mg palovarotene peaked at 4 hours post-dose for both subject populations; the mean 
terminal half-life ranged from 9.7 to 13 hours.  Palovarotene was absorbed and eliminated in a 
similar manner for both populations, and pharmacokinetic parameters were similar at both dose 
levels based on geometric mean ratios and CIs for Cmax, AUC(0-∞), and AUC(0-t). 
Palovarotene was primarily metabolized by CYP3A4.  Five metabolites, 6,7-dihydroxy (M1), 6-
hydroxy (M2), 7-hydroxy (M3), 6-oxo (M4a), and 7-oxo (M4b) were observed for palovarotene 
in the clinical pharmacology studies.  M1 was present in very low concentrations, usually below 
the limit of quantification (LOQ).  Following administration of 14C-radiolabeled palovarotene, 
97% of the dose was recovered in the feces and 3.2% in the urine.  Overall, the metabolite profile 
was qualitatively similar to that reported in all the animal species. 
In healthy subjects, 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), decreased slightly by 14% with prednisone (a weak 
CYP3A4 inhibitor), and did not change consistently with midazolam (a CYP3A4 substrate).  
Palovarotene did not impact the pharmacokinetics of concomitantly administered drugs, 
including oral prednisone and midazolam. 
Co-administration of palovarotene with food resulted in a 40% increase in AUC0-∞ and a 16% 
increase in Cmax compared with administration under fasted conditions. Additionally, Tmax 
appeared to be slightly shorter for fasted subjects dosed with palovarotene.  Opening the capsule 
and sprinkling the contents onto soft food did not affect the PK of palovarotene.  No clinically 
relevant differences in palovarotene pharmacokinetics were found between young males and 
elderly males and between elderly males and elderly females. 

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A population PK model was used to simulate palovarotene administration in pediatric patients in 
order to assess the appropriateness of weight-based dosing in skeletally immature children.  The 
simulations identified weight-adjusted doses that provide derived steady-state exposures 
(AUC0-τ, Cmax,ss, and Cmin,ss) within the range of those for adults after receiving the 10- and 
20-mg doses. 
1.1.3.2.2 Palovarotene Phase 2 Interventional Studies 
The Phase 2 interventional studies for which subjects with FOP have received treatment include:  
• Study PVO-1A-201 provided a preliminary assessment of palovarotene efficacy across 
two different dosing regimens following 6 weeks of treatment for a flare-up relative to 
placebo (ie, flare-up only regimen).  Forty subjects were randomized (3:3:2) within 
1 week of a flare-up to receive either 10 mg palovarotene daily for 2 weeks followed by 
5 mg daily for 4weeks (10/5 mg); 5 mg palovarotene for 2 weeks followed by 2.5 mg for 
4 weeks (5/2.5 mg); or placebo for 6 weeks.  After the 6-week flare-up treatment period, 
subjects began a 6-week follow-up period during which no study drug was administered.   
• Study PVO-1A-202/Part A, an open-label extension of Study PVO-1A-201, evaluated the 
long-term safety and efficacy of prior palovarotene treatment after an additional 
12 months of follow-up.  Open-label palovarotene was administered to all subjects, 
including any randomized to placebo during Study PVO-1A-201, experiencing additional 
eligible flare-ups (ie, flare-up only regimens).  Subjects were treated with high dose 
palovarotene (10 mg palovarotene for 2 weeks followed by 5 mg for 4 weeks) regimen 
for 6 weeks, followed by a 6-week period in which no study drug was administered. 
• Study PVO-1A-202/Part B (corresponds to Study PVO-1A-204 in France) included 
chronic daily doses (5 mg) of palovarotene in subjects with at least 90% skeletal 
maturity.  During a flare-up, all subjects received higher dose/longer duration treatment 
with palovarotene (20 mg for 4 weeks followed by 10 mg for 8 weeks).  This 
“chronic/flare-up” regimen is the dosing regimen employed in the current study.  
• 
Study PVO-1A-202/Part C (corresponds to Study PVO-1A-204 in France, ongoing) 
extends the chronic/flare-up palovarotene regimen to all subjects, including skeletally 
immature children. 
Preliminary data from the Phase 2 program and the NHS is based on 150 prospectively assessed 
flare-ups.  Administration of the 20/10 mg palovarotene flare-up regimen resulted in a 72% 
reduction in new HO volume relative to untreated flare-ups.  The results were similar with the 
10/5 mg flare-up regimen (75% reduction).  There was a 48% reduction in new HO volume in 
flare-ups treated with the 20/10 mg chronic/flare-up regimen.  The proportion of flare-ups with 
any new HO was lowest with the 20/10 mg chronic/flare-up regimen (21%) versus the other 
regimens (untreated: 34%, 10/5 flare-up: 29%, 20/10 flare-up: 41%); the 20/10 mg 
chronic/flare-up regimen also had the lowest incidence of flare-ups with baseline edema.  

P R  O T O C O L P V O- 1 A -3 0 1, A M E N D M E N T 5
P A G E 37
O F 1 5 1
C L E M E N TI A P H AR  M A C E U TI C A L S IN C .
3 0 O C T O B ER
2 0 2 0
P R  O PR I E T AR Y  A N D C O N FI D E N TI A L
1. 1. 3. 2. 3 P al o v ar ote ne S afet y
C o nsiste nt wit h ot her reti n oi ds, t he m ost c o m m o nl y re p orte d a d verse e ve nts acr oss all 
pal o var ote ne d osi n g re gi me ns i n t he F O P i nter ve nti o nal st u dies were m uc oc uta ne o us a n d 
der mat ol o gic e ve nts s uc h as dr y s ki n a n d li ps, er yt he ma, a n d pr urit us.  I n g e neral, t he i n ci de nce, 
t otal n u m ber, d urati o n a n d se verit y of m uc oc ut a ne o us a n d der mat ol o gic e v e nts i ncreas e d wit h 
i ncreasi n g pal o v ar ote ne d ose.  T hese A Es g e nerall y res ol ve d wit h o ut se q uelae after c o m pleti o n 
of pal o var ote n e treat me nt.  M usc ul os keletal e ve nts s uc h as art hral gia, pai n i n e xtre mit y, a n d 
c o n diti o n a g gra vate d (t he Me dical Dicti o nar y f or R e g ulat or y Acti vities [  Me d DR  A]  preferre d 
ter m use d t o ca pt ur e re p orts of F O P flare- u ps)  were als o c o m m o nl y re p orte d.
T he maj orit y of a d verse e ve nts i n t he pal o var ot e n e P hase 2 st u dies i n F O P were mil d or 
m o derate i n se v erit y.
I n t he c urre nt st u d y, a n d i n t he o n g oi n g F O P P hase 2 st u d y, s u bjects e nr oll e d wit h o pe n 
e pi p h yses u n der g o k n ee (a nteri or/ p osteri or [  A P]  vie w) a n d h a n d- wrist ra di o gra p hs 
( p osteri or/a nteri or [ P A]  vie w) f or assess me nt of e pi p h yseal gr o wt h plate; a n d li near a n d k nee 
hei g ht meas ure me nts f or assess me nt of gr o wt h.  T he m ost c o m m o n e pi p h yseal gr o wt h plate 
a b n or malit y is gr o wt h rec o ver y li nes ( de nse meta p h ysical li nes) at b ot h baseli ne a n d 
p ost- baseli ne ti me p oi nts.  P ote ntial pre mat ure cl os ure of t he e pi p h ysis is cl osel y m o nit ore d a n d 
data are re vi e we d q u arterl y b y a n i n de pe n de nt D ata M o nit ori n g C o m mittee ( D M C).  Pre mat ure 
e pi p h yseal cl os ure h as bee n o bser ve d i n s u bjects i n t he i nter ve nti o nal F O P st u dies t hat ha ve bee n 
re p orte d as seri o us a d v erse e ve nts.  A nal ysis of t h e S A Es s u g gests t hat t he ris k of pre mat ure 
e pi p h yseal f usi o n is hi g her i n s u bjects wit h o pe n e pi p h yseal gr o wt h plates w h o ha ve recei v e d t he 
flare- u p d osi n g re gi me n.  T he fi n di n g of pre m at ur e e pi p h yseal cl os ure has bee n see n acr oss all 
a ges alt h o u g h t he p ote nti al i m pact o n gr o wt h is li kel y t o be great er i n t he y o u n gest, m ost 
s keletall y i m mat ure s u bjects, gi ve n li mitati o ns i n ti me t o attai n a greater perce nt of t heir fi nal 
a d ult hei g ht.
St u d y O bjecti ves
2. 1 
Pri m ar y O bjecti ves
T he pri mar y o bje cti ves are:
•
T o e val uate t he effi cac y of pal o var ote ne i n decreasi n g heter ot o pic ossificati o n ( H O) i n 
a d ult a n d pe diatric s u bjects wit h F O P as assess e d b y l o w- d ose, w h ole b o d y c o m p ute d 
t o m o gra p h y ( W B C T), e x cl u di n g hea d, as c o m p are d t o u ntreate d s u bjects fr o m 
Cle me ntia’s F O P nat ural hist or y st u d y o ver 2 4 m o nt hs.
•
T o e val uate t he s afet y of pal o var ote ne i n a d ult a n d pe diatric s u bjects wit h F O P.
2. 2 
Sec o n d ar y O bjecti ves
•
T o e val uate t he effect of pal o var ote ne o n flare- u p rate a n d pr o p orti o n of s u bjects 
re p orti n g at least o ne flare- u p.
•
T o e val uate t he effect of pal o var ote ne o n ra n g e of m oti o n (R  O M) as assess e d b y t he 
C u m ulati ve A nal o g ue J oi nt I n v ol ve me nt Scale f or F O P ( C AJI S).

P R  O T O C O L P V O- 1 A -3 0 1, A M E N D M E N T 5
P A G E 3 8 O F 1 5 1
C L E M E N TI A P H AR  M A C E U TI C A L S IN C .
3 0 O C T O B ER
2 0 2 0
P R  O PR I E T AR Y  A N D C O N FI D E N TI A L
•
T o e val uate t he effect of pal o var ote ne o n p h ysi cal f u ncti o n usi n g a ge-a p pr o priate f or ms 
of t he F O P- P h ysical F u n cti o n Q uesti o n naire ( F O P- P FQ ).
•
T o e val uate t he effect of pal o var ote ne o n p h ysi cal a n d me ntal healt h usi n g 
a ge-a p pr o priate f or ms of t he Patie nt R e p orte d O ut c o mes Meas ure me nt I nf or mati o n 
S yste m ( PR  O MI S) Gl o b al Healt h Scale.
•
T o e val uate t he p h ar mac o ki netics of pal o var ote ne.
2. 3 
Sec o n d ar y O bjecti ve ( P art B)
•
T o c o nti n ue t o pr o vi de p al o var ote ne t o a d ult a n d pe diatric s u bjects wit h F O P a n d t o 
m o nit or l o n ger-ter m safet y
2. 4 
Sec o n d ar y O bjecti ve ( P art C)
•
T o i m ple me nt safet y meas ures base d o n D M C r ec o m me n dati o ns i n or der t o e ns ure t hat 
assess me nts of safet y c o nti n ue f or u p t o 2 years p ost last d ose of st u d y treat me nt f or 
s keletall y i m mat ure s u bjects
St u d y Desi g n
3. 1  
O ver vie w of t he St u d y Desi g n
A P hase 3, m ultice nter, o pe n-la bel st u d y i n a d ult a n d pe diatric s u bjects wit h F O P  will be 
c o n d ucte d i n t hree parts: Part A, t he mai n part of t he st u d y; Part B, t he 2 4- m o nt h e xte nsi o n a n d 
Part C, t he u p- t o- 2-year p ost -treat me nt peri o d f or s keletall y i m mat ure s u bjects.  S o urces of 
s u bjects eli gi ble f or e nr oll me nt i n t he M O V E Trial  will i ncl u de: ( 1) s u bjects fr o m St u d y 
P V O- 1 A- 0 0 1 (t he n at ural hist or y st u d y [  N H S] ); ( 2) a d diti o nal s u bjects cli nicall y dia g n ose d wit h 
F O P wit h t he R 2 06 H  A C VR 1 m utati o n or ot her F O P varia nts re p ort e d t o be ass ociate d wit h 
pr o gressi ve H O ( w h o ha ve n ot pre vi o usl y partici pate d i n a n y Cle me ntia-s p o ns ore d trials); a n d 
( 3) St u d y P V O- 1 A- 2 0 2 or St u d y P V O- 1 A- 2 0 4 s u bjects w h o ca n n ot r ecei ve t he c hr o nic/flare- u p 
re gi me n d ue t o c o u ntr y of resi de nce or t h ose tr a veli n g l o n g dista nces t o partici pate i n t he P hase 2 
trial.  U p t o a ma xi m u m of 1 1 0 s u bjects will be e nr olle d i nt o t he M O V E Trial ( u p t o 9 9  wit h t he 
R 2 06 H  m utati o n a n d n o pre vi o us e x p os ure t o p al o var ote ne, a n d u p t o 1 1  wit h ot her m utati o ns or 
pre vi o us partici pati o n i n t he P hase 2 trials).  I n Part A, q ualifie d s u bjects will recei ve c hr o nic 
d osi n g wit h pal o var ote ne f or u p t o 2 4 m o nt hs a n d u n der g o flare- u p- base d tr eat me nt s h o ul d t he y 
e x perie n ce a n eli gi ble flare- u p or tra u matic e v e nts.
As of 0 4 Dec 2 0 1 9 all s u bjects <  1 4 years of a ge were re q uir e d t o i nterr u pt st u d y dr u g d ue t o a 
partial cli nical h ol d place d o n t he pal o var ote ne cli nical de vel o p me nt pr o gra m b y t he U S F D A. 
Treat me nt will s u bse q ue ntl y n ot be restarte d i n c hil dre n < 1 4 years of a g e.
T he effi cac y of pal o var ote ne treat me nt i n Part A of t he M O V E Tri al, as meas ure d b y t he c ha n ge 
i n ne w H O v ol u me o ver 2 4 m o nt hs, will be c o m pare d t o t hat o bser v e d i n u ntreate d s u bjects w h o 
partici pate d i n t he N H S.  

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In Part B, the study will be extended for an additional 24 months in order to provide the 
chronic/flare-up palovarotene dosing regimen to all subjects until commercial availability; and to 
obtain longer-term safety data.  No new subjects will be enrolled into Part B.   
Subjects will follow all assessments as outlined in Table 1 and Table 2. 
In Part C, annual post last dose of study treatment assessments for up to 2 years will be obtained 
in subjects who were skeletally immature at the time of study treatment discontinuation in order 
to obtain longer-term safety data. No new subjects will be enrolled into Part C. Subjects will 
follow assessments as outlined in Table 3 for as long as they are not 100% skeletally mature. 
Adverse events will be assessed at every site and remote visit during chronic and flare-up-based 
treatment as well as annually for up to 2 years post last dose of study treatment.  In case of early 
termination or withdrawal of a subject, every reasonable effort will be made by the study staff to 
have the subject return to the site in order to complete all end-of-treatment (EOT) and end-of-
study (EOS) evaluations.  The end of Study PVO-1A-301 will occur when the last subject has 
completed the last study visit (ie, last subject last visit). 
Travel arrangements to the site for subjects and caregivers will take into consideration subjects’ 
disability in a manner that will minimize any possible injury to subjects.  For example, ground 
travel could utilize an ambulance if deemed necessary; air travel could consist of first class 
seating, or use of a private jet or air ambulance; and hotel accommodations could consist of 
disability accessible rooms.  It should be noted that all travel arrangements are to be made in 
consultation with the Investigator so that the safety of the subject is always fully considered. 
A global addendum (dated 15Apr2020) to Study PVO-1A-301 Amendment 4 detailed temporary 
procedural measures related to the COVID-19 pandemic. The temporary measures were to be 
followed during the COVID-19 pandemic and until such time as the situation resolves, at which 
point the protocol assessments were to return to those specified in the current approved protocol 
effective at that time. Investigators were to determine the feasibility of dosing on a subject-by-
subject basis, depending on the ability to conduct safety monitoring and providing subjects an 
adequate supply of study drug, in accordance with local requirements. These recommendations 
were to remain in place for as long as the COVID-19 pandemic warnings are in effect in 
territories participating in the trial. The timing of when the pandemic is declared over may vary 
on a country-by-country basis as well as between sites in the same country, and as such the 
temporary measures may remain in place for differing periods of time per country/site.  
 
The global addendum (dated 15Apr2020) to Study PVO-1A-301 Amendment 4 was provided to 
study sites to ensure the safety of trial participants, maintain compliance with good clinical 
practice, minimize risks to trial integrity, and ensure compliance with local policies. Sites were 
to use the addendum as a basis to create a study-specific risk management plan that addressed the 
impact of COVID-19 on Study PVO-1A-301. In addition, a risk mitigation assessment was to be 
performed for each subject at the site in order to determine how their participation might be 
impacted.  Sites were to ensure that appropriate measures were taken to ensure the safety of FOP 
subjects in light of the ongoing COVID-19 pandemic, taking into consideration local Ethics 
Committee and Competent Authority guidance, as well as the ability of individual Investigators 

PROTOCOL PVO-1A-301, AMENDMENT 5 
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and sites to adequately monitor subject safety.   Notwithstanding this temporary addendum 
subject visit assessments that could not be done per protocol were to be reported as deviations. 
 
