Clinical trial NCT03312634
Conditions: Fibrodysplasia Ossificans Progressiva
Keywords: Interventional study Clinical trial phase 3 Efficacy and safety Heterotopic ossification Flare-up Palovarotene Retinoic acid receptor agonist Retinoic acid receptor gamma agonist Clementia Myositis Ossificans Progressiva Munchmeyer's Disease FOP FOP variants
Sponsor: Clementia Pharmaceuticals Inc.
Start date: 2017-11-30; Completion date: 2022-09-07
Enrollment: 107 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by heterotopic ossification (HO) often associated with painful, recurrent episodes of soft tissue swelling (flare-ups) that lead to ankyloses of major joints with cumulative and irreversible loss of movement and disability.

Detailed description:
One of the primary objectives was to evaluate the efficacy of palovarotene in decreasing new HO in participants with FOP as assessed by low-dose, whole body computed tomography (WBCT), excluding head, compared to untreated participants from Clementia's FOP natural history study (Study PVO-1A-001, NHS). The other primary objective was to evaluate the safety of palovarotene in participants with FOP.

This study was conducted in three parts. Part A was the main part of the study, Part B, the 2-year (24-month) extension and Part C was an up-to-2-year post last dose of study treatment follow-up for skeletally immature participants.

Participants in Part A and B received a chronic/flare-up dosing regimen of palovarotene for up to 4 years (48 months) as follows:

* Chronic treatment: orally administered 5 mg palovarotene once daily.
* Flare-up treatment: orally administered 20 mg palovarotene once daily for 4 weeks (28 days) followed by orally administered 10 mg palovarotene once daily for 8 weeks (56 days). Flare-up treatment may be extended until the Investigator determines that the flare-up has resolved.

Note that all dosing was weight-adjusted in skeletally immature participants (those under the age of 18 years with less than 90% skeletal maturity on hand/wrist x-rays performed at Screening).

In part C, participants who were enrolled in Parts A or B who discontinued the study and were skeletally immature were invited back to participate in the off-treatment safety follow-up. No new participants were enrolled into Part C.

Arms: arm 1: Participants received 5 mg palovarotene once daily for up to 48 months; and 20 mg palovarotene once daily for 28 days, followed by 10 mg for 56 days for flareups. (Dosing was adjusted for weight in skeletally immature subjects.)
Interventions: intervention 1: Palovarotene
Intervention descriptions: intervention 1: Palovarotene was taken orally once daily at approximately the same time each day following a meal.

Protocol documents:
Prot_002.pdf: 
Pa ge 1 of 1
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St u d y Title a n d N u m ber: A P hase 3, Effic ac y a n d Safet y St u d y of Oral P al o var ote ne f or t he Treat me nt 
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of Fi br o d ys pl asi a Ossific a ns Pr o gressi v a ( F O P)
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PROTOCOL PVO-1A-301, AMENDMENT 5 
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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:  
 
 
 
 
 
 
 
 
 
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PROTOCOL PVO-1A-301, AMENDMENT 5 
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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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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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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 
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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 
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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 
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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 
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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 
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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 
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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 
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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 
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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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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.  


PROTOCOL PVO-1A-301, AMENDMENT 5 
PAGE 23 OF 151 
CLEMENTIA PHARMACEUTICALS INC. 
30 OCTOBER 2020 
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 
 
 
 


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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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PROPRIETARY AND CONFIDENTIAL 
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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PROPRIETARY AND CONFIDENTIAL 
• 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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PROPRIETARY AND CONFIDENTIAL 
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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PROPRIETARY AND CONFIDENTIAL 
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. 


PROTOCOL PVO-1A-301, AMENDMENT 5 
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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. 


PROTOCOL PVO-1A-301, AMENDMENT 5 
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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 


PROTOCOL PVO-1A-301, AMENDMENT 5 
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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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PROPRIETARY AND CONFIDENTIAL 
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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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. 


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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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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, 


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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 
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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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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. 


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 7 5O 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. 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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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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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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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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• 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. 


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 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
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
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
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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PROPRIETARY AND CONFIDENTIAL 
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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SAP_003.pdf: 




Statistical Analysis Plan 
 
13 December 2022 
Study PVO-1A-301 (MOVE Trial) 
 
Version 1.3.1 
Clementia Pharmaceuticals  
 
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TABLE OF CONTENTS 
1 
OVERVIEW AND INVESTIGATIONAL PLAN .........................................................................6 
1.1 
Context for Version 1.3.1...................................................................................................6 
1.2 
Context for Version 1.3......................................................................................................6 
1.3 
Context for Version 1.2......................................................................................................6 
1.4 
Context for Version 1.1......................................................................................................6 
1.5 
Study Design ......................................................................................................................7 
1.6 
Objectives ..........................................................................................................................8 
1.6.1 
Primary Objectives ............................................................................................8 
1.6.2 
Secondary Objectives ........................................................................................8 
1.7 
Determination of Sample Size ...........................................................................................9 
1.8 
Study Plan ........................................................................................................................11 
1.9 
Modifications to the Statistical Section of the Protocol ...................................................11 
1.9.1 
Modifications to the Statistical Section of Protocol Amendment #1 ..............11 
1.9.2 
Modifications to the Statistical Section of Protocol Amendment #2 ..............11 
1.9.3 
Modifications to the Statistical Section of Protocol Amendment #3 ..............11 
1.9.4 
Modifications to the Statistical Section of Protocol Amendment #4 ..............12 
1.9.5 
Modifications to the Statistical Section of Protocol Amendment #5 ..............12 
1.10 
Statistical Modifications to the Statistical Analysis Plan .................................................12 
1.10.1 
Statistical Modifications to the Statistical Analysis Plan, V1.0 ......................12 
1.10.2 
Statistical Modifications to the Statistical Analysis Plan, V1.1 ......................12 
1.10.3 
Statistical Modifications to the Statistical Analysis Plan, V1.2 ......................14 
1.10.4 
Statistical Modifications to the Statistical Analysis Plan, V1.3 ......................14 
1.10.5 
Statistical Modifications to the Statistical Analysis Plan, V1.3.1 ...................15 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ..............................................................15 
2.1 
Analysis Endpoints ..........................................................................................................15 
2.1.1 
Demographic and Baseline Characteristics .....................................................15 
2.1.2 
Prior or Concomitant Medications ..................................................................17 
2.1.3 
Efficacy Endpoints ..........................................................................................17 
2.1.4 
Safety Endpoints ..............................................................................................21 
2.1.5 
Imaging Performance and Quality Metrics .....................................................27 
2.1.6 
Pharmacokinetic Endpoints .............................................................................29 
2.1.7 
Compliance ......................................................................................................29 
2.2 
Disposition of Subjects ....................................................................................................30 
2.3 
Analysis Populations ........................................................................................................31 
2.4 
Statistical Methods ...........................................................................................................32 
2.4.1 
Demographic and Baseline Characteristics .....................................................32 
2.4.2 
Prior or New Onset Medication .......................................................................32 
2.4.3 
Study Drug Exposure ......................................................................................33 


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2.4.4 
Analyses of Efficacy Endpoints ......................................................................34 
2.4.5 
Analysis of Safety Endpoints ..........................................................................45 
2.4.6 
Analyses of Imaging Performance and Quality Metrics..................................54 
2.4.7 
Analyses of Pharmacokinetic Endpoints .........................................................55 
2.4.8 
Duration of Flare-up Treatment .......................................................................57 
2.4.9 
Duration of Non-Flare-up Treatment ..............................................................57 
3 
INTERIM ANALYSIS .................................................................................................................57 
3.1 
Early Efficacy Testing .....................................................................................................57 
3.2 
Futility Testing .................................................................................................................58 
3.3 
Third Interim Analysis .....................................................................................................58 
4 
SOFTWARE DOCUMENTATION .............................................................................................59 
5 
REFERENCES .............................................................................................................................60 
6 
APPENDICES ..............................................................................................................................61 
6.1 
PROMIS T-Score Conversions ........................................................................................61 
6.2 
Potentially Clinically Significant Abnormalities criteria .................................................62 
 
 
LIST OF TABLES 
Table 1. 
NHS WBCT Scan Results by Body Region ............................................................................. 9 
Table 2. 
Power of MOVE Study Primary Efficacy Analysis Assuming 80 Subjects 
Enrolled with the R206H Mutation and No Previous Palovarotene Exposure ....................... 10 
Table 3. 
Sample Derivations for the Percentage of Worst Score for the FOP-PFQ ............................. 20 
Table 4. 
Rescaled PROMIS Global Health Scale Scores ..................................................................... 21 
Table 5. 
Clinical Laboratory Parameters .............................................................................................. 24 
Table 6. 
NHS List of Medications ........................................................................................................ 33 
Table 7. 
Observed MOVE Follow-up at Each Planned Analysis ......................................................... 40 
Table 8. 
Analyses to be Conducted at Interim Analysis #3 .................................................................. 58 
 
 
 
 
 


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ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse events 
AUC 
area under the concentration versus time curve 
CAJIS 
Cumulative Analogue Joint Involvement Scale 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
Cmin 
trough plasma concentration, taken 24 hours after dose and prior to subsequent 
dose  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
EP 
Enrolled Population 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FOP 
Fibrodysplasia Ossificans Progressiva 
FOP-PFQ 
FOP-Physical Function Questionnaire 
GEE 
generalized estimating equation 
HO 
heterotopic ossification 
ICH 
International Council for Harmonisation 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHS 
Natural History Study 
PAS 
Pharmacokinetic Analysis Set 
PK 
pharmacokinetic(s) 
PPC 
Premature physeal closure 
PPS 
Per Protocol Set 
PROMIS 
Patient Reported Outcomes Measurement Information System 
ROM 
Range of motion 
SAE 
serious adverse event 
SAS 
Safety Analysis Set 
SAP 
statistical analysis plan 
SD 
standard deviation 
Tmax 
time to maximum plasma concentration 
WBCT 
whole body computed tomography 
wLME 
weighted linear mixed effect  
 
 


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1 
OVERVIEW AND INVESTIGATIONAL PLAN 
1.1 
Context for Version 1.3.1 
This amendment is introduced to make several clarifications in preparation for the writing of the 
final CSR. 
1.2 
Context for Version 1.3 
This amendment is introduced in preparation for the writing of the final CSR. 
1.3 
Context for Version 1.2 
This amendment is introduced after the third interim analysis. It introduces edits, including 
changes to existing analyses and additions of new analyses, to be included in the interim CSR for 
Study PVO-1A-301 (MOVE Trial) to be included in the palovarotene marketing authorization 
application for FOP.  
1.4 
Context for Version 1.1 
This amendment is introduced after the second interim analysis but before the planned third 
interim analysis (anticipated to be held in mid-May 2020). The futility boundary was crossed at 
the second interim analysis, signifying that the prespecified Bayesian compound Poisson 
distribution model with square-root transformation indicated that the trial was unlikely to show 
sufficient evidence of benefit. The independent data monitoring committee (DMC) informed the 
sponsor of this outcome on January 15, 2020, and the efficacy assessments were subsequently 
unblinded to the sponsor. 
Based on additional post-hoc analyses presented to the DMC on January 21, 2020, the DMC 
noted that using the square-root transformation of the data in the primary analysis appears to 
have moved the statistical conclusion from significant therapeutic benefit to showing futility of 
the treatment. The DMC also noted that the dilemma created by these highly disparate results 
precludes a confident conclusion about futility. As such, the DMC recommended that additional 
analyses be conducted and provided to them for consideration at the next interim analysis. 
US FDA instituted a partial clinical hold on dosing of palovarotene due to premature physeal 
closure (PPC) for subjects <14 years of age on December 4, 2019; as of the finalization of this 
SAP amendment, dosing has not yet resumed for these subjects. Dosing on all other subjects not 
subject to US FDA’s partial clinical hold was interrupted following the January 21, 2020 DMC 
meeting while the protocol amendment allowing the continuation of the study after the futility 
outcome and incorporating the additional analyses requested by the DMC was reviewed by 
regulatory agencies, IRBs, and investigational sites. These subjects had palovarotene dosing 
interrupted on or around January 24, 2020. The sponsor allowed dosing to resume as of March 
26, 2020, provided each individual site had obtained Ethics Committee approval to do so and the 
site was able to fulfil regulatory and operational requirements. Subjects were expected to restart 
dosing over a span of weeks due to these logisitical considerations. 
Note that Sections 1.3 (Study design), 1.4 (Objectives), 1.5 (Determination of sample size) and 
1.6 (Study plan) were unchanged from the SAP V1.0, which was finalized prior to the first 


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interim analysis. New content began in Section 1.7 (Modifications to the statistical section of the 
protocol). 
1.5 
Study Design 
Study PVO-1A-301 (referred to as the MOVE Trial) is a Phase 3, multicenter, open-label study 
in adult and pediatric subjects with fibrodysplasia ossificans progressiva (FOP) which 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-treatment period for skeletally immature subjects. Sources of 
subjects eligible for enrollment in the MOVE Trial include: (1) subjects from Study 
PVO-1A-001 (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 heterotopic ossification (HO) (who have not previously participated in any 
Clementia-sponsored study); and (3) subjects in Study PVO-1A-202 or Study PVO-1A-204 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. Approximately 110 subjects  subjects will be enrolled 
into the MOVE Trial (approximately 99 with the R206H mutation and no previous exposure to 
palovarotene, and approximately 11 with other mutations or previous participation in the Phase 2 
trials) In Part A, qualified subjects will  receive chronic dosing with palovarotene for up to 24 
months and undergo flare-up treatment should they experience an eligible flare-up or traumatic 
event. 
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. 
This is an open-label study, with the comparator arm being subject data from the NHS. The 
efficacy of palovarotene treatment in the MOVE Trial, as measured by the change in new HO 
volume (the primary efficacy endpoint), will be compared to that observed in untreated subjects 
who participated in the NHS. 
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. 
There are three formal interim efficacy analyses and a final analysis planned; an additional 
descriptive analysis occurred before the first formal interim efficacy analysis to be included in 
the then-planned marketing authorization filing for episodic palovarotene prevention of HO in 
patients with FOP. The interim efficacy analyses will be conducted to assess whether efficacy of 


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the chronic/flare-up regimen is sufficiently demonstrated prior to the completion of the study. 
The study will not stop early if an interim efficacy analysis meets the efficacy criteria (pre-
specified to trigger potential early submission for marketing authorization); subjects will 
continue treatment until completion of two years of palovarotene treatment. 
A futility analysis will be conducted at the second and third interim analyses to assess whether 
the study should be stopped due to insufficient evidence of efficacy. 
The statistical analyses and summary tabulations described in this Statistical Analysis Plan 
(SAP) will provide the basis for the results sections of the MOVE clinical study reports. 
1.6 
Objectives  
1.6.1 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. 
1.6.2 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 (CAJIS) for FOP. 
• 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. 
• Part B: To continue to provide palovarotene to adult and pediatric subjects with FOP and 
to monitor longer-term safety. 
• Part C: To implement safety measures in order to ensure that assessments of safety 
continue for up to 2 years post last dose of study treatment for skeletally immature 
subjects. 