Chronic Treatment: Part A 
Subjects will receive orally administered 5 mg palovarotene once daily (weight-adjusted for 
skeletally immature subjects [ie, subjects under the age of 18 years with less than 90% skeletal 
maturity on hand-wrist radiography at Screening]; see Table 4) for chronic dosing for up to 
48 months.  Note: all weight-based dosing, both chronic and flare-up, will cease when subjects 
achieve ≥90% skeletal maturity based on hand-wrist radiography, but radiographic assessment of 
the growth plate (performed at Months 6, 12, 18, and 24) will continue until these subjects 
achieve 100% closure of the growth plate at both locations.  Additional radiographic assessments 
will be performed at Study Months 3, 9, 15, or 21 in those subjects who (1) received the flare-up 
dosing regimen in the period of time since their last radiographic assessment; and (2) had not 
achieved 100% skeletally maturity on their last radiographic assessment.  For 5 mg palovarotene, 
weight equivalent doses for <20 kg, 20 to <40 kg, 40 to <60 kg, and ≥60 kg will be 2.5 mg, 
3 mg, 4 mg, and 5 mg, respectively.  All subjects will undergo the procedures and assessments 
specified in the Schedule of Assessments in Table 1, including low-dose, WBCT (excluding 
head) at Screening and at site visits at Months 6, 12, 18, and 24.   
In order to ensure consistent interpretation of the acquired images, a central imaging laboratory 
will perform blinded reads of all images obtained in this study as well as those obtained from the 
natural history study (control group) using standardized procedures as documented in the Image 
Acquisition Guidelines and Independent Review Charter.  Remote visits (eg, at home, at a local 
medical facility, or via video-conference or telephone contact from clinical site personnel) will 
occur at Week 6 and at Study Months 3, 9, 15, and 21 unless the Investigator deems that a site 
visit is necessary; urine pregnancy tests will be performed each month for females of 
childbearing potential (FOCBP). 
Chronic Treatment: Part B 
The assessments and procedures conducted in Part A will continue into Part B except that 
WBCT imaging will be performed annually at Months 36 and 48. 
Flare-up-based Treatment: Parts A and B 
Subjects and/or their parents/caregivers will report potential flare-up symptoms to site personnel; 
such symptoms include, but are not limited to, pain, swelling, redness, decreased range of 
motion, stiffness, and warmth.  Only one symptom is required to define a flare-up.  If these 
symptoms are consistent with previous flare-ups, include a subject-reported onset date, and are 
confirmed by the Investigator as associated with a flare-up, subjects will immediately begin 
flare-up-based treatment. 

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PROPRIETARY AND CONFIDENTIAL 
• Palovarotene 20 mg for 4 weeks (28 days) once daily.  The first dose will be taken upon 
flare-up or traumatic event confirmation by the Investigator (Flare-up Day 1).   
To be followed by: 
• Palovarotene 10 mg for 8 weeks (56 days) once daily.  For a total flare-up treatment 
duration of 12 weeks (84 days). 
Flare-up-based dosing should also be initiated if the Investigator confirms the presence of a 
substantial high-risk traumatic event likely to lead to a flare-up. 
If the Investigator deems it necessary, the subject can be evaluated at the clinical site to confirm 
the presence of a flare-up.  Based on clinical signs and symptoms as determined by the 
Investigator, treatment may be extended in 4-week intervals while on-treatment with 10 mg 
palovarotene, and continue until the flare-up resolves and the 4-week extension treatment has 
been completed. 
Subjects will be provided with the appropriate dose of study drug to be used to initiate treatment 
with palovarotene when a flare-up or traumatic event is confirmed by the Investigator. 
All dosing, be it chronic or flare-up, will be weight-adjusted in subjects under the age of 18 years 
with less than 90% skeletal maturity on hand-wrist radiography at Screening (Table 4).   
Table 4. 
Weight-Adjusted Palovarotene Doses for Skeletally Immature (<90%) 
Subjects and Dose De-escalation Dosing for All Subjects 
Weight Range 
Category 
20-mg 
Equivalent 
15-mg 
Equivalent* 
10-mg 
Equivalent 
7.5-mg 
Equivalent* 
5-mg 
Equivalent 
2.5-mg 
Equivalent* 
<20 kg 
10 mg 
7.5 mg 
5 mg 
3 mg 
2.5 mg 
1 mg 
20 to <40 kg 
12.5 mg 
10 mg 
6 mg 
4 mg 
3 mg 
1.5 mg 
40 to <60 kg 
15 mg 
12.5 mg 
7.5 mg 
5 mg 
4 mg 
2 mg 
≥60 kg 
20 mg 
15 mg 
10 mg 
7.5 mg 
5 mg 
2.5 mg 
* 
In the event of dose de-escalation from 20-mg, 10-mg, or 5-mg equivalents, respectively.   
 
If the subject experiences intolerable side effects, the dose may be reduced to the next lower dose 
as shown in Table 4; if the subject is already receiving the lowest possible dose, then study drug 
will be discontinued.  In the event the subject required dose de-escalation due to an intolerable 
side effect for a previous flare-up, then the dose the subject will receive for a subsequent flare-up 
will be determined by the Investigator and the Medical Monitor.  If there is evidence of partial or 
complete premature growth plate closure (with or without growth deceleration) study drug may 
be continued, interrupted, de-escalated, or discontinued.  Dose modification decisions will be 
made by the Investigator upon review of the subject’s clinical and radiographic information, and 
following discussion of the risk/benefit with the subject/parent.  The Investigator may also 
consult with the sponsor and the DMC. 
Should a subject experience an intercurrent flare-up (defined as a new flare-up location or 
marked worsening of an original flare-up), or if the Investigator confirms the presence of a 

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PROPRIETARY AND CONFIDENTIAL 
substantial high-risk traumatic event likely to lead to a flare-up, at any time during flare-up-
based treatment, the 12-week dosing regimen will restart upon new intercurrent flare-up or 
traumatic event confirmation by the Investigator (ie, 4 weeks of 20 mg palovarotene followed by 
8 weeks of 10 mg palovarotene [or weight-based equivalents]).  A Flare-up Cycle will include 
the first flare-up or traumatic event and any subsequent intercurrent flare-ups or traumatic events 
during the same dosing period.  Flare-Up Cycle Safety Day 1 is defined as the first day that study 
drug is administered for the first flare-up or traumatic event during that cycle.  Safety 
assessments will be performed on Flare-up Cycle Safety Day 1 and every 12 weeks thereafter 
until treatment of the last flare-up or traumatic event in the flare-up cycle is completed.  If any 
flare-up in a cycle has not resolved after 12 weeks, treatment and safety assessments will be 
extended and 10 mg palovarotene (or the weight-based equivalent) will be administered in 
4-week intervals until all flare-ups resolve and flare-up-based treatment has been completed.  It 
is possible that subjects may experience more than one Flare-up Cycle during the study.   
Subjects receiving flare-up-based treatment will undergo the procedures and assessments 
specified in the Schedule of Assessments in Table 2.  All assessments will occur remotely, unless 
the Investigator deems it necessary to evaluate subjects at the clinical site. 
Once all flare-ups or traumatic events in a cycle have resolved and flare-up-based treatment has 
been completed, subjects will resume chronic treatment with 5 mg palovarotene once daily 
(weight-adjusted doses for skeletally immature subjects). 
Subjects currently receiving flare-up-based treatment in Study PVO-1A-202 or 
Study PVO-1A-204 will not enroll into Study PVO-1A-301 until flare-up treatment is complete 
and at least 4 weeks have elapsed since the last flare-up symptom. 
Up to 2-year follow-up Part C: 
Annual post last dose of study treatment assessments for up to 2 years will be obtained in 
subjects who were skeletally immature at the time of study treatment discontinuation in order to 
obtain longer-term safety data. Assessments will include knee and hand-wrist radiographs, linear 
and knee height growth assessments, physical examination, body weight, vital signs, low-dose 
WBCT scan (excluding head), prior/concomitant medications, and adverse events. 
No new subjects will be enrolled into Part C. Subjects who were enrolled in Parts A or B who 
have discontinued the study will be invited back to participate in the off-treatment Part C safety 
follow-up. 
 
3.2 
Study Rationale 
Clinical data obtained from the Phase 2 interventional studies, as well as recent animal 
pharmacology data, have contributed to the understanding of FOP disease progression, the risk 
factors leading to HO formation, and the potential utility of palovarotene in preventing HO 
formation. 

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FOP is a disease that is characterized by HO that may develop spontaneously or after soft tissue 
trauma, vaccinations, or influenza infections.  The HO accumulates throughout life, resulting in 
segments, sheets, and ribbons of extra bone throughout the body and across joints, progressively 
restricting movement.  While HO formation may be preceded by signs and symptoms of a 
flare-up such as pain, swelling, redness, decreased range of motion, stiffness, and warmth, the 
biological process that results in the formation of HO may begin before the onset of symptoms.  
Thus, the optimal treatment for FOP might be similar to other chronic diseases that are 
characterized by acute exacerbations/relapses, followed by variable-length periods of apparent 
disease quiescence (eg, relapsing/remitting multiple sclerosis) during which clinical symptoms 
are not observed. It is hypothesized that daily treatment in the absence of flare-up symptoms, 
which will ensure exposure to palovarotene when the endochondral process starts, together with 
increasing the dose immediately upon symptom onset (the chronic/flare-up regimen), may be a 
better approach than treating only when clinical symptoms are present (the flare-up only 
regimen). 
Under the original protocol, subjects from the NHS and new subjects clinically diagnosed with 
FOP with the R206H ACVR1 mutation (who had not previously participated in any Clementia 
study) were eligible for enrollment.  In addition to these subjects, this study (under 
Amendment 1) will allow for the enrollment of new subjects with other FOP mutations.  This 
will enable these subjects, who also experience progressive HO, to receive treatment with 
palovarotene.  Amendment 1 will also allow for the enrollment of Study PVO-1A-202 or 
Study PVO-1A-204 subjects who cannot currently receive the chronic/flare-up regimen due to 
country of residence or those traveling long distances to participate in the Phase 2 trial.  This will 
provide for optimal palovarotene treatment and reduced travel burden for these subjects. 
The primary analysis of the MOVE study will be restricted to palovarotene-naïve subjects with 
the R206H ACVR1 mutation, compared to untreated subjects from the NHS.  As the MOVE 
study control is data from the NHS, the subject populations should match as closely as possible 
between the two studies.  Subjects with FOP mutations other than R206H will not be included in 
the primary analysis due to the limited number of patients with these mutations (estimated as 3% 
of the world’s known FOP population of approximately 800 individuals – or approximately 24 
subjects) and because the NHS only enrolled subjects with the R206H ACVR1 mutation.  
Subjects who previously participated in the palovarotene Phase 2 program will also not be 
included in the primary analysis due to their previous episodic exposure to palovarotene prior to 
the initiation of the MOVE study dosing regimen.  However, these two groups of subjects are 
being allowed to participate in the MOVE study in order to provide the palovarotene dosing 
regimen that has demonstrated the best efficacy results to date, allowing collection of efficacy 
and safety data within the context of a clinical trial that will be summarized descriptively, while 
also reducing subject burden. 
The study was extended in Part B for an additional 24 months in order to provide the 
chronic/flare-up palovarotene dosing regimen to all subjects until commercial availability; and to 
obtain longer-term safety data. 
As of 04Dec2019, all subjects < 14 years of age were required to interrupt study drug due to a 
partial clinical hold placed on the PVO clinical development program by the US FDA. Treatment 

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will subsequently not be restarted in children < 14 years of age as subjects remained off 
treatment for such a prolonged period of time as to render any further data to inform additional 
benefit/risk uninterpretable in this patient population. 
Part C was added to implement safety measures based on DMC recommendations, given the 
serious identified risk of premature physeal closure, in order to ensure that assessments of safety 
continue for up to 2 years post last dose of study treatment in Part A/B for skeletally immature 
subjects, who stopped treatment for any reason. 
3.3 
Dose Justification 
FOP is an extremely rare, chronic, severely disabling disease characterized by periods of relative 
disease quiescence interspersed with episodic flare-ups and the formation of HO that is 
irreversible and the disability is permanent.  Because the risks of under-treatment are very high 
FOP should be treated aggressively in order to evaluate the maximal potential treatment benefit, 
while carefully monitoring for potential safety concerns.  The dose regimens selected for the 
current study address these aspects of the disease and are based on emerging nonclinical and 
clinical data: 
• Chronic dosing regimen: In a non-injury-based mouse model of FOP that recapitulates 
much of the clinical phenotype observed in patients, including spontaneous HO 
formation, chronic daily treatment with palovarotene at an HED of approximately 5 mg 
prevented HO formation.  Importantly in this R206H FOP-relevant animal model, the 
dosing regimen did not impair long bone growth but partially normalized the abnormal 
growth plate histology and shortened long bones that are key phenotypic features of this 
model.  The results raised the possibility that chronic daily palovarotene dosing may be a 
major component of an optimized clinical dosing strategy.   
• Flare-up dosing regimen: The rationale for increasing the chronic palovarotene dose at 
the time of a flare-up comes from both the animal pharmacology and available clinical 
trial results.  The nonclinical data from two different mouse models of FOP demonstrated 
a dose-related decrease in HO volume; and suggested that flare-up-based treatment using 
an HED of 20 mg may be necessary to optimally prevent HO following an injury 
(equivalent to a flare-up in humans).  The Phase 2 program has evaluated four different 
palovarotene dosing regimens, three flare-up-based episodic treatment regimens and one 
chronic/flare-up regimen.  Preliminary clinical data on 103 prospectively assessed 
flare-ups demonstrated an approximate 45% reduction in the proportion of flare-ups with 
new HO, and an approximate 75% decrease in new HO volume, in those flare-ups treated 
with palovarotene 10/5 mg over 6 weeks compared to placebo/untreated flare-ups; and an 
approximate 65% reduction in proportion of flare-ups with new HO and an approximate 
98% reduction in HO volume in those flare-ups treated with the chronic/flare-up regimen 
20/10 mg over 12 weeks (the regimen in the current study) compared to 
placebo/untreated flare-ups.  These data provide a strong rationale for the continued 
evaluation of palovarotene as a potential treatment of FOP, and the selection of chronic 
daily administration of 5 mg palovarotene, with dose escalation to 20 mg once daily for 
4 weeks followed by 10 mg for 8 weeks (with treatment extension possible per 

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PROPRIETARY AND CONFIDENTIAL 
Investigator discretion for persistent flare-ups) for all subjects.  The dosage will be 
adjusted for weight in skeletally immature children.   
• While it is recognized that flare-ups can occur in the absence of any apparent causative 
factor, there is a high risk that substantial traumatic events such as surgery; intramuscular 
immunization; mandibular blocks for dental work; muscle fatigue; blunt muscle trauma 
from bumps, bruises, or falls; or influenza-like viral illnesses can induce flare-ups and 
progressive HO formation.9  In one survey of FOP patients, flare-ups were induced in 
two-thirds of falls and resulted in permanent loss of movement in 93% of patients.Error! 
Reference source not found.  Thus, subjects experiencing substantial high-risk traumatic events 
that the Investigators deem likely to lead to a flare-up will be treated with the flare-up 
regimen. 
It is acknowledged that palovarotene plasma exposure in humans receiving treatment with this 
regimen will be similar to or greater than the threshold for adverse effects in juvenile rats, adult 
rats, or adult dogs.  The toxicological effects were primarily mucocutaneous (in adult animals) 
and skeletal (in juvenile animals after chronic exposure).  Current safety monitoring in the 
Phase 2 and current Phase 3 studies has confirmed mucocutaneous adverse effects that are 
managed with prophylactic treatment or dose reduction.  In addition, monitoring of the growth 
plate revealed that the most common finding was dense metaphyseal lines in approximately 70% 
of subjects at both baseline and post-baseline time points.  Premature epiphyseal closure has also 
been observed in the Phase 2 study and in the current study.  Therefore, careful safety monitoring 
and dose modification procedures for intolerable side effects will be employed in the current 
study.   
3.4 
Appropriateness of Measures 
3.4.1 Imaging  
A number of different imaging modalities have been utilized in patients presenting with soft 
tissue swelling/masses including plain radiographs, computed tomography (CT) scan,Error! 
Reference source not found. magnetic resonance imaging (MRI),Error! Reference source not found. and 
radionuclide bone scan.Error! Reference source not found.  Most are performed at the time of the initial 
flare-up as part of the diagnostic evaluation and prior to the diagnosis of FOP.  Following the 
accurate diagnosis of FOP, imaging is not routinely performed4 as such imaging does not play a 
role in the supportive care offered to patients.  Although most of the experience with 
documentation of HO following a flare-up has been with x-ray, it has been noted that CT scans 
may allow earlier detection of new areas of HO.Error! Reference source not found. 
Flare-up site, low-dose CT scan was found to be more sensitive to the detection and 
quantification of new HO following a flare-up in the initial interventional Phase 2 study 
(PVO-1A-201) compared to plain radiograph.  The Natural History Study (PVO-1A-001) 
demonstrated the utility of whole body CT scan (WBCT) at documenting the presence, location, 
and quantification of whole body HO, including new HO formation at 12-months.  This also 
assesses HO in areas remote to flare-up symptoms, which more accurately reflects the status of 
the subject at follow-up.  For these reasons, the imaging modality utilized in the current study to 

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assess the primary and secondary endpoints will be low-dose, whole body CT scan (excluding 
head).   
In order to ensure consistency and standardization, interpretation of the acquired hand-wrist and 
knee radiographs for subjects under the age of 18 years and WBCT scans for the assessment of 
HO from the MOVE Trial, as well as from the NHS comparator, will be performed in a blinded 
fashion by a central imaging laboratory by two independent radiologists using standardized 
procedures as documented in the Image Acquisition Guidelines and Independent Review 
Charter.  The maximal possible radiation exposure for imaging procedures conducted during 
Study PVO-1A-301 is 28.9 mSv over 48 months or approximately 10.2 mSv annually for the 
first 2 years in Part A; and 4.1 mSv annually for the last 2 years in Part B or C.  These estimates 
are much lower than those discussed in the 21 March 2017 American Association of Physicists 
in Medicine Position Statement on Radiation Risks from Medical Imaging Procedures, stating 
there is no convincing epidemiological evidence of increased cancer incidence or mortality from 
radiation doses below 100 mSv.Error! Reference source not found. 
3.4.2 Measures of Functional Disability and General Health 
Two key measures of functional disability include: 
• The Cumulative Analogue Joint Involvement Scale (CAJIS) for FOP is an objective 
measure of joint movement completed by the Investigators to document total joint 
involvement.  This scale, which was developed by the Investigators from the Center for 
Research in FOP and Related Disorders, assesses functional disability by categorizing 
range of motion across 12 joints (shoulder, elbow, wrist, hip, knee, ankle on both right 
and left), and three body regions (cervical spine [neck], thoracic/lumbar spine and jaw) 
with each joint/region assessed as: 0=uninvolved; 1=affected; 2=functionally ankylosed.  
The total score range is 0-30.  The CAJIS is provided in Appendix 1. 
• The FOP-Physical Function Questionnaire (FOP-PFQ) is a disease-specific 
patient-reported outcome measure of physical impairment.  The FOP-PFQ was developed 
by Clementia based on the FDA Guidance for Industry, “Patient Reported Outcome 
Measures: Use in Medical Product Development to Support Labeling Claims”.  This 
patient-reported outcome instrument was developed to assess the relationship between 
patient reports of physical impairment due to HO, thereby providing evidence of HO as a 
clinically meaningful endpoint.  Age-appropriate forms provide a measure of functional 
impairment experienced by subjects and include questions related to activities of daily 
living and physical performance.  These data are analyzed as a percent of the total 
possible score, with higher percentages representing greater functional impairment.  The 
adult and pediatric versions of the FOP-PFQ are provided in Appendix 2. 
The baseline data from the Natural History Study (PVO-1A-001) demonstrated clear correlations 
of these endpoints with age, but minimal to no change over 12 months.Error! Reference source not found.  
As it is anticipated that change in untreated comparator subjects over 48 months may be 
minimal, these questionnaires are being evaluated as exploratory endpoints only. 

P R  O T O C O L P V O- 1 A -3 0 1, A M E N D M E N T 5
P A G E 47
O F 1 5 1
C L E M E N TI A P H AR  M A C E U TI C A L S IN C .
3 0 O C T O B ER
2 0 2 0
P R  O PR I E T AR Y  A N D C O N FI D E N TI A L
St u d y E n d p oi nts
4. 1 
Pri m ar y E n d p oi nt
T he pri mar y e n d p oi nt is t he a n n ualize d c ha n g e i n ne w  H O v ol u me as assesse d b y l o w- d ose, 
W B C T (e xcl u di n g hea d) c o m pare d t o u ntreate d s u bjects fr o m t he N H S o ver 2 4 m o nt hs.
4. 2
Sec o n d ar y E n d p oi nts
T he f oll o wi n g sec o n dar y e n d p oi nts will be assesse d i n Parts A a n d B : 
1. T he pr o p orti o n of s u bjects ( ke y sec o n d ar y e n d p oi nt)  wit h a n y ne w H O.
2. T he c ha n g e fr o m bas eli ne i n t he n u m ber of b o d y re gi o ns wit h ne w H O.
3. T he pr o p orti o n of s u bjects re p orti n g flare- u ps.
4. T he flare- u p rate per s u bject- m o nt h e x p os ure.
4. 3 
E x pl or at or y E n d p oi nts
T he f oll o wi n g e x pl orat or y e n d p oi nts will be assesse d i n Parts A a n d B:
1. C ha n ge fr o m bas eli ne i n R  O M assesse d b y C AJI S.
2. C ha n ge fr o m bas eli ne i n p h ysical f u ncti o n usi n g a ge-a p pr o priate f or ms of t he F O P- P FQ .
3. C ha n ge fr o m bas eli ne i n p h ysical a n d me ntal f u n cti o n f or s u bjects ≥1 5 years ol d a n d 
me ntal f u ncti o n f or s u bjects < 1 5 years ol d usi n g a ge a p pr o pri ate f or ms of t he PR  O MI S 
Gl o bal Healt h Scale.
Selecti o n of St u d y P o p ul ati o n
T he tar get st u d y p o p ulati o n c o nsists of a d ult a n d pe diatric s u bjects  wit h F O P.  S o urces of 
s u bjects eli gi ble f or e nr oll me nt i n t he M O V E Trial  will i ncl u de: ( 1) s u bjects fr o m 
St u d y P V O- 1 A- 0 0 1 (t he nat ural hist or y st u d y [  N H S] ), ( 2) a d diti o nal s u bjects cli nicall y 
dia g n ose d wit h F O P wit h t he R 2 06 H  A C VR 1 m utati o n or ot her F O P m utati o ns re p orte d t o be 
ass ociate d wit h pr o gressi ve H O ( w h o ha ve n ot pr e vi o usl y partici pate d i n a n y 
Cle me ntia-s p o ns ore d trials), a n d ( 3) St u d y P V O 1 A - 2 0 2 or St u d y P V O- 1 A- 2 0 4 s u bjects w h o 
ca n n ot c urre ntl y recei ve t he c hr o nic/fl are- u p re gi m e n d ue t o c o u ntr y of resi de nce or t h os e 
tra veli n g l o n g dista nces t o partici pate i n t he P hase 2 trial.
5. 1 
St u d y P o p ul ati o n
As of 0 4 Dec 2 0 1 9 all s u bjects <  1 4 years of a ge were re q uir e d t o i nterr u pt st u d y dr u g d ue t o a 
partial cli nical h ol d place d o n t he pal o var ote ne cli nical de vel o p me nt pr o gra m b y t he U S F D A. 
Treat me nt will s u bse q ue ntl y n ot be restarte d i n c hil dre n < 1 4 years of a g e.
5. 1. 1 I ncl usi o n Criteri a
S u bjects m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o be eli g i ble f or e nr oll me nt:

PROTOCOL PVO-1A-301, AMENDMENT 5 
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30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
1. Written, signed, and dated informed subject/parent consent; and for subjects who are 
minors, age-appropriate assent (performed according to local regulations). 
2. Male or female at least 4 years of age. 
3. Previous participation in the NHS; or clinically diagnosed with FOP, with the R206H 
ACVR1 mutation or other FOP variants reported to be associated with progressive HO 
(who have not previously participated in any Clementia-sponsored study); or participants 
in Study PVO-1A-202 or Study PVO-1A-204 who cannot currently receive the 
chronic/flare-up regimen due to country of residence or those traveling long distances to 
participate in the Phase 2 trial. 
4. No flare-up symptoms within the past 4 weeks, including at the time of enrollment. 
5. Females of child-bearing potential must have a negative blood or urine pregnancy test 
(with sensitivity of at least 50 mIU/mL) prior to administration of palovarotene.  Male 
and FOCBP subjects must agree to remain abstinent from heterosexual sex during 
treatment and for 1 month after treatment or, if sexually active, to use two effective 
methods of birth control during and for 1 month after treatment.  Additionally, sexually 
active FOCBP subjects must already be using two effective methods of birth control 1 
month before treatment is to start.  Specific risk of the use of retinoids during pregnancy, 
and the agreement to remain abstinent or use two effective methods of birth control will 
be clearly defined in the informed consent and the subject or legally authorized 
representatives (eg, parents, caregivers, or legal guardians) must specifically sign this 
section. 
6. Must be accessible for treatment and follow-up, and be able to undergo all study 
procedures.  Subjects living at distant locations from the investigational site must be able 
and willing to travel to a site for the initial and all on-site follow-up visits.  Subjects must 
be able to undergo low-dose, WBCT (excluding head) without sedation. 
5.1.2 Exclusion Criteria 
Subjects with any of the following exclusion criteria will not be eligible for enrollment: 
1. Weight <10 kg. 
2. If 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. 
3. Exposure to synthetic oral retinoids other than palovarotene within 4 weeks prior to 
screening. 
4. Concurrent treatment with tetracycline or any tetracycline derivatives due to the potential 
increased risk of pseudotumor cerebri. 

PROTOCOL PVO-1A-301, AMENDMENT 5 
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PROPRIETARY AND CONFIDENTIAL 
5. History of allergy or hypersensitivity to retinoids, gelatin, or lactose (note that lactose 
intolerance is not exclusionary). 
6. Concomitant medications that are strong inhibitors or inducers of cytochrome P450 
(CYP450) 3A4 activity; or kinase inhibitors such as imatinib (see Section 5.2.1). 
7. Amylase or lipase >2x above the upper limit of normal (ULN) or with a history of 
chronic pancreatitis. 
8. Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
>2.5x ULN. 
9. Fasting triglycerides >400 mg/dL with or without therapy. 
10. Female subjects who are breastfeeding. 
11. Subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, 
endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant 
disease. 
12. Subjects experiencing suicidal ideation (type 4 or 5) or any suicidal behavior within the 
past month as defined by the Columbia-Suicide Severity Rating Scale (C-SSRS). 
13. Simultaneous participation in another interventional clinical research study (other than 
palovarotene studies) within 4 weeks prior to Screening; or within five half-lives of the 
investigational agent, whichever is longer. 
14. 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. 
 
5.2 
Prior and Concomitant Medications and Other Study Restrictions 
5.2.1 Prior and Concomitant Medications for Subjects Receiving Palovarotene 
Subjects must be willing to receive treatment per the standard of care as noted in the FOP 
Treatment Guidelines 2011 which, for acute flare-ups, may or may not include corticosteroids 
(eg, prednisone at 2 mg/kg PO to a maximum dose of 100 mg daily) for 4 days.Error! Reference source 
not found.  Ideally, corticosteroids will have been initiated within 24 hours after the start of a 
flare-up.  Initiation of corticosteroids after 24 hours will be based on the clinical judgment of the 
Investigator taking into consideration the subject’s flare-up symptoms and location, and in 
consultation with the subject’s primary physician, if necessary.  Other standard-of-care 
medications are also permitted. 
The following medications are not allowed during palovarotene treatment (chronic or flare-up-
based treatment): 

PROTOCOL PVO-1A-301, AMENDMENT 5 
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30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
• Vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, herbal 
preparations, or fish oil are not permitted from the day before the start of treatment until 
the last day of treatment. 
• Synthetic oral retinoids other than palovarotene are not permitted in the 30 days prior to 
treatment until the last day of treatment. 
• 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.  If the subject experiences 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. 
• Strong inhibitors of cytochrome CYP450 3A4 are known to alter the metabolism of 
palovarotene.  Thus, concurrent oral medications identified as strong inhibitors of 
CYP450 3A4 (see Appendix 3) are excluded.  If during the study, the subject must take a 
strong inhibitor of CYP450 3A4, the study drug is to be discontinued for the duration of 
treatment.  Prior to restarting treatment with palovarotene, an appropriate wash-out 
period (five half-lives) must be considered (see Appendix 3). 
• Strong inducers of cytochrome CYP450 3A4 are also known to alter the metabolism of 
palovarotene.  Thus, concurrent oral medications identified as strong inducers of CYP450 
3A4 (see Appendix 3) are excluded.  If during the study, the subject must take a strong 
inducer of CYP450 3A4, the study drug may continue, but the Medical Monitor should 
be notified. 
• Kinase inhibitors such as imatinib, and other drugs used off-label as potential treatments 
for FOP such as rapamycin, as reported in the literature.28,29  A washout period of 5 
half-lives is required prior to enrollment into the study. 
Skin and mucous membrane reactions are the most common side effects associated with 
treatment with retinoids, therefore a subject leaflet describing recommended treatment for the 
most common mucocutaneous AEs will be distributed to each subject at the initiation of study 
treatment.  These treatments may also be recommended as prophylaxis per Investigator 
discretion. 
5.2.2 Other Restrictions 
Male and FOCBP subjects must either commit to true abstinence from heterosexual sex or agree 
to use two effective methods of birth control during treatment, and for 1 month after treatment 
has ended.  Sexually active FOCBP subjects must already be using two effective methods of 
birth control 1 month before treatment is to start.  Abstinence from heterosexual sex is only 
acceptable as “true abstinence.”  True abstinence occurs when it is in line with the preferred and 
usual lifestyle of the subject.  Periodic abstinence from heterosexual sex (such as calendar, 

PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 51 OF 151 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
ovulation, symptothermal, post-ovulation methods), the rhythm method, and withdrawal are not 
acceptable methods of contraception.     
Specific risks of the use of retinoids during pregnancy, and the agreement to remain abstinent 
from heterosexual sex or to use two effective methods of birth control will be clearly defined in 
the informed consent form.  Subjects or legally authorized representatives (eg, parents, 
caregivers, or legal guardians) must sign this specific section.  Two effective forms of birth 
control consist of the concurrent use of at LEAST one highly effective method of birth control as 
described in Appendix 4. 
It is well recognized that retinoids are teratogens with a high risk of fetal abnormalities should 
women become pregnant during treatment with such agents.  The risk of pregnancy will be 
carefully described and acknowledgement of the need to remain abstinent or use two effective 
methods of birth control will be explicitly elicited in the informed consent.  In addition, 
pregnancy tests (urine or blood) will be conducted as specified in Table 1 and Table 2.  
In the unlikely 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 within 24 hours 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. 
5.3 
Subject Withdrawal or Early Termination from Study 
Subjects can voluntarily withdraw from the study at any time for any reason.  All reasonable 
effort should be made by the study personnel to determine the reason for withdrawal.  Subjects 
will be considered lost to follow-up if no response is received in spite of 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 6.5. 
If any subject enrolled in Part C chooses to enroll in another clinical trial, all reasonable efforts 
should be made by the study personnel to have the subject continue on Study PVO-1A-301 until 
their final study completion visit. 
In the event of an early termination or discontinuation of study drug, all reasonable efforts should 
be made by the study personnel to have the subject complete all study assessments per the 
schedule of assessments. 
5.4 
Replacement of Subjects 
Subjects may be replaced at the discretion of the sponsor. 

P R  O T O C O L P V O- 1 A -3 0 1, A M E N D M E N T 5
P A G E 5 2 O F 1 5 1
C L E M E N TI A P H AR  M A C E U TI C A L S IN C .
3 0 O C T O B ER
2 0 2 0
P R  O PR I E T AR Y  A N D C O N FI D E N TI A L
St u d y Dr u g A d mi nistr ati o n
6. 1 
I de ntit y of St u d y Dr u g
Pal o var ote ne is a w hite t o off- w hite cr ystalli ne p o w der wit h t he c h e mical n a me 4-[ ( E)- 2-
( 5, 5, 8, 8-tetra met h yl- 3- p yraz ol- 1- yl met h yl- 5,6,7, 8 -tetra h y dr o- n a p ht hale n- 2- yl)- vi n yl] -be nz oi c 
aci d.  Pal o var ote n e is a n orall y bi oa vailable R A Rγ selecti ve a g o nist.  T he str uct ure of 
pal o var ote ne is s h o w n i n Fi g ure 1.
Fi g ure 1.  
C he mic al Str uct ure of P al o v ar ote ne
6. 2 
P ac k a gi n g, L a beli n g, a n d St or a ge
St u d y dr u g s u p plies pr o vi de d f or t his st u d y will be ma n ufact ure d u n d e r G o o d Ma n ufact uri n g 
Practices a n d will be s uita ble f or h u ma n us e.  Pal o var ote ne  will be pr o vi de d i n p o w der-fille d 
o pa q ue har d gelati n ca ps ules usi n g sta n dar d U S P/ E P gra de e x ci pie nts i n t he f oll o wi n g d osa ge 
stre n gt hs: 1 0, 5, 4, 3, 2. 5, 2, 1. 5, a n d 1 m g (see Secti o n 3. 1) .  Ca ps ules will be pac k a ge d i n 
a p pr o priatel y siz e d b ottles desi g ne d f or ma xi m u m pr otecti o n.
St u d y dr u g will be st ore d i n a sec ure d area at t he st u d y site wit h li mite d access.  All st u d y dr u g is 
t o be st ore d at r o o m te m perat ur e ( n ot a b o ve 3 0C/ 86
F) a n d pr ot ecte d fr o m li g ht a n d h u mi dit y.
6. 3  
R a n d o miz ati o n a n d Bli n di n g
T his is a n o pe n-la bel st u d y a n d d oes n ot i n v ol ve ra n d o mizati o n or st u d y dr u g bli n di n g.
6. 4  
A d mi nistr ati o n
S u bjects will recei ve orall y a d mi nistere d 5 m g pal o var ote ne d ail y ( or wei g ht-a dj uste d f or 
s keletall y i m mat ure s u bjects, Ta ble 4)  f or c hr o nic d osi n g f or u p t o 4 8 m o nt hs.  T he first da y t hat 
st u d y dr u g is a d mi nistere d f or c hr o nic treat me nt will be defi ne d as St u d y D a y 1.  Details f or 
ha n dli n g, pre pari n g, st ori n g, a n d discar di n g st u d y dr u g will be pr o vi de d t o s u bjects.
S u bjects will re p ort p ote ntial flare- u p s y m pt o ms or tra u matic e v e nts t o site pers o n nel, a n d if 
c o nfir me d b y t he I n v esti gat or as ass oci ate d wit h a flare- u p or, i n t he case of tra u ma, li kel y t o 
lea d t o a flare- u p, s u bjects will i m me diatel y be gi n flare- u p- base d treat me nt wit h pal o var ote ne 
2 0  m g f or 4 wee ks ( 2 8 da ys) f oll o we d b y pal o var ote ne 1 0 m g f or 8  wee ks ( 56 da ys), f or a t otal 
d urati o n of 1 2  wee ks ( 8 4 da ys).  Base d o n cli nical si g ns a n d s y m pt o ms as deter mi ne d b y t he 
I n v esti gat or, treat me nt ma y be e xte n d e d i n 4- wee k i nter vals w hile o n-treat me nt wit h 1 0 m g 
pal o var ote ne, a n d c o nti n ue u ntil t he flare- u p res ol ves a n d 4- wee k e xt e nsi o n treat me nt has bee n 
c o m plete d.  Flare- u p d osi n g will be wei g ht-a dj uste d f or s keletall y i m mat ure (< 9 0 %) s u bjects 
( Ta ble 4).  S u bjects will be pr o vi de d wit h t he a p pr o priate d ose of st u d y dr u g t o be use d t o i nitiate 

PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 53 OF 151 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
PROPRIETARY AND CONFIDENTIAL 
treatment with palovarotene when a flare-up or traumatic event is confirmed by the Investigator.  
Should a subject experience an intercurrent flare-up or traumatic event at any time during flare-
up-based treatment, the 12-week dosing regimen will restart upon confirmation by the 
Investigator (ie, 4 weeks of 20 mg palovarotene followed by 8 weeks of 10 mg palovarotene [or 
weight-based equivalents]). 
Once all flare-ups or traumatic events in a cycle have resolved and flare-up-based treatment has 
been completed, subjects will resume chronic treatment with 5 mg palovarotene once daily 
(weight-adjusted doses for skeletally immature subjects). 
The dose of study drug taken each day during chronic and flare-up-based treatment and a daily 
assessment of whether a subject is experiencing the onset of flare-up symptoms will be 
documented in the subject dosing diary.  Subjects who experience the onset of flare-up 
symptoms during chronic treatment or flare-up symptoms at a different site other than the one 
being treated during flare-up-based treatment should contact the site as soon as possible. 
Many FOP patients experience difficulty swallowing intact capsules or tablets due to ankylosis 
of the jaw.  In order to facilitate drug administration, subjects or caregivers may sprinkle the 
contents of the capsule onto specific foods as specified in the dosing instructions.  Subjects 
should be instructed to take study drug orally following a full meal at approximately the same 
time each day and 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 study drug, subjects and caregivers will be instructed to wear protective 
gloves when handling the study drug capsule. 
6.5 
Dose Modification 
Should a subject experience an AE 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 AE and if appropriate, will instruct the subject 
to decrease the dose of study drug to the next lower dose as shown in Table 4 (Section 3.1).  
Dose modification may also be required due to potential bone safety findings as described in the 
Bone Safety Management Plan (see Section 7.3.3).  
If the subject does not have the proper dosage strength in his/her possession, the clinical site will 
make immediate arrangements to ship the appropriate study drug to the subject.  If the subject is 
already receiving the lowest possible dose, then study drug will be discontinued.  The subject 
should then be followed until resolution or improvement of the AE.  Should the AE remain 
intolerable despite dose reduction, then study drug will be permanently discontinued, and the 
subject will continue to be followed with all study procedures performed per protocol. 
Should a subject experience an AE that requires immediate discontinuation of study drug (eg, 
acute pancreatitis), then study drug will be discontinued.  The Investigator will follow-up on all 
AEs observed or reported by the subject up to the end of the reporting period or until follow-up 
is no longer necessary.  In the event the subject required dose de-escalation due to an intolerable 
side effect for a previous flare-up, then the dose the subject will receive for a subsequent flare-up 
will be determined by the Investigator and the Medical Monitor.  