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1.7 
Determination of Sample Size 
The sample size required for the MOVE Trial was determined via simulation based on the 
available WBCT HO volumes from the NHS and the observed efficacy of palovarotene 
treatment in Phase 2. The NHS will serve as the external control group with, for the purposes of 
the determination of sample size, the assumption that 45 subjects will have baseline, 1-year, and 
1.5-year WBCT HO volumes and 45 subjects will have baseline, 1-year, and 2-year WBCT HO 
volumes. It is also assumed that approximately 50% of these 90 subjects will enter the Phase 3 
study to begin palovarotene treatment.   
There are three interim efficacy analyses – with futility analyses at the second and third interim 
analyses – and a final analysis planned. Assuming a one-sided, overall type I error rate of 2.5%, 
the Lan-DeMets alpha-spending function with O’Brien-Fleming parameterization was used to 
determine stopping boundaries (see Section 0 for additional details). 
Available pairs of NHS WBCT scans for 65 subjects taken one year apart and read using the 
original NHS single-reader process were used to tabulate the number of body regions with new 
HO and the mean and standard deviation (SD) of new HO volume in each body region (Table 1). 
The original 15 body regions from the NHS WBCT scans were mapped to approximate the 9 
body regions that will be used in the MOVE Trial. The mean (SD) number of body regions with 
new HO per subject in approximately one year was 0.707 (1.11), i.e., there were 46 body regions 
with new HO in 65 subjects.   
Table 1. 
NHS WBCT Scan Results by Body Region 
Body region 
Number of 
observations 
Number of 
regions with 
new NO 
Proportion of 
regions with 
new HO 
Volume change given new HO in 
region (in thousands mm3) 
Mean 
SD 
Neck, upper spine and chest 
64 
12 
0.19 
25.83 
21.06 
Shoulder (left, right) 
130 
7 
0.05 
4.69 
3.08 
Elbow, hand and wrist (left, 
right) 
125 
1 
0.01 
31.27 
- 
Lower spine and abdomen 
65 
11 
0.17 
16.22 
19.24 
Hip (left, right) 
130 
9 
0.07 
81.17 
89.65 
Knee and distal lower 
extremity (left, right) 
128 
6 
0.05 
9.04 
14.64 
 
Simulations to assess power were conducted as follows: 
1. A subject-level rate of body regions with new HO were randomly drawn from a gamma 
distribution with mean = 0.707 and SD = 1.11.   
2. Using the subject-level rate, the numbers of regions with new HO for each WBCT scan 
were simulated using a Poisson distribution. The rate was scaled to the duration of time 
between each WBCT scan and the previous WBCT scan. 


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3. Given the number of regions with new HO, the specific body regions with new HO were 
randomly selected assuming equal probability across regions. 
4. For each body region with new HO, the increase in HO volume was simulated from a 
gamma distribution parameterized with the mean and SD in Table 1.   
a. For the elbow, hand and wrist (left, right), the SD was assumed to be equal to the 
mean. 
5. The resulting dataset was analyzed as described in Section 0 at the scheduled analysis 
time points.   
Note that drawing subject-level rates of body regions with new HO from a gamma distribution 
and then drawing from Poisson distributions using these subject-level rates implies that the 
marginal distribution of the number of body regions with new HO follows a negative binomial 
distribution, which requires much less restrictive assumptions than a Poisson distribution and 
does not tend to result in an underestimate of the variance.   
The simulated power is summarized in Table 2 given the specified testing sequence, 80 subjects 
enrolled into the MOVE Trial with the R206H mutation and no previous palovarotene 
experience (including approximately 45 subjects from the NHS) and the NHS serving as the 
external control group with 45 subjects with baseline, 1-year and 1.5-year WBCT HO volumes 
and 45 subjects with baseline, 1-year and 2-year WBCT HO volumes; it is assumed that the full 
NHS dataset will be available at the first interim analysis. 
Table 2. 
Power of MOVE Study Primary Efficacy Analysis Assuming 80 Subjects 
Enrolled with the R206H Mutation and No Previous Palovarotene Exposure 
Scenario 
 
Cumulative Probability 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 
 
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 volume of new HO 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 2 shows that the type I error rate is 
maintained under the null hypothesis of no palovarotene treatment effect. 
Note that Protocol Amendment 2 increased the number of subjects enrolled from approximately 
90 to a maximum of 110 (up to 99 with the R206H mutation and no previous exposure to 
palovarotene; up to 11 with other mutations and previous participation in the Phase 2 trials). This 


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increase in the number of enrolled subjects, implemented late in enrollment to allow sites to 
screen already-scheduled patients and enroll those found to be eligible, does not substantially 
change the power of the trial or have a significant impact on the primary or secondary statistical 
analyses. 
Additional details of the operating characteristics of the Bayesian analysis including its chance of 
producing erroneous conclusions and the reliability of treatment effect estimates will be included 
in a separate simulation report, which will be included in the interim clinical study report as an 
appendix. 
1.8 
Study Plan 
The schedule of the safety, efficacy, and pharmacokinetic (PK) assessments can be found in the 
Protocol in Table 1 and Table 2.  
1.9 
Modifications to the Statistical Section of the Protocol 
1.9.1 Modifications to the Statistical Section of Protocol Amendment #1 
The method for the primary efficacy analysis (a Bayesian analysis of a compound Poisson 
distribution) described in Protocol Amendment 1 and this SAP is different from the method 
included in the original protocol dated 10 July 2017 (weighted linear mixed effects model). The 
method and accompanying power simulations in the original protocol were based on a March 
2017 evaluation of the available NHS 12-month WBCT data. In a subsequent dataset, increased 
variability in the change from baseline in new HO resulted in a substantive power decrease for 
the weighted linear mixed effects model. Therefore, additional modeling and simulation work 
was undertaken to assess whether alternative models or transformations would be more 
appropriate methods of analyzing the data, and thus maintain the power of the MOVE Trial. This 
resulted in changes to the primary efficacy analysis method as well as the simulations underlying 
sample size determination. Additionally, the Lan-DeMets alpha-spending function with Pocock 
parameterization was revised to O’Brien-Fleming parameterization based on FDA scientific 
advice. 
1.9.2 Modifications to the Statistical Section of Protocol Amendment #2 
Rather than at successive 6-month intervals after the first interim analysis, the timing of the 
second and third interim analyses were clarified; they were to be performed when all subjects in 
the Principal EP have completed (i.e., have WBCT data) 12 months and then 18 months of 
follow-up, respectively. 
1.9.3 Modifications to the Statistical Section of Protocol Amendment #3 
Protocol Amendment 3 added a 2-year extension to the study; the first 24 months, i.e., the 
original study is designated Part A, and the 2-year extension is designated Part B.  
Note that the current scope of this document remains Part A. The SAP may be amended again to 
describe analyses conducted on data collected in Part B. 


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1.9.4 Modifications to the Statistical Section of Protocol Amendment #4 
Protocol Amendment 4 followed the second interim analysis at which the futility boundary was 
crossed, signifying that the prespecified Bayesian compound Poisson distribution model with 
square-root transformation indicated that the trial was unlikely to show sufficient evidence of 
benefit. The DMC informed the sponsor of this outcome on January 15, 2020, and the efficacy 
assessments were subsequently unblinded to the sponsor. 
Based on additional post-hoc analyses presented to the DMC on January 21, 2020, the DMC 
noted that using the square-root transformation of the data in the primary analysis appears to 
have moved the statistical conclusion from significant therapeutic benefit to showing futility of 
the treatment. The DMC also noted that the dilemma created by these highly disparate results 
precludes a confident conclusion about futility. As such, the DMC recommended that additional 
analyses be conducted and provided to them for consideration at the next (ie, third) interim 
analysis. Therefore, the study continued and the protocol was amended to allow for the 
continuation and to include these analyses requested by the DMC. 
1.9.5 Modifications to the Statistical Section of Protocol Amendment #5 
No changes were made to the statistical section. The protocol amendment added assessments for 
spinal health carried out on low dose WBCT scans collected in the study. Part C was also added. 
1.10 Statistical Modifications to the Statistical Analysis Plan 
1.10.1 Statistical Modifications to the Statistical Analysis Plan, V1.0 
The primary and secondary efficacy analyses described in Protocol Amendment 1 do not include 
explanatory covariates. Because recent studies – Clementia’s NHS as well as other studies – 
suggest that age may be important for flare-up rate and the formation of new HO, age (<18, ≥18 
years) and additional categorical variable sex (Male, Female) is included in the primary and 
secondary efficacy analyses. 
The analysis of the secondary endpoints proportion of subjects with any new HO and number of 
body regions with new HO will both be conducted using the Bayesian compound Poisson model 
used in the primary efficacy analysis; in fact, the inference is identical for these two secondary 
endpoints. Within the compound Poisson model, 𝜃ଵ,ଵ<1 implies both a lower proportion of 
subjects with any new HO and a smaller number of body regions with new HO for 
palovarotene-treated subjects.   
1.10.2 Statistical Modifications to the Statistical Analysis Plan, V1.1 
SAP Version 1.1 introduces methods to address the prolonged interruptions in subject dosing in 
MOVE due to two events: 
1) US FDA instituted a partial clinical hold on dosing of palovarotene due to premature 
physeal closure (PPC) for subjects <14 years of age. This hold was effective December 4, 


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2019; as of the finalization of this SAP amendment, dosing has not yet resumed for these 
subjects. 
2) Dosing on all subjects not subject to US FDA’s partial clinical hold was interrupted 
following the January 21, 2020 DMC meeting while the protocol amendment allowing 
the continuation of the study after the futility outcome and incorporating the additional 
analyses requested by the DMC was reviewed by regulatory agencies, IRBs, and 
investigational sites. These subjects had palovarotene dosing interrupted on or around 
January 24, 2020. Following clearance received from several regulatory agencies 
including FDA to reinitiate dosing in subjects age 14 and above, the sponsor allowed 
dosing to resume as of March 26, 2020, provided each individual site obtains Ethics 
Committee approval to do so and the site is able to fulfil regulatory and operational 
requirements. Subjects were expected to restart dosing over a span of weeks due to these 
logisitical considerations. 
Specifically, analyses of all efficacy endpoints will include assessments collected on or before 
these interruptions, unless otherwise specified. (Assessments were to continue as planned during 
the interruptions.) Analyses in which all timepoints are included, irrespective of dosing 
interruption, will also be conducted for the primary analysis (and additional analysis without the 
square-root transformation) and secondary analyses to aid in the interpretation of the efficacy. 
The sponsor also notes that after the DMC communicated to the sponsor that the pre-specified 
futility boundary had been crossed, the sponsor became unblinded to all study data. With these 
considerations, all subsequent analyses of efficacy data will be supplied without applying 
thresholds for success or futility, as these thresholds are no longer relevant.  
SAP Version 1.1 also  
• Provides a detailed description of the wLME analysis designated as the primary efficacy 
analysis in the original clinical protocol and reintroduced as a supportive analysis in 
Protocol Amendment 4.   
• Introduces several age (years) by sex partitions for use in subgroup analyses, including 
<8 for Females and <10 for Males vs. ≥8 for Females and ≥10 for Males; and <13 for 
Females and <15 for Males vs. ≥13 for Females and ≥15 for Males. These are intended to 
inform the benefit/risk assessment for younger subjects at risk of PPC. 
• Adds a subgroup of Asian subjects (to support interactions with global regulatory 
authorities). 
• Describes a sensitivity analysis in which the impact of the difference in WBCT visit 
schedules between MOVE and NHS is assessed by analyzing the data as if the WBCT 
assessments in MOVE were conducted annually rather than biannually. This is intended 
to investigate whether the differences in visit schedules introduced bias, with and without 
use of the square-root transformation. 
• Defines exploratory endpoints of incidence and volume of “catastrophic HO” based on 
the observation – made after unblinding of the second interim analysis – that a minority 
of subjects develop large amounts of HO in a year; post-hoc cut-offs of at least 
50,000 mm3 and 30,000 mm3 of new HO are used. 


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• Describes the analyses to be conducted at the third interim analysis, the results of which 
will be provided to the DMC to assess efficacy and make a benefit:risk assessment. No 
predefined efficacy rules for success or futility will be used.   
1.10.3 Statistical Modifications to the Statistical Analysis Plan, V1.2 
SAP Version 1.2 introduces the following changes: 
• Clarifies that drawing subject-level rates of body regions with new HO from a gamma 
distribution and then drawing from Poisson distributions using these subject-level rates 
implies that the marginal distribution of the number of body regions with new HO 
follows a negative binomial distribution, which requires much less restrictive 
assumptions than a Poisson distribution and does not tend to result in an underestimate of 
the variance.   
• Notes that additional details of the operating characteristics of the Bayesian compound 
Poisson analysis, including its chance of producing erroneous conclusions and the 
reliability of treatment effect estimates, will be included in a separate simulation report. 
• Clarifies the secondary and exploratory endpoint definitions to add timepoints at which 
the endpoints will be compared between NHS and MOVE. 
• Clarifies the definitions of treatment-emergent AEs and post-treatment AEs. 
• Removes summaries of retinoid-associated AEs, as they already appear in the AE tables. 
• Clarifies that a listing of traumas leading to flare-up will be generated. 
• Adds summaries of imaging performance, i.e., intra-reader agreement and inter-reader 
agreement, and quality metrics. 
• Adds summaries of dosing compliance. 
• Clarifies the wLME analysis method by adding pseudocode. 
• Clarifies the methods used to prepare the dataset for application of the Bayesian 
compound Poisson analyses and square-root transformation, including the methods used 
to ‘zero out’ negative changes in HO volume. 
• Clarifies the purpose, timing and conduct of the sensitivity analyses. 
• Updates the list of subgroups to be studied to be consistent with feedback from FDA. 
• Adds analyses for the HO-based secondary analyses and simplifies the analyses of the 
flare-up-based secondary endpoints.  
• Adds summaries of growth velocity. 
• Summarizes duration of flare-up treatment and duration of non-flare-up treatment, which 
are used in the summary of compliance. 
1.10.4 Statistical Modifications to the Statistical Analysis Plan, V1.3 
SAP Version 1.3 introduces the following additions: 
• Adds Principal Restart Full Analysis Set (Principal RFAS) Population 
• Adds Supplementary Restart Full Analysis Set (Supplementary RFAS) Population 
• Defines baseline for analyses for the Principal RFAS and Supplementary RFAS 
• Adds Part C Analysis Population 


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1.10.5 Statistical Modifications to the Statistical Analysis Plan, V1.3.1 
SAP Version 1.3.1 introduces the following additions: 
• Clarifies that IA3 is considered the final analysis for efficacy, with an additional follow-
up analysis including all WBCTs read for HO volume. 
• Clarifies that analyses included in the interim CSR are not planned to be rerun for the 
final CSR. 
2 
STATISTICAL AND ANALYTICAL PROCEDURES 
Data analyses will be performed for the MOVE Trial study period. Where applicable, the 
analyses will incorporate data from the NHS for comparative purposes. The analysis results will 
be presented by two treatment groups (palovarotene and untreated). The list of analysis endpoints 
described below is specific to the MOVE Trial, unless otherwise specified. The incorporation of 
NHS data is described in Section 2.2, Section 2.3, and Section 2.4. 
2.1 
Analysis Endpoints 
2.1.1 Demographic and Baseline Characteristics 
Demographic Characteristics 
The following demographic characteristics will be summarized: 
• Sex (Male, Female) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• Asian (Yes, No)  
• Age (years) 
• Age group (<12, ≥12, <14, ≥14, <17, <18, ≥18 years, ≥12 - <17 years) 
• Age by sex (<8 for Females and <10 for Males, ≥8 for Females and ≥10 for Males; ≥8 - 
<14 for Females and ≥10 - <14 for Males)  
Medical or Surgical History 
This information will be coded using the most current version of the Medical Dictionary for 
Regulatory Activities (MedDRA). FOP history will also be summarized. 