P R  O T O C O L P V O- 1 A -3 0 1, A M E N D M E N T 5
P A G E 5 4 O F 1 5 1
C L E M E N TI A P H AR  M A C E U TI C A L S IN C .
3 0 O C T O B ER
2 0 2 0
P R  O PR I E T AR Y  A N D C O N FI D E N TI A L
If t here is e vi de nce of partial or c o m plete pre mat ure gr o wt h plate cl os ure ( wit h or wit h o ut 
gr o wt h decel erati o n) st u d y dr u g ma y be c o nti n ue d, i nterr u pte d, de-escalate d, or disc o nti n ue d.  
D ose m o dificati o n decisi o ns will be ma de b y t he I n vesti gat or u p o n re vie w of t he s u bject’s 
cli nical a n d ra di o gra p hic i nf or mati o n, a n d f oll o wi n g disc ussi o n of t he ris k/ be nefit wit h t he 
s u bject/ pare nt.  T he I n vesti gat or ma y als o c o ns ult wit h t he s p o ns or a n d t he D M C.
6. 6 
St u d y Dr u g Acc o u nt a bilit y
T he I n vesti gat or h as t he ulti mate res p o nsi bilit y f or t he st u d y dr u g acc o u nta bilit y at t he st u d y site.  
T he I n vesti gat or or a desi g nate d i n di vi d ual (e g, p h ar macist or a n ot h er a p pr o priate pers o n) will 
mai ntai n rec or ds of t he st u d y dr u g ’s deli ver y t o t h e st u d y site a n d t o t he s u bject, t he i n ve nt or y at 
t he site ( use d a n d u n use d pr o d uct c o ntai ners), t he use b y eac h s u bj ect, a n d t he ret ur n t o t he 
s p o ns or or alter nati ve dis p ositi o n of u n use d me dicati o n.  T he st u d y dr u g m ust be ke pt i n a l oc ke d 
area t h at is m o nit ore d f or te m perat ur e at least o nc e per da y .  Access t o st u d y dr u g will be 
restricte d t o a ut h ori ze d st u d y pers o n nel a n d us e d o nl y i n acc or da n ce wit h t h e a p pr o ve d pr ot oc ol.  
At t he c o ncl usi o n of t he st u d y, a n y re mai ni n g st u d y dr u g s u p plies will be ret ur ne d t o t he s p o ns or
or its desi g n ee.  T he s p o ns or or its desi g nee will e ns ure t hat a fi nal re p ort of st u d y dr u g 
acc o u nta bilit y is pre pare d a n d  mai ntai ne d b y t he I n vesti gat or.  T he I n v esti gat or a grees n ot t o 
s u p pl y or a d mi nister st u d y dr u g t o a n y pers o n e xce pt t h ose s u bjects partici pati n g i n t his st u d y.
6. 7  
Assess m e nt of S u bject C o m pli a nce
C o m plia nce will be base d o n t he a m o u nt of st u d y dr u g dis pe nse d t o t he s u bject a n d ret ur ne d t o 
t he site.
St u d y P r oce d ures a n d  Assess me nts
7. 1
Scree ni n g, Recr uit me nt, a n d I nf or me d C o nse nt
I n di vi d uals wit h F O P will lear n a b o ut t his P hase 3, o pe n-la bel st u d y t hr o u g h t heir partici pati o n 
i n St u dies P V O- 1 A- 0 0 1 ( N H S), P V O- 1 A- 2 0 2, a n d P V O- 1 A- 2 0 4, a n d t hr o u g h t he F O P 
c o m m u nit y ( p h ysicia ns, patie nt s u p p ort gr o u ps, a n d ot her c o ntacts).  A ma xi m u m of u p t o 
1 1 0 s u bjects will be e nr olle d i nt o t he M O V E Trial ( u p t o 9 9 wit h t he R 2 06 H  m utati o n a n d n o 
pre vi o us e x p os ure t o p al o var ote ne, a n d 1 1  wit h ot her m utati o ns or pre vi o us partici pati o n i n t he 
P hase 2 trials), a n d recei ve c hr o nic d osi n g f or u p t o 2 4 m o nt hs i n Part A a n d u p t o a n a d diti o nal 
2 4  m o nt hs i n Part B; a n d u n der g o flare- u p- base d tr eat me nt s h o ul d t he y e x perie nce a n eli gi ble 
flare- u p c o nfir me d b y t h e I n vesti gat or.
Part C was a d de d f or s keletall y i m mat ure s u bjects w h o st o p pe d ta ki n g st u d y me dicati o n f or a n y 
reas o n bef ore c o m pleti o n of Part A/ B.  Part C i ncl u des yearl y visits f or u p t o a 2- year f oll o w- u p 
peri o d f oll o wi n g last d ose  wit h a t otal s u bject partici pati o n of n o m ore t ha n 4 years.  Ma xi m u m 
le n gt h of st u d y partici pati o n is 4 8 m o nt hs (+ 1 m o nt h). N o d osi n g will occ ur d uri n g Part C.
D ue t o t he b ur de n of tra v el, s u bjects ma y u n der g o a n IR B-a p pr o ve d re m ote c o nse nt/asse nt 
pr ocess t hat will i ncl u de a disc ussi o n wit h t he site re pres e ntati ve of t he st u d y re q uire me nts a n d 
ris ks.  Si g ne d c o nse nts will be e maile d or fa x e d bet wee n site a n d s u bjects.  P ote ntial 
s u bjects/ pare nts wis hi n g t o partici pate m ust si g n t he i nf or me d c o ns e nt/asse nt per l ocal 
re q uire me nts pri or t o u n d er g oi n g a n y st u d y-relate d pr oce d ures.  R e m ote c o nse nt/asse nt will 

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allow the screening process to begin prior to the initial site visit, should the Investigator deem it 
relevant. 
As per the global addendum (dated 15Apr2020) to Study PVO-1A-301 Amendment 4, 
Investigators, in consultation with their site IRB/EC, are required to inform subjects of the 
temporary changes (during the COVID-19 global pandemic) to the study conduct and monitoring 
plans that could impact them and their willingness to continue participation in the trial.  The 
method of communication to subjects (e.g., email, phone call, information letter) and 
documentation of subject/caregiver acknowledgement is to be performed and documented in 
accordance with local regulations/EC requests and guidance. All contacts with subjects must be 
filed in the source records. 
 
7.2 
Safety Assessments 
Subjects will follow all procedures and undergo all assessments as outlined in the Schedule of 
Assessments in Table 1, Table 2, and Table 3 as appropriate, unless a subject is unable to 
undergo a procedure due to safety concerns (eg, risk of flare-up) or physical limitation (pain or 
locked position). 
7.2.1 Medical History 
A medical history, including FOP history, is to be documented at Screening for each subject. 
For subjects receiving flare-up-based treatment, the flare-up assessment will include current 
flare-up location, symptoms, and probable cause documented on Flare-up Day 1. 
7.2.2 Physical Examination 
A physical examination of all body systems is to be documented at Screening and every 
6 months in Part A (Months 6, 12, 18, and 24) and Part B (Months 30, 36, 42, and 48), Part A or 
B EOT/EOS and Part C (Years 1 and 2 or SC post last dose of study treatment) for each subject. 
The physical examination will monitor for objective changes and for possible adverse reactions 
associated with therapy.  Any post-baseline abnormal physical examination findings assessed as 
clinically significant will be recorded as adverse events. 
7.2.3 Body Weight and Linear Growth Assessments  
All subjects will have body weight assessed at Screening and every 3 months in Part A (Months 
3, 6, 9, 12, 15, 18, 21, and 24) and Part B (Months 27, 30, 33, 36, 39, 42, 45, and 48), Part A or B 
EOT/EOS and Part C (Years 1 and 2 or SC post last dose of study treatment).   
For subjects receiving flare-up-based treatment in Parts A and B, body weight will also be 
recorded at Flare-up Cycle Safety Day 1 and every 12 weeks thereafter during safety assessments 
until treatment of the last flare-up or traumatic event in the flare-up cycle is completed.   
Subjects 18 years of age and older will have linear growth assessed by stadiometer at Screening 
in Part A.  Subjects under the age of 18 years enrolled with open epiphyseal growth plates will 

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have linear growth assessments (in triplicate) by stadiometer and knee height measurements (in 
triplicate) at Screening and every 6 months (Months 6, 12, 18, and 24).  Once a subject is 
18 years old, triplicate linear growth and knee height assessments will no longer be required.  
The 6-month assessments of linear growth in subjects under the age of 18 years will continue in 
Part B (Months 30, 36, 42, and 48), Part A or B EOT/EOS and Part C (Years 1 and 2 or SC post 
last dose of study treatment) 
Linear growth measurements will be performed by trained and qualified study personnel at the 
same time of day for each assessment, if possible.  The stadiometric measurement instructions 
will include practices that reduce measurement error including calibration of equipment, proper 
subject positioning, and measurement capture.  The same examiner should be used whenever 
possible to standardize the performance of procedures and minimize the inter-examiner 
variability.  Measurement of knee height will also be standardized. 
In addition, the length of bilateral tibia and femur will be assessed by WBCT scan every 
6 months up to Month 24 in Part A; and annually up to Month 48 in Part B; and annually in the 
NHS. 
7.2.4 Vital Signs 
Vital signs (temperature, respiratory rate, blood pressure, and heart rate) will be assessed at 
Screening and every 3 months in Part A (Months 3, 6, 9, 12, 15, 18, 21, and 24) and Part B 
(Months 27, 30, 33, 36, 39, 42, 45, and 48), Part A or B EOT/EOS and Part C (Years 1 and 2 or 
SC post last dose of study treatment) for each subject.   
For subjects receiving flare-up-based treatment in Parts A and B, vital signs will be assessed at 
Flare-up Cycle Safety Day 1 and every 12 weeks thereafter during safety assessments until the 
treatment of the last flare-up or traumatic event in the flare-up cycle is completed.   
Blood pressure will preferably be measured on the same arm at the same position and with the 
same instrument at each visit.  If a subject is unable to have blood pressure performed on the 
same arm, the alternate arm or leg will be used.  Blood pressure and heart rate will be obtained 
following a resting period of at least 5 minutes.  Automatic blood pressure devices are not 
allowed due to the risk of over-inflation and potential tissue injury.  To minimize the potential 
for a flare-up at the cuff site when measuring blood pressure, pump the cuff slowly to a 
maximum of 140 mm Hg.  DO NOT measure blood pressure on an arm with a flare-up. 
7.2.5 Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be performed at Screening and every 6 months in 
Part A (Months 6, 12, 18, and 24), Part B (Months 30, 36, 42, and 48), and Part A or B 
EOT/EOS for each subject.   
To ensure consistent generation and interpretation of results, a central ECG laboratory will 
perform the analysis using standardized procedures.  The Investigator will be provided ECG 
interpretations from the central ECG laboratory, and will review and assess all abnormal results 
for clinical significance.  Any post-baseline ECG abnormalities assessed as clinically significant 
will be recorded as AEs. 

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7.2.6 Clinical Laboratory Tests 
Blood and urine samples will be collected for hematology, biochemistry (includes lipids), and 
urinalysis testing at Screening and every 6 months in Part A (Months 6, 12, 18, and 24), Part B 
(Months 30, 36, 42, and 48), and Part A or B EOT/EOS for each subject. 
For subjects receiving flare-up-based treatment in Parts A and B, blood and urine samples will be 
collected at Flare-up Cycle Safety Day 1, and every 12 weeks thereafter during safety 
assessments until treatment of the last flare-up or traumatic event in the flare-up cycle is 
completed.  Subjects with normal or non-clinically significant abnormal laboratory results 
observed within 1 month of starting flare-up-based treatment will not need to have Flare-up 
Day 1 laboratory tests repeated.  The Investigator will determine whether subjects with clinically 
significant abnormal laboratory results in the most recent assessment will need to be re-assessed 
prior to beginning flare-up-based treatment.  The only exception is for pregnancy testing, which 
must always be performed monthly during chronic treatment; and at the start of each flare-up 
cycle and every 4 weeks thereafter until treatment of the last flare-up or traumatic event in the 
flare-up cycle is completed.  However, if a pregnancy test was performed within 4 weeks prior to 
the start of a flare-up or traumatic event, treatment of the flare-up or traumatic event will not be 
delayed pending repeat pregnancy testing.  
Blood and urine samples may be collected remotely (eg, at the subject’s home) by qualified 
study personnel or at a local medical facility according to standard operating procedures and 
applicable regulations.  When possible, samples will be collected under fasting conditions.  
Samples will be packaged and shipped to the designated laboratory for testing.  To ensure 
consistent generation and interpretation of results, a central testing laboratory will perform the 
analysis of clinical laboratory samples.  If results are needed promptly (eg, Screening for 
eligibility), testing can be completed at a local, qualified laboratory.  If urinalysis results are 
abnormal, a microscopic evaluation will be completed. 
The total blood volume drawn from a subject over the course of the entire study (48 months) will 
range from approximately 66 mL (in the case of no flare-ups) to 182 mL (in the case of two 
expected flare-ups treated per year, or a total of eight flare-ups treated during the entire study).  
In the event that 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, as outlined in 
the clinical safety laboratory manual.  This will ensure that the total blood volume drawn is 
within the established limits. 
The Investigator will be provided all laboratory results and will review and assess out-of-range 
findings for clinical significance.  Any post-baseline abnormal laboratory value assessed as 
clinically significant will be recorded as an AE.  It is recognized that performing phlebotomy in 
subjects with FOP is very challenging due to their multiple ankyloses and the potential to cause 
injury resulting in a flare-up following multiple attempts.  The Investigator will be notified about 
any protocol-specified safety laboratory test that could not be obtained despite at least 
two attempts.  Should this occur, or for those samples that were drawn but were not usable (eg, 
quantity not sufficient, clotted, sample lost, etc.), the Investigator will assess the subject’s 
condition and determine whether repeated attempts should be made to obtain the missing 

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laboratory data for that time point, or reassessed at the next scheduled time point based on the 
subject’s current clinical status (eg, AEs, vital signs) and previous laboratory measures. 
Table 5 presents the clinical laboratory parameters that will be assessed in this study. 
Table 5. 
Clinical Laboratory Parameters 
Biochemistry: 
Sodium 
Globulin 
Potassium 
Alkaline phosphatase (ALP) 
Chloride 
Aspartate aminotransferase (AST) 
Bicarbonate 
Alanine aminotransferase (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 
 
Lipid Profile: 
Triglycerides 
Total cholesterol 
 
High-density lipoprotein (HDL) 
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 
Urinalysis1: 
pH 
Blood (free hemoglobin) 
Protein 
Nitrite 
Glucose 
Urobilinogen 
Ketones 
Specific gravity 
Bilirubin 
Color & appearance 
1 If results are abnormal, then a microscopic evaluation will be completed. 
 