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FOP History 
The following FOP history will be summarized: 
• Age at diagnosis (years) 
• Time since FOP diagnosis (years) (Until enrollment, i.e., informed consent) 
• Great toe malformations (yes/no) 
o If yes, age when noted (years) 
o Surgically repaired? (yes/no) 
• Other associated clinical findings (frequency table for findings, e.g., cervical spine 
malformations, hearing loss, etc.) 
• Osteochondromas (yes/no, with frequency table for location, e.g., tibia, femur, etc.) 
• How was the diagnosis made? (frequency table for method, i.e., clinical symptoms, 
genotyping, imaging w/ modality) 
• Were there any misdiagnoses before proper diagnosis was made? (yes/no, with frequency 
table for misdiagnosis, e.g., Aggressive Juvenile Fibromatosis, Lymphedema, Soft Tissue 
Sarcoma, Other (with frequency table for free text entries) 
• Any family history of FOP? (yes/no) 
o If yes, family member with disease (Mother, Father, Both, Unknown) 
o Other family members with FOP symptoms? (Brother, Sister, Both, Unknown, 
None) 
o How was diagnosis made in family member? (frequency table for diagnostic, i.e., 
Clinical Symptoms, Genotyping, Biopsy, Unknown) 
Flare-up History 
The following flare-up history will be summarized: 
• Subject with any history of a flare-up (yes/no) 
• Age at 1st flare-up (years) 
• Time since 1st flare-up (years) 
• Location of first flare-up 


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• Number of flare-ups within the past 12 months 
• Time since last flare-up (months) 
• Location of last flare-up 
• Symptoms of last flare-up 
• Cause of last flare-up 
• Last flare-up bone formation (yes/no) 
• Last flare-up movement restriction 
2.1.2 Prior or Concomitant Medications 
All medications taken within 30 days before study drug initiation and until the end of the study 
are to be reported in the case report form (CRF) pages.   
All medications captured in the MOVE study will be coded using the using WHODrug Global; 
for NHS, all medications not appearing on the prespecified list were also coded using this 
dictionary.  
• Prior medications are those the subject used prior to first dose of study drug. Prior 
medications can be discontinued before first dose of study drug or can be ongoing during 
the treatment phase. 
• Concomitant medications are any treatments received by the subject after first dose of 
study drug, during the treatment-emergent period (Section 2.1.3). Concomitant 
medications first received after first dose of study drug will also be referred to as new 
onset medications. 
• New onset medications are concomitant medications first received after the first dose of 
study drug. 
A given medication can be classified as a prior medication, as a concomitant medication, and as 
a new onset medication. Note that these categories are not mutually exclusive. A medication 
initiated prior to first dose of study drug and continued during the treatment-emergent period will 
be prior and concomitant. 
2.1.3 Efficacy Endpoints 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the annualized change in new HO volume as assessed by 
low-dose, WBCT, excluding head. The annualized change in new HO volume will be compared 
between treated and untreated subjects. WBCT scans are performed at baseline, Month 12, 


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Month 24 and Month 36 in the NHS and at baseline, Month 6, Month 12, Month 18 and Month 
24 in the MOVE Trial. WBCT scans may also be performed at the time of early study 
discontinuation. 
As described in the MOVE Trial and NHS Independent Review Charter, HO volume is assessed 
by two independent readers blinded to study and timepoint, with adjudication by a third 
independent reader. HO volume is measured by body region with the baseline scan. The 
following 9 anatomical regions will be used to describe HO location: 
• Right chest, neck, shoulder through mid-humerus 
• Left chest, neck, shoulder through mid-humerus 
• Mid Torso: torso below shoulder regions and above iliac crests 
• Right arm: mid-humerus through hand 
• Left arm: mid-humerus through hand 
• Right hip: iliac crest, hip through mid-femur 
• Left hip: iliac crest, hip through mid-femur 
• Right lower leg: mid-femur through foot 
• Left lower leg: mid-femur through foot 
In post-baseline scans, the presence of new HO within each body region and, if present, the HO 
volume within the body region, are measured. The primary efficacy analysis described in 
Section 0 models the number of body regions with new HO compared to the previous scan and 
the volume of new HO within each body region with new HO compared to the previous scan as 
the unit of measurement.   
Note that the primary endpoint includes annualized HO based on the new HO observed up to 
Month 24 in MOVE and up to Month 36 in NHS. The sponsor believes that the new HO 
observed between Month 24 and Month 36 in NHS is relevant and that annualization is sufficient 
to protect against bias. Sensitivity analyses to assess impact of differences in length of follow-up 
between NHS and MOVE are described in Section 2.4.4. 
The primary efficacy endpoint, as well as the secondary endpoints that depend on the efficacy 
imaging, will not be summarized in the descriptive analysis to be conducted before the first 
formal interim efficacy analysis, due to the ongoing nature of the blinded reads. 
Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be assessed: 
• The proportion of subjects with any new HO at Month 12 (key secondary endpoint). 


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• The number of body regions with new HO at Month 12. 
• The proportion of subjects reporting flare-ups at Month 12. 
• The flare-up rate per subject-month exposure through Month 24. 
Note that only MOVE flare-ups with ≥2 symptoms will be included in the derivation of the 
proportion of subjects reporting flare-ups and flare-up rate per subject-month exposure. This will 
better align the MOVE derivation with the definition of flare-up in the NHS, which required >1 
symptom. 
The secondary endpoints that depend on the efficacy imaging, i.e., the proportion of subjects 
with any new HO and the number of body regions with new HO, will not be summarized in the 
descriptive analysis to be conducted before the first formal interim efficacy analysis, due to the 
ongoing nature of the blinded reads.  
Exploratory Efficacy Endpoints 
The following exploratory efficacy variables will be assessed: 
• Change from baseline in ROM assessed by CAJIS through Month 24 in MOVE and 
NHS. 
• Change from baseline in physical function through Month 24 in MOVE and NHS, using 
age-appropriate forms of the FOP-PFQ. 
• 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, through Month 24 in MOVE and NHS. 
• Incidence and volume of catastrophic HO per year, i.e., new HO >50,000 mm3; and new 
HO >30,000 mm3 at Month 12 and Month 24. 
ROM Assessed by CAJIS 
Range of motion will be assessed using the CAJIS. The assessments will be performed on 12 
joints (shoulder, elbow, wrist, hip, knee, and ankle on both the right and left sides), and three 
body regions (jaw, cervical spine [neck], and thoracic/lumbar spine). Each joint/region will be 
scored as: 0 = uninvolved; 1 = partially involved; and 2 = ankylosed/completely involved.   
The CAJIS Total score will be calculated as the sum of the scores of all joints/regions and ranges 
from 0 (no involvement) to 30 (maximally involved). 
The CAJIS Upper Extremities subscore will be calculated as the sum of the scores from six joints 
(shoulder, elbow, and wrist on both the right and left sides) and one region (cervical spine 
[neck]) and ranges from 0 (no involvement) to 14 (maximally involved).  


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The CAJIS Mobility subscore (lower extremity) will be calculated as the sum of scores from six 
joints (hip, knee, and ankle on both the right and left sides) and ranges from 0 (no involvement) 
to 12 (maximally involved).  
FOP-Physical Function Questionnaire (FOP-PFQ) 
Age-appropriate forms of the FOP-PFQ will be administered to subjects. The adult form will be 
administered to subjects ≥15 years old. For subjects between 8 and 14 years of age, both the 
pediatric self-completed and the pediatric proxy-completed forms will be administered. The 
proxy-completed form will be used for analyses unless only the self-completed form is available. 
The FOP-PFQ consists of 28 questions on the adult form and 26 questions on the pediatric form 
scored on a scale from 1 to 5, with lower scores indicating more difficulty. 
The total score will be calculated as: 
• The sum of the scores from each question and ranges from 28x1 = 28 to 28x5 = 140 for 
the adult form. 
• The sum of the scores from each question and ranges from 26x1 = 26 to 26x5 = 130 for 
the pediatric form. 
If a subject is missing some (but not more than 20%) of the contributing question scores, the total 
score will be calculated as the average observed score multiplied by the number of expected 
question scores. For example, the total score would be calculated as the average of the 
non-missing scores x 28 for the adult form.   
As the analysis for FOP-PFQ will be performed across all subjects (adult and pediatric) and the 
number of contributing questions differs, the scores will be transformed to reflect a percentage of 
worst score. The percentage of worst score ranges from 0% to 100% with 0% indicating the best 
possible function and 100% indicating the worst possible function. Table 3 illustrates some 
sample derivations of the percentage of worst score. 
Table 3. 
Sample Derivations for the Percentage of Worst Score for the FOP-PFQ 
Sample 
Subject 
Observed 
FOP-PFQ 
Score 
Lowest 
Possible 
Score 
Highest 
Possible 
Score 
Range of 
Possible 
Scores 
Distance = 
Highest 
- Observed 
Distance/ 
Range 
Percentage 
of Worst 
Score 
1 
45 
15 
75 
60 
30 
0.500 
50.0% 
2 
40 
15 
75 
60 
35 
0.583 
58.3% 
3 
35 
15 
75 
60 
40 
0.667 
66.7% 
4 
30 
15 
75 
60 
45 
0.750 
75.0% 
5 
25 
15 
75 
60 
50 
0.833 
83.3% 
 
PROMIS Global Health Scale 
An age-appropriate form of the PROMIS Global Health short form will be provided to subjects 
(or parent proxy). The adult form will be provided to subjects 15 years and older. For subjects 


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between 8 and 14 years of age, both the pediatric self-completed and the pediatric 
proxy-completed forms will be provided. The proxy-completed form will be used for analysis 
unless only the self-completed form is available. 
The PROMIS Global Health short form consists of 10 questions on the adult form and nine 
questions on the pediatric form scored on varying scales.   
For the adult form, Global Physical Health and Global Mental Health scores will be calculated. 
The Global Physical Health score will be calculated as the sum of scores from Questions 3, 6, 7, 
and 8, and will range from 4 (worse health) to 20 (better health). The Global Mental Health score 
will be calculated as the sum of scores from Questions 2, 4, 5, and 10, and will range from 4 
(worse health) to 20 (better health). In the calculation of the Global Physical Health and Global 
Mental Health scores, the following questions will be rescaled as shown in Table 4. 
Table 4. 
Rescaled PROMIS Global Health Scale Scores 
Question(s) 
Score 
Rescaled Score 
7 
0 
5 
 
1-3 
4 
 
4-6 
3 
 
7-9 
2 
 
10 
1 
8 and 10 
1 
5 
 
2 
4 
 
3 
3 
 
4 
2 
 
5 
1 
 
If a subject is missing any of the contributing scores, the Global Physical Health or Global 
Mental Health score will not be calculated.   
For the pediatric form, only a total score will be calculated as the sum of scores from the first 
seven questions and will range from 7 (worse health) to 35 (better health). If a subject is missing 
some (but not more than three) of the contributing question scores, the total score will be 
calculated as the average observed score multiplied by the number of expected question scores. 
For example, the total score would be calculated as the average of the non-missing scores x 7. 
Global Physical Health and Global Mental Health scores and total scores will be converted to 
T-scores for analysis as described in Appendix 6.1. A T-score of 50 is normal and increments of 
10 ± 1 standard deviation away from the norm. A T-score <50 indicates worse health, while a 
T-score >50 indicates better health. Note that higher values indicate better health. 
2.1.4 Safety Endpoints 
Safety evaluations will include adverse event (AE) and serious AE (SAE) reporting, 
electrocardiograms, vital signs (temperature, respiratory rate, blood pressure, and heart rate), 


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physical examination, body weight/BMI , knee and linear height, laboratory parameters 
(hematology, biochemistry, and urinalysis), urine pregnancy tests for FOCBP, radiographic 
imaging and whole body computed tomography (WBCT), concomitant medication reporting, and 
the age-appropriate C-SSRS.   
Adverse Event Variables 
Adverse Event Observation Periods 
• A Pre-treatment AE is an AE with an onset date before the first dose of study drug. 
• TEAEs are AEs with (first dose date of study drug) ≤ (AE start date) ≤ (last dose date of 
study drug +7 days for all AEs, i.e., non-serious and serious AEs).  
o  A chronic TEAE is a TEAE with an onset date during chronic treatment 
o A flare-up TEAE is a TEAE with an onset date during flare-up treatment 
• Post-treatment AEs are AEs with a start date > last dose date + 7 days for All AEs 
(non-serious and serious AEs).    
Note that subjects may have multiple independent flare-up treatment cycles, each potentially 
with associated AEs, within the study.  
For the efficacy interim analysis and final analysis, treatment emergence for chronic or flare-up 
treatment is determined based on the subject’s dosing diary. For all other pre-lock analyses, 
treatment emergence is determined using the subject’s planned dosing log if insufficient diary 
data is available, with the date of the extract of data for the interim analysis used as the end date 
for TEAE assignment purposes.  
Any AE with a missing start date is considered TEAE. For TEAEs that have a partial date where 
the day is missing, if the month is the same month as a flare-up treatment was given, then the 
TEAE will be defined as a TEAE associated with flare-up dosing.  
All AEs (including SAEs) will be coded using a current or recent version of MedDRA. Adverse 
event severity will be assessed and reported according to criteria defined in the protocol (mild, 
moderate, severe). Adverse event causality will also be assessed in terms of relationship to study 
drug and reported according to criteria described in the protocol (not related, possibly related, 
probably related, definitely related).   
The occurrence of AEs (including SAEs) will be recorded from the time of signed informed 
consent until the end of the study.   
Deaths 
Deaths after the first dose of study drug are either on-treatment or post-treatment: 


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• Deaths on-treatment: deaths occurring after the first dose of study drug and up to 7 days 
after the last dose of study drug 
• Death post-treatment: deaths occurring more than 7 days after the last dose of study drug 
until 30 days after last dose of study drug  
Laboratory Safety Variables 
Clinical laboratory data will include hematology, biochemistry (including lipids and serum 
pregnancy test (when applicable)), and urinalysis. Clinical laboratory values will be converted to 
conventional units; conventional units will be used in all listings and tables.   
Hematology, biochemistry, and urinalysis data will be collected at Screening and every 6 months 
(Months 6, 12, 18, and 24). For subjects receiving flare-up treatment, blood and urine samples 
will be collected every 12 weeks during safety assessments until the end of the flare-up cycle.  
The laboratory parameters will be classified as listed in Table 5. 


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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. 
 
Electrocardiogram Variables 
A 12-lead electrocardiogram (ECG) will be performed at Screening and every 6 months 
(Months 6, 12, 18, and 24). Mean heart rate, RR, PR, QRS, QT, QTcF, and QTcB will be 
determined using centralized readings. 
The abnormal ECG categories are defined as follows: 
Rhythm 
• Atrial premature complexes 
• Ventricular premature complexes 
• Sinus arrhythmia 
• Sinus tachycardia 


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Conduction 
• Nonspecific intraventricular conduction delay 
• Right bundle branch block 
• Incomplete right bundle branch block 
• Left posterior fascicular block 
• Left bundle branch block 
• Incomplete left bundle branch block 
Morphology/Chamber Enlargement 
• Left ventricular hypertrophy 
• Left ventricular hypertrophy with repolarization abnormality 
Axis Deviation 
• Right axis deviation 
• Left axis deviation 
Myocardial Infarction 
• Pathologic Q waves 
• Acute ST elevation MI 
• Acute non-ST elevation MI 
ST Segment/T Waves/U Waves 
• Early repolarization 
• Nonspecific ST and T wave abnormality 
• Nonspecific ST elevation 
• Nonspecific U wave abnormalities 
Vital Signs Variables 
Vital sign variables include heart rate, systolic blood pressure, diastolic blood pressure, 
respiratory rate and temperature. These assessments will be performed at Screening, every 3 
months (Months 3, 6, 9, 12, 15, 18, 21 and 24), 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. 
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 old who are receiving 
palovarotene will be assessed for suicidal ideation and behavior using the C-SSRS at Screening 
and every 3 months (Months 6, 9, 12, 15, 18, 21, and 24); and as part of every Flare-Up Cycle 
Safety Assessment. The adult form will be used for subjects ≥12 years old and the pediatric form 
will be used for subjects 8 to 11 years old. 


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Knee and Hand/Wrist Radiographs and WBCTs for Assessment of Bilateral Hand/Wrist 
and Knee Epiphyseal Growth Plate 
All subjects under the age of 18 years enrolled into the MOVE Trial will undergo hand/wrist 
radiographs (posterior/anterior (PA) view, preferably on the left side) and knee radiographs (AP 
view) at baseline and every 6 months (Months 6, 12, 18, and 24) to determine bone age 
(hand/wrist only) and skeletal maturity. Knee and hand/wrist radiograph assessments will be 
performed at Months 3, 9, 15, 21, etc. 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. Once a subject has achieved 100% skeletal maturity (i.e., epiphyseal 
closure of all assessed growth plates) as determined by the knee and hand/wrist radiographs, 
further radiographs will no longer be necessary. Determination of epiphyseal closure requires 
consensus, with differences in the two assessments undergoing adjudication. 
Although the WBCT scans obtained in the NHS and MOVE Trial are used primarily to quantify 
change in HO volume, they will also be used to assess for potential adverse effects on bilateral 
hand/wrist and left knee growth plates as well as long bone growth of growing children. 
All radiographs and WBCT scans will be assessed by two independent musculoskeletal 
radiologists at a central imaging laboratory using standardized procedures to ensure consistent 
and accurate assessment. Bone age will be the average of the two independently assessed bone 
ages. 
The following parameters will be assessed:  
• Hand/wrist and knee radiograph images 
o Epiphyseal growth plate abnormalities assessment. Abnormalities to be reported 
include: 
 Frayed metaphyseal edge 
 Cupping 
 Calcinosis (punctate or streaky calcifications, not orderly closure of the 
physes) 
 Widening of the epiphyses 
 Sclerosis of the adjacent growing bone (metaphyseal edge) 
 Under-mineralization or osteopenia of the adjacent growing bone 
 Dense metaphyseal lines (also known as growth recovery lines) 
o Epiphyseal growth plate closure assessment 
o Bone age (years, months), if applicable (hand/wrist only) 


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• Hand/wrist and knee WBCT safety images 
o Epiphyseal growth plate abnormalities assessment 
Standardized Stadiometry and Knee Height for Assessments of Linear Growth 
Subjects under the age of 18 years enrolled with open epiphyseal growth plates will have linear 
growth assessments (in triplicate) by stadiometer at Screening and every 6 months (Months 6, 
12, 18, and 24). Measurement of knee height using a standard caliper will also be performed (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 measurement will no longer be required. 
WBCT Measurements of Femur and Tibia Lengths 
Although the WBCT scans obtained in the NHS and MOVE Trial are used primarily to quantify 
change in HO volume, they will also be used to assess the length of the femur and tibia 
bilaterally on all subjects aged 17 years and below. 
Evaluation of Bilateral Hips by WBCT Safety Read 
Although the WBCT scans obtained in the NHS and MOVE Trial are used primarily to quantify 
change in HO volume, they will also be used to assess potential adverse effects on the femoral 
head related to avascular necrosis of the hip (AVN).  
Two independent radiology reviewers will qualitatively assess the hip joints on WBCT scan to 
determine whether there is evidence of AVN. Discrepancies in the reads will be adjudicated. 
Each hip will be assessed for presence or absence of AVN and, if present, the degree of change 
from the baseline scan and previous scan. 
Trauma Leading to Flare-up 
In MOVE, subjects can initiate flare-up dosing for substantial high-risk traumatic events likely to 
lead to a flare up. A listing of traumatic events and whether the trauma resulted in a confirmed 
flare-up will be generated. 
2.1.5 Imaging Performance and Quality Metrics  
The imaging Independent Review Charter (V7.1) describes the process for reading efficacy and 
safety imaging in the MOVE and NHS studies. It also describes an exercise comprised of 
secondary reviews, i.e., rereads of a subset of cases by the independent reviewers, of low-dose 
WBCT efficacy, radiograph and low-dose WBCT safety review types. The goal of the exercise is 
to characterize the intra-reader agreement and the inter-reader agreement for each of these 
review types. 


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Intra-Reader Agreement 
The imaging vendor will randomly select sixteen study subjects for WBCT efficacy, eight study 
subjects for WBCT safety and four study subjects for radiograph read types, with a minimum of 
two timepoints each, for re-evaluation by the same reviewer at least 3 weeks after the initial 
radiology review. Discrepancies identified within the completed secondary review cases will be 
reviewed by the vendor as described below: 
Discrepancies are defined as below: 
• 
Low-dose WBCT Efficacy Review Any difference in post-TP1 scans as follows: 
o disagreement on the presence/absence of new HO in any region in the post-TP1 
scan compared to the TP1 Consensus scan  
o [|diff change|/(mean (change)) >20% AND |diff change|>10000] OR |diff 
change|>25000, where diff change is the difference in the change in new HO 
compared to the TP1 consensus scan between secondary read and the original 
read and mean (change) is the average of the change in new HO volume. 
• Radiograph Review:  
Any difference as follows: 
o any difference in the assessment of presence of epiphyseal abnormalities in either 
the knee and/or hand/wrist (i.e., No vs. Not Evaluable vs. Yes)  
o any difference in the assessment of any epiphyseal abnormality change from TP1 
and/or from prior timepoint in either the knee and/or the hand/wrist (i.e., not 
present vs. no change vs. improved vs. worse vs. unknown) 
o any difference in selected epiphyseal abnormality(ies) per location  
o any difference in epiphyseal growth plate closure assessment (i.e., no (closed) vs. 
not evaluable vs. yes, partially closed vs. yes, open for any location (distal radius, 
distal ulna, proximal tibia, or distal femur, as applicable)) 
o any difference in skeletal maturity assessment  
• Low-dose WBCT Safety Review:  
Any difference as follows: 
o any difference in the assessment of presence of femoral head abnormalities (i.e., 
no vs. not evaluable vs. yes) 
o any difference in the presence of hand/wrist and/or knee epiphyseal abnormalities 
(i.e., no vs. not evaluable vs. yes) 


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o any difference in the assessment of any epiphyseal abnormality change from TP1 
and/or from prior timepoint in either the knee and/or hand/wrist (i.e., not present 
vs. no change vs. improved vs. worse vs. unknown) 
o any difference in selected abnormality(ies) per location. 
Given the granularity of the discrepancy evaluation, discrepancies of 30% or more are expected 
to occur for each review type.  
Inter-Reader Agreement 
To determine inter-reader agreement, the radiologists participating in primary radiology reviews 
will read a subset of eight study subjects for WBCT efficacy, eight study subjects for WBCT 
safety and four study subjects for radiograph read types, with a minimum of two timepoints each, 
randomly selected by Parexel’s image management and review system at least 3 weeks after the 
initial radiology review. Discrepancies identified within the completed secondary review cases 
will be reviewed by Parexel as described below. Discrepancies are defined in IRC Section 14.1.1 
(Intra-Reader Agreement). 
If a secondary review results in discrepancies for more than 30% of the timepoints for a reviewer 
for each review type, Parexel medical personnel will review the discrepancies to assess whether 
preventative actions as described in IRC Section 14.2 (Quality Monitoring) are required. 
2.1.6 Pharmacokinetic Endpoints 
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. 
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. Pharmacokinetic blood samples will be collected at pre-dose 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. 
2.1.7 Compliance 
Compliance is defined as (duration of treatment/expected duration of treatment). Calculation of 
duration of treatment is described in Section 2.4.8 and Section 2.4.9.  
The expected duration of treatment is calculated as following: 


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• For non-flare-up treatment, expected duration of treatment is calculated as (last 
non-flare-up dose date – first non-flare-up dose date) – (sum of (all flare-up cycle dosing 
periods) + 1. 
• For flare-up treatment, expected duration of treatment is calculated as total of expected 
flare-up cycle dosing periods across all flare-up cycles. Each expected flare-up cycle 
dosing period is defined as (last flare-up cycle dose date – first flare-up cycle dose date + 
1).  
Compliance will be summarized for the Principal FAS with descriptive statistics. Compliance in 
category (<80%, ≥80%) will also be summarized for counts and percentages of subjects. 
2.2 
Disposition of Subjects 
This section describes the disposition for treatment status, subject status and the patient 
populations. 
Screened subjects are defined as all subjects who sign the informed consent. 
Enrolled subjects include all subjects who sign the informed consent and meet all eligibility 
criteria of the MOVE Trial. 
For subjects in the MOVE Trial, the total number of subjects for each of the following categories 
will be presented in a table: 
• Screened subjects 
• Screen failure subjects and the reasons for screen failure 
• Enrolled subjects  
• Enrolled and treated subjects including by whether the subjects crossed over from the 
NHS 
• Subjects who permanently discontinued study drug by reason for discontinuing study 
drug;  
• Subjects who completed the MOVE Trial  
• Subjects who discontinued the MOVE Trial by reason for discontinuing study 
For all categories of subjects (except for the screened category), percentages will be calculated 
using the number of enrolled subjects as the denominator. Reasons for study drug 
discontinuation will be presented in tables giving numbers and percentages. The NHS subject 
disposition will be summarized using the categories above, where applicable. 


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All critical or major deviations potentially impacting efficacy analyses and other major/critical 
deviations will be summarized in tables giving numbers and percentages of deviations by 
treatment group. 
Additionally, the analysis populations will be summarized in a table by subject counts based on 
the enrolled populations (see definitions in Section 2.3). 
2.3 
Analysis Populations 
The MOVE Trial 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. For the 
NHS, the Principal Enrolled Population will include all subjects enrolled. 
• 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 measurement.  
• 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. 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 measurement and with 
no major protocol deviation that are expected to interfere with assessments of the primary 
endpoint. Note that no analyses using the Principal PPS are planned after the interim CSR 
used to support the global regulatory filings. 
• The Principal Safety Set (Principal SS) includes all enrolled subjects with the R206H 
ACVR1 mutation 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 with the 
R206H ACVR1 mutation receiving at least one dose of palovarotene and providing 
evaluable pharmacokinetic data in the current study. 
• Principal Restart Full Analysis Set (Principal RFAS) includes all enrolled subjects in the 
Principal EP who restarted palovarotene therapy after January 2020 and have at least two  
assessments on or after restart e.g. 2 WBCT scans for HO volume measurements in the 
MOVE trial. Analyses involving this population will primarily be descriptive and will 
include records after palovarotene restart. 


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• Part C Analysis Set includes all skeletally immature subjects who stopped taking study 
medication for any reason before completion of Part A/B and had at  least one follow-up 
visit following last dose. All analyses involving this population will be descriptive. 
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 SS, the Supplementary PS, and the Supplementary RFAS, with these populations 
defined analogously as above for the subjects with the R206H ACVR1 mutation. (Due to the 
limited sample size, there is no Supplementary PPS.) The Principal populations will be used for 
all analyses described in this SAP. The Supplementary populations will be supportive and 
summarized separately and, unless otherwise specified, will not be used in hypothesis testing. 
2.4 
Statistical Methods 
2.4.1 Demographic and Baseline Characteristics 
Continuous data will be summarized using the number of subjects with data available, mean, SD, 
median, minimum and maximum for each treatment group. Categorical and ordinal data will be 
summarized using number and percentage of subjects in each treatment group.   
Parameters will be summarized for the Principal FAS, PPS, and SS and the Supplementary FAS 
and SS. The respective NHS populations will also be presented, where applicable. 
Parameters will be summarized for a subset of characteristics for the Principal RFAS using the 
first record after restart. 
Parameters described in Section 2.1.1 will be summarized by treatment group and overall using 
descriptive statistics.   
Medical and surgical history will be summarized by SOC and PT sorted by decreasing frequency 
of SOC and by decreasing frequency of PT within SOC in the MOVE analysis populations. 
P-values for demographic and baseline characteristics will not be calculated.   
No specific description of the safety parameters will be provided at baseline. If relevant, the 
baseline values will be described along with each safety analysis.  
2.4.2 Prior or New Onset Medication 
The prior and new onset medications will be summarized based on the enrolled populations as 
follows: 
• Prior medications (excluding systemic glucocorticosteroids) in the MOVE study 
discontinued prior to the first dose of study drug  
• Prior medications (excluding corticosteroids) in the MOVE study ongoing at the first 
dose of study drug 


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• New onset medications in the MOVE study (excluding corticosteroids)  
• Concomitant medications are any treatments received by the subject after first dose of 
study drug, and include prior ongoing medications and new onset medications received 
after first dose of study drug  
The medications will be summarized according to the WHODrug Global by Anatomic 
Therapeutic Class (ATC) and preferred term in the MOVE study. The ATC Class 3 name will be 
presented if available, and if not available the ATC class 2 name will be presented.  
Systemic gluococorticosteroids will be summarized analogously. New onset medications 
(excluding corticosteroids) and new onset corticosteroids will be summarized by whether the 
medication was started during chronic treatment or flare-up treatment.   
In addition, the NHS only recorded usage of a specific list of medications (Table 6). A summary 
table presenting the new onset medications in both the MOVE and NHS studies will be 
presented. In that particular table, only medications that are listed in Table 6 will be included. 
Table 6. 
NHS List of Medications 
Prednisone 
Montelukast 
Narcotics 
Other oral steroids 
Cromolyn 
Calcium 
Celecoxib 
Etidronate 
Vitamin D 
Ibuprofen 
Pamidronate 
Other 
Indomethacin 
Zoledronate 
 
Naproxen 
Other bisphosphonates 
 
Other non-steroidal anti-
inflammatory (NSAID) medications 
Systemic retinoids 
 
Topical NSAIDs 
Thalidomide 
 
Acetaminophen or similar 
Antihistamine 
 
 
The tables for prior and new onset medications will be sorted by decreasing frequency of ATC 
followed by the generic names based on the overall incidence in the MOVE analysis populations. 
The table summarizing the medications listed in Table 6 will be sorted by decreasing frequency 
of the drug name listed in the MOVE analysis population. 
Corticosteroids used for flare-up treatment is defined as any systemic gluococorticosteroid  
initiated within 9 days after the start of a flare-up cycle , or initiated within 14 days prior to the 
flare-up visit or identified on the electronic case report form as a flare-up treated with 
corticosteroids in the NHS Study.  
2.4.3 Study Drug Exposure 
The extent of study drug exposure will be assessed and summarized based on the safety 
populations.   


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The extent of study drug exposure is defined as: last study drug date – first study drug date + 1. 
This calculation is regardless of unplanned study drug interruptions. 
The duration of chronic dosing, the number of subjects with at least one chronic dose reduction, 
the number of dose reductions by type (e.g., 5 to 2.5 mg), the number of subjects with interrupted 
study drug during chronic dosing and the number of subjects discontinuing study drug during 
chronic dosing will be summarized.    
The number of subjects with flare-up dosing, the duration of flare-up dosing overall and by high 
or low flare-up-based dosing, the number of subjects with at least one flare-up dosing reduction 
by type, the number of subjects with interrupted study drug during flare-up dosing, the number 
of subjects discontinuing study drug during flare-up dosing will be summarized.   
For chronic and flare-up dosing, a dose reduction is defined as sustained dosing under the 
expected dose, i.e., underdosing for at least 2 consecutive doses. 
2.4.4 Analyses of Efficacy Endpoints 
The efficacy endpoints will be analyzed using the Principal FAS. Analyses using the Principal 
PPS will be performed as noted. Listings will be generated for the Supplementary FAS.  
Note that no statistical inference is planned to be included in the descriptive analysis to be 
conducted before the first formal interim efficacy analysis; the inference described in this section 
will be conducted for the three interim efficacy analyses. 
In order to address the prolonged interruptions in dosing in subjects <14 years old upon US 
FDA’s institution of a partial clinical hold due to premature physeal closure (PPC) on December 
4, 2019 and interruptions in dosing for the remaining subjects on January 24, 2020 due to the 
crossing of the futility boundary at the second interim analysis, analyses of all efficacy endpoints 
will include assessments collected on or before these interruptions, unless otherwise specified. 
(Assessments were to continue as planned during the interruptions.) For IA3, analyses in which 
all timepoints (available at IA3) are included, irrespective of dosing interruption, will also be 
conducted for the primary analysis (and additional analysis without the square-root 
transformation) and secondary analyses to aid in the interpretation of the efficacy results.  
Note that, due to the prolonged interruption, IA3 provides the best description of efficacy of 
palovarotene and is determined to be the ‘final analysis’ for efficacy.  
Additional analyses will be performed after database lock in which all WBCTs are included. 
E.g., an analysis comparing annualized new HO volume with NHS will be performed using GEE 
– Bayesian analyses are not planned.A separate analysis will also be performed for subjects who 
re-started palovarotene after the interruptions described above in the Principal RFAS. Baseline 
will be defined as as the first WBCT scan obtained after re-start that was not obtained during a 
flare-up or within 1 month of the end of a flare-up. 


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The sponsor also notes that because the futility boundary was crossed at the second interim 
analysis, all subsequent analyses of efficacy data will be supplied without applying thresholds for 
success or futility, as these thresholds are no longer relevant. 
Analyses of Primary Efficacy Endpoint 
Primary Analysis  
The primary efficacy endpoint is the annualized change in new HO volume (as assessed by 
WBCT). 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 square-root 
transformation is used to reduce the influence of outliers. Transformation of volumetric changes 
has been used in related contexts. For example, a log transformation has been used to model 
volumetric increases in the kidneys of subjects with autosomal dominant polycystic kidney 
disease1,2. 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, 𝑍. The number of body 
regions with new HO in subject 𝑖 for WBCT scan 𝑗 with duration 𝑤௜௝ (the time between scan 𝑗 
and the previous scan) is distributed as  
𝐾௜௝~𝑃𝑜𝑖𝑠൫𝜆௜,௝∗𝑤௜௝∗𝜃ଵ,௧(௜௝)൯; 
log (𝜆௜,௝) = log(𝜆௜) + 𝛽ଵ𝑋ଵ,௜+ 𝛽ଶ𝑋ଶ,௜,௝ 
The subject-level rate 𝜆௜ follows a gamma distribution and accounts for potential correlation in 
measurements from the same subject; 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. 
Therefore, the marginal distribution of the number of body regions with new HO follows a 
negative binomial distribution, which requires much less restrictive assumptions than a Poisson 
distribution and does not tend to result in an underestimate of the variance.   
Letting 𝜃ଵ,଴= 1, the variable 𝜃ଵ,ଵ is the multiplicative effect of palovarotene treatment on the 
rate of body regions with new HO. Covariates are included in the analysis of the number of body 
regions with new HO to adjust for potential explained differences in the rate of new HO based on 
the subject’s sex, 𝑋ଵ,௜, and age at time of scan, 𝑋ଶ,௜,௝. Age at the time of scan is represented as a 
factor variable with 0 for <18 years old and 1 for ≥18 years old. Covariate effects 
exp (𝛽ଵ) and exp(𝛽ଶ) are multiplicative effects of sex and age on the rate of body regions with 
new HO. 
The new HO volume (square-root of the volumetric increase in that region) in region 𝑟, ඥ𝑍௜௝௥, 
where new HO has occurred for subject i in scan j is assumed to be distributed as: 
ඥ𝑍௜௝௥/1000~𝑁ቆ𝛼∗𝛼௥∗𝜃ଶ,௧(௜௝), 𝛼௥
ଶ
𝜏௧(௜௝)
ቇ. 