7.2.7 Pregnancy Testing 
For female subjects of child bearing potential receiving palovarotene, a blood or urine pregnancy 
test (with sensitivity of at least 50 mIU/mL) will be conducted monthly and Part A or B 
EOT/EOS.  If the Screening test is positive, the subject will not be eligible for study 
participation.  Any positive pregnancy test during study participation will result in immediate 
discontinuation of study drug.  If a subject becomes pregnant during the study, she will be 
followed throughout her pregnancy and the health status of the baby will be verified.  Subjects 
will be reassessed for changes in child bearing status (females only) and pregnancy prevention 

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measures (females and males) every 3 months and given counsel on pregnancy prevention and 
birth control methods as appropriate. 
7.2.8 Adverse Events 
Adverse event monitoring will be conducted throughout the study for all subjects. The AE, SAE 
and death reporting period begins at the time of informed consent and continues through Part 
A/B EOS +30 days (for subjects not participating in Part C) or Part C SC + 30 days.   
The Investigator will follow-up on all AEs observed or reported by the subject up to the end of 
the reporting period or until follow-up is no longer necessary.  The Investigator will follow-up on 
SAEs until they are considered resolved or the outcome is known.  Limb/joint AEs reported by 
subjects with open epiphyses will be evaluated by clinical and radiographic assessments deemed 
appropriate by the Investigator. 
Definitions, documentation, and reporting of AEs are described in Section 9.1.  Serious adverse 
events must be reported within 24 hours as described in Section 9.1.8. 
7.2.9 Concomitant Medications 
Prior/concomitant medications will be assessed at every site and remote visit during chronic 
treatment, flare-up-based treatment, Part A or B EOT/EOS and Part C (Years 1 and 2 or SC post 
last dose of study treatment). 
See Section 5.2 for restrictions for concomitant medications. 
7.3 
Special Safety Assessments 
In light of the established safety profile of the currently marketed oral systemic retinoids and 
hypothesized potential concerns, clinical and laboratory monitoring of selected AEs and 
laboratory abnormalities in subjects in this study is indicated.  The following potential safety 
issues will be monitored in the study. 
7.3.1 Columbia-Suicide Severity Rating Scale 
In accordance with the Guidance for Industry: Suicidal Ideation and Behavior: Prospective 
Assessment of Occurrence in Clinical Trials, 2012, all subjects 8 years of age and older who are 
receiving palovarotene will be assessed for suicidal ideation and behavior using the C-SSRS (see 
Appendix 5A) at Screening and every 3 months in Part A (Months 6, 9, 12, 15, 18, 21, and 24); 
in Part B (Months 27, 30, 33, 36, 39, 42, 45, and 48) and Part A or B EOT/EOS and as part of 
every Flare-Up Cycle Safety Assessment in Parts A and B.   
The adult form will be used for subjects 12 years and older and the pediatric form will be used 
for subjects 8 to 11 years old (see Appendix 5B).  Study personnel administering the 
questionnaire will receive formal training to ensure accuracy and consistency in application of 
the instrument. 
Any subject reporting a type 4 or 5 suicidal ideation or any suicidal behavior within 1 month 
prior to Screening will not be eligible to receive study drug.  Any subject experiencing a type 4 

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or 5 suicidal ideation or any suicidal behavior while receiving study drug will have study drug 
immediately withheld.  All such subjects will be referred by the Investigator to a mental health 
professional for evaluation and counseling as appropriate. 
7.3.2 Knee and Hand-Wrist Radiographs 
Due to the potential for palovarotene to cause adverse effects on long-bone growth, subjects 
under the age of 18 years at the time of enrollment (Screening) with open epiphyses will have 
follow-up knee (AP view) and hand-wrist radiographs (PA view, preferable on the left side) 
every 6 months in Part A (Months 6, 12, 18, and 24), Part B (Months 30, 36, 42, and 48) and Part 
A or B EOT/EOS. Subjects who are skeletally immature at the time of study drug 
discontinuation and entering Part C (Y1 and Y2 or SC post last dose of study treatment) will 
have follow-up knee (AP view) and hand-wrist radiographs (PA view, preferable on the left side) 
every year.  Additional radiographic assessments will be performed every 3 months in Parts A 
and B in those subjects who (1) received the flare-up dosing regimen in the period of time since 
their last radiographic assessment; and (2) had not achieved 100% skeletally maturity on their 
last radiographic assessment.   
Subjects enrolling from the NHS and Phase 2 studies that underwent knee and hand-wrist 
radiographs within 1 month of Screening will not need to have radiographs repeated at 
Screening.  At the Screening/Study Day 1 visit, in order to obtain a more rapid assessment of the 
subject’s skeletal maturity so that dosing can be determined while the subject is on site, sites may 
have the subject’s bone age also assessed by qualified physician staff. 
Once a subject has achieved 100% skeletal maturity (defined as closure of all assessed 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 locations, then only the location 
that is still maturing would need to be monitored. 
All radiographs will be read by a central imaging laboratory to ensure consistent assessment of 
the radiographs.  The Investigator will be provided 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 AE. 
7.3.3 Bone Safety Management Plan 
To enhance subject safety monitoring, a Bone Safety Management Plan has been developed to 
supplement per-protocol safety monitoring.  Of note, in addition to the knee and hand-wrist 
radiographs described above in Section 7.3.2, WBCT scans acquired from subjects under the age 
of 18 years in both Study PVO-1A-301 and the NHS will be reviewed in a blinded fashion by 
two independent radiologists to assess the growth plate morphology of bilateral hands-wrists and 
knees.  Reviews of WBCT scans from all subjects regardless of age will also monitor hip 
morphology for signs of avascular necrosis (AVN), warranted due to the association of 
corticosteroids with AVN and the presence of AVN of the femoral head in wild-type rats treated 
with high dose palovarotene.  WBCT scans will be reviewed for spinal health including fracture 
assessment. 
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. 

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Safety findings of these bone images may trigger additional follow-up images and/or dose 
modification, as discussed in the Bone Safety Management Plan. 
7.3.4 Mucocutaneous Effects (Skin and Mucous Membrane Toxicity Profile) 
At every study visit during palovarotene treatment, subjects will be assessed for AEs, including 
mucocutaneous AEs (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 9.1.4), all mucocutaneous AEs will be rated according to the 
most recent version of the Common Terminology Criteria for Adverse Events (CTCAE), Version 
4.03, 14 June 2010 (see Appendix 6).  In the event of a subject-report of a mucocutaneous AE, 
dermatologic photographs may be taken for review by a dermatologist.  Permission to obtain 
dermatologic photographs will be requested in the informed consent/assent document(s).  
If any mucocutaneous effects are observed, symptomatic therapy (eg, analgesics, skin emollients, 
lip moisturizers, artificial tears, or other helpful treatments) may be administered if deemed 
necessary by the Investigator.  In addition, the Investigator may recommend prophylactic use of 
these therapies at the start of palovarotene treatment.  Dose reduction as described in Section 6.5 
is recommended for intolerable mucocutaneous effects that would otherwise result in study drug 
discontinuation.  If a subject is already receiving the lowest possible dose, then study drug will 
be discontinued. 
Although palovarotene has not been proven to be phototoxic, precautionary measures for 
phototoxicity are recommended for subjects who are receiving palovarotene.  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). 
7.3.5 Serum Lipids 
A complete lipid profile will be performed as part of the biochemistry testing at Screening and 
every 6 months in Part A (Months 6, 12, 18, and 24), Part B (Months 30, 36, 42, and 48), and 
Part A or B EOT/EOS (excepting Part C) for all subjects. During flare-up-based treatment in 
Parts A/B, a complete lipid profile will be performed as part of the biochemistry testing at Flare-
up Cycle Safety Day 1 and then every 12 weeks thereafter until treatment of the last flare-up or 
traumatic event within a Flare-up Cycle is completed. 
If, during the palovarotene treatment, serum triglyceride levels are ≥800 mg/dL, the study drug 
should be immediately discontinued, with follow-up assessments performed per protocol. 
7.3.6 Liver Enzymes 
Liver enzymes will be monitored as part of the biochemistry testing at Screening and every 
6 months in Part A (Months 6, 12, 18, and 24), Part B (Months 30, 36, 42, and 48), and Part A or 
B EOT/EOS (excepting Part C) for all subjects. During flare-up-based treatment in Parts A/B, a 
liver enzyme profile will be performed as part of the biochemistry testing at Flare-up Cycle 
Safety Day 1 and then every 12 weeks thereafter until treatment of the last flare-up or traumatic 
event within a Flare-up Cycle is completed. 

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During palovarotene treatment, drug therapy 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 >2× ULN, unexplained 
abdominal pain, malaise, nausea, and/or vomiting. 
Liver toxicity evaluation will follow the Guidance for Industry Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation (July 2009) (Appendix 7). 
7.3.7 Lipase/Amylase 
Amylase and lipase will be monitored as part of the biochemistry testing at Screening and every 
6 months in Part A (Months 6, 12, 18, and 24), Part B (Months 30, 36, 42, and 48), and Part A or 
B EOT/EOS (excepting Part C) for all subjects. During flare-up-based treatment in Parts A/B, a 
lipase/amylase profile will be performed as part of the biochemistry testing at Flare-up Cycle 
Safety Day 1 and then every 12 weeks thereafter until treatment of the last flare-up or traumatic 
event within a Flare-up Cycle is completed. 
Lipase and/or amylase increases during the course of 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 as per the 
Investigator’s judgment, with follow-up assessments performed per protocol. 
7.3.8 Central Nervous System 
Retinoid use has been associated with a number of cases of benign intracranial hypertension 
(also known as pseudotumor cerebri), some of which involved concomitant use of tetracyclines. 
The cases of benign intracranial hypertension were manifested with symptoms and signs such as 
severe headache, nausea and vomiting, and visual disturbances, and may be associated with 
papilledema.  Headache generally occurs within 3 to 4 hours of starting therapy and remits 
spontaneously. 
However, headache of unusual characteristics (eg, severity, location, pattern) to the subject 
should lead to contacting the Investigator.  In case of such headache, it is at the discretion of the 
Investigator to refer subjects receiving palovarotene treatment for neurological and/or 
ophthalmological examination to rule out benign intracranial hypertension.  Headache will be 
assessed using the standard AE severity scale (see Section 9.1). 
7.3.9 Hearing and Visual Disturbances 
Hearing loss is a common finding in individuals with FOP.  In Study PVO-1A-001 (NHS), 42% 
of subjects (48 of 114) reported hearing loss at baseline.  However, impaired hearing also has 
been reported in subjects taking retinoids.  Thus, hearing tests will occur at baseline (or at 

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Month 6, or the next possible visit, if they were not obtained at screening) and at Months 12 and 
24 in Part A, Months 36, and 48 in Part B, and Part A or B EOT/EOS (excepting Part C).   
Hearing will be assessed with age-appropriate audiometry behavior testing.  The assessments 
will determine auditory thresholds in response to speech and frequency-specific stimuli 
presented through earphones.  In addition, The Investigator should refer subjects receiving 
palovarotene treatment who experience tinnitus or hearing impairment to specialized care for 
further evaluation.  The subject with a confirmed diagnosis of hearing impairment (felt to be 
related to the study drug) should be discontinued from treatment, based on a benefit-risk 
assessment. 
An ophthalmological examination should be carried out in all subjects receiving palovarotene 
treatment who are experiencing unexplained visual difficulties. 
Corneal opacities have occurred in subjects receiving retinoids and were reversible upon drug 
discontinuation.  Subjects receiving palovarotene treatment with corneal opacities should be 
assessed by an ophthalmologist. 
Decreased night vision has been reported during retinoid therapy.  The onset in some subjects 
can be sudden; therefore, subjects receiving palovarotene treatment should be informed and 
warned to be cautious when driving or operating vehicles at night. 
7.3.10 Teratogenicity 
Palovarotene must not be used by female subjects who are or may 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 short periods of time.  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, and premature births have 
been 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 palate.  Documented 
internal abnormalities with other retinoids include: central nervous system abnormalities 
(including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial 
nerve deficit); cardiovascular abnormalities; thymus gland abnormality; and parathyroid 
hormone deficiency.  In some cases, death has occurred with other retinoids with certain of the 
abnormalities previously noted. 

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7.4 
Efficacy Assessments 
7.4.1 Low-Dose, Whole Body Computed Tomography 
All subjects will undergo a low-dose, WBCT scan (excluding head) every 6 months in Part A 
(Months 6, 12, 18, and 24) and annually in Part B (Months 36 and 48), Part A or B EOT/EOS 
and Part C (Y1 and Y2 or SC post last dose of study treatment). Of note, the last low-dose, 
WBCT scan (excluding head) from the NHS will be used as the baseline assessment for those 
subjects enrolling from the NHS as long as the scans were performed within 1 month of 
Screening/Study Day 1.  The last low-dose, WBCT scan (excluding head) from 
Study PVO-1A-202 or Study PVO-1A-204 will be used as the baseline assessment for those 
subjects on chronic treatment enrolling from Phase 2, as long as the scans were performed within 
6 months of Study Day 1.  All other subjects (ie, subjects who will start chronic treatment during 
Study PVO-1A-301) will undergo a low-dose, WBCT scan (excluding head) at 
Screening/Study Day 1. 
Interpretation of the CT scan will document the absence or presence of HO across various body 
regions, volume of total body HO, presence and volume of new HO at follow-up visits, and 
spinal health.  All images will be interpreted by a central imaging core laboratory using 
standardized procedures detailed in an imaging charter. 
7.4.2 FOP-Physical Function Questionnaire 
On clinic days when multiple assessments are to be performed, the age-appropriate FOP-PFQ 
and the age-appropriate PROMIS Global Health Scale should be completed (in that order) by the 
subject/parent before any other procedures are completed on those visit days. 
To evaluate the effect of palovarotene on physical function, age-appropriate forms of the 
FOP-PFQ will be administered at Screening and every 6 months in Part A (Months 6, 12, 18, and 
24), Part B (Months 30, 36, 42, and 48), and Part A or B EOT/EOS for each subject. 
The adult form of the FOP-PFQ will be completed by subjects 15 years of age and older (see 
Appendix 2A).  Three Pediatric FOP-PFQ (FOP-PFQ-P) forms will be utilized in subjects under 
the age of 15 years: a self-completed form developed for 8- to 14-year-olds (see Appendix 2B), a 
proxy-completed form developed for 5- to 14-year-olds (see Appendix 2C), and a 
proxy-completed form developed for 2- to 4-year-olds (see Appendix 2D). 
Study personnel will be trained on the administration of the instruments and subjects (and 
parents of subjects under the age of 15 years) will be provided specific instructions on how to 
complete the instrument independently. 
7.4.3 PROMIS Global Health Scale 
To evaluate the effect of palovarotene on physical and mental health in subjects ≥15 years of 
age, and mental health in subjects <15 years of age, age-appropriate forms of the PROMIS 
Global Health Scales will be administered at Screening and every 6 months in Part A (Months 6, 
12, 18, and 24), Part B (Months 30, 36, 42, and 48), and Part A or B EOT/EOS for each subject. 

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The adult form of the PROMIS Global Health Scale will be administered to subjects 15 years of 
age and older (see Appendix 8A).  Two PROMIS Pediatric Global Health Scale forms will be 
utilized in subjects under the age of 15 years: a self-completed form developed for 8- to 
14-year-olds and a proxy-completed form developed for subjects under the age of 15 years (see 
Appendix 8B and Appendix 8C, respectively). 
Study personnel will be trained on the administration of the instruments and subjects (and 
parents of subjects under the age of 15 years) will be provided specific instructions on how to 
complete the instrument independently. 
7.4.4 Cumulative Analogue Joint Involvement Scale 
Range of motion will be assessed by the Investigator using CAJIS (see Appendix 1) at Screening 
and every 6 months in Part A (Months 6, 12, 18, 24), Part B (Months 30, 36, 42, and 48) and Part 
A or B EOT/EOS for each subject.  The CAJIS should be assessed by the same Investigator at 
each time point.  All Investigators will be trained to administer the CAJIS prior to subject 
enrollment. 
7.5 
Pharmacokinetics 
Pharmacokinetics of palovarotene dosing will be assessed at the first 3-month safety assessment 
during chronic-based treatment; if samples cannot be obtained during the first 3-month safety 
assessment, then they can be obtained during any subsequent 3-month safety visit in the first 
24 months (ie, in Part A).   
Pharmacokinetics will also be assessed twice during flare-up dosing: once during the 20-mg 
regimen at any time between Study Days 4 to 28, and once during the 10-mg regimen at any time 
between Study Days 32 and 84, for the first treated flare-up only.  If this is not possible for the 
first treated flare-up, pharmacokinetic blood samples can be obtained during any subsequent 
flare-up dosing in the first 24 months (ie, in Part A).  Pharmacokinetic blood samples will be 
collected at predose and 3, 6, 10, and 24 hours post-dose. 
The following parameters will be determined where possible by model independent analysis 
using WinNonlin™: Cmax,ss, Cmin,ss, Tmax,ss, AUC0-24ss, λz, t½z, and CL/F. 
The determination of palovarotene plasma concentrations will be performed using a validated 
LC-MS/MS method, and exploration of any relationships with palovarotene exposure will be 
performed.  The time of sample collection as it relates to the time of dosing on the PK days will 
be recorded. 
Detailed instructions for collection, storage, labeling, and shipment of all samples will be 
provided in the Laboratory Manual. 
7.6 
Genotyping 
On Screening/Study Day 1, a blood sample will be collected and the ACVR1 gene-coding region 
will be sequenced by a central genotyping laboratory to assess for the presence of an 
FOP-associated mutation of the ACVR1 gene for new subjects or for subjects who have not 
undergone previous genotyping as part of Study PVO-1A-001.  Subjects enrolling from Study 

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PVO-1A-202 or Study PVO-1A-204 do not need to undergo repeat genotyping.  Any subject 
enrolled who does not have an ACVR1 mutation known to be associated with FOP will be 
discontinued.  If the Investigator has any reason to believe a subject does not possess an FOP 
mutation, enrollment may be delayed until the genotype is confirmed. 
7.7 
Data Monitoring Committee 
A Data Monitoring Committee (DMC) will be established to review safety information 
periodically and on an ad hoc basis as outlined in the DMC Charter, which is maintained 
separately from the study protocol.  The DMC can recommend temporary or permanent stopping 
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 analyses (see Section 8.7).  In addition to the Investigator, the DMC will make 
recommendations for potential dose modifications in the event of treatment-related adverse bone 
effects as described in the Bone Safety Management Plan. 
The DMC will include members with relevant clinical expertise, including a good understanding 
of the safety of retinoids.  The methodology and the operating procedures for the safety reviews 
will be developed by the Chairperson in collaboration with the sponsor and will be documented 
in the DMC Charter. 
7.8 
Temporary Measures (Procedures Related to COVID-19 Pandemic) 
 
Procedures related to COVID-19 pandemic 
Temporary measures put in place for the conduct of Study PVO-1A-301 (MOVE study) during 
the COVID-19 pandemic will continue until such time as the situation resolves, at which point 
the protocol assessments will return to those specified.  Investigators will determine the 
feasibility of dosing on a subject-by-subject basis, depending on the ability to conduct safety 
monitoring and providing subjects an adequate supply of study drug, in accordance with local 
requirements.  These recommendations will remain in place for as long as the COVID-19 
pandemic warnings are in effect in territories participating in the trial. The timing of when the 
pandemic is declared over may vary on a country-by-country basis as well as between sites in the 
same country, and as such the temporary measures may remain in place for differing periods of 
time per country/site.  
 