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The scale of new HO volume is modeled in the thousands. Letting 𝜃ଶ,଴= 1, the variable 𝜃ଶ,ଵ is 
the multiplicative effect of palovarotene treatment on the new HO volume conditional on new 
HO occurring. The 𝛼௥ are region-specific variables that contribute to the mean of new HO and 
the variance;the restrictions 𝛼௥=𝛼௥ᇱ where r and r’ are a left and right region pair are included, 
i.e., right chest and left chest, right arm and left arm, right hip and left hip, and right lower leg 
and left lower leg. The precision variables, 𝜏଴ and 𝜏ଵ, introduce flexibility by allowing variability 
to differ between new HO volume in treated subjects and untreated subjects.  
The prior distributions for the variables in the Bayesian compound Poisson distribution are the 
following: 
𝜆௜
~
𝐺𝑎𝑚𝑚𝑎(𝑎, scale = 𝑏)
𝛽ଵ, 𝛽ଶ
~
𝑁(0, 2ଶ)
𝑎, 𝑏
~
𝐺𝑎𝑚𝑚𝑎(1,1)
𝛼
~
𝑁(0, 1)
𝛼௥
~
𝑈𝑛𝑖𝑓(0, 4)
𝜏଴, 𝜏ଵ
~
𝐺𝑎𝑚𝑚𝑎(1, 0.01)
𝜃ଵ,ଵ, 𝜃ଶ,ଵ
~
𝑈𝑛𝑖𝑓(0, 2).
 
All gamma distributions are parameterized as the shape and rate, except as noted for 𝜆௜. 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. 
In this SAP, new HO is deemed to be present in a body region if the volume of net new HO is 
greater than zero, i.e., the change in volume of HO in a region between two timepoints is 
positive. (Volumes of individual lesions are not assessed; the net volume of HO in a body region 
is reported.). Any regions with amounts of new HO<0 mm3, i.e., reductions in the volume of HO 
over time (which can happen due to bone remodeling or measurement variability), will be 
represented as having no new HO and the volumes will be set to zero in the analysis. 
Missing timepoints for subjects, i.e., assessments not conducted, assessments conducted but not 
evaluable for the presence of HO or volume of HO, or assessments for which HO volume for at 
least 50% of body regions is not evaluable or not available, will not be imputed. Body regions 
with non-evaluable HO volume at a timepoint will be represented as having no new HO and the 
volumes will be set to zero in the analysis.  
As described in the MOVE and NHS Independent Review Charter, adjudication is by timepoint. 
When adjudicated, analysis will use the adjudication assessment of volume of new HO. When 
not adjudicated, the average of the two readers’ amounts of HO for each body region will be 
used, assigning a volume of 0 mm3 if the reader does not measure due to the qualitative 
assessment of no new HO. 
Using the Bayesian compound Poisson model described above, the efficacy ratio 𝛾 is calculated 
as the treatment effect on the mean number of body regions with new HO, 𝜃ଵ,ଵ, multiplied by the 


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treatment effect on new HO volume conditional on new HO occurring, 𝜃ଶ,ଵ, expressed as 𝛾=
𝜃ଵ,ଵ∗𝜃ଶ,ଵ. Random samples generated via Gibbs sampling from the posterior distribution of 𝜃ଵ,ଵ 
and 𝜃ଶ,ଵ will be used to compute the posterior probability that 𝛾< 1 to determine statistical 
significance.    
Additional Analyses 
The primary efficacy analysis described above will be repeated without the square-root 
transformation. As noted by the DMC after the second interim analysis, using the square-root 
transformation of the data in the primary analysis was impactful in that it appeared to have 
moved the statistical conclusion from significant therapeutic benefit to showing futility of the 
treatment.   
Furthermore, as is explained later in this section, the square-root transformation together with the 
more frequent WBCT efficacy assessments in MOVE relative to NHS seem to introduce a bias 
against palovarotene in the primary analysis. 
Also, with its square-root transformation reducing the influence of subjects with unusually large 
amounts of new HO, the primary analysis is expected to be less powerful relative to the analysis 
without the square-root transformation if an effect of palovarotene is to reduce the chance of 
catastrophic HO as is suggested in the results observed thus far in MOVE (and was also observed 
in post-hoc analyses of flare-up-based imaging endpoints in earlier studies).  
For these reasons, while acknowledging that it is post-hoc, the sponsor believes that the Bayesian 
compound Poisson analysis without the square-root transformation is the more appropriate 
analysis of the primary endpoint, relative to the Bayesian compound Poisson analysis with the 
square-root transformation. The Bayesian analysis without square root transformation is referred 
to as the analysis of primary interest. 
When performed without the square-root transformation, the new HO volume in region 𝑟, 𝑍௜௝௥, 
where new HO has occurred for subject i in scan j is assumed to be distributed as: 
𝑍௜௝௥/1000~𝑁ቆ𝛼∗𝛼௥∗𝜃ଶ,௧(௜௝), 𝛼௥
ଶ
𝜏௧(௜௝)
ቇ. 
The prior distributions for the variables in this Bayesian compound Poisson distribution are the 
following: 
𝜆௜
~
𝐺𝑎𝑚𝑚𝑎(𝑎, scale = 𝑏)
𝛽ଵ, 𝛽ଶ
~
𝑁(0, 2ଶ)
𝑎, 𝑏
~
𝐺𝑎𝑚𝑚𝑎(1,1)
𝛼
~
𝑁(0, 10ଶ)
𝛼௥
~
𝑈𝑛𝑖𝑓(0, 4)
𝜏଴, 𝜏ଵ
~
𝐺𝑎𝑚𝑚𝑎(1,100)
𝜃ଵ,ଵ, 𝜃ଶ,ଵ
~
𝑈𝑛𝑖𝑓(0, 2).
 


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The Bayesian compound Poisson model will be fitted using the R statistical computing language 
and environment. The R programs will be run using v3.5.0 or later; packages used, including 
version number, will be identified in the CSR. 
Additional supportive analyses including the weighted mixed linear effect (wMLE) analysis with 
and without the square-root transformation will also be performed. The wLME analysis without 
the square-root transformation was previously the primary efficacy analysis, before the Bayesian 
compound Poisson analysis was added in Amendment 1 of the protocol. This wLME analysis 
without square-root transformation is referred to as the alternative analysis of primary interest. 
A subject-level random effect will be used to account for the correlation among repeated 
measures on the same subject as subjects may contribute follow-up from both the NHS and the 
current study. Baseline HO volume divided by age will be the only covariate included in the 
model, in addition to the factor identifying study of origin. The LME model will be fitted using 
only a subject’s observations associated with the longest follow-up in the NHS and the current 
study with weights used to account for the different lengths of observed subject follow-up. 
Missing at random will be assumed for the primary analysis and no imputation of missing data 
performed. 
The wLME analyses will be run using SAS 9.4 or higher. The code will use the following 
structure: 
proc mixed data=data; 
                class treat usubjid; 
                model annrate_newho = treat basetot_bage /s; 
                random usubjid; 
                lsmeans treat/pdiff=control('0') cl; 
    weight fup; 
run; 
 
In this code, treat is a binary indicator for study (1=MOVE, 0=NHS); usubjid is a unique 
identifier of subjects (used across all FOP studies); annrate_newho is the annualized rate of new 
HO; and fup is follow-up in years. 
The Bayesian compound Poisson analysis and wLME analysis without square-root 
transformation and including all assessments on or before December 4, 2019, for subjects <14 
years old on the date of their assessment and assessments on or before January 24, 2020, for all 
other subjects, will be repeated using the Principal PPS after the third interim analysis.   
Descriptive statistics summarizing the total HO by study visit, change in HO volume by study 
visit, and change in HO volume from baseline by study visit will be provided. Tables 
summarizing annualized new HO will also be produced. Summaries will also be provided by 
body region. Summaries of new HO coincident with flare-ups and not coincident with flare-ups 
will also be generated. Summaries of annualized mean New HO, conditional on new HO 
volume>0 mm3, will be created. HO listings will also be generated. 
Missingness, including frequency of WBCT not collected and regions that are not evaluable, will 
be summarized. Frequency of negative new HO, i.e., apparent reductions in HO overall and by 
body region (defined below), will also be summarized. 


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Handling of Reductions in HO 
Please note that, as referenced above, the Bayesian compound Poisson models with and without 
square-root transformation assume non-negative changes in HO volume for each subject for each 
region, and any apparent reductions in HO volume over time (i.e., negative new HO volumes) 
are “zeroed out”, i.e., replaced with zero. (All analyses of square-root transformed new HO 
volumes require non-negative new HO volume in order for the square-root transformation to be 
applied.) In contrast, because wLME is a regression method, it is less specialized and can 
accommodate the negative values when applied to non‑transformed data.   
However, in order to understand the relative contributions to the results of 1) zeroing out the 
negative changes; 2) square-root transformation of the zeroed out new HO volumes; 3) using a 
body-region or overall whole body based analysis; 4) using data on intervals between WBCTs, 
not just the first and last timepoint; 5) Bayesian compound Poisson analysis; we will run five 
wLME “series”: 
1. Raw, untransformed data (i.e., including all negative values) 
2. Zero out overall whole-body new HO without square-root transformation 
3. Zero out overall whole-body new HO with square-root transformation 
4. Zero out by region [by visit] without square-root transformation 
5. Zero out by region [by visit] with square-root transformation 
For series 2 and 3, the sum of new HO at the last timepoint, i.e., changes from baseline including 
negatives, is added across body regions. If negative, the sum is replaced with zero. For series 3, 
the sum is square-root transformed. Then the sum – or square-root of the sum – is divided by 
time in years, resulting in the annualized new HO. 
For series 4 and 5, negative changes in HO volume by region (from previous visit) are replaced 
with 0. For series 5, the square-root of each change is taken. These numbers are then added 
across timepoints and body regions and their sums are divided by time in years, resulting in 
annualized new HO. This method for constructing annualized new HO, with and without 
square-root transformation, yields wLME analyses that are the closest analogs to the Bayesian 
compound Poisson analyses. 
Note that in applying the square-root transformation to zeroed out new HO for intervals, wLME 
using series 5 should be subject to the same bias as is attributed to the Bayesian compound 
Poisson primary analysis illustrated later in this section. 
Control of Type I Error 
Ninety-nine palovarotene-naïve subjects with the R206H ACVR1 mutation were enrolled into 
the current trial and are to be followed for 2 years. There were to be three early interim efficacy 
analyses and one final analysis. Futility was declared at the second interim analysis, but the study 
continued. The final analysis for Part A will occur when all subjects have completed 2-year 
follow-up.  (Note that, as described, due to the prolonged palovarotene interruption prior to the 
completion of Part A, IA3 is designated the final analysis.) 


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The first interim analysis was to take place when approximately 35 MOVE subjects complete 
1 year of follow-up with the second and third interim analyses occurring when all subjects in the 
Principal EP have the opportunity to have complete (i.e., have WBCT data) 12 months and then 
18 months of follow-up, respectively. It was assumed that the full NHS dataset will be available 
at the first interim analysis. 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 enroll in the MOVE study per 
month, the percentage of subject follow-up for each analysis is summarized in Table 7 where 
values with an asterisk indicate approximate information based on expected accrual rates and 
total planned accrual in the Principal EP.  
Table 7. 
Observed MOVE Follow-up at Each Planned Analysis  
Analysis 
Observed MOVE follow-up 
Percentage of follow-up available 
Interim #1 
35 subjects with 12 months 
*45 subjects with 6 months 
66% 
Interim #2 
*80 enrolled subjects with 12 months 
*35 subjects with 18 months 
80% 
Interim #3 
*80 enrolled subjects with 18 months 
*35 subjects with 24 months 
92% 
Final 
80 enrolled subjects with 24 months  
100% 
 
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, in the scenario above.   
The one-sided significance thresholds for the Lan-DeMets alpha spending function with an 
O’Brien-Fleming boundary will be recalculated at the time of each interim analysis based on the 
estimate of the information fraction. The estimate of the information fraction is a fraction in 
which the numerator is the sum of the time between the baseline WBCT assessments and the last 
timepoint for each subject for NHS and MOVE assessments; the denominator is the sum of the 
time between the baseline WBCT assessments and the expected last timepoint (at the time of the 
final analysis) for each subject for NHS and MOVE assessments.  
At the final analysis, the information fractions at the previously conducted interim analyses will 
be re-calculated using the observed information, i.e., the sum of the time between the baseline 
WBCT assessments and the last timepoint for each subject for NHS and MOVE assessments. 
The critical p-value for the final analysis will be set such that the remaining alpha is spent. The 
information fraction at the final analysis will be set to 100%. 
Study success was to be declared if the posterior probability that palovarotene reduces the 
change in new HO volume is greater than 1 minus the one-sided significance threshold. For 


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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 in the scenario 
above. Because the futility boundary was crossed at the second interim analysis, i.e., the 
posterior probability that 𝛾< 0.7 (at least a 30% reduction in annualized new HO volume on the 
square-root scale) was less than 5%, all subsequent analyses of efficacy data will be supplied 
without applying thresholds for success or futility, as these thresholds are no longer relevant. 
Sensitivity Analyses 
The following sensitivity analyses will be conducted after the third interim analysis to examine 
the robustness of the Bayesian compound Poisson analysis without the square-root 
transformation, unless otherwise specified. All assessments on or before December 4, 2019, for 
subjects <14 years old on the date of their assessment and assessments on or before January 24, 
2020, for all other subjects, will be used. Note that, given the consistency of results between the 
Bayesian compound Poisson and wLME analyses observed at the second and third interim 
analyses, the sensitivity analyses below will utilize both methodologies, as described. The results 
may be summarized jointly in forest plots, as appropriate. 
To assess impact of differences between NHS and MOVE:   
• Adjustment for additional baseline covariates: This sensitivity analysis will extend the 
primary efficacy analysis to include additional baseline covariates. These will include 
baseline HO volume divided by age, age, sex, months since last flare-up, and CAJIS. The 
palovarotene treatment effect will be estimated using the Bayesian compound Poisson 
distribution with all covariates included. A similar wLME will also be performed. 
• Propensity score analysis: The propensity score, defined as the conditional probability of 
being treated given the baseline covariates, can be used to balance the baseline covariates 
across treatment groups.3 Therefore, it can reduce potential bias due to imbalances in the 
distributions of demographic and disease characteristics between the NHS and MOVE 
Trial. The propensity scores will be derived from a logistic regression model with the 
following covariates: baseline HO volume divided by age, age, sex, months since last 
flare-up, and CAJIS. Each subject’s propensity score will be estimated from the logistic 
regression model, and subjects will be grouped by quartiles of their propensity scores. 
Propensity score quartile will be used as the only covariate in the Bayesian compound 
Poisson analysis. wLME will be conducted for each quartile and overall using the 5-level 
factor as a covariate (in addition to treatment). 
• Restriction to subjects contributing follow-up for both the NHS and MOVE Trial: This 
analysis will use the wLME analysis method on the subset of the MOVE subjects who 
transitioned from the NHS and have annualized rates of new HO for both studies. 
Baseline HO volume divided by age will be the only covariate included in the model, in 
addition to the factor identifying the study of origin. 
• As requested by regulatory agencies, a matched pairs analysis – including subjects who 
participated in either MOVE or NHS but not both studies – was performed. Caliper-
matching used propensity scores described in this SAP. The analysis used a paired t-test. 