The study visits and assessments to be conducted during this period are listed below: 
Study Visits and Assessments  
1) For subjects aged under 14 years that are still participating in the study but not 
currently receiving palovarotene treatment as per the global partial clinical hold 
or for any other reason, they will complete Part A or B EOT/EOS and be invited to 
participate in Part C and undergo assessments outlined in Table 3. 
2) For subjects aged 14 years and older who are being considered for re-starting 
palovarotene treatment but have NOT yet re-started, the following minimum 
assessments are to be done via remote monitoring (video conference/phone calls) by 
the Investigator (or delegated study staff):  

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a. Chronic visits every 3-6 months (per protocol): assess for childbearing status 
(females only) and pregnancy prevention measures, CAJIS, ConMeds, 
adverse events, review subject diary, PROMIS Global Health Scale*, FOP-
PFQ* (*assessments that can occur remotely but are not required as these are 
not essential to ensure subjects’ safety).  
b. For females of childbearing status: if pregnancy testing did not continue 
monthly per protocol post the study medication interruption then at a 
minimum a self-administered urine pregnancy test is to be done within 4 
weeks before re-starting palovarotene treatment.  
c. All subjects should have laboratory assessments (hematology, biochemistry, 
urinalysis) within 4 weeks before re-starting palovarotene treatment. 
d. All subjects who were skeletally immature at the last assessment will have a 
hand-wrist and knee radiographs within 12 weeks before re-starting 
palovarotene treatment. For on-treatment subjects who have not reached at 
least 90% skeletal maturity radiograph assessments should continue per 
protocol either on site or remotely. 
 
 
Site staff will also assess the subject’s ability to restart remotely.  
3) For subjects 14 years and over that plan to reinitiate dosing, once dosing is 
reinitiated following the required approvals for restart (Ethics Committee and 
Competent Authority), the following minimum assessments that cannot be 
performed via remote monitoring must be performed either at the clinical site, at the 
subject’s home (by Symphony nursing) or at a local medical facility in order for the 
Investigator to adequately monitor the safety of subjects:  
a. Via remote monitoring (telephone or video conferencing) by Investigator (or 
delegated study staff): 
i. Chronic visits (per protocol schedule every 3 and/or 6 months): C-
SSRS, assess for childbearing status (females only) and pregnancy 
prevention measures, CAJIS, ConMeds, adverse events, PROMIS 
Global Health Scale*, FOP PFQ* (*assessments that can occur 
remotely but are not required as these are not essential to ensure 
subjects’ safety), study drug dispensing  
ii. Flare up visits (per protocol schedule): C-SSRS, ConMeds, adverse 
events, study drug dispensing  
b. Via home visit by Symphony nursing/local assessment 
i. Chronic visits per protocol schedule (every 3 and/or every 6 months): 
body weight, vital signs, hematology, biochemistry, urinalysis, self-
administered pregnancy test (monthly), ConMeds, adverse events, 
review subject diary  
ii. Flare up visits (per protocol schedule): vital signs, body weight, 
hematology, biochemistry, urinalysis, self-administered pregnancy 
testing, ConMeds, adverse events, review subject diary  
4) Based on the known safety profile of palovarotene to date in FOP patients, the 
following assessments can be postponed as determined by the Sponsor and 
individual site Investigators, as they do not constitute assessments where a safety 

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concern has been raised. The below assessments were also deemed acceptable to 
postpone by the DMC chair. 
a. To date low dose whole-body CT has not indicated a safety concern of 
avascular necrosis of the hip. Any concerns for avascular necrosis of the hip 
based on clinical assessment should be followed up;  
b. For subjects who have reached at least 90% skeletal maturity radiograph 
assessments may be postponed given the low risk of early growth plate 
closure as well as growth plate abnormalities; 
c. Linear height and knee height (Subjects 14 years and older are at or near adult 
height indicated by skeletal maturity of at least 90%);  
d. ECG (FOP patients can have ECG abnormalities, ECG changes noted in 
subjects on Palovarotene were similar to those seen in the untreated subjects 
in the Natural History Study. Clinical concerns of abnormal ECG findings 
should continue to be followed);  
e. Hearing evaluation (As a class, retinoids can cause abnormal hearing. 
Evaluation should be performed if there is clinical concern);  
f. Physical exam (Palovarotene has been shown to cause retinoid skin reactions 
which can be assessed remotely);  
 
Individual subjects may require assessments if there is a clinical concern as identified 
by the Investigator. Protocol deviations that have an impact on subject safety should 
be notified immediately to CRO/Sponsor as it may necessitate an urgent safety 
measure notification to competent authorities and ethics committees in some 
countries.  
5) End of Treatment/End of Study Assessments:  
a. The following assessments should be performed via remote monitoring 
(telephone or video conferencing) by Investigator (or delegated study staff):  
i. C-SSRS, assess for childbearing status (females only) and pregnancy 
prevention measures, CAJIS, Con-Meds, adverse events, PROMIS 
Global Health Scale, FOP PFQ 
b. The following assessments should be performed at the subject’s home (by 
Symphony nursing) or at a local medical facility: Body weight, vital signs, 
hematology, biochemistry, urinalysis, pregnancy test (monthly), ConMeds, 
adverse events, review subject diary 
6) Once on-site visits resume, the following assessments should be performed on 
site as well as any assessment that was not obtained via remote monitoring or 
Symphony nurse:  
a. X-rays, Whole-Body CT, Linear and Knee Height, Physical Exam, Hearing 
Test, ECG.  
7) Informed Consent/Subject Communication: In consultation with their site IRB/EC, 
Investigators are required to inform subjects of the temporary changes (during the 
COVID-19 global pandemic) to the study conduct and monitoring plans that could 
impact them and their willingness to continue participation in the trial.  The method 
of communication to subjects (e.g., email, phone call, information letter) and 
documentation of subject/caregiver acknowledgement is to be performed and 

P R  O T O C O L P V O- 1 A -3 0 1, A M E N D M E N T 5
P A G E 6 9O F 1 5 1
C L E M E N TI A P H AR  M A C E U TI C A L S IN C .
3 0 O C T O B ER
2 0 2 0
P R  O PR I E T AR Y  A N D C O N FI D E N TI A L
d oc u me nte d i n acc or da n ce wit h l ocal re g ulati o ns/ E C re q uests a n d g ui da nce. All 
c o ntacts wit h s u bjects m ust be file d i n t he s o urce rec or ds.
A ris k miti gati o n assess me nt will be perf or me d f or eac h s u bj ect at t he site i n or der t o deter mi ne 
h o w t heir partici pati o n m a y be i m pacte d.  Sites m ust e ns ure t hat a p pr o priat e meas ures are ta ke n 
t o e ns ure t he safet y of F O P s u bjects i n li g ht of t he o n g oi n g C O VI D- 1 9 p a n de mic, ta ki n g i nt o 
c o nsi derati o n l ocal Et hics C o m mittee a n d C o m pete nt A ut h orit y g ui da nce, as well as t he a bilit y 
of i n di vi d ual I n v esti gat ors a n d sites t o a de q uatel y m o nit or s u bject safet y.
St atistic al C o nsi der ati o ns
8. 1  
Ge ner al C o nsi der ati o ns
T his st u d y is i nte n de d t o assess w het her a c hr o nic d osi n g re gi me n, c o m bi ne d wit h hi g her d oses 
d uri n g ti mes of flare- u ps, will re d uce ne w H O f or mati o n.  As t his is a n o pe n-la bel st u d y wit h n o 
ra n d o mize d c o ntr ol gr o u p, use of s u bject data fr o m St u d y P V O- 1 A- 0 0 1 ( Nat ural Hist or y St u d y 
[  N H S] ) o ver 2 4 m o nt hs will f or m t he basis f or a c o ntr ol ar m.  T heref ore, t he pri mar y c o m p aris o n 
of o utc o mes fr o m t his st u d y will be ma de t o data c ollecte d fr o m t he N H S i n or der t o deter mi ne 
w het her t he c hr o nic/flare- u p re gi me n pr o vi des b e nefit o ver t he u ntr eate d c o n diti o n ( data fr o m 
t he N H S).  I n a d diti o n, t he pri mar y efficac y a n al ysis will be restricte d t o M O V E s u bjects w h o 
ha ve t he R 2 06 H  m utati o n a n d w h o ha ve n ot pre vi o usl y bee n treat e d wit h pal o var ote ne.  T hese 
restricti o ns i ncrease t he v ali dit y of t he c o m paris o n t o t he N H S hist oric al c o ntr ol w hic h o nl y 
e nr olle d s u bjects wit h t he R 2 06 H  m utati o n a n d n o pre vi o us pal o var ote ne e x p os ure.
T his secti o n c o ntai ns a brief o ver vie w of t he statistical a nal yses pla n ne d f or t his st u d y.  Details 
of all pla n ne d a n al yses will be pr o vi de d i n t he f or mal statistical a nal ysis pla n ( S A P). 
8. 2 
S a m ple Size  Deter mi n ati o n
T he sa m ple size re q uire d f or t his P hase 3 st u d y was deter mi ne d via si m ulati o n base d o n t he 
a vaila ble W B C T H O v ol u mes fr o m t he N H S a n d t he o bser ve d efficac y of pal o var ote ne 
treat me nt i n t he P hase 2 st u dies.  T he N H S will ser ve as t he e xter nal c o ntr ol gr o u p,  wit h t he 
e x pectati o n t hat 4 5 s u bje cts will ha ve baseli ne, 1- year , a n d 1. 5- year W B C T H O v ol u mes a n d 
4 5 s u bjects will ha ve bas eli ne, 1- year , a n d 2- y ear W B C T H O v ol u mes.  It is als o a ntici pate d t hat 
a p pr o xi matel y 5 0 % of t h ese 9 0 s u bjects will e nter t he P hase 3 st u d y t o be gi n pal o var ote ne 
treat me nt.
T here are t hr ee i nteri m efficac y a nal yses a n d a fi n al a nal ysis pla n ne d.  Ass u mi n g a o ne-si de d, 
o verall t y pe I err or rate of 2. 5 %, t he La n- De M ets al p ha-s pe n di n g f u n cti o n wit h O’ Brie n - Fl e mi n g 
para meterizati o n was us e d t o deter mi ne st o p pi n g b o u n daries (see Secti o n 8. 5. 2 f or a d diti o nal 
details).  T he si m ulate d p o wer is s u m marize d i n T a ble 6 , gi ve n t he s pecifie d testi n g se q ue nce 
a n d 8 0 s u bjects ori gi nall y pla n ne d f or e nr oll me nt i nt o t he c urre nt st u d y wit h t he R 2 06 H  m utati o n 
a n d n o pre vi o us pal o var ote ne e x perie nce (i ncl u di n g a p pr o xi matel y 4 5 s u bjects fr o m t he N H S).  
N ote t hat t he i ncrease i n t he n u m ber of e nr olle d s u bjects will n ot s u bsta ntiall y c ha n ge t he p o wer 
of t he trial or ha v e a si g nifica nt i m pact o n t he pri mar y or sec o n dar y statistical a nal yses.

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Table 6. 
Power of MOVE Study Primary Efficacy Analysis Assuming 
80 Subjects Enrolled with the R206H Mutation and No Previous 
Palovarotene Exposure 
Scenario 
 
Cumulative Prob. of Success 
% Reduction 
HO Volume 
Conditional 
on New HO 
in a Body 
Region 
% Reduction 
in Number of 
Regions with 
New HO 
 
Interim #1 
Interim #2 
Interim # 3 
Final 
0% 
0% 
 
0.006 
0.010 
0.013 
0.021 
50% 
30% 
 
0.507 
0.789 
0.886 
0.922 
HO=heterotopic ossification. 
 
The primary efficacy analysis comparing the annualized change in new HO volume between 
subjects treated with palovarotene and untreated subjects has an overall probability of study 
success of 0.92 if palovarotene treatment reduces the number of regions with new HO by 30% 
and reduces the new HO volume conditional on new HO in a per body region by 50%.  With this 
treatment effect, the probability of declaring study success is 0.51, 0.79, and 0.89 at the first, 
second, and third interim analyses, respectively.  Table 6 shows that the type I error rate is 
maintained under the null hypothesis of no palovarotene treatment effect.   
8.3 
Disposition of Subjects 
Screened subjects will be defined as any subject who has signed the informed consent form.  
Screened subjects who complete screening and met all eligibility criteria will be eligible for 
palovarotene treatment.   
8.4 
Analysis Populations 
In Part A, the MOVE subjects will be grouped into the following populations for analysis: 
• The Principal Enrolled Population (Principal EP) includes all subjects with the R206H 
ACVR1 mutation who have not previously been treated with palovarotene and who sign 
the informed consent form and meet all eligibility criteria of the MOVE Trial. 
• The Principal Full Analysis Set (Principal FAS) includes all enrolled subjects in the 
Principal EP who have a baseline HO volume measurement and at least one post-baseline 
HO volume measurement in the MOVE trial.  For efficacy comparisons to the NHS, the 
Principal FAS will also include subjects enrolled in the NHS with available baseline and 
at least one post-baseline HO volume measurements.  
• The Principal Per-Protocol Set (Principal PPS) is a subset of the Principal FAS including 
subjects with no major protocol deviations that are expected to interfere with assessments 
of the primary endpoint, and with at least 80% compliance to the study drug regimen, 
over the first 24 months of participation in the study.  For efficacy comparisons to the 
NHS, the Principal PPS will also include subjects in the NHS with available baseline and 

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at least one post-baseline HO volume measurements and with no major protocol 
deviations over 24 months that are expected to interfere with assessments of the primary 
endpoint. 
• The Principal Safety Set (Principal SS): includes all enrolled subjects receiving at least 
one dose of palovarotene in the current study.  For safety comparisons to the NHS, the 
Principal SS will also include subjects enrolled in the NHS with available post-baseline 
follow-up.  
• The Principal Pharmacokinetic Set (Principal PS) includes all enrolled subjects receiving 
at least one dose of palovarotene and providing evaluable pharmacokinetics data in the 
current study. 
Subjects who do not have the R206H ACVR1 mutation or who have received previous treatment 
with palovarotene will comprise the Supplementary EP, the Supplementary FAS, the 
Supplementary PPS, the Supplementary SS, and the Supplementary PS, with these populations 
defined analogously as above for the subjects with the R206H ACVR1 mutation. 
8.5 
Statistical Methods 
8.5.1 Extent of Exposure 
The extent of study treatment will be assessed, and summary statistics will be presented for the 
SS populations. 
8.5.2 Analyses of Efficacy Endpoints 
8.5.2.1 Primary Efficacy Analysis 
The primary efficacy endpoint is the annualized change in new HO volume (as assessed by low-
dose WBCT) over 24 months in Part A.  The change in new HO volume is calculated by 
summing the increase in HO volume across all body regions for which new HO has occurred, 
where the increase in HO volume per region is defined as the square root of the volumetric 
increase in that region.  The change in new HO volume is modeled using a Bayesian compound 
Poisson distribution.  The Bayesian compound Poisson distribution assumes that the change in 
new HO volume can be modeled as a compound distribution of the number of body regions with 
new HO, 𝐾, and the new HO volume per region where new HO has occurred.  The number of 
body regions with new HO in subject 𝑖 for WBCT scan 𝑗 with duration 𝑤𝑖𝑗 (the time between 
scan 𝑗 and the previous scan) is distributed as  
𝐾𝑖𝑗~𝑃𝑜𝑖𝑠(𝜆𝑖∗𝑤𝑖𝑗∗𝜃1,𝑡(𝑖𝑗)). 
The subject-level rate 𝜆𝑖 follows a gamma distribution and 𝑡(𝑖𝑗) is an indicator function equal to 
1 if the subject was on treatment at the time of the 𝑗th WBCT scan and 0 if the subject was not 
on treatment.  Letting 𝜃1,0 = 1, the variable 𝜃1,1 is the multiplicative effect of palovarotene 
treatment on the mean number of body regions with new HO.  The new HO volume in region 𝑟 
where new HO has occurred for subject i in scan j is assumed to be distributed as 

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𝑍𝑖𝑗𝑟~𝑁(𝛼∗𝛼𝑟∗𝜃2,𝑡(𝑖𝑗), 𝛼𝑟
2
𝜏𝑡(𝑖𝑗)
). 
Letting 𝜃2,0 = 1, the variable 𝜃2,1 is the multiplicative effect of palovarotene treatment on the 
new HO volume conditional on new HO occurring.  
The primary efficacy analysis comparing the annualized change in new HO volume between 
subjects treated with palovarotene and untreated subjects is performed by calculating the ratio of 
the annual mean change in HO volume in palovarotene treated subjects to untreated subjects 
using the Principal FAS and assuming missing at random.  Using the Bayesian compound 
Poisson model described above, this ratio is calculated as the treatment effect on the rate of body 
regions with new HO,  𝜃1,1, multiplied by the treatment effect on new HO volume conditional on 
new HO occurring, 𝜃2,1,  expressed as 𝛾= 𝜃1,1 ∗𝜃2,1.  Random samples generated via Gibbs 
sampling from the posterior distribution of 𝜃1,1 and 𝜃2,1 will be used to compute the posterior 
probability that 𝛾< 1 to determine statistical significance.  The primary efficacy analysis 
described above will be repeated without the square-root transformation.  Additional supportive 
analyses including the weighted mixed linear effect (wLME) analysis with and without the 
square-root transformation will also be performed.  
Approximately 80 palovarotene-naïve subjects with the R206H ACVR1 mutation will be 
enrolled into the current study and will be followed for 2 years in Part A.  There will be three 
early interim efficacy analyses and one final analysis in Part A.  The first interim analysis will 
occur when 35 subjects complete 1 year of follow-up; the second and third interim analyses will 
occur when all subjects enrolled in the Principal EP have completed (ie, have WBCT data) 
12 months and then 18 months of follow-up, respectively.  The interim analyses will include the 
Month 6 WBCT results when that is the only observation available from a subject in the current 
study.  While study success may be declared after one of the interim analyses or at the final 
analysis in Part A, all subjects will continue until completing 48 months of treatment. 
Accrual of 80 palovarotene-naïve subjects with the R206H ACVR1 mutation is expected to take 
place in approximately 10 months to 1 year and it is assumed that the full NHS dataset will be 
available at the first interim.  The amount of statistical information at each interim analysis can 
be approximated by the sum of the follow-up in each study divided by the total expected.  The 
total follow-up expected across the NHS and the MOVE Trial is 317.5 years (NHS: 45∗1.5 years 
+ 45∗2.0 years; MOVE: 80∗2.0 years).  Assuming eight subjects enrolled in the MOVE study 
per month, the percentage of patient follow-up for each analysis is 66%, 80%, and 92% at the 
first, second, and third interim analysis, respectively.  Using these percentages, the alpha level 
threshold used to determine treatment effect significance at each analysis was derived using the 
Lan-DeMets alpha-spending function with O’Brien-Fleming parameterization and assuming a 
one-sided, overall type I error rate of 2.5%.  The one-sided significance thresholds are 0.0058, 
0.0103, 0.0156, and 0.0190 for the first, second, and third interim analyses, and the final 
analysis, respectively.  Study success will be declared if the posterior probability that 
palovarotene reduces the annualized change in new HO volume is greater than 1 minus the one-
sided significance threshold.  For example, the posterior probability that palovarotene reduces 
the annualized change in new HO volume must be greater than 0.9810 to declare study success at 
the final analysis.  A futility analysis was conducted for the second interim analysis based on the 