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To assess impact of differences in length of follow-up between NHS and MOVE: 
• Analysis restricting subjects to specific durations of follow-up: The WBCT dataset will 
be restricted to observations associated up to 1-year – interpreted as assessments within 
the first 15 months of study participation (i.e., midway between Month 12 and Month 18 
for MOVE) – and, separately, with up to 2-years of follow-up – interpreted as 
assessments within the first 27 months of study participation. The analysis method will be 
wLME. 
To assess impact of missing data in MOVE: 
• Missing data sensitivity analysis using a tipping point approach: Subjects who 
discontinue the MOVE study will have volume of new HO imputed using the 
wLME-modeled treatment effect. The multiple imputations will be scaled to induce 0%, 
25%, 50%, 75%, and 100% reductions in the palovarotene treatment effect. The 0% 
corresponds to subjects who discontinue the MOVE Trial having the same distribution 
for number of body regions with new HO and change in HO volume per region as the 
MOVE subjects who did not discontinue; and 100% corresponds to subjects who 
discontinued the MOVE Trial having the same distributions as the NHS subjects. Missing 
data will be imputed for the visits in MOVE that were either missed or would have been 
missed due to study discontinuation prior to December 4, 2019 / January 24, 2020. 
Analyses in which subjects who discontinue the NHS have volume of new HO imputed 
may also be considered, while noting that the majority of subjects who discontinued NHS 
did so to enroll in an interventional study, e.g., MOVE or less frequently, Study PVO-
1A-201.   
To assess robustness of efficacy signal against choice of wLME as post-hoc analysis: 
• Analysis using generalized estimating equations (GEE): A GEE model will be fit to the 
annualized change in new HO and the empirical variance estimator will be used for 
inference. Weights will be used to account for the different lengths of observed subject 
follow-up. Baseline HO volume divided by age will be included in the model as a 
covariate and a compound-symmetric working correlation matrix will be used. The GEE 
model takes a different approach to account for within-subject correlation compared to 
the primary analysis. 
To assess consistency of efficacy signal across subgroups: 
• Subgroup analyses: The subgroup analyses will also be performed for all efficacy 
endpoints to examine the consistency of the estimated treatment effect by sex (Male, 
Female), Asian ancestry (Yes, No), and age (≥12, ≥14, ≥18, ≥12 – <17 years) and age by 
sex (<8 years for Females or <10 years for Males; ≥8 years for Females or ≥10 years for 
Males; ≥8 – <14 for Females or ≥10 – <14 years for Males).   
The inferential analysis method used in the subgroup analyses will be Bayesian 
compound Poisson analysis and wLME for new HO volume by age and age by sex, and 
for wLME for all other endpoints and factors, with the exception of the above 


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contingency table analysis of proportions of subjects with new HO and flare-ups; this 
analysis will employ Fisher’s exact test. 
To assess impact of the difference in WBCT visit schedules between MOVE and NHS:  
• The impact of the difference in WBCT visit schedules between MOVE and NHS is 
assessed by analyzing the data as if the WBCT assessments in MOVE were conducted 
annually rather than biannually. This is intended to investigate whether the differences in 
visit schedules introduced bias, with and without use of the square-root transformation. 
Estimates of 𝛾, 𝜃ଵ,ଵ, 𝜃ଶ,ଵ will be compared between Bayesian compound Poisson analyses, 
with and without square-root transformation, with the observed biannual MOVE WBCT 
and with the dataset collapsed to simulate annual MOVE WBCT assessments.  
It must be noted, however, that this analysis does not eliminate the effect of the more 
frequent assessments in MOVE; as described in the MOVE and NHS Independent 
Review Charter, radiologists only measured the amount of HO if they first determined 
there was new HO relative to the previous timepoint. If there was no new HO, the volume 
from the previous assessment was carried forward. Because the read process for the 
12-month timepoint used the 6-month assessment and the read process for the 24-month 
assessment used the 18-month assessment, this analysis can investigate only the bias 
introduced by the differences in visit schedules into the analysis, not the differences in 
visit schedules per se. 
In any case, the sponsor believes that the differences in visit schedules could result in 
biases of the event rate treatment effect 𝜃ଵ,ଵ against palovarotene and growth rate 
treatment effect 𝜃ଶ,ଵ in favor of palovarotene but that, in the absence of the square-root 
transformation, these biases are offset, yielding an unbiased estimate of 𝛾= 𝜃ଵ,ଵ∗𝜃ଶ,ଵ.  
With the square-root transformation, however, the bias against palovarotene in the event 
rate treatment effect 𝜃ଵ,ଵ is unchanged, while the bias on growth rate treatment effect 
𝜃ଶ,ଵin favor of palovarotene is reduced, yielding a bias in 𝛾 against palovarotene. 
Consider identical growth events in NHS and MOVE of 8000 mm3 that is split across two 
six-month intervals in the MOVE study as 4000 mm3 in the first 6-month interval and 
4000 mm3 in the next 6-month interval. This registers as two events in one year on 
MOVE, but just one event in NHS. Similarly, the growth rate, conditional on there being 
an event, is 2X higher in NHS than MOVE, i.e., 8000/4000=2, in the absence of a 
square-root transformation. With a square-root transformation, however, the growth rate 
per event is only 1.4X higher in NHS than MOVE, i.e., √8000/√4000 ~ 1.41.   
A similar comparison of analyses will be performed with wLME, where negative values 
are zeroed out by region and then square-root transformed, because the bias illustrated 
above from the square-root transformation should also affect this annualized HO 
endpoint, which is constructed using new HO observed at each visit. 


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Analyses of Secondary Efficacy Endpoints 
Proportion of Subjects with Any New HO (Key Secondary Endpoint) and Number of Body 
Regions with New HO 
The proportion of subjects with any net new HO (at Month 12) – and number of body regions 
with any net new HO (at Month 12) – will be compared between the MOVE and NHS groups 
using the Bayesian compound Poisson model used in the primary efficacy analysis. (New HO is 
deemed to be present in a body region qualitatively if the volume of net new HO is greater than 
zero, i.e., the change in volume of HO in a region between two timepoints is positive when new 
HO is identified qualititatively) Gibbs sampling from the posterior distribution will be generated 
to compute the posterior distribution of 𝜃ଵ,ଵ, the multiplicative effect of palovarotene treatment 
on the rate of body regions with new HO. Because, within the compound Poisson model, 𝜃ଵ,ଵ<1 
implies both a lower proportion of subjects with any new HO and a smaller number of body 
regions with new HO for palovarotene-treated subjects, the inference is identical for these two 
secondary endpoints. The probability of this ratio being less than 1 must be greater than 0.975 to 
declare statistical significance.     
Inference on 𝜃ଵ,ଵ from the sensitivity analysis analyzing the data as if the WBCT assessments in 
MOVE were conducted annually rather than biannually will also be relevant, given the concerns 
about bias in estimating 𝜃ଵ,ଵ even in the absence of square root transformation will be 
summarized. 
Tables will be provided summarizing the number and percentage of subjects with any net new 
HO by study visit and overall. In these tables, Month 12 incidence will be compared using an 
exact test for the difference in proportions. 
Tables will also be provided summarizing the number of body regions with new HO by study 
visit and overall. The body regions with new HO will also be summarized by study visit and 
overall. In these tables, Month 12 counts will be compared using a negative binomial regression. 
Flare-up Rate Per Subject-Month Exposure 
The flare-up rate per subject-month exposure will be compared using a negative binomial 
regression on the number of flare-ups. An offset variable equal to the log of the number of years 
of follow-up will be included to convert the estimate to annualized rate. 
In the NHS study, events were considered flare-ups when two or more flare-up signs were 
reported. This is different from the MOVE study, which defines a flare-up as an event with one 
or more flare-up sign. The analysis of the proportion of subjects reporting flare-ups will restrict 
the MOVE flare-ups to those events that match the NHS study definition. 
Descriptive tables will be provided summarizing the number of flare-ups and the rate of flare-ups 
by study visit, by age group and overall. 
Proportion of Subjects Reporting Flare-ups 


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The proportion of subjects reporting flare-ups will be compared between untreated and treated 
subjects using an exact test for the difference in proportions. 
As with flare-up rate analysis, this analysis will be performed restricting the MOVE flare-ups to 
those events that match the NHS study definition. 
Descriptive tables will be provided summarizing the number and percentage of subjects with any 
flare-up by study visit, by age group, and overall. 
Analyses of Exploratory Endpoints 
The exploratory efficacy endpoints, including change from baseline in CAJIS Total score, CAJIS 
Upper Extremities subscore and CAJIS Mobility subscore; FOP-PFQ total score; and PROMIS 
Global Physical Health and Global Mental Health T-scores; will be summarized by visit using 
descriptive statistics for the Principal FAS and presented for the Supplementary FAS in listings.  
Additional exploratory endpoints of incidence and volume of “catastrophic HO” will also be 
described and compared between MOVE and NHS for the Principal FAS. It has been observed – 
after unblinding at the second interim analysis – that a minority of subjects develop large 
amounts of HO in a year; the incidence of subjects with at least 50,000 mm3 and 30,000 mm3 of 
new HO across all body regions in each year of study will be summarized.  
 
2.4.5 Analysis of Safety Endpoints 
Safety analyses will be provided by chronic, flare-up dosing and overall, unless otherwise 
specified.   
General Rules 
All safety analyses will be performed on the safety populations defined in Section 2.3, unless 
otherwise specified, using the following rules: 
• The baseline value when summarizing overall visits is defined as the last available value 
prior to the first chronic dose of study drug. 
• The baseline value when summarizing over flare-up visits only is defined as the last 
available value prior to or on the date of first dose of flare-up treatment within the 
particular cycle. For the NHS study, the baseline value when summarizing over flare-up 
visits is defined as the value on the Day 1 visit of the corresponding flare-up. 
• The potentially clinically significant  (PCS) values for pre specified lab, vital sign and 
ECG variables  are  values according to predefined criteria/thresholds (see Appendix 6.2). 
• For AEs, the following conventions for partial or completely missing date imputations 
will be implemented: 


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o If the start date is completely missing, the start date is imputed as the date of first 
dose and the AE is considered treatment emergent and assigned to the chronic dosing 
period. 
o If the day and month of the start date are missing and the start year is the same as the 
year of first dose, the start date is imputed as the date of first dose and the AE is 
considered treatment emergent and assigned to the chronic dosing period. If the start 
year is prior to the year of first dose, the start date is imputed as January 1 of the year 
and the AE is not considered treatment emergent. 
o If the day of the start date is missing and the start month and year is within a period of 
time within a flare-up treatment, the start date is imputed as the date of the flare-up 
treatment in the same month as the AE, and the AE is considered treatment emergent 
and assigned to the flare-up dosing period. Otherwise, if the day of the start date is 
missing and the start month and year is on or after the date of first dose, the start date 
is imputed as the date of first dose or the first day of the month of the AE, whichever 
is later, and the AE is considered treatment emergent and assigned to the chronic 
dosing period. Otherwise, if the start month and year is before the month and year of 
first dose, then the start date is imputed as the first day of the month of the AE, and 
the AE is not treatment emergent.  
o Partial AE end dates will be imputed as the last day of the month or year for missing 
end dates. Completely missing end dates will be imputed as the date of last known 
treatment exposure for the subject. 
• For concomitant medications, the following conventions for partial or completely missing 
date imputations will be implemented: 
o If the start date and end date are completely missing, then the start date is imputed as 
the date of informed consent, the end date is the date of last assessment for the 
subject, and the concomitant medication would be considered both prior and 
concomitant and assigned to both the chronic dosing period and flare-up period (if 
applicable to the subject). 
o Partial start dates are imputed as the first day of the month (if only missing the day) 
or January 1 (if missing day and month), and partial end dates are imputed as the last 
day of the month (if missing the day only), or December 31 (if missing the day and 
month). Prior Medications would then be defined as any medications that started prior 
to the date of first dose. Concomitant medications for chronic dosing would be 
defined as medications taken at any point in time during the chronic treatment period. 
Concomitant medications for flare-up dosing would be defined as medications taken 
at any point in time during any flare up cycle, per imputed or non-imputed dates. 
o Lab data identified as having a “Flare X” visit name will be assigned to a flare-up 
cycle based on the date of the lab data and the visit date window as in the following 
algorithm: 


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 If an observation has a designation of “Flare X” for the visit, then the date of the 
observation will be compared to the dates of dosing for flare-up cycles and weeks. 
 If the observation falls within 14 days of a known flare-up dose cycle and week 
date, then it is assigned to that particular flare-up cycle and week.  
Summaries of WBCT, C-SSRS (suicide ideation/behavoir), laboratory data, vital signs, 
linear/knee height, weight/BMI , electrocardiograms, and prior/concomitant medications will 
include the NHS data, where applicable. 
Analyses of Adverse Events 
The primary focus of AE summaries will be on TEAEs in the treatment period. Pre-treatment 
and post-treatment AEs will be described separately. 
Adverse event incidence tables by SOC and PT will be sorted by decreasing frequency incidence 
of SOC and by decreasing incidence of PT within SOC. The number (n) and percentage (%) of 
subjects experiencing an AE will be presented by treatment (chronic dosing, flare-up dosing and 
total palovarotene [overall]) . Multiple occurrences of the same event in the same subject will be 
counted only once. The denominator for computation of percentages is the safety population for 
the chronic dosing and overall group and the number of subjects in the safety population with 
flare-up dosing for the flare-up dosing group.  TEAEs by Pediatric Subjects (<18 years) and 
Adult Subjects (>=18 years) are summarized 
The following TEAE summaries will be generated for the safety populations: 
Analysis of Treatment-Emergent Adverse Events 
• Overview of TEAEs, summarizing number (%) of subjects with 
o TEAEs 
o TEAEs possibly related to treatment 
o TEAEs by maximal severity 
o Treatment-emergent SAEs 
o Treatment-emergent SAEs possibly related to treatment 
o TEAEs leading to dose modification or interruption of study drug 
o TEAEs leading to permanent study drug and study discontinuation  
o TEAEs leading to death 
• All TEAEs by primary SOC and PT, showing number (%) of subjects with at least one 
TEAE  
• All TEAEs with incidence ≥ 5% in the overall group by primary SOC and PT. 
• All TEAEs by maximal severity, presented by primary SOC and PT, showing number 
(%) of subjects with at least one TEAE by severity (i.e., mild, moderate or severe) 
• All TEAEs by relationship, presented by primary SOC and PT, showing number (%) of 
subjects with at least one TEAE by relationship (i.e., not related, at least possibly related) 


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• All TEAEs leading to Dose Modification of Study Drug 
• All TEAEs leading to Dose Interruption 
• All TEAEs leading to Permanent Discontinuation of Study Drug 
• All TEAEs leading to Study Discontinuation 
Analyses of Pre-Treatment AEs 
• All pre-treatment AEs by primary SOC and PT, showing number (%) of subjects with at 
least one pre-treatment AE  
Analyses of Post-Treatment AEs 
• All post-treatment AEs by primary SOC and PT, showing number (%) of subjects with at 
least one post-treatment AE 
o Post-treatment SAEs 
o Post-treatment SAEs possibly related to treatment 
o Post-treatment AEs by maximal severity 
o Post-treatment AEs leading to permanent study drug and study discontinuation  
o Post-treatment AEs leading to death 
Listing will be provided for all pre-treatment AEs, all TEAEs, all SAEs, all TEAEs leading to 
dose modification or interruption of study drug, all TEAEs leading to permanent study drug 
discontinuation, all deaths, and all post-treatment AE categories noted above. 
Analyses of Laboratory Variables 
The summary statistics of all laboratory variables, including raw values and changes from 
baseline, will be calculated for each visit. Central lab values will be summarized; if local labs 
exist but no central labs are available, then local labs will be summarized. Summary tables will 
be provided for all treatment visits, both chronic and flare-up visits. For these tables, the baseline 
value for the MOVE trial is the last available value prior to or on the date of first dose of chronic 
treatment. For the NHS study, the baseline value is the value taken at the Day 1 visit. 
Summary tables will also be provided for flare-up treatment visits only using date of flare-up 
dosing to derive change from baseline. For flare-up treatment, subjects may contribute more than 
one observation for summaries due to multiple cycles of flare-up treatment. Each cycle of 
flare-up treatment will be summarized separately. For these tables, the baseline value for the 
MOVE trial is the last available value prior to or on the date of first dose of flare-up treatment 
within the cycle. For the NHS study, the baseline value is taken at Day 1 of each individual 
flare-up. In addition, for all laboratory parameters, the mean and mean change from baseline at 
all chronic visits and all flare-up cycle safety visits will be plotted separately. 
The incidence of potentially clinically significant (PCSs) at any time (see Appendix 6.2 for the 
criteria defining potentially clinically significant (PCS) for clinical laboratory parameters) during 


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the treatment period will be summarized. One summary table will be presented for all chronic 
visits (non-flare-up visits in the NHS) and for flare-up treatment visits. For derivation purposes 
for chronic visits, the baseline value for the MOVE trial is the last available value prior to or on 
the date of first dose of chronic treatment. For the NHS study, the baseline value is the value 
taken on the Day 1 visit. For flare-up summaries, the baseline value for the MOVE trial is the 
last available value prior to or on the date of first dose of flare-up treatment with the cycle. For 
the NHS study, the baseline value is the value taken on the Day 1 visit of the corresponding 
cycle. 
A focus will be on new-onset PCS values, i.e., subjects with pre-existing PCS values at baseline 
will not be considered to have new onset values after start of study drug. Pre-treatment was 
defined as the last value prior to initiation of chronic treatment.For flare-up treatment, PCS will 
be summarized at the subject-level and the flare-up level. Flare-up analyses may include subjects 
multiple times as a subject may have more than one flare-up treatment cycle within the study, 
whereas the subject-level analyses will include each subject once, summarizing at least one post-
baseline PCS abnormality across all flare-up cycles. 
All PCS values will be presented in a subject-based separate listing as well including baseline 
values, PCS values and follow-up values. 
Pregnancy test results for females of child-bearing potential were provided as subject listings. 
Analyses of ECG Variables 
The summary statistics of all ECG variables (ECG values and changes from baseline) will be 
calculated for each visit. Mean heart rate, RR, PR, QRS, QT, QTcF, and QTcB will be 
determined using centralized readings. 
Absolute QTc interval prolongation QTcF, and QTcB will be summarized at baseline and post-
baseline, using counts of subjects and the following criteria: 
• QTc interval >450 msec 
• QTc interval >480 msec 
• QTc interval >500 msec 
• QTc interval increases from baseline >30 msec 
• QTc interval increases from baseline >60 msec 
The incidence of ECG abnormalities at any time (see Section 0 for the abnormality list) during 
the treatment period will be summarized by visit and category (rhythm, conduction, 
morphology/chamber enlargement, axis deviation, myocardial infarction, ST 
Segment/T waves/U waves). 
New onset ECG PCS values will be summarized for chronic treatment visits. Subjects with 
pre-existing ECG PCS values at baseline will not be considered to have new onset values after 
start of study drug. PCS will be summarized at the subject-level. For flare-up treatment, PCS will 
be summarized at the subject-level. The PCS list is provided in Appendix 6.2. 


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All PCS values will be presented in a subject-based separate listing as well including baseline 
values, PCS values and follow-up values.  
All ECG abnormalities (rhythm, conduction, morphology/chamber enlargement, axis deviation, 
myocardial infarction, ST Segment/T waves/U waves), with specific abnormality will be 
provided in a by subject listing. 
Analyses of Vital Sign Variables 
The summary statistics of all vital sign variables (vital signs values and changes from baseline) 
will be calculated for each visit. Summary tables will be provided for all treatment visits, both 
chronic and flare-up visits. For these tables, the baseline value for the MOVE trial is the last 
available value prior to or on the date of first dose of chronic treatment. For the NHS study, the 
baseline value is the value taken at the Day 1 visit. Summary tables will also be provided for 
flare-up treatment visits only using date of flare-up dosing to derive change from baseline. For 
flare-up treatment, subjects may contribute more than one observation for summaries due to 
multiple cycles of flare-up treatment. Each cycle of flare-up treatment will be summarized 
separately. For these tables, the baseline value for the MOVE trial is the last available value prior 
to or on the date of first dose of flare-up treatment within the cycle. For the NHS study, the 
baseline value is taken at Day 1 of each individual flare-up. 
The incidence of PCSs at any time (see Appendix 6.2 for the PCS list) during the treatment 
period will be summarized in the same manner as lab PCS tables.   
All PCS values will be presented in a separate listing as well.  
Analyses of C-SSRS Variables 
The palovarotene treated and NHS untreated subjects who report any type of suicidal ideations in 
the Columbia-Suicide Severity Rating Scale (C-SSRS) or any suicidal behavior during the study 
will be presented in listings. 
A tabular summary of subjects with any type of suicidal ideation or behavior will be presented.  
A listing will summarize any subject with Type 4 or 5 suicidal ideation or any suicidal behavior. 
Analysis of Hearing Assessments 
Hearing was assessed via age-specific pure tone audiogram monitoring via baseline and follow-
up age-specific hearing evaluation tests. A listing will summarize by-subject results. 
Pregnancy and Teratogenicity Assessment 
Pregnancy and pregnancy outcomes were monitored throughout the study. A listing will 
summarize by-subject results. 
 


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Bone Safety Assessments 
Two events led to a prolonged treatment interruption period. The first interruption occurred 
following a partial clinical hold issued by the US Food and Drug Administration (FDA) on the 4 
December 2019 for subjects under 14 years of age in palovarotene clinical studies due to the 
identification of the risk of PPC. The second interruption occurred following the outcome of the 
PVO-1A-301 second interim analysis that crossed the threshold for futility, which resulted in the 
per-protocol treatment discontinuation of subjects ≥14 years of age on 24 January 2020.  
 
Bone safety data will be described for following time periods:  
 
The Original Baseline Period 
The original baseline period will be defined by the original baseline through February 2020.  
 
The Interruption (Off-treatment) Period 
The baseline for the off-treatment period is the earlier of the first assessment while off-treatment 
or the assessment within 1 month prior to the last dose of palovarotene. Bone growth 
assessments during the interruption period included subjects in the off-treatment population, 
which was defined as subjects <18 years of age at first study entry who interrupted palovarotene 
after the clinical hold date and did not re-initiate treatment and who had an off-treatment baseline 
and post-off-treatment baseline visit.  
  
The end of the interruption period occurred either at the end-of-treatment/end of study visit if the 
subject discontinued from the study, at the end-of-study visit if they completed the study, at the 
new baseline if the subject re-initiated palovarotene treatment.  
 
The New Baseline Period 
A new baseline was established by the re‑initiation of palovarotene dosing following the 
interruption period. New baseline bone growth assessments includes all subjects who had a new 
baseline and a post-new baseline visit and received at least one dose of palovarotene after the 
new baseline visit date. The new baseline visit date was defined as the date of the last visit prior 
to the re‑initiation of palovarotene treatment following the interruption period.  
 
Note that bone safety analysis will also be performed based on premature physeal closure status. 
 
Analyses of Knee and Hand/Wrist Radiographs and WBCTs for Assessment of Bilateral 
Hand/Wrist and Knee Epiphyseal Growth Plate 
The summary statistics of bone age and the difference between bone age and chronological age 
(ratio of change from baseline in bone age to change from baseline in chronological age) will be 
calculated for each visit.   


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Figures will include a by-subject spaghetti plot of the bone age by chronological age, and a 
summary figure by sex and age group (4-10, 11-18) with femur length and tibia length on the 
y-axis and visit on the x-axis. Similar figures will be produced using chronological age in place 
of bone age. 
Summary tables of growth plate abnormalities identified in radiographs (MOVE Trial only) will 
include the following: 
• Number and proportion of subjects with any abnormality at baseline, and by specific 
abnormality (e.g., growth recovery lines, sclerosis, etc.) 
• Number and proportion of subjects with any new post-baseline or prior time point 
abnormality, and by specific abnormality 
• Number and proportion of subjects with any new post-baseline or prior time point 
worsening, and by specific abnormality 
• Number and proportion of subjects with improvement from baseline or prior time point 
abnormality, and by specific abnormality   
Summary tables of growth plate abnormalities identified in WBCT safety reads (MOVE Trial 
and NHS) will include the following:   
• Number and proportion of subjects with any abnormality at baseline, and by specific 
abnormality (e.g., growth recovery lines, sclerosis, etc.) 
• Number and proportion of subjects with any new post-baseline or prior time point 
abnormality, and by specific abnormality 
• Number and proportion of subjects with any new post-baseline or prior time point 
worsening, and by specific abnormality 
• Number and proportion of subjects with improvement in baseline or prior time point 
abnormality, and by specific abnormality 
Listings of all subjects with premature growth plate closure will be provided. 
Bone Age 
Bone age is  assessed by hand/wrist radiographs..  To normalize change in bone age over time, the 
ratio of change from baseline in bone age to change from baseline in chronological age will be 
calculated such that a ratio of 1 indicates the same progression over time, while a ratio >1 indicates 
faster progression of bone age relative to chronological age Descriptive statististics will be 
analyzed by timepoint.  
Bone age will also be assessed by age category and premature physeal closure (PPC) status. 
Analyses of Knee Alignment 


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Summary statistics of lateral distal femoral angles will be calculated for each visit and new-onset 
potentially clinically significant knee lateral distal femoral angles (i.e. angles outside of the 
physiological range defined as 78.9 to 84.9 degrees). Listings will also be generated for subjects 
meeting PCS criteria overall and by PPC status.  
Analyses of Standardized Stadiometry and Knee Height for Assessments of Linear Growth 
The summary statistics of linear height for age z-score and knee height (values and changes from 
baseline) will be calculated for each visit. Figures will include height z-scores over time and 
knee height over time. In addition, summary statistics of weight for age z-score and BMI (kg/m2) 
for age z-score (values and changes from baseline) will be calculated for each visit and plotted 
against age. 
The z-scores will be calculated by using US Centers for Disease Control and Prevention (CDC) 
growth charts, using the SAS macro from http://www.who.int/childgrowth/software/en/. (Note 
that the derivation of the z-scores depends on sex and age in months.) 
Growth velocity will also be summarized in tables and figures. The calculation of growth 
velocity will be performed as follows: ((Current Height – Previous Height)/(duration 
(days)=(current date – previous date))) * 365.25 = Annualized Growth Velocity (cm/year). In 
addition to providing the calculated growth velocities per time period for each subject, the data 
will also be categorized according to worst growth velocity and last growth velocity by the 
following three categories: <4 cm/year; 4 to 5 cm/year; and >5 cm/year. 
Growth assessments (linear height, knee height, and femur and tibia lengths and growth velocity 
over 12 months) will also be assessed by age category, treatment status  and  premature physeal 
closure (PPC) status. 
Analyses of WBCT Measurements of Femur and Tibia Lengths The summary statistics of femur 
and tibia lengths (values and changes from baseline) will be calculated for each visit. Femur and 
tibia lengths will be summarized for the following subgroups: 
• Male, Age 4-10 years 
• Male, Age 11-18 years 
• Female, Age 4-10 years 
• Female, Age 11-18 years 
• Female Age ≤8, Male Age ≤10 years 
• Female Age >8 to <14, Male Age >10 to <14 years 
• Age ≥14 years 
Figures will include spaghetti plots of the femur and tibia change from baseline by chronological 
age. 
Leg Length Discrepancies 
Leg length discrepancies will  be calculated by the difference in right and left femur and tibia 
lengths as measured by low-dose WBCT. Potential clinically meaningful leg length differences 


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(ie, >1.5 cm difference) were  compared with untreated NHS subjects by age category and  PPC 
status. 
 
 
 
Analyses of Evaluation of Bilateral Hips by WBCT Safety Read 
Summary tables of hip abnormalities identified in WBCT safety reads (MOVE Trial and NHS) 
will include the following: 
• Number and proportion of subjects with possible, probable, or definite avascular necrosis 
(AVN) at baseline, and by specific abnormality (e.g., subchondral lucency, 
osteosclerosis, etc.) 
• Number and proportion of subjects with any new post-baseline or prior time point AVN, 
and by specific abnormality 
• Number and proportion of subjects with any new post-baseline or prior time point 
worsening in AVN, and by specific abnormality 
• Number and proportion of subjects with improvement in baseline or prior time point 
AVN, and by specific abnormality 
Assessments for Spinal Health 
WBCT scan assessments described above, will also be used to analyze spinal bone mineral 
density, bone strength, bone mineral content  and fractures, utilizing biomechanical computed 
tomography (BCT) analysis. These results will be compared to NHS subjects (Study PVO-1A-
001). To assess potential effect of palovarotene on these parameters modeling will be performed 
at month 12 with comparison to NHS subjects. Additionally descriptive statistics will be 
provided for each timepoint. 
 
 
2.4.6 Analyses of Imaging Performance and Quality Metrics 
Intra-Reader Agreement 
For low-dose WBCT efficacy reviews, secondary reads will be summarized for the count and 
frequency of discrepancies for the post-baseline timepoints. Coefficients of variation, i.e., ratios 
of the standard deviation to the mean will also be computed by region and overall, for volumes 
of HO and for volumes of new HO, i.e., differences between timepoints. 


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For radiograph review and low-dose WBCT safety review, counts and frequencies for 
differences will be summarized. 
Inter-Reader Agreement 
Summary identical to those described above for intra-reader agreement will be performed to 
describe inter-reader agreement. 
Summaries of differences for the primary reads, e.g., adjudication rates, will also be summarized. 
2.4.7 Analyses of Pharmacokinetic Endpoints 
Pharmacokinetic analyses will be conducted using the Principal PS and the Supplementary PS. 
Pharmacokinetic Sample Concentrations 
Blood samples for PK assessment of palovarotene will be collected 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. During flare-up dosing, blood samples for PK assessment of palovarotene will be collected 
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, PK blood samples can be obtained during any 
subsequent flare-up dosing. Pharmacokinetic blood samples will be collected at pre-dose and 3, 
6, 10, and 24 hours post dose. 
The determination of palovarotene plasma concentrations will be performed using a validated 
LC-MS/MS method. The time of sample collection as it relates to the time of dosing on the PK 
days will be recorded. 
Plasma concentrations of palovarotene will be listed by subject, treatment group (chronic 
treatment (5 mg or weight equivalent dose) or flare-up-based treatment (10 mg and 20 mg or 
weight equivalent dose)), and scheduled time. Concentrations will be summarized with 
descriptive statistics (N, number of participants with non-missing data (n), mean, SD, coefficient 
of variation [CV], median, minimum, and maximum) by treatment group and scheduled time 
using the Principal PS and Supplementary PS populations. Coefficient of variation will only be 
displayed if n ≥ 3. Unscheduled timepoints will only be listed and not summarized. Plasma 
concentrations below the limit of quantification (BQL) will be set to 0. Data will be rounded for 
reporting purposes only, with data presented to three significant figures except for CV% which 
will be presented to 1 decimal place.  
Figures of individual plasma concentration versus actual time profiles for palovarotene will be 
produced by treatment group and dose on both linear and semi-log scales for the Principal PS 
and Supplementary PS populations. Mean plasma concentration versus nominal time curves will 
be plotted by treatment group and dose on both linear and semi-log scales for the Principal PS 
and Supplementary PS populations.  