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pre-specified criteria using square-root transformation and additional analyses without the 
square-root transformation.  Based on feedback received by the DMC following the second 
interim analysis, the futility analysis  conducted at the third analyses will use the predefined 
model with and without square-root transformation to assess whether the study shows 
insufficient evidence of efficacy.  If the efficacy criteria have not been met by the final analysis 
of Part A the study may be terminated.  Stopping the study for futility will be considered if the 
posterior probability that 𝛾< 0.7 (at least a 30% reduction in annualized new HO volume on the 
square-root scale) is less than 5%. and taking into consideration additional analyses performed 
without the square-root transformation. 
The primary efficacy analysis will be repeated using the Principal PPS.  Further details regarding 
primary analysis and the planned sensitivity analyses are provided in the Statistical Analysis 
Plan.  The primary efficacy endpoint will be summarized for the Supplementary FAS and PPS. 
8.5.2.2 Secondary Efficacy Analysis 
The secondary efficacy endpoints will be analyzed using the Principal FAS and PPS populations.  
Treatment effect estimates will be generated for Part A, and overall for data obtained in Parts A 
and B. 
The proportion of subjects with any new HO and the change in the number of body regions with 
any new HO will be analyzed using the Bayesian compound Poisson distribution used for the 
primary efficacy analysis.  The variables in that model can be used to construct the hypothesis 
test for both of these secondary efficacy endpoints. 
The proportion of subjects with any flare-ups and the flare-up rate per subject-month exposure 
will be analyzed using a Bayesian Poisson distribution.     
The secondary efficacy endpoints will be summarized for the Supplementary FAS and PPS. 
8.5.3 Safety 
Safety evaluations will include AE and SAE reporting, ECGs, vital signs (temperature, 
respiratory rate, blood pressure, and heart rate), physical examination, body weight and height, 
laboratory parameters (hematology, biochemistry, and urinalysis), urine pregnancy tests for 
FOCBP, and concomitant medication reporting.  Safety analyses will use the Principal SS, and 
separately, the Supplementary SS.  Safety will be summarized for Part A and overall for data 
obtained in Parts A, B and C. Where appropriate, comparisons to safety information from the 
NHS will be made. 
Safety evaluations will include AE and SAE reporting, vital signs (temperature, respiratory rate, 
blood pressure, and heart rate), physical examination, body weight and height, and concomitant 
medication reporting. Safety will be summarized for Part C.   
Evaluation of subjects under the age of 18 enrolled with open epiphyseal growth plates will 
include knee (AP view) and hand-wrist radiographs (PA view) for assessment of epiphyseal 
growth plate and distal femoral angle, WBCT scans for growth plate assessments of the bilateral 
hand-wrist and knee, tibial and femoral long bone lengths, and stadiometry and knee height (in 

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PROPRIETARY AND CONFIDENTIAL 
triplicate) for assessment of linear growth. Safety will be summarized for Part A and overall for 
data obtained in Parts A, B and C In addition, bilateral assessments of hip growth plate 
morphology for AVN will be performed in all subjects.   
All safety data collected and captured in the eCRF will be included in data listings sorted by 
domain, subject and time point, or as appropriate.  Mean changes from pre-treatment to on 
treatment will generally be tabulated by protocol-specified time points, while the number of 
subjects with potentially clinically significant values at pre-treatment and at each endpoint will 
be presented.  The last non-missing baseline value will be used as the pre-treatment value for that 
parameter. 
8.5.3.1 Adverse Events 
Adverse events will be classified using the MedDRA coding dictionary.  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 CTCAE, Version 4.03, 14June2010. 
Tabulations will include an overall incidence of at least one AE, incidence within body system, 
and incidence by preferred term (including by severity and relationship to study drug).  Each 
subject may only contribute once (ie, first occurrence) to each of the incidence rates, regardless 
of the number of occurrences.  Incidences (denominators and percentages) for selected gender-
specific AEs will be adjusted by the number of males or females, as appropriate. 
8.5.4 Suicide Ideation 
The number of subjects who report any type 4 or 5 suicide ideations in the C-SSRS or any 
suicide behavior during the study will be presented in listings (see Appendix 5A and  
Appendix 5B). 
8.5.5 Clinical Laboratory Findings 
Change in clinical laboratory findings, vital signs, and other continuous safety parameters will be 
assessed descriptively, with pre-treatment, on-treatment, and change from pre-treatment values 
calculated.  For purposes of this analysis, pre-treatment will be the last values prior to initiation 
of chronic dosing. 
Group-mean plots (mean and standard error) over time will be provided. 
The number and percentage of subjects with potentially clinically significant (PCS) values will 
be summarized.  A focus will be on new-onset PCS values, ie, subjects with pre-existing PCS 
values at pre-treatment will not be considered to have new-onset values on-treatment. 
8.6 
Pharmacodynamics 
Exploratory analyses will be performed to assess potential exposure relationships. 

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8. 7 
I nteri m A n al yses
I nteri m effi cac y a nal yses will be c o n d ucte d u n der t he a us pices of t he D M C t o assess w het her 
effic ac y is s uffici e ntl y de m o nstrate d pri or t o t he c o m pleti o n of t he st u d y.  T he st u d y will n ot st o p 
earl y if a n i nteri m effic ac y a nal ysis meets t he efficac y criteria ( pre-s p ecifie d t o tri g ger p ote ntial 
earl y s u b missi o n f or mar keti n g a ut h orizati o n); s u bjects will c o nti n ue treat me nt u ntil c o m pleti o n 
of 4 8 m o nt hs of pal o var ote ne treat me nt.  T h e pre-s pecifie d si g nifica n ce t hr es h ol ds t o declare 
st u d y s uccess at e ac h i nteri m efficac y a n al ysis is descri be d i n Secti o n 8. 5. 2. 1.   
A f utilit y a nal ysis was c o n d ucte d f or t he s ec o n d i nteri m a nal ysis base d o n t he pre-s p ecifie d 
criteria usi n g s q uare-r o ot tra nsf or mati o n a n d a d diti o nal a nal yses wit h o ut t he s q uare-r o ot 
tra nsf or mati o n.  Base d o n fee d bac k recei v e d b y t he D M C f oll o wi n g t he sec o n d i nteri m a nal ysis, 
t he f utilit y a nal ysis c o n d ucte d at t he t hir d a n al yses will use t he pre defi n e d m o del wit h a n d 
wit h o ut s q uare-r o ot tra nsf or mati o n t o assess w het her t he st u d y s h o ws i ns ufficie nt e vi de nce of 
effic ac y.  If t he efficac y criteria h a ve n ot bee n m et b y t he fi nal a nal ysis of Part A t he st u d y ma y 
be ter mi nate d.  St o p pi n g t he st u d y f or f utilit y will be c o nsi dere d if t he p osteri or pr o ba bilit y t hat 
𝛾 < 0. 7 (at least a 3 0 % re d u cti o n i n a n n ualize d ne w H O v ol u me o n t he s q uare-r o ot scale) is less 
t ha n 5 % a n d ta ki n g i nt o c o nsi derati o n a d diti o nal a nal ysis perf or me d wit h o ut t he s q uare-r o ot 
tra nsf or mati o n.
A d diti o nal s u p p orti ve a nal yses i ncl u di n g t he pri mar y a nal ysis wit h o ut t he s q uare-r o ot 
tra nsf or mati o n of t he d ata a n d t he wL M E a nal ysis will be perf or me d.
Pr oce d ur al, Et hic al, Re g ul at or y, a n d A d mi nistr ati ve C o nsi der ati o ns
9. 1  
A d verse E ve nt a n d Seri o us A d verse E ve nt D oc u me nt ati o n, Se verit y Gr a di n g, a n d 
Re p orti n g
9. 1. 1  
A d verse E ve nt
A n A E is a n y u nt o war d me dical occ urre n ce i n a s u bject or cli nical i n vesti g ati o n s u bject
a d mi nistere d a p har mace utical pr o d uct d uri n g t he c o urse of a st u d y a n d w hic h d oes n ot 
necessaril y ha ve t o ha v e a ca usal rel ati o ns hi p wit h t his treat me nt.  A n A E ca n t heref ore b e a n y 
u nfa v ora bl e a n d u ni nte n d e d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or 
disease te m p orall y ass o ciate d wit h t he use of a me dici nal (i n vesti gati o nal) pr o d uct, w het her or 
n ot c o nsi dere d relate d t o t he me dici nal pr o d uct.
Disease, si g ns, s y m pt o ms, a n d/ or la b orat or y a b n or malities alrea d y e xisti n g pri or t o t he use of t he
pr o d uct are n ot c o nsi dere d A Es after a d mi nistrati o n of t he st u d y pr o d uct u nless t he y re occ ur 
after t he s u bject has r ec o vere d fr o m t he pre-e xisti n g c o n diti o n or t he y re prese nt a n e x acer bati o n 
i n i nte nsit y or fre q ue nc y.
O nl y a cli nicall y si g nifica nt la b orat or y test a b n or malit y, p h ysical e xa mi nati o n fi n di n g, or ot her 
o bjecti ve fi n di n g s h o ul d be re p ort e d as a n A E, w het her it re prese nts a n e xacer bati o n or a ne w 
a b n or malit y.

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9.1.2 Serious Adverse Event or Adverse Drug Reaction 
An SAE (experience) or reaction is any untoward medical occurrence that results in any of the 
following outcomes and at any dose:  
• Death. 
• Life threatening situation (the subject was at risk of death at the time of the event).  It 
does not refer to the hypothetical risk of death if the AE 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 an SAE 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). 
9.1.3 Adverse Event Documentation 
Adverse event or SAE reports will be completed for all AEs.  Signs and symptoms of each AE 
should be described in detail: nature, date of onset, end date, severity, relationship to study drug, 
and action taken and outcome. 
9.1.4 Severity of Adverse Events 
The term severity is used to describe the intensity of a specific event. 
The severity of AEs will be categorized as follows: 
• Mild: events that are easily tolerated with no disruption of normal daily activity. 
• Moderate: events that cause sufficient discomfort to interfere with daily activity and/or 
require a simple dose medication. 
• Severe: 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, 14 June 2010.  Sites will be provided with specific criteria 
for the coding of AEs. 

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9.1.5 Causality Assessment 
Causality assessment by the Investigator in terms of relationship to study drug is required for 
purposes of reporting AEs.  To promote consistency between the Investigators, the following 
definitions should be taken into consideration along with good clinical and scientific judgment 
when determining the relationship of study drug to an AE: 
• 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. 
9.1.6 Action Taken With Study Drug 
The action taken to remedy the reported/observed AEs will be defined as follows: 
• None 
• Study drug dosage modified 
• Study drug dosage interrupted 
• Study drug permanently discontinued 
9.1.7 Outcome of Adverse Event 
The outcome of the AEs will be recorded as follows: 
• Event resolved with no sequelae 
• Event resolved with sequelae 
• Event ongoing 
• Death 

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PROPRIETARY AND CONFIDENTIAL 
9.1.8 Reporting of Serious Adverse Event 
All SAEs must be reported within 24 hours to the appropriate Clinical Safety Group: 
North America 
SAE hotline: 
Tel: 1.888.483.7729 
Fax: 1.888.529.3580 or 1.919.654.3836 
E-mail: RTPSafety@ppd.com 
Latin America 
SAE hotline: 
Tel: +55.11.4504.4801 
Fax: +55.11.3958.0983 
E-mail: LATSafety@ppd.com 
EMEA/APAC 
SAE hotline: 
Tel: +44.1223.374.240 
Fax: +44.1223.374.102 
E-mail: EMEAASIASafetyCentral.SM@ppd.com 
The Investigator will be requested to complete and transmit to the sponsor or designee the SAE 
information using the electronic reporting form, or a paper form should the electronic system not 
be available. 
The Investigator will inform the sponsor or designee within 24 hours of any findings with the use 
of the study drug that may suggest significant hazards, contraindications, SAEs, and precautions 
pertinent to the safety of the study drug. 
The sponsor or designee will notify the regulatory authorities within the required time frames for 
all SAEs subject to expedited reporting, either due to their nature (“serious”) or due to the 
significant, unexpected information they provide. 
The Investigator will notify the Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) of SAEs occurring during the trial likely to affect the safety of trial subjects or 
the conduct of the trial. 
9.1.9 Pregnancy 
If any female subject or partner of a male subject becomes or is found to be pregnant during their 
participation in the study, the site will submit this information on a Pregnancy Reporting Form to 
the sponsor or designee.  The subject will be followed up through their pregnancy and the health 
status of the baby will be verified.  The study site will record the pregnancy on the AE and the 
pregnancy reporting forms. 

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9.1.10 Follow-Up of Adverse Events and Serious Adverse Events 
The AE, SAE and death reporting period begins at the time of informed consent and continues 
through Part A/B EOS +30 days (for subjects not participating in Part C) or Part C SC + 30 days. 
Adverse events will be assessed at every site and remote visit.  The Investigator will follow-up 
on all AEs observed or reported by the subject up to the end of the reporting period or until 
follow-up is no longer necessary.  Investigator will follow-up on SAEs until they are considered 
resolved or the outcome is known.  Limb/joint AEs reported by subjects with open epiphyses 
will be evaluated by clinical and radiographic assessments deemed appropriate by the 
Investigator. 
9.2 
Administrative Requirements 
9.2.1 Informed Consent Form 
It should be noted that the word “parents” is used throughout this protocol to denote the legally 
authorized representatives (eg, parents, caregivers, or legal guardians) of subjects under the age 
of 18 years. 
Prior to participation in the clinical study, the Investigator and/or delegate must fully explain to 
the subjects/parents all aspects of the study that are relevant to the decision of participation in the 
trial.  The Informed Consent Form (ICF) is documented by means of a written, signed, and dated 
subject/parent consent form (or age-appropriate assent form) per local requirements, prior to the 
start of the study.  Age-appropriate assent forms will be completed for all subjects under the age 
of 18 years.  Potential subjects/parents may undergo an IRB-approved remote consent.  The ICF 
will be written in a language and in a form understandable to the subjects/parents.  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. 
One signed and dated copy of the ICF will be given (or emailed/faxed in the case of remote 
consent) to the subject/parent 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 trial in his/her 
medical chart. 
Institutions, Investigators, contract research organizations (CROs), etc., 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 (EU) Directive on Data Protection, and any other similar 
regulations or legislation). 
9.2.2 Ethical Conduct of the Study 
The clinical study will be conducted in accordance with the protocol, in addition to the ethical 
principles that have their origin in the Declaration of Helsinki (see Appendix 9), inclusive of any 
subsequent amendment(s), and that are consistent with the ICH GCP, EU Directive 2001/20/EC, 

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PROPRIETARY AND CONFIDENTIAL 
US FDA Code of Federal Regulations and other applicable local regulatory requirements, which 
ever affords the greater subject protection. 
9.2.3 Ethics Board Approval  
The IRB/IEC will be in compliance with the ICH GCP and local regulatory requirements.  It 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 institution/site.  The committee will review the science, medical aspects, 
and ethics of the clinical study. 
The following documents will be submitted to and reviewed by the IRB/IEC: 
• Final study protocol/amendment(s) 
• Investigator’s Brochure 
• Written ICF and consent/assent form updates 
• Written information to be provided to subject/parent 
• Subject recruitment procedures 
• Information about payments and compensation available to subjects 
• Investigator’s 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/assent documents to be used in the clinical study must 
be approved by the IRB/IEC, prior to initiation of the study.  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 the members, their 
qualifications and affiliations.  The IRB/IEC will conduct continuing review of the ongoing 
study at an appropriate interval. 
The Investigator will be responsible for ensuring the initial approval of the clinical study 
protocol, written ICF, consent form updates, subject recruitment, 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 SAEs likely to affect the safety of the subjects, 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. 

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PROPRIETARY AND CONFIDENTIAL 
9.2.4 Subject Confidentiality 
Any research information obtained about the subject in this study will be kept confidential in 
accordance with all relevant national and international laws governing data privacy and security.  
The subject’s name or any other identifying information will not appear in any reports published 
as a result of this study. 
However, information obtained from individual subject’s participation in the study may be 
disclosed with his/her express written consent to the health care providers for the purpose of 
obtaining appropriate medical care.  The subject’s medical records/charts and tests with his/her 
name on them may be made available to the appropriate CRO, the sponsor, its potential eventual 
partners, and any other regulatory authorities.  This is for the purpose of verifying information 
obtained for this study.  Confidentiality will be maintained throughout the study within the 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 behind locked 
doors, under the supervision of the study Investigator and will not be transferred outside of the 
investigator 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 be able to remain in the study.  No new 
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 in order to preserve the scientific integrity and quality of the study. 
9.2.5 Amendments to the Protocol 
Modifications to the protocol are only possible by approved protocol amendments authorized by 
the study sponsor.  All protocol amendments will be approved by the appropriate regulatory 
authorities as well as each IRB 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 study subject. 
9.2.6 Protocol Deviations 
The protocol must be read thoroughly and the instructions followed exactly.  Any major 
deviation to the protocol has to be reported as soon as possible to the sponsor.  The governing 
reporting guidelines for protocol deviations must be adhered to by the Investigator. 
9.2.7 Study Termination 
This study may be prematurely terminated, if in the opinion of the Investigator or the sponsor, 
there is sufficient 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: 
• Determination of unexpected, significant, or unacceptable risk to subjects. 
• Failure to enroll subjects at an acceptable rate. 