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Pharmacokinetic Parameters 
Plasma concentrations versus time data will be analyzed using a standard non-compartmental 
model using Phoenix WinNonlin® (version 8.0 or later) or SAS applications. Actual collection 
time will be used in the calculation of plasma PK parameters.  
The following steps describe how observed concentrations will be used to compute AUC if some 
PK concentrations are unavailable: 
• If PK concentration are missing at 0 and 24 hours, then the AUC and all PK parameters 
cannot be calculated. 
• If the 0-hour concentration is missing, the 24-hour concentration will be used to impute 
the missing 0-hour concentration. 
• If the 24-hour concentration is missing, the 0-hour concentration will be used to impute 
the missing 24-hour concentration. 
• Invalid 24-hour concentrations will be replaced with the 0-hour concentrations. 
Twenty-four-hour concentrations will be determined to be invalid if the concentration is 
greater than the 10-hour concentration as it will be assumed to have been obtained after 
the next day dose instead of before the next day dose. 
• Invalid pre-dose concentrations will be replaced with the 24-hour concentration. The 
pre-dose concentrations will be determined to be invalid if the concentrations are higher 
than any other concentrations following dosing as it will be assumed to have been 
obtained after dosing instead of before dosing. 
• The following concentrations must be available to calculate the AUC: 3, 6, and 10-hour 
concentrations. 
At least three data points not including Tmax must be available to calculate λz (imputed 24-hour 
concentration can be used). 
The following parameters will be determined where possible:  
Parameter 
Definition 
Cmax,ss 
The maximum observed plasma concentration at steady state 
Tmax,ss 
The time from dosing at which Cmax is observed 
AUC0-24ss 
The area under the plasma concentration vs time curve, from time zero to 24 hours post-dose 
during the steady state dosing interval, calculated by the linear trapezoidal method 
Cmin,ss 
The minimum observed plasma concentration at steady state 
λz 
Terminal elimination rate constant 
t½z 
Terminal elimination half-life 
CL/F 
Apparent clearance following extravascular administration 
 


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For each treatment group and dose, descriptive statistics will be provided for all PK parameters 
using the Principal PS and the Supplementary PS populations; descriptive statistics for all 
parameters except Tmax will include N, n, mean, SD, CV%, geometric mean, median, minimum 
and maximum. Tmax will be summarized using median, minimum, and maximum. 
2.4.8 Duration of Flare-up Treatment 
For subjects receiving flare-up treatment, duration of flare-up treatment (days) is defined as total 
flare-up cycle dosing periods (days) across all flare-up cycles.   
For a flare-up cycle, the flare-up cycle dosing period (days) is defined as days that subjects 
received flare-up-based treatment and is calculated as (last dose date of the flare-up cycle – first 
date of the flare-up cycle – days where flare-up medications were not taken/interrupted during 
the flare-up cycle + 1). 
2.4.9 Duration of Non-Flare-up Treatment  
Based on the study design, subjects are assumed to be on non-flare-up-based treatment from the 
date they received the first non-flare-up treatment unless they receive flare-up-based treatment. 
Thus, duration of non-flare-up treatment (days) will be calculated as (last non-flare-up treatment 
date - first non-flare-up treatment date – duration of flare-up treatment (days) - days where 
non-flare-up medications were not taken/interrupted + 1). Duration of flare-up treatment (days) 
is defined in Section 2.4.8. 
3 
INTERIM ANALYSIS 
There were to be three early interim efficacy analyses and one final analysis in Part A, in 
addition to a descriptive analysis of safety and non-imaging efficacy endpoints, which was to be 
included in the interim CSR for the NDA for episodic palovarotene prevention of HO in patients 
with FOP. Hypothesis testing was to be performed using group sequential methods. 
Approximately 80 subjects with the R206H mutation and no previous palovarotene experience 
were to be enrolled into the MOVE Trial and would be followed for 2 years. The first interim 
analysis was to occur when 35 subjects complete 1 year of follow-up, the second and third 
interim analyses were to occur when all subjects in the Principal EP had completed (i.e., have 
WBCT data) 12 months and then 18 months of follow-up, respectively. 
3.1 
Early Efficacy Testing 
The primary efficacy analysis model and the one-sided significance threshold for each analysis 
are described in Section 0. Study success was to 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. Under the assumptions in Section 1.6, the probability of 
declaring statistical significance at the interims is summarized in Table 2. 


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3.2 
Futility Testing  
A futility analysis was conducted for the second interim analysis based on the pre-specified 
criteria using square-root transformation and additional analyses without the square-root 
transformation. Because the futility boundary was crossed at the second interim analysis, all 
subsequent analyses of efficacy data will be supplied without applying thresholds for success or 
futility, as these thresholds are no longer relevant. 
That said, at the request of the DMC, an analysis is planned to occur consistent with the planned 
timing of the third interim analysis, i.e., when all subjects in the Principal EP have completed 18 
months of follow-up. The purpose is to re-evaluate the risk benefit ratio, both overall and in 
younger subjects with FOP. Because the dataset was unblinded to the sponsor after the second 
interim analysis, results at this third interim analysis will be shared with the sponsor – and the 
sponsor may participate in the conduct of the analyses. 
3.3 
Third Interim Analysis 
An informal analysis will occur at the time of the planned third interim analysis. Table 8 lists the 
efficacy analyses that will be performed at this analysis.  
Note that the third interim analysis dataset will also be summarized in the interim MOVE CSR 
for Study PVO-1A-301 (MOVE Trial) to be included in the palovarotene NDA and MAA for 
FOP. The efficacy analyses described in Table 8 will be included, in addition to the additional 
analyses, sensitivity analyses, analyses of secondary efficacy endpoints, and analyses of 
exploratory endpoints described in Section 2.4.4. Safety analyses in Section 2.1.4, analyses of 
imaging performance in Section 2.1.5 and analyses of pharmacokinetic endpoints in Section 
2.1.6 will also be included. Further analyses may be added, as appropriate. 
Further note that analyses included in the interim CSR are not planned to be rerun for the final 
CSR. 
 
Table 8. 
Analyses to be Conducted at Interim Analysis #3 
Analysis 
Method  
Cutoff 
Trans. 
Subset 
Subjects 
Reason 
Analysis of 
primary interest 
Bayesian 
comp. P. 
04Dec2019 for 
subjects <14 y.o., 
24Jan2020 for 
subjects>=14.y.o. 
None 
All Subjects 
Sponsor believes this is the 
more appropriate Bayesian 
analysis of efficacy 
Alternative 
analysis of 
primary interest 
wLME 
04Dec2019 for 
subjects <14, y.o., 
24Jan2020 for 
subjects>=14.y.o. 
None 
All Subjects 
Explore if results of Bayesian 
analysis are consistent with 
results from simplified 
approach 
Square-root 
transformation 
Bayesian 
comp.P. 
04Dec2019 for 
subjects <14, y.o., 
Sq. 
Root 
All Subjects 
Show inconsistency of results 
with square-root transformation 


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4 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS Version 9.4 or higher, unless 
otherwise noted. 
The Bayesian compound Poisson models will be fitted using the R statistical computing 
language and environment. The R programs will be run using v3.5.0 or later; packages used, 
including version number, will be identified in the CSR. 
 
 
24Jan2020 for 
subjects>=14.y.o. 
to results without square-root 
transformation 
Alternative 
method w/ 
square-root 
transformation  
wLME 
04Dec2019 for 
subjects <14, y.o., 
24Jan2020 for 
subjects>=14.y.o. 
Sq. 
Root 
All Subjects 
Show that there is also an 
inconsistency of results with 
square-root transformation 
under simplified approach 
Include scans 
after dosing 
stopped 
Bayesian 
comp. P 
All timepoints 
None 
All Subjects 
Explore if results when with 
only scans done before dosing 
interrupted are consistent with 
results using all timepoints  
Include scans 
after dosing 
stopped and 
square-root 
transformation 
Bayesian 
comp.P. 
All timepoints 
Sq. 
Root 
All Subjects 
Protocol-specified primary 
analysis (ignoring dosing 
interruptions) 
Older Population 
Cutoff 1 
Bayesian 
comp. P 
04Dec2019 for 
subjects <14, y.o., 
24Jan2020 for 
subjects>=14.y.o. 
None 
Girls >=13 
y.o., boys 
>= 15 y.o. 
Explore if results differ by age 
Younger 
Population 
Cutoff 1 
Bayesian 
comp. P 
04Dec2019 for 
subjects <14, y.o., 
24Jan2020 for 
subjects>=14.y.o. 
None 
Girls < 13 
y.o., boys < 
15 y.o. 
Explore if results differ by age 
Older Population 
Cutoff 2 
Bayesian 
comp. P 
04Dec2019 for 
subjects <14, y.o., 
24Jan2020 for 
subjects>=14.y.o. 
None 
Girls>=8 
y.o., 
boys>=10 
y.o. 
Explore if results differ by age 
Younger 
Population 
Cutoff 2 
Bayesian 
comp. P 
04Dec2019 for 
subjects <14, y.o., 
24Jan2020 for 
subjects>=14.y.o. 
None 
Girls<8 y.o., 
boys<10 
y.o. 
Explore if results differ by age 
 


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5 
REFERENCES 
1 
Grantham JJ, Torres VE, Chapman AB, et al. Volume progression in polycystic kidney disease. N 
Engl J Med 2006;354:2122-2130. 
2 
Torres VE, Chapman AB, Deyvust O, et al. Tolvaptan in patients with autosomal dominant 
polycystic kidney disease. N Engl J Med 2012; 367:2407-2418 
3 
D'Agostino, RB., Jr., Tutorial in Biostatistics: Propensity Score Methods for Bias Reduction in 
the Comparison of a Treatment to a Non-Randomized Control Group. Statistics in Medicine, 
1998, 17, 2265-2281. 
4 
R Core Team (2018). R: A language and environment for statistical computing. R Foundation for 
Statistical Computing, Vienna, Austria. URL https://www.R-project.org/. 
5 
Hays, R. D., Bjorner, J., Revicki, R. A., Spritzer, K. L., & Cella, D. (2009). Development of 
physical and mental health summary scores from the Patient Reported Outcomes Measurement 
Information System (PROMIS) global items. Quality of Life Research, 18(7),873-80. (PMCID: 
PMC2724630) URL 
http://www.healthmeasures.net/images/PROMIS/manuals/PROMIS Global Scoring Manual.pdf 
 
 


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6 
APPENDICES 
6.1 
PROMIS T-Score Conversions 
The following conversion tables5 allow a user to convert Global Physical Health, Global Mental 
Health, and Total scores into T-scores. T-score distributions are standardized such that a 50 
represents the average (mean) for the US general population, and the standard deviation around 
that mean is 10 points. A high score always represents more of the concept being measured. 
Thus, a subject who has a T-score of 60 is one standard deviation better (healthier) than the 
general population. 
Adult Global Physical Health 
 
Adult Global Mental Health 
Raw Score 
T-Score 
Standard Error 
 
Raw Score 
T-Score 
Standard Error 
4 
16.2 
4.8 
 
4 
21.2 
4.6 
5 
19.9 
4.7 
 
5 
25.1 
4.1 
6 
23.5 
4.5 
 
6 
28.4 
3.9 
7 
26.7 
4.3 
 
7 
31.3 
3.7 
8 
29.6 
4.2 
 
8 
33.8 
3.7 
9 
32.4 
4.2 
 
9 
36.3 
3.7 
10 
34.9 
4.1 
 
10 
38.8 
3.6 
11 
37.4 
4.1 
 
11 
41.1 
3.6 
12 
39.8 
4.1 
 
12 
43.5 
3.6 
13 
42.3 
4.2 
 
13 
45.8 
3.6 
14 
44.9 
4.3 
 
14 
48.3 
3.7 
15 
47.7 
4.4 
 
15 
50.8 
3.7 
16 
50.8 
4.6 
 
16 
53.3 
3.7 
17 
54.1 
4.7 
 
17 
56.0 
3.8 
18 
57.7 
4.9 
 
18 
59.0 
3.9 
19 
61.9 
5.2 
 
19 
62.5 
4.2 
20 
67.7 
5.9 
 
20 
67.6 
5.3 
 
Pediatric Self-Completed Total 
 
Pediatric Proxy-Completed Total 
Raw Score 
T-Score 
Standard Error 
 
Raw Score 
T-Score 
Standard Error 
7 
16.0 
3.4 
 
7 
14.7 
2.9 
8 
17.1 
3.6 
 
8 
15.3 
3.1 
9 
18.3 
3.7 
 
9 
16.0 
3.2 
10 
19.7 
3.8 
 
10 
16.9 
3.4 
11 
21.2 
3.8 
 
11 
18.1 
3.6 
12 
22.8 
3.7 
 
12 
19.4 
3.7 
13 
24.4 
3.6 
 
13 
21.0 
3.8 


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Pediatric Self-Completed Total 
 
Pediatric Proxy-Completed Total 
Raw Score 
T-Score 
Standard Error 
 
Raw Score 
T-Score 
Standard Error 
14 
26.1 
3.6 
 
14 
22.7 
3.8 
15 
27.6 
3.5 
 
15 
24.4 
3.7 
16 
29.2 
3.5 
 
16 
26.1 
3.7 
17 
30.8 
3.5 
 
17 
27.7 
3.7 
18 
32.4 
3.6 
 
18 
29.4 
3.8 
19 
34.0 
3.6 
 
19 
31.2 
3.8 
20 
35.6 
3.6 
 
20 
32.9 
3.8 
21 
37.2 
3.6 
 
21 
34.6 
3.8 
22 
38.8 
3.6 
 
22 
36.2 
3.8 
23 
40.4 
3.6 
 
23 
37.9 
3.9 
24 
42.1 
3.7 
 
24 
39.7 
4.0 
25 
43.9 
3.7 
 
25 
41.7 
4.0 
26 
45.7 
3.6 
 
26 
43.6 
3.9 
27 
47.5 
3.6 
 
27 
45.4 
3.8 
28 
49.2 
3.6 
 
28 
47.3 
3.9 
29 
51.1 
3.7 
 
29 
49.3 
4.1 
30 
53.3 
3.9 
 
30 
51.8 
4.4 
31 
55.7 
4.2 
 
31 
54.5 
4.7 
32 
58.3 
4.5 
 
32 
57.3 
5.0 
33 
61.1 
4.9 
 
33 
60.2 
5.4 
34 
64.2 
5.4 
 
34 
63.2 
6.0 
35 
67.5 
6.1 
 
35 
66.1 
6.5 
 
6.2 
Potentially Clinically Significant Abnormalities criteria 
PCS Criteria for Laboratory Parameters 
Laboratory Parameter 
PCS Low 
PCS High 
Aspartate aminotransferase (AST) 
N/A 
3 x ULN 
Alanine aminotransferase (ALT) 
N/A 
3 x ULN 
Amylase 
N/A 
3 x ULN 
Lipase 
N/A 
3 x ULN 
Total bilirubin 
N/A 
>2 mg/dL 
Total thyroxine (T4) 
<4.0 mcg/dL 
>13.0 mcg/dL 
Total cholesterol 
N/A 
>300 mg/dL 
Triglycerides 
N/A 
>400 mg/dL 
White blood cell (WBC) count 
<2.8 x 103/mm3 
>16 x 103/mm3 


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Laboratory Parameter 
PCS Low 
PCS High 
Hemoglobin 
<9.5 g/dL 
>19.0 g/dL
Hematocrit 
<34% 
>54%
Platelet count 
<75 x 103/mm3 
>700 x 103/mm3
AST, ALT and total bilirubin 
N/A 
AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
PCS Criteria for ECG Parameters 
Parameter 
PCS Low 
PCS High 
PR Interval 
None 
1) >200 msec only OR
2) increase from baseline ≥20 msec only OR
3) >200 msec and increase from baseline ≥20 msec
QRS Interval 
None 
1) >100 msec only OR
2) increase from baseline ≥10 msec only OR
3) >100 msec and increase from baseline ≥10 msec
QT Interval 
None 
1) >500 msec only OR
2) increase from baseline ≥60 msec only OR
3) >500 msec and increase from baseline ≥60 msec
QTcF and QTcB Interval 
None 
1) >500 msec only OR
2) increase from baseline ≥60 msec only OR
3) >500 msec and increase from baseline ≥60 msec
PCS Criteria for Vital Signs 
Vital Sign 
PCS Low 
PCS High 
Sitting SBP (mm Hg) 
     Aged 0-12 years 
<60 mm Hg OR a decrease of 20 mm Hg or 
more from baseline 
>150 mm Hg OR an increase of 20 mm Hg
or more from baseline
     Aged >12 years 
<86 mm Hg OR a decrease of 25 mm Hg or 
more from baseline 
>180 mm Hg OR an increase of 25 mm Hg
or more from baseline
Sitting DBP (mm Hg) 
     Aged 0-12 years 
<30 mm Hg OR a decrease of 15 mm Hg or 
more from baseline 
>90 mm Hg OR an increase of 15 mm Hg
or more from baseline
     Aged >12 years 
<48 mm Hg OR a decrease of 20 mm Hg or 
more from baseline 
>110 mm Hg OR an increase of 20 mm Hg
or more from baseline
Heart rate 
1) <55 bpm OR
2) decrease of ≥20 bpm from baseline OR
3) <55 bpm AND decrease from baseline of
≥20 bpm
1) >120 bpm AND increase from baseline
≥20 bpm OR
2) >140 bpm