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PROPRIETARY AND CONFIDENTIAL 
• Insufficient adherence to protocol requirements. 
• Insufficient complete and/or evaluable data. 
• Plans to modify, suspend, or discontinue the development of palovarotene. 
Should the study be closed prematurely, all study materials must be returned to the sponsor.  If 
the study is closed prematurely due to safety concerns, all subjects exposed to the investigational 
drug will be followed for safety with the length of follow-up determined based on the safety risk. 
9.2.8 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 participating 
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. 
9.3 
Data Quality Assurance 
As per 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 course of the study.  In addition, 
inspections may be conducted by regulatory bodies at their discretion. 
If sites receive a request for an inspection or written or oral inquiries regarding any aspect of the 
institution’s or Investigator’s activities related to this study from a regulatory authority, the 
Investigator must immediately notify the sponsor and the appropriate CRO of the request.  
Following this inspection and/or audit, the Investigator must notify the sponsor of any violation 
or deficiency noted by the regulatory authority. 
9.4 
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 trial 
data are accurate, complete, as well as verifiable from source documents, and finally that the 
conduct of the trial 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. 

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9.5 
Data Capture and Management 
The sponsor or designee will provide the study 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 the data entered in each subject’s eCRF.  
Source documentation supporting the eCRF data should indicate the subject’s participation in the 
study and document the dates and details of study procedures, AEs, and subject status. 
The Investigator, or designated representative, should complete the eCRF as soon as possible 
after information is collected, preferably on the same day that a subject is seen for an 
examination, treatment, or any other study procedure.  Any outstanding entries must be entered 
immediately after the final examination.  An explanation should be given for all missing data. 
9.6 
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. 
9.7 
Publication 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 towards the 
development of palovarotene and may be disclosed to 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 journal.  A Publications Committee, 
comprised of Investigators participating in the study and representatives from the sponsor, as 
appropriate, will be formed to oversee the publication of the study results, which will reflect the 
experience of all participating study centers.  Subsequently, individual Investigators may publish 
results from the study in compliance with their agreement with the sponsor. 
9.8 
Coordinating Investigator 
The Coordinating Investigator will be designated from among the participating study 
Investigators by the Sponsor prior to database lock.  The Coordinating Investigator will approve 
the final clinical study report for Study PVO-1A-301. 

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I n vesti g at or A gree me nt
I h a ve rea d Pr ot oc ol P V O- 1 A- 3 0 1 A me n d m e nt 5, date d 3 0 Oct o ber 2 0 2 0:
M O V E Trial: A P hase 3, Effi cac y a n d Safet y St u d y of Oral Pal o var ote ne f or t he Treat me nt of 
Fi br o d ys plasia Ossifica ns Pr o gressi va ( F O P).
I a gree t o c o n d uct t he st u d y as detaile d herei n a n d i n c o m plia nce wit h I C H G ui deli nes f or G o o d 
Cli nical Practices a n d a p plica ble re g ulat or y re q uir e me nts a n d t o i nf or m all w h o assist me i n t he 
c o n d uct of t his st u d y of t heir res p o nsi bilities a n d o bli gati o ns.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I n v esti gat or ( pri nte d n a me)
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I n v esti gat or si g nat ure
Date
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_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I n v esti gati o nal site or na me of i nstit uti o n a n d l ocati o n ( pri nte d)

P R  O T O C O L P V O- 1 A -3 0 1, A M E N D M E N T 5
P A G E 8 5 O F 1 5 1
C L E M E N TI A P H AR  M A C E U TI C A L S IN C .
3 0 O C T O B ER
2 0 2 0
P R  O PR I E T AR Y  A N D C O N FI D E N TI A L
Refere nces
1. Lilijest hr o m M, B o gar d B. T he Gl o bal K n o w n F O P P o p ulati o n. I n: F O P Dr u g De vel o p me nt 
F or u m. B ost o n, M A; 2 0 16 .
2. 
Ba ujat G, C h o q uet R , B o ué e S, et al. Pre vale nce of fi br o d ys plasia ossifica ns pr o gressi va ( F O P) i n 
Fra nce: a n esti mate base d o n a rec or d li n ka ge of t w o nati o nal data bases. Or p ha net J R are Dis. 
2 0 17 ; 1 2( 1): 1 2 3. d oi: 1 0. 1 1 86 /s 1 3 0 2 3- 0 17 - 06 7 4- 5
3.
K itter ma n J A, K a nta nie S, R oc ke D M, K a pla n F S. Iatr o ge nic har m ca use d b y dia g n ostic err ors i n 
fi br o d ys plasia ossifica ns pr o gressi va. Pe diatrics. 2 0 0 5; 1 16 ( 5):e6 5 4-6 6 1. d oi: 1 0. 1 5 4 2/ pe ds. 2 0 0 5-
0 46 9
4. Pi g n ol o R J, S h ore E M, K a pla n F S. Fi br o d ys plasia ossifica ns pr o gressi va: cli nical a n d ge netic 
as pects. Or p ha net J R are Dis. 2 0 1 1;6 ( 8 0). d oi: 1 0. 1 1 86 / 17 5 0- 1 17 2-6 - 8 0
5. 
C o n n or J M, E va ns D A. Fi br o d ys plasia ossifica ns pr o gressi va. T he cli nical feat ures a n d nat ural 
hist or y of 3 4 patie nts. J B o ne J oi nt S ur g Br. 1 9 8 2;6 4( 1):7 6 - 8 3.
6 . K a pla n F S, Glaser D L. T h oracic i ns ufficie nc y s y n dr o me i n patie nts wit h fi br o d ys plasia ossifica ns 
pr o gressi va. Cli n R e v B o ne Mi ner Meta b. 2 0 0 5; 3( 3- 4): 2 1 3- 2 16 . d oi: 1 0. 1 3 8 5/ B M M: 3: 3- 4: 2 1 3
7 . K a pla n F S, Z asl off M A, K itter ma n J A, S h ore E M, H o n g C C, R oc ke D M. Earl y m ortalit y a n d 
car di ores pirat or y fail ure i n patie nts wit h fi br o d ys plasia ossifica ns pr o gressi va. J B o ne J oi nt S ur g 
A m. 2 0 1 0; 9 2( 3):6 86 - 6 9 1. d oi: 1 0. 2 1 06 /J BJ S.I. 0 07 0 5
8. K a pla n F S, Ta bas J A, Ga n n o n F H, Fi n kel G, Ha h n G V, Z asl off M A. T he hist o pat h ol o g y of 
fi br o d ys plasia ossifica ns pr o gressi va. A n e n d oc h o n dral pr ocess. J B o ne J oi nt S ur g A m. 
1 9 9 3;7 5( 2): 2 2 0- 2 3 0.
9. K a pla n F S, Le Merrer M, Glaser D L, et al. Fi br o d ys plasia ossifica ns pr o gressi va. Best Pract R es 
Cli n R he u mat ol. 2 0 0 8; 2 2( 1). d oi: 1 0. 1 0 16 /j. ber h. 2 0 07 . 1 1. 0 07
1 0.  Glaser D L, R oc ke D M, K a pla n F S. Catastr o p hic falls i n patie nts w h o ha ve fi br o d ys plasia 
ossifica ns pr o gressi va. Cli n Ort h o p. 1 9 9 8;( 3 46 ): 1 1 0- 1 16 .
1 1. K a pla n F S, Pi g n ol o R J, S h ore E M. Fr o m m ysteries t o me dici nes: dr u g de vel o p me nt f or 
fi br o d ys plasia ossifica ns pr o gressi va. E x pert O pi n Or p ha n Dr u gs. 2 0 1 3; 1( 8):6 37 -6 4 9. 
d oi: 1 0. 1 5 17 / 2 16 7 87 07 . 2 0 1 3. 8 2 5 2 0 8
1 2. K a pla n F S, S h ore E M. Deraili n g heter ot o pic ossificati o n a n d R  AR i n g t o g o. Nat Me d. 
2 0 1 1; 17 ( 4): 4 2 0- 4 2 1. d oi: 1 0. 1 0 3 8/ n m 0 4 1 1- 4 2 0
1 3. S hi m o n o K , T u n g W- E, Mac oli n o C, et al. P ote nt i n hi biti o n of heter ot o pic ossificati o n b y n uclear 
reti n oic aci d rece pt or- ga m ma a g o nists. Nat Me d. 2 0 1 1; 17 ( 4): 4 5 4- 46 0. d oi: 1 0. 1 0 3 8/ n m. 2 3 3 4

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14. 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. 
15. Pacifici M, Cossu G, Molinaro M, Tato F. Vitamin A inhibits chondrogenesis but not 
myogenesis. Exp Cell Res. 1980;129(2):469-474. 
16. Koyama E, Golden EB, Kirsch T, et al. Retinoid signaling is required for chondrocyte maturation 
and endochondral bone formation during limb skeletogenesis. Dev Biol. 1999;208(2):375-391. 
doi:10.1006/dbio.1999.9207 
17. Williams JA, Kondo N, Okabe T, et al. Retinoic acid receptors are required for skeletal growth, 
matrix homeostasis and  growth plate function in postnatal mouse. Dev Biol. 2009;328(2):315-
327. doi:10.1016/j.ydbio.2009.01.031 
18. Kennedy KAM, Porter T, Mehta V, et al. Retinoic acid enhances skeletal muscle progenitor 
formation and bypasses inhibition by bone morphogenetic protein 4 but not dominant negative 
beta-catenin. BMC Biol. 2009;7. doi:10.1186/1741-7007-7-67 
19. Yasuhara R, Yuasa T, Williams JA, et al. Wnt/beta-catenin and retinoic acid receptor signaling 
pathways interact to regulate chondrocyte function and matrix turnover. J Biol Chem. 
2010;285(1):317-327. doi:10.1074/jbc.M109.053926 
20. Armstrong RB, Ashenfelter KO, Eckhoff C, Levin AA, Shapiro SS. General and Reproductive 
Toxicology of Retinoids. In: The Retinoids: Biology, Chemistry, and Medicine. 2nd ed. New 
York: Raven Press; 1994:545-572. 
21. Lindhout D, Golding RP, Taets van Amerongen AH. Fibrodysplasia ossificans progressiva: 
current concepts and the role of CT in acute changes. Pediatr Radiol. 1985;15(3):211-213. 
22. Hagiwara H, Aida N, Machida J, Fujita K, Okuzumi S, Nishimura G. Contrast-enhanced MRI of 
an early preosseous lesion of fibrodysplasia ossificans  progressiva in a 21-month-old boy. AJR 
Am J Roentgenol. 2003;181(4):1145-1147. doi:10.2214/ajr.181.4.1811145 
23. Zhang D, Schwarz EM, Rosier RN, Zuscik MJ, Puzas JE, O’Keefe RJ. ALK2 functions as a BMP 
type I receptor and induces Indian hedgehog in chondrocytes during skeletal development. J Bone 
Miner Res Off J Am Soc Bone Miner Res. 2003;18(9):1593-1604. 
doi:10.1359/jbmr.2003.18.9.1593 
24. Reinig JW, Hill SC, Fang M, Marini J, Zasloff MA. Fibrodysplasia ossificans progressiva: CT 
appearance. Radiology. 1986;159(1):153-157. doi:10.1148/radiology.159.1.3952301 
25. American Association of Physicists in Medicine. AAPM Position Statement on Radiation Risks 
from Medical Imaging Procedures. 
https://www.aapm.org/org/policies/details.asp?id=318&type=PP&current=true. Published March 
21, 2017. Accessed February 8, 2018. 

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26. Pignolo RJ, Baujat G, Brown MA, et al. Natural history of fibrodysplasia ossificans progressiva: 
cross-sectional analysis of annotated baseline phenotypes. Orphanet J Rare Dis. 2019;14(1):98. 
doi:10.1186/s13023-019-1068-7 
27. The International Consortium on Fibrodysplasia Ossificans Progressiva. The medical 
management of fibrodysplasia ossificans progressiva: current treatment considerations. F. S. 
Kaplan, E. M. Shore, R. J. Pignolo, eds. Clin Proc Int Consort FOP. 2011;4:1-100. 
28. Kaplan FS, Andolina JR, Adamson PC, et al. Early clinical observations on the use of imatinib 
mesylate in FOP: A report of seven cases. Bone. July 2017. doi:10.1016/j.bone.2017.07.019 
29. Agarwal S, Loder S, Brownley C, et al. Inhibition of Hif1alpha prevents both trauma-induced and 
genetic heterotopic ossification. Proc Natl Acad Sci U S A. December 2015. 
doi:10.1073/pnas.1515397113 
 

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Appendices 
Appendix 1.  Cumulative Analogue Joint Involvement Scale for FOP 
 
 
 

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Appendix 2A.  Adult FOP-Physical Function Questionnaire 
(Self-Completed for Subjects Age 15 Years and Older) 
 
 

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Appendix 2B.  Pediatric FOP-Physical Function Questionnaire 
(Self-Completed for Subjects Ages 8 to 14 Years) 
 

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Appendix 2C.  Pediatric FOP-Physical Function Questionnaire 
(Proxy-Completed for Subjects Ages 5 to 14 Years) 
 
 
 

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Appendix 2D.  Pediatric FOP-Physical Function Questionnaire 
(Proxy-Completed for Subjects Ages 2 to 4 Years) 
 

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Appendix 3.  CYP450 3A4 Inducers or Inhibitors: Exclusionary Medications 
 
STRONG  
INDUCERS 
Half-life 
STRONG 
INHIBITORS 
Half-life 
Carbamazepine a 
Phenobarbital  
Phenytoin  
Rifabutin  
Rifampin 
St John’s Wort b 
Troglitazone 
Avasimibe 
18-55 hrs, 12-17 hrs 
53-140 hrs 
24 hrs 
16-69 hrs 
3-4 hrs 
43.1 hrs 
16-34 hrs 
20 hrs 
Boceprevir 
Clarithromycin  
Conivaptan 
Delavirdine  
Fluvoxamine  
Grapefruit juice 
Imatinib 
Indinavir  
Itraconazole d 
Ketoconazole  
Lopinavir/ritonavir 
Mibefradil  
Nefazodone  
Nelfinavir  
Posaconazole 
Ritonavir  
Saquinavir  
Telaprevir 
Telithromycin 
Troleandomycin  
Voricanozole 
Suboxone 
 
3.4 hrs 
5-7 hrs 
5-8 hrs 
6 hrs 
8-28hrs 
NAc 
18-20 hrs 
1.4-2.2 hrs 
15-27 hrs, 64 hrs 
8 hrs 
5-6 hrs 
17-25 hrs 
2-4 hrs 
3.5-5 hrs 
20-66 hrs 
3-5 hrs 
7-12 hrs 
9-11 hrs (at steady state) 
10 hrs 
1.05 hrs 
6-9 hrs (dose-dependent) 
24-42 hrs 
a Half-life 18-55 hrs after a single dose and 12-17 hrs after multiple doses 
b Major ingredient hyperium’s half-life 
c NA: not available 
d Half-life 15-27 hrs after a single dose and 64 hrs at steady-state 
 

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Appendix 4.  Methods of Birth Control 
Highly effective methods of birth control:  
• 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 
 
 

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Appendix 5A.  Adult Columbia-Suicide Severity Rating Scale (Subjects Ages 12 Years and 
Older) 
Adult C-SSRS to be used for Screening for all subjects 12 years of age and older: 
 
COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS) 
Screening 
Version 1/14/09 
 Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@childpsych.columbia.edu  
© 2008 The Research Foundation for Mental Hygiene, Inc.

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Adult C-SSRS to be used for visits after Screening for all subjects 12 years of age and older: 
 
 
 
 
 
 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
© 2008 The Research Foundation for Mental Hygiene, Inc. 

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SUICIDAL IDEATION 
Ask  questions  1  and  2.    If  both  are  negative,  proceed  to  “Suicidal  Behavior”  s
e
ct io n.  If  the  answer  t
o
  question  2  is  “yes”, 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”,  complete  “Intensity  of  Ideation”  s
e
ct io n  below. 
 
Since Last 
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.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
If yes, describe: 
 
 
Yes       No 
 □ 
  
 
  □ 
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 
oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 Yes      No 
 □ 
   
  □ 
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, 
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 
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: 
 
 
 Yes      No 
 □ 
  
 
  □ 
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  
definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
 
Yes       No 
 □ 
  
 
 
  □ 
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. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
If yes, describe: 
 
 
 Yes      No 
 □ 
  
 
  □ 
INTENSITY OF IDEATION 
The following features 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).  
                                             
Most Severe Ideation:             _____                      _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Frequency 
How many 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 long 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 on 
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                                             (0) Does not apply 
____ 
Reasons for Ideation 
What sort of reasons did you have for 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  couldn’t  go  on  living  with  this  pain  or  how  you  were  feeling)  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) 
                                                                                                                 (0)  Does not apply 
 
 
 
 
____ 
Version 1/14/09 

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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
Visit 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, 
this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly 
lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). 
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get 
sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
□ 
  
 
 
 □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□ 
  
 
 
 □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around 
neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything? 
If yes, describe: 
 
Yes      No 
□ 
  
 
 
 □ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
 
 
Yes      No 
□ 
  
 
 
 □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, 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, writing a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes      No 
□ 
  
 
 
 □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□ 
  
 
 
 □ 
Suicide: 
   Yes    No 
□ 
   
 □ 
Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact; third-degree burns 
less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 20% of body; 
extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious 
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away 
before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter Code 
 
 
 
______ 
 

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Appendix 5B.  Pediatric Columbia-Suicide Severity Rating Scale (Subjects Ages 8 to 
11 Years) 
Pediatric C-SSRS to be used for Screening for subjects 8 to 11 years old:
 
 
 

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Pediatric C-SSRS to be used for visits after Screenings for subjects 8 to 11 years old: 
 
 
 

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Appendix 6.  Retinoid-Specific Adverse Events to be Assessed for Severity by CTCAE 
Criteria (Version 4.03, 14 June 2010) 
 
Adverse Event 
CTCAE Page Number 
Corneal ulcer 
22 
Conjunctivitis 
22 
Dry eye 
23 
Keratitis 
24 
Night blindness 
24 
Chelitis 
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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Appendix 7.  Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation 
    
 
Guidance for Industry 
Drug-Induced Liver Injury:  
Premarketing Clinical 
Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER)  
 
July 2009 
Drug Safety 
 
 

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Appendix 8A.  PROMIS Global Health Scale 
(Self-Completed for Subjects Age 15 Years and Older) 
 

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Appendix 8B.  PROMIS Pediatric Global Health Scale 
(Self-Completed for Subjects Ages 8 to 14 Years) 
 
 

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Appendix 8C.  PROMIS Pediatric Global Health Scale 
(Proxy-Completed for Subjects Ages Less Than 15 Years) 
 
 

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Appendix 9.  Declaration of Helsinki 
 

